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Dual inhibitor shows early promise for DLBCL
The small-molecule inhibitor CUDC-907 can provide disease control in patients with relapsed or refractory lymphoma and multiple myeloma (MM), according to researchers.
In a phase 1 trial, CUDC-907 produced responses in a small number of patients with diffuse large B-cell lymphoma (DLBCL).
And more than half of patients had stable disease while on CUDC-907, including those with MM, DLBCL, Hodgkin lymphoma (HL), and other lymphomas.
However, a majority of patients in this trial—84%—discontinued treatment due to confirmed progressive disease or signs of progression.
These results were published in The Lancet. The trial was sponsored by Curis, Inc., the company developing CUDC-907, and the Leukemia and Lymphoma Society.
“The data from the phase 1 monotherapy trial for CUDC-907, especially in heavily pretreated patients with relapsed/refractory DLBCL are very encouraging, and we look forward to data emerging from the current phase 2 trial in patients with MYC-altered DLBCL,” said study author Anas Younes, MD, of the Memorial Sloan Kettering Cancer Center in New York, New York.
CUDC-907 is an oral, dual inhibitor of class I and II histone deacetylases (HDACs), as well as class I PI3K enzymes. Specifically, CUDC-907 is designed to inhibit HDACs 1, 2, 3, 6, and 10 and PI3K-alpha, delta, and beta isoforms.
Between Jan 23, 2013, and July 27, 2015, the phase 1 trial of CUDC-907 enrolled 44 patients who were refractory to or had relapsed after 2 or more previous regimens. The patients’ median age was 63 (range, 22-83), and they had received a median of 5 prior treatments (range, 2-10).
Four patients had MM, 12 had HL, and 12 had DLBCL. The remaining 16 patients had other types of lymphoma, including lymphoplasmacytic lymphoma (n=3), small lymphocytic lymphoma (n=3), mantle cell lymphoma (n=3), follicular lymphoma (n=2), T-cell lymphoma (n=2), marginal zone lymphoma (n=1), Burkitt lymphoma (n=1), and gray zone lymphoma (n=1).
Treatment
CUDC-907 was given in a standard 3 + 3 dose-escalation design at 4 different dosing schedules—once daily, twice weekly, 3 times weekly, and daily for 5 days followed by a 2-day break (5/2)—in 21-day cycles.
Patients continued to receive CUDC-907 until disease progression or other treatment discontinuation criteria were met. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase 2 dose.
Ten patients were sequentially assigned to CUDC-907 once-daily (MTD 60 mg), 12 to twice-weekly (MTD 150 mg), 15 to 3-times-weekly (MTD 150 mg), and 7 to the 5/2 dosing schedule (MTD 60 mg).
Safety
Four dose-limiting toxicities (DLTs) occurred in 3 of 40 DLT-evaluable patients. The DLTs were diarrhea and hyperglycemia in 1 patient on 60 mg once daily, hyperglycemia in 1 patient on 150 mg twice weekly, and diarrhea in 1 patient on 150 mg 3 times weekly. There were no DLTs in patients on the 5/2 schedule.
The incidence of grade 3 or higher adverse events (AEs) was 43% (19/44). The most common of these AEs were thrombocytopenia (20%, n=9), neutropenia (7%, n=3), and hyperglycemia (7%, n=3).
Twenty-five percent of patients (11/44) had serious AEs. Three of these events were considered treatment-related. They were epistaxis and the DLTs of diarrhea and hyperglycemia.
AEs led to dose reductions in 6 patients (14%) and treatment discontinuation in 7 patients (16%).
Efficacy
Thirty-seven patients were evaluable for response, and 5 of these patients responded (14%). All responses—2 complete and 3 partial responses—occurred in patients with DLBCL.
Twenty-one of the response-evaluable patients (57%) had stable disease. This included 1 patient with DLBCL, 2 with MM, 8 with HL, and 10 with the “other” types of lymphoma.
The remaining 11 patients progressed (30%)—3 with DLBCL, 2 with MM, 2 with HL, and 4 with other lymphomas.
Thirty-seven patients (84%) discontinued CUDC-907 because of progressive disease or clinical signs of progressive disease at the data cutoff.
Based on the clinical activity of CUDC-907 in patients with relapsed/refractory DLBCL, particularly those with MYC alterations, Curis has initiated a phase 2 trial of the drug in these patients. The recommended phase 2 dose is 60 mg on the 5/2 dosing schedule. 
The small-molecule inhibitor CUDC-907 can provide disease control in patients with relapsed or refractory lymphoma and multiple myeloma (MM), according to researchers.
In a phase 1 trial, CUDC-907 produced responses in a small number of patients with diffuse large B-cell lymphoma (DLBCL).
And more than half of patients had stable disease while on CUDC-907, including those with MM, DLBCL, Hodgkin lymphoma (HL), and other lymphomas.
However, a majority of patients in this trial—84%—discontinued treatment due to confirmed progressive disease or signs of progression.
These results were published in The Lancet. The trial was sponsored by Curis, Inc., the company developing CUDC-907, and the Leukemia and Lymphoma Society.
“The data from the phase 1 monotherapy trial for CUDC-907, especially in heavily pretreated patients with relapsed/refractory DLBCL are very encouraging, and we look forward to data emerging from the current phase 2 trial in patients with MYC-altered DLBCL,” said study author Anas Younes, MD, of the Memorial Sloan Kettering Cancer Center in New York, New York.
CUDC-907 is an oral, dual inhibitor of class I and II histone deacetylases (HDACs), as well as class I PI3K enzymes. Specifically, CUDC-907 is designed to inhibit HDACs 1, 2, 3, 6, and 10 and PI3K-alpha, delta, and beta isoforms.
Between Jan 23, 2013, and July 27, 2015, the phase 1 trial of CUDC-907 enrolled 44 patients who were refractory to or had relapsed after 2 or more previous regimens. The patients’ median age was 63 (range, 22-83), and they had received a median of 5 prior treatments (range, 2-10).
Four patients had MM, 12 had HL, and 12 had DLBCL. The remaining 16 patients had other types of lymphoma, including lymphoplasmacytic lymphoma (n=3), small lymphocytic lymphoma (n=3), mantle cell lymphoma (n=3), follicular lymphoma (n=2), T-cell lymphoma (n=2), marginal zone lymphoma (n=1), Burkitt lymphoma (n=1), and gray zone lymphoma (n=1).
Treatment
CUDC-907 was given in a standard 3 + 3 dose-escalation design at 4 different dosing schedules—once daily, twice weekly, 3 times weekly, and daily for 5 days followed by a 2-day break (5/2)—in 21-day cycles.
Patients continued to receive CUDC-907 until disease progression or other treatment discontinuation criteria were met. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase 2 dose.
Ten patients were sequentially assigned to CUDC-907 once-daily (MTD 60 mg), 12 to twice-weekly (MTD 150 mg), 15 to 3-times-weekly (MTD 150 mg), and 7 to the 5/2 dosing schedule (MTD 60 mg).
Safety
Four dose-limiting toxicities (DLTs) occurred in 3 of 40 DLT-evaluable patients. The DLTs were diarrhea and hyperglycemia in 1 patient on 60 mg once daily, hyperglycemia in 1 patient on 150 mg twice weekly, and diarrhea in 1 patient on 150 mg 3 times weekly. There were no DLTs in patients on the 5/2 schedule.
The incidence of grade 3 or higher adverse events (AEs) was 43% (19/44). The most common of these AEs were thrombocytopenia (20%, n=9), neutropenia (7%, n=3), and hyperglycemia (7%, n=3).
Twenty-five percent of patients (11/44) had serious AEs. Three of these events were considered treatment-related. They were epistaxis and the DLTs of diarrhea and hyperglycemia.
AEs led to dose reductions in 6 patients (14%) and treatment discontinuation in 7 patients (16%).
Efficacy
Thirty-seven patients were evaluable for response, and 5 of these patients responded (14%). All responses—2 complete and 3 partial responses—occurred in patients with DLBCL.
Twenty-one of the response-evaluable patients (57%) had stable disease. This included 1 patient with DLBCL, 2 with MM, 8 with HL, and 10 with the “other” types of lymphoma.
The remaining 11 patients progressed (30%)—3 with DLBCL, 2 with MM, 2 with HL, and 4 with other lymphomas.
Thirty-seven patients (84%) discontinued CUDC-907 because of progressive disease or clinical signs of progressive disease at the data cutoff.
Based on the clinical activity of CUDC-907 in patients with relapsed/refractory DLBCL, particularly those with MYC alterations, Curis has initiated a phase 2 trial of the drug in these patients. The recommended phase 2 dose is 60 mg on the 5/2 dosing schedule.
The small-molecule inhibitor CUDC-907 can provide disease control in patients with relapsed or refractory lymphoma and multiple myeloma (MM), according to researchers.
In a phase 1 trial, CUDC-907 produced responses in a small number of patients with diffuse large B-cell lymphoma (DLBCL).
And more than half of patients had stable disease while on CUDC-907, including those with MM, DLBCL, Hodgkin lymphoma (HL), and other lymphomas.
However, a majority of patients in this trial—84%—discontinued treatment due to confirmed progressive disease or signs of progression.
These results were published in The Lancet. The trial was sponsored by Curis, Inc., the company developing CUDC-907, and the Leukemia and Lymphoma Society.
“The data from the phase 1 monotherapy trial for CUDC-907, especially in heavily pretreated patients with relapsed/refractory DLBCL are very encouraging, and we look forward to data emerging from the current phase 2 trial in patients with MYC-altered DLBCL,” said study author Anas Younes, MD, of the Memorial Sloan Kettering Cancer Center in New York, New York.
CUDC-907 is an oral, dual inhibitor of class I and II histone deacetylases (HDACs), as well as class I PI3K enzymes. Specifically, CUDC-907 is designed to inhibit HDACs 1, 2, 3, 6, and 10 and PI3K-alpha, delta, and beta isoforms.
Between Jan 23, 2013, and July 27, 2015, the phase 1 trial of CUDC-907 enrolled 44 patients who were refractory to or had relapsed after 2 or more previous regimens. The patients’ median age was 63 (range, 22-83), and they had received a median of 5 prior treatments (range, 2-10).
Four patients had MM, 12 had HL, and 12 had DLBCL. The remaining 16 patients had other types of lymphoma, including lymphoplasmacytic lymphoma (n=3), small lymphocytic lymphoma (n=3), mantle cell lymphoma (n=3), follicular lymphoma (n=2), T-cell lymphoma (n=2), marginal zone lymphoma (n=1), Burkitt lymphoma (n=1), and gray zone lymphoma (n=1).
Treatment
CUDC-907 was given in a standard 3 + 3 dose-escalation design at 4 different dosing schedules—once daily, twice weekly, 3 times weekly, and daily for 5 days followed by a 2-day break (5/2)—in 21-day cycles.
Patients continued to receive CUDC-907 until disease progression or other treatment discontinuation criteria were met. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase 2 dose.
Ten patients were sequentially assigned to CUDC-907 once-daily (MTD 60 mg), 12 to twice-weekly (MTD 150 mg), 15 to 3-times-weekly (MTD 150 mg), and 7 to the 5/2 dosing schedule (MTD 60 mg).
Safety
Four dose-limiting toxicities (DLTs) occurred in 3 of 40 DLT-evaluable patients. The DLTs were diarrhea and hyperglycemia in 1 patient on 60 mg once daily, hyperglycemia in 1 patient on 150 mg twice weekly, and diarrhea in 1 patient on 150 mg 3 times weekly. There were no DLTs in patients on the 5/2 schedule.
The incidence of grade 3 or higher adverse events (AEs) was 43% (19/44). The most common of these AEs were thrombocytopenia (20%, n=9), neutropenia (7%, n=3), and hyperglycemia (7%, n=3).
Twenty-five percent of patients (11/44) had serious AEs. Three of these events were considered treatment-related. They were epistaxis and the DLTs of diarrhea and hyperglycemia.
AEs led to dose reductions in 6 patients (14%) and treatment discontinuation in 7 patients (16%).
Efficacy
Thirty-seven patients were evaluable for response, and 5 of these patients responded (14%). All responses—2 complete and 3 partial responses—occurred in patients with DLBCL.
Twenty-one of the response-evaluable patients (57%) had stable disease. This included 1 patient with DLBCL, 2 with MM, 8 with HL, and 10 with the “other” types of lymphoma.
The remaining 11 patients progressed (30%)—3 with DLBCL, 2 with MM, 2 with HL, and 4 with other lymphomas.
Thirty-seven patients (84%) discontinued CUDC-907 because of progressive disease or clinical signs of progressive disease at the data cutoff.
Based on the clinical activity of CUDC-907 in patients with relapsed/refractory DLBCL, particularly those with MYC alterations, Curis has initiated a phase 2 trial of the drug in these patients. The recommended phase 2 dose is 60 mg on the 5/2 dosing schedule.
MicroRNA could be used to treat DLBCL, team says
A microRNA known as miR-181a dampens signals from the NF-κB pathway and affects the pathogenesis of diffuse large B-cell lymphoma (DLBCL), according to research published in Blood.
The study showed that, by reducing NF-κB signaling, miR-181a hinders tumor cell proliferation and survival.
And the effect is more pronounced in activated B-cell-like (ABC) DLBCL than in germinal center B-cell-like (GCB) DLBCL.
The researchers therefore believe miR-181a could be used to treat ABC DLBCL.
“The miR-181a microRNA is one of the first examples of a pathway that deactivates NF-κB at multiple levels, functioning as a master regulator,” said study author Izidore S. Lossos, MD, of the University of Miami Miller School of Medicine in Florida.
“In certain tumors, there is no expression of this microRNA, which allows cells to propagate. We believe miR-181a could eventually be used
therapeutically.”
To understand the role of miR-181a in the different types of DLBCL, Dr Lossos and his colleaguese studied both cell lines and mouse models.
The team found that miR-181a levels were significantly lower in ABC DLBCL than in GCB DLBCL.
When they increased miR-181a expression in DLBCL cell lines, the researchers observed a reduction in NF-κB activity and a decrease in cell proliferation and survival. These effects were more potent in ABC DLBCL than in GCB DLBCL.
When the researchers increased miR-181a expression in the mouse models, they observed a significant reduction in tumor growth and a significant increase in animal survival, but only in ABC DLBCL. In GCB DLBCL, there were no significant changes compared to controls.
The researchers said the ability of miR-181a to reduce NF-κB levels may be why the presence of miR-181a has been linked to better outcomes for certain DLBCL patients. Previous studies by Dr Lossos’s group have shown that DLBCL patients whose tumors contain more miR-181a have better prognoses.
With the current study, the team found that miR-181a is a master regulator, turning off a number of genes in the NF-κB pathway, including CARD11, a known DLBCL oncogene, and a number of transcription factors that drive NF-κB signaling.
“We knew that miR181a was biomarker for survival,” Dr Lossos said. “This explains the mechanisms behind it.”
In addition to providing a better understanding of the NF-κB pathway, these results provide hope that miR-181a could be used to improve treatment for patients with ABC DLBCL.
“We are trying to develop miR-181a as a potential therapy,” Dr Lossos said. “But we are only at the beginning. Much more work needs to be done. It will not be a simple journey, but we are sure it can be done and tested in humans eventually to see that it indeed will improve patients’ outcomes.”
A microRNA known as miR-181a dampens signals from the NF-κB pathway and affects the pathogenesis of diffuse large B-cell lymphoma (DLBCL), according to research published in Blood.
The study showed that, by reducing NF-κB signaling, miR-181a hinders tumor cell proliferation and survival.
And the effect is more pronounced in activated B-cell-like (ABC) DLBCL than in germinal center B-cell-like (GCB) DLBCL.
The researchers therefore believe miR-181a could be used to treat ABC DLBCL.
“The miR-181a microRNA is one of the first examples of a pathway that deactivates NF-κB at multiple levels, functioning as a master regulator,” said study author Izidore S. Lossos, MD, of the University of Miami Miller School of Medicine in Florida.
“In certain tumors, there is no expression of this microRNA, which allows cells to propagate. We believe miR-181a could eventually be used
therapeutically.”
To understand the role of miR-181a in the different types of DLBCL, Dr Lossos and his colleaguese studied both cell lines and mouse models.
The team found that miR-181a levels were significantly lower in ABC DLBCL than in GCB DLBCL.
When they increased miR-181a expression in DLBCL cell lines, the researchers observed a reduction in NF-κB activity and a decrease in cell proliferation and survival. These effects were more potent in ABC DLBCL than in GCB DLBCL.
When the researchers increased miR-181a expression in the mouse models, they observed a significant reduction in tumor growth and a significant increase in animal survival, but only in ABC DLBCL. In GCB DLBCL, there were no significant changes compared to controls.
The researchers said the ability of miR-181a to reduce NF-κB levels may be why the presence of miR-181a has been linked to better outcomes for certain DLBCL patients. Previous studies by Dr Lossos’s group have shown that DLBCL patients whose tumors contain more miR-181a have better prognoses.
With the current study, the team found that miR-181a is a master regulator, turning off a number of genes in the NF-κB pathway, including CARD11, a known DLBCL oncogene, and a number of transcription factors that drive NF-κB signaling.
“We knew that miR181a was biomarker for survival,” Dr Lossos said. “This explains the mechanisms behind it.”
In addition to providing a better understanding of the NF-κB pathway, these results provide hope that miR-181a could be used to improve treatment for patients with ABC DLBCL.
“We are trying to develop miR-181a as a potential therapy,” Dr Lossos said. “But we are only at the beginning. Much more work needs to be done. It will not be a simple journey, but we are sure it can be done and tested in humans eventually to see that it indeed will improve patients’ outcomes.”
A microRNA known as miR-181a dampens signals from the NF-κB pathway and affects the pathogenesis of diffuse large B-cell lymphoma (DLBCL), according to research published in Blood.
The study showed that, by reducing NF-κB signaling, miR-181a hinders tumor cell proliferation and survival.
And the effect is more pronounced in activated B-cell-like (ABC) DLBCL than in germinal center B-cell-like (GCB) DLBCL.
The researchers therefore believe miR-181a could be used to treat ABC DLBCL.
“The miR-181a microRNA is one of the first examples of a pathway that deactivates NF-κB at multiple levels, functioning as a master regulator,” said study author Izidore S. Lossos, MD, of the University of Miami Miller School of Medicine in Florida.
“In certain tumors, there is no expression of this microRNA, which allows cells to propagate. We believe miR-181a could eventually be used
therapeutically.”
To understand the role of miR-181a in the different types of DLBCL, Dr Lossos and his colleaguese studied both cell lines and mouse models.
The team found that miR-181a levels were significantly lower in ABC DLBCL than in GCB DLBCL.
When they increased miR-181a expression in DLBCL cell lines, the researchers observed a reduction in NF-κB activity and a decrease in cell proliferation and survival. These effects were more potent in ABC DLBCL than in GCB DLBCL.
When the researchers increased miR-181a expression in the mouse models, they observed a significant reduction in tumor growth and a significant increase in animal survival, but only in ABC DLBCL. In GCB DLBCL, there were no significant changes compared to controls.
The researchers said the ability of miR-181a to reduce NF-κB levels may be why the presence of miR-181a has been linked to better outcomes for certain DLBCL patients. Previous studies by Dr Lossos’s group have shown that DLBCL patients whose tumors contain more miR-181a have better prognoses.
With the current study, the team found that miR-181a is a master regulator, turning off a number of genes in the NF-κB pathway, including CARD11, a known DLBCL oncogene, and a number of transcription factors that drive NF-κB signaling.
“We knew that miR181a was biomarker for survival,” Dr Lossos said. “This explains the mechanisms behind it.”
In addition to providing a better understanding of the NF-κB pathway, these results provide hope that miR-181a could be used to improve treatment for patients with ABC DLBCL.
“We are trying to develop miR-181a as a potential therapy,” Dr Lossos said. “But we are only at the beginning. Much more work needs to be done. It will not be a simple journey, but we are sure it can be done and tested in humans eventually to see that it indeed will improve patients’ outcomes.”
Drug ‘not powerful enough’ to treat CTCL
mycosis fungoides
Results of a phase 2 trial suggest the drug APO866 is not suitable for the treatment of relapsed or refractory cutaneous T-cell lymphoma (CTCL).
Researchers said APO866 had “a reasonable toxic effect,” but it was “not powerful enough,” so the trial was stopped early.
Two of the 14 patients studied achieved a partial response during the trial, but there were no complete responses, and most patients withdrew from the study early.
The researchers described these results in a letter to JAMA Dermatology. The study was initially sponsored by Apoxis SA and later by TopoTarget A/S, which is now known as Onxeo after merging with BioAlliance Pharma.
According to Onxeo, APO866 is an injectable molecule that induces apoptosis by inhibiting the biosynthesis of NAD+ from niacinamide, which is essential for the cellular metabolism, protein modification, and calcium-dependent messenger synthesis.
In the phase 2 trial, researchers tested APO866 in 14 patients with relapsed or refractory CTCL. The patients were 19 to 83 years of age, and half were female.
Eight patients had mycosis fungoides, 3 had Sézary syndrome, 1 had CD30+ anaplastic large-cell lymphoma, 1 had poikilodermic mycosis fungoides, and 1 had CD30- nonepidermotropic CTCL. One patient had stage IB disease, 2 had stage IIA, 3 had stage IIB, and 8 had stage IVA.
The patients received a continuous intravenous infusion, via pump, of APO866 at 0.126 mg/m2/h over the course of 96 hours. Patients received this treatment every 28 days for a total of 3 cycles.
Five patients completed all 3 treatment cycles and had no major protocol violations. Nine patients discontinued treatment early due to consent withdrawal (n=2), early disease progression (n=5), or adverse events (AEs, n=2).
At week 8, 1 patient had achieved a partial response to treatment, 4 patients had stable disease, 5 had progressed, and 4 patients were not evaluable because they had withdrawn from the study.
At week 16, 1 patient had a partial response (not the same patient as at week 8), 4 patients had stable disease, and 9 patients were not evaluable due to withdrawal.
There were a total of 141 AEs, and 77 of these were considered related to APO866. Most patients (n=12) had mild to moderate AEs, but there were 7 serious AEs thought to be treatment-related. These included pyrexia, lymphopenia (n=2), spondylitis, Staphylococcal sepsis, rhabdomyolysis, and thrombocytopenia.
There were 4 deaths, but they were not considered drug-related.
The researchers said these results suggest APO866 should not be pursued as a treatment for CTCL. However, as the drug induces immunosuppression and has insulin-mimicking effects, it might prove useful for treating other conditions.
mycosis fungoides
Results of a phase 2 trial suggest the drug APO866 is not suitable for the treatment of relapsed or refractory cutaneous T-cell lymphoma (CTCL).
Researchers said APO866 had “a reasonable toxic effect,” but it was “not powerful enough,” so the trial was stopped early.
Two of the 14 patients studied achieved a partial response during the trial, but there were no complete responses, and most patients withdrew from the study early.
The researchers described these results in a letter to JAMA Dermatology. The study was initially sponsored by Apoxis SA and later by TopoTarget A/S, which is now known as Onxeo after merging with BioAlliance Pharma.
According to Onxeo, APO866 is an injectable molecule that induces apoptosis by inhibiting the biosynthesis of NAD+ from niacinamide, which is essential for the cellular metabolism, protein modification, and calcium-dependent messenger synthesis.
In the phase 2 trial, researchers tested APO866 in 14 patients with relapsed or refractory CTCL. The patients were 19 to 83 years of age, and half were female.
Eight patients had mycosis fungoides, 3 had Sézary syndrome, 1 had CD30+ anaplastic large-cell lymphoma, 1 had poikilodermic mycosis fungoides, and 1 had CD30- nonepidermotropic CTCL. One patient had stage IB disease, 2 had stage IIA, 3 had stage IIB, and 8 had stage IVA.
The patients received a continuous intravenous infusion, via pump, of APO866 at 0.126 mg/m2/h over the course of 96 hours. Patients received this treatment every 28 days for a total of 3 cycles.
Five patients completed all 3 treatment cycles and had no major protocol violations. Nine patients discontinued treatment early due to consent withdrawal (n=2), early disease progression (n=5), or adverse events (AEs, n=2).
At week 8, 1 patient had achieved a partial response to treatment, 4 patients had stable disease, 5 had progressed, and 4 patients were not evaluable because they had withdrawn from the study.
At week 16, 1 patient had a partial response (not the same patient as at week 8), 4 patients had stable disease, and 9 patients were not evaluable due to withdrawal.
There were a total of 141 AEs, and 77 of these were considered related to APO866. Most patients (n=12) had mild to moderate AEs, but there were 7 serious AEs thought to be treatment-related. These included pyrexia, lymphopenia (n=2), spondylitis, Staphylococcal sepsis, rhabdomyolysis, and thrombocytopenia.
There were 4 deaths, but they were not considered drug-related.
The researchers said these results suggest APO866 should not be pursued as a treatment for CTCL. However, as the drug induces immunosuppression and has insulin-mimicking effects, it might prove useful for treating other conditions.
mycosis fungoides
Results of a phase 2 trial suggest the drug APO866 is not suitable for the treatment of relapsed or refractory cutaneous T-cell lymphoma (CTCL).
Researchers said APO866 had “a reasonable toxic effect,” but it was “not powerful enough,” so the trial was stopped early.
Two of the 14 patients studied achieved a partial response during the trial, but there were no complete responses, and most patients withdrew from the study early.
The researchers described these results in a letter to JAMA Dermatology. The study was initially sponsored by Apoxis SA and later by TopoTarget A/S, which is now known as Onxeo after merging with BioAlliance Pharma.
According to Onxeo, APO866 is an injectable molecule that induces apoptosis by inhibiting the biosynthesis of NAD+ from niacinamide, which is essential for the cellular metabolism, protein modification, and calcium-dependent messenger synthesis.
In the phase 2 trial, researchers tested APO866 in 14 patients with relapsed or refractory CTCL. The patients were 19 to 83 years of age, and half were female.
Eight patients had mycosis fungoides, 3 had Sézary syndrome, 1 had CD30+ anaplastic large-cell lymphoma, 1 had poikilodermic mycosis fungoides, and 1 had CD30- nonepidermotropic CTCL. One patient had stage IB disease, 2 had stage IIA, 3 had stage IIB, and 8 had stage IVA.
The patients received a continuous intravenous infusion, via pump, of APO866 at 0.126 mg/m2/h over the course of 96 hours. Patients received this treatment every 28 days for a total of 3 cycles.
Five patients completed all 3 treatment cycles and had no major protocol violations. Nine patients discontinued treatment early due to consent withdrawal (n=2), early disease progression (n=5), or adverse events (AEs, n=2).
At week 8, 1 patient had achieved a partial response to treatment, 4 patients had stable disease, 5 had progressed, and 4 patients were not evaluable because they had withdrawn from the study.
At week 16, 1 patient had a partial response (not the same patient as at week 8), 4 patients had stable disease, and 9 patients were not evaluable due to withdrawal.
There were a total of 141 AEs, and 77 of these were considered related to APO866. Most patients (n=12) had mild to moderate AEs, but there were 7 serious AEs thought to be treatment-related. These included pyrexia, lymphopenia (n=2), spondylitis, Staphylococcal sepsis, rhabdomyolysis, and thrombocytopenia.
There were 4 deaths, but they were not considered drug-related.
The researchers said these results suggest APO866 should not be pursued as a treatment for CTCL. However, as the drug induces immunosuppression and has insulin-mimicking effects, it might prove useful for treating other conditions.
Lenalidomide prolongs PFS, not OS, in rel/ref MCL
Photo by Esther Dyson
Results of the phase 2 SPRINT trial suggest lenalidomide compares favorably to other single-agent therapies for patients with relapsed/refractory mantle cell lymphoma (MCL).
Patients who received lenalidomide had a significantly higher overall response rate and significantly longer progression-free survival (PFS) compared to patients who received single-agent therapy chosen by investigators.
However, there was no significant difference between the treatment arms with regard to overall survival (OS).
In addition, there were more treatment-related adverse events (AEs) in the lenalidomide arm than the investigator’s choice arm.
These results were published in The Lancet Oncology. The study was funded by Celgene Corporation, the company developing lenalidomide.
“The SPRINT study provided the first head-to-head, randomized, controlled study of single-agent lenalidomide compared with a range of single-agent comparators in previously treated MCL,” said study author Marek Trneny, MD, of Charles University Hospital in Prague, Czech Republic.
“The study demonstrated a statistically significant reduction in the risk of disease progression or death for lenalidomide over investigator’s choice in patients with relapsed/refractory MCL.”
The study enrolled 254 patients with relapsed/refractory MCL who were ineligible for intensive chemotherapy or hematopoietic stem cell transplant. The patients’ median age was 68.5 (range, 44-88), and they had received a median of 2 previous treatment regimens (range, 1-≥4).
Treatment
The patients were randomized (2:1) to receive lenalidomide orally at 25 mg on days 1-21 every 28 days until progressive disease or intolerability (n=170) or single-agent investigator’s choice (n=84), which included rituximab, gemcitabine, fludarabine, chlorambucil, and cytarabine. Patients who progressed on investigator’s choice could cross over to the lenalidomide arm.
In all, 167 patients in the lenalidomide arm and 83 patients in the investigator’s choice arm received at least 1 dose of treatment. In the investigator’s choice arm, 33% of patients received rituximab, 24% got gemcitabine, 22% fludarabine, 13% chlorambucil, and 8% cytarabine.
After disease progression on investigator’s choice, 46% of patients crossed over to the lenalidomide arm.
Before cycle 6, half of the patients in the lenalidomide arm and two-thirds of those in the investigator’s choice arm had discontinued treatment. After discontinuation, 46% of patients in the lenalidomide arm and 50% in the investigator’s choice arm received 1 or more new antilymphoma therapies (excluding crossover patients).
The investigators said the proportion of patients who responded to subsequent therapies or had progressive disease did not substantially differ whether they had previously been randomized to lenalidomide or investigator’s choice.
Efficacy
As of the data cutoff point (March 7, 2014), the median follow-up was 15.9 months (range, 7.6 to 31.7).
The overall response rate was 40% in the lenalidomide arm and 11% in the investigator’s choice arm (P<0.001). The complete response rates were 5% and 0%, respectively (P=0.04). The median duration of response was 16 months and 10.4 months, respectively.
Lenalidomide significantly prolonged PFS. The median PFS was 8.7 months in the lenalidomide arm and 5.2 months in the investigator’s choice arm. The hazard ratio was 0.61 (P=0.004).
There was no significant difference in OS between the treatment arms. The median OS was 27.8 months in the lenalidomide arm and 21.2 months in the investigator’s choice arm. The hazard ratio was 0.89 (P=0.45)
A total of 128 patients (50%) died. Most deaths occurred during follow-up, and the most frequent cause of death was underlying lymphoma.
Safety
The incidence of treatment-related AEs was 84% in the lenalidomide arm and 60% in the investigator’s choice arm.
The most common grade 3 or higher AEs—in the lenalidomide and investigator’s choice arms, respectively—were neutropenia (44% vs 34%) without increased risk of infection, thrombocytopenia (18% vs 28%), leukopenia (8% vs 11%), and anemia (8% vs 7%).
The incidence of any-grade nasopharyngitis was 15% in the lenalidomide arm and 6% in the investigator’s choice arm. The incidence of upper respiratory tract infection was 12% and 6%, respectively. Febrile neutropenia was reported in 6% and 2% of patients, respectively.
Growth factors were used more often in the lenalidomide arm than the investigator’s choice arm—30% and 23%, respectively. But platelet transfusions were used less often in the lenalidomide arm—4% and 11%, respectively.
Photo by Esther Dyson
Results of the phase 2 SPRINT trial suggest lenalidomide compares favorably to other single-agent therapies for patients with relapsed/refractory mantle cell lymphoma (MCL).
Patients who received lenalidomide had a significantly higher overall response rate and significantly longer progression-free survival (PFS) compared to patients who received single-agent therapy chosen by investigators.
However, there was no significant difference between the treatment arms with regard to overall survival (OS).
In addition, there were more treatment-related adverse events (AEs) in the lenalidomide arm than the investigator’s choice arm.
These results were published in The Lancet Oncology. The study was funded by Celgene Corporation, the company developing lenalidomide.
“The SPRINT study provided the first head-to-head, randomized, controlled study of single-agent lenalidomide compared with a range of single-agent comparators in previously treated MCL,” said study author Marek Trneny, MD, of Charles University Hospital in Prague, Czech Republic.
“The study demonstrated a statistically significant reduction in the risk of disease progression or death for lenalidomide over investigator’s choice in patients with relapsed/refractory MCL.”
The study enrolled 254 patients with relapsed/refractory MCL who were ineligible for intensive chemotherapy or hematopoietic stem cell transplant. The patients’ median age was 68.5 (range, 44-88), and they had received a median of 2 previous treatment regimens (range, 1-≥4).
Treatment
The patients were randomized (2:1) to receive lenalidomide orally at 25 mg on days 1-21 every 28 days until progressive disease or intolerability (n=170) or single-agent investigator’s choice (n=84), which included rituximab, gemcitabine, fludarabine, chlorambucil, and cytarabine. Patients who progressed on investigator’s choice could cross over to the lenalidomide arm.
In all, 167 patients in the lenalidomide arm and 83 patients in the investigator’s choice arm received at least 1 dose of treatment. In the investigator’s choice arm, 33% of patients received rituximab, 24% got gemcitabine, 22% fludarabine, 13% chlorambucil, and 8% cytarabine.
After disease progression on investigator’s choice, 46% of patients crossed over to the lenalidomide arm.
Before cycle 6, half of the patients in the lenalidomide arm and two-thirds of those in the investigator’s choice arm had discontinued treatment. After discontinuation, 46% of patients in the lenalidomide arm and 50% in the investigator’s choice arm received 1 or more new antilymphoma therapies (excluding crossover patients).
The investigators said the proportion of patients who responded to subsequent therapies or had progressive disease did not substantially differ whether they had previously been randomized to lenalidomide or investigator’s choice.
Efficacy
As of the data cutoff point (March 7, 2014), the median follow-up was 15.9 months (range, 7.6 to 31.7).
The overall response rate was 40% in the lenalidomide arm and 11% in the investigator’s choice arm (P<0.001). The complete response rates were 5% and 0%, respectively (P=0.04). The median duration of response was 16 months and 10.4 months, respectively.
Lenalidomide significantly prolonged PFS. The median PFS was 8.7 months in the lenalidomide arm and 5.2 months in the investigator’s choice arm. The hazard ratio was 0.61 (P=0.004).
There was no significant difference in OS between the treatment arms. The median OS was 27.8 months in the lenalidomide arm and 21.2 months in the investigator’s choice arm. The hazard ratio was 0.89 (P=0.45)
A total of 128 patients (50%) died. Most deaths occurred during follow-up, and the most frequent cause of death was underlying lymphoma.
Safety
The incidence of treatment-related AEs was 84% in the lenalidomide arm and 60% in the investigator’s choice arm.
The most common grade 3 or higher AEs—in the lenalidomide and investigator’s choice arms, respectively—were neutropenia (44% vs 34%) without increased risk of infection, thrombocytopenia (18% vs 28%), leukopenia (8% vs 11%), and anemia (8% vs 7%).
The incidence of any-grade nasopharyngitis was 15% in the lenalidomide arm and 6% in the investigator’s choice arm. The incidence of upper respiratory tract infection was 12% and 6%, respectively. Febrile neutropenia was reported in 6% and 2% of patients, respectively.
Growth factors were used more often in the lenalidomide arm than the investigator’s choice arm—30% and 23%, respectively. But platelet transfusions were used less often in the lenalidomide arm—4% and 11%, respectively.
Photo by Esther Dyson
Results of the phase 2 SPRINT trial suggest lenalidomide compares favorably to other single-agent therapies for patients with relapsed/refractory mantle cell lymphoma (MCL).
Patients who received lenalidomide had a significantly higher overall response rate and significantly longer progression-free survival (PFS) compared to patients who received single-agent therapy chosen by investigators.
However, there was no significant difference between the treatment arms with regard to overall survival (OS).
In addition, there were more treatment-related adverse events (AEs) in the lenalidomide arm than the investigator’s choice arm.
These results were published in The Lancet Oncology. The study was funded by Celgene Corporation, the company developing lenalidomide.
“The SPRINT study provided the first head-to-head, randomized, controlled study of single-agent lenalidomide compared with a range of single-agent comparators in previously treated MCL,” said study author Marek Trneny, MD, of Charles University Hospital in Prague, Czech Republic.
“The study demonstrated a statistically significant reduction in the risk of disease progression or death for lenalidomide over investigator’s choice in patients with relapsed/refractory MCL.”
The study enrolled 254 patients with relapsed/refractory MCL who were ineligible for intensive chemotherapy or hematopoietic stem cell transplant. The patients’ median age was 68.5 (range, 44-88), and they had received a median of 2 previous treatment regimens (range, 1-≥4).
Treatment
The patients were randomized (2:1) to receive lenalidomide orally at 25 mg on days 1-21 every 28 days until progressive disease or intolerability (n=170) or single-agent investigator’s choice (n=84), which included rituximab, gemcitabine, fludarabine, chlorambucil, and cytarabine. Patients who progressed on investigator’s choice could cross over to the lenalidomide arm.
In all, 167 patients in the lenalidomide arm and 83 patients in the investigator’s choice arm received at least 1 dose of treatment. In the investigator’s choice arm, 33% of patients received rituximab, 24% got gemcitabine, 22% fludarabine, 13% chlorambucil, and 8% cytarabine.
After disease progression on investigator’s choice, 46% of patients crossed over to the lenalidomide arm.
Before cycle 6, half of the patients in the lenalidomide arm and two-thirds of those in the investigator’s choice arm had discontinued treatment. After discontinuation, 46% of patients in the lenalidomide arm and 50% in the investigator’s choice arm received 1 or more new antilymphoma therapies (excluding crossover patients).
The investigators said the proportion of patients who responded to subsequent therapies or had progressive disease did not substantially differ whether they had previously been randomized to lenalidomide or investigator’s choice.
Efficacy
As of the data cutoff point (March 7, 2014), the median follow-up was 15.9 months (range, 7.6 to 31.7).
The overall response rate was 40% in the lenalidomide arm and 11% in the investigator’s choice arm (P<0.001). The complete response rates were 5% and 0%, respectively (P=0.04). The median duration of response was 16 months and 10.4 months, respectively.
Lenalidomide significantly prolonged PFS. The median PFS was 8.7 months in the lenalidomide arm and 5.2 months in the investigator’s choice arm. The hazard ratio was 0.61 (P=0.004).
There was no significant difference in OS between the treatment arms. The median OS was 27.8 months in the lenalidomide arm and 21.2 months in the investigator’s choice arm. The hazard ratio was 0.89 (P=0.45)
A total of 128 patients (50%) died. Most deaths occurred during follow-up, and the most frequent cause of death was underlying lymphoma.
Safety
The incidence of treatment-related AEs was 84% in the lenalidomide arm and 60% in the investigator’s choice arm.
The most common grade 3 or higher AEs—in the lenalidomide and investigator’s choice arms, respectively—were neutropenia (44% vs 34%) without increased risk of infection, thrombocytopenia (18% vs 28%), leukopenia (8% vs 11%), and anemia (8% vs 7%).
The incidence of any-grade nasopharyngitis was 15% in the lenalidomide arm and 6% in the investigator’s choice arm. The incidence of upper respiratory tract infection was 12% and 6%, respectively. Febrile neutropenia was reported in 6% and 2% of patients, respectively.
Growth factors were used more often in the lenalidomide arm than the investigator’s choice arm—30% and 23%, respectively. But platelet transfusions were used less often in the lenalidomide arm—4% and 11%, respectively.
Drug shows early promise for rel/ref NHL
Blinatumomab, a CD19/CD3 bispecific T-cell engager antibody construct, can produce durable responses in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL), according to a phase 1 study.
Among patients who received the maximum-tolerated dose (MTD) of blinatumomab, the overall response rate (ORR) was nearly 70%, and the median duration of response was more than 400 days.
However, there was a high rate of neurologic events, particularly among patients who received higher doses of the drug.
Ralph Bargou, MD, of Wuerzburg University Hospital in Germany, and his colleagues conducted this study and reported the results in the Journal of Clinical Oncology.
The study was supported by Amgen (and Micromet before its acquisition by Amgen), the companies developing blinatumomab.
The study enrolled 76 patients with relapsed/refractory NHL. Most patients (n=52) had indolent NHL. Subtypes included follicular lymphoma (FL, n=28), mantle cell lymphoma (MCL, n=24), diffuse large B-cell lymphoma (DLBCL, n=14), and “other” (n=10).
The “other” category included lymphoplasmacytic lymphoma (n=2), small lymphoplasmacytic lymphoma (n=1), immunocytoma (n=1), Waldenstrom’s macroglobulinemia (n=1), marginal zone NHL (n=1), marginal zone B-cell lymphoma (n=1), marginal zone lymphoma (n=1), chronic lymphocytic leukemia (n=1), and small lymphoplasmacytic lymphoma/chronic lymphocytic leukemia (n=1).
The patients’ median age was 65 (range, 20-80), and the median number of prior treatment regimens was 3 (range, 1-10).
Dosing, toxicity, and discontinuation
This phase 1, dose-escalation study had a 3 + 3 design. Blinatumomab was given over 4 or 8 weeks at 7 different dose levels, ranging from 0.5 μg/m2/day to 90 μg/m2/day.
The researchers found that neurologic events were dose-limiting, and 60 μg/m2/day was the MTD.
Five patients experienced dose-limiting toxicities, including a grade 2 mental disorder (15 μg/m2/day), a case of grade 4 metabolic acidosis due to grand mal seizure (30 μg/m2/day), 2 cases of grade 3 encephalopathy (90 μg/m2/day), and 1 case of grade 3 seizure and aphasia (90 μg/m2/day).
Forty-two patients received treatment in the formal dose-escalation phase. Thirty-four additional patients were recruited to evaluate the antilymphoma activity of blinatumomab and test strategies for mitigating neurologic events at the MTD.
The researchers found that stepwise dosing (5 μg/m2/day to 60 μg/m2/day) plus pentosan polysulfate SP54 (n=3) prompted no treatment discontinuations.
However, single-step (n=5) dosing led to 2 discontinuations, and double-step (n=24) dosing led to 7 discontinuations. All were due to neurologic events.
The most clinically relevant adverse events were neurologic in nature. The overall incidence of these events, regardless of causality, was 71%. The incidence of grade 3 neurologic events was 22%.
Twenty percent of patients experienced serious neurologic events, including encephalopathy (8%), aphasia (4%), and headache (3%). There were no grade 4 or 5 neurologic events.
Response
Among patients treated at the MTD (60 μg/m2/day), the ORR was 69% (24/35). The ORR was 50% at 90 μg/m2/day (2/4), 20% at 15 μg/m2/day (3/15), and 17% at 30 μg/m2/day (1/6).
Complete responses (CRs) occurred in 1 patient at the 15 μg/m2/day dose, 1 at the 30 μg/m2/day dose, 1 at the 90 μg/m2/day dose, and 8 at the 60 μg/m2/day dose. Unconfirmed CRs (CRus) occurred in 5 patients at the 60 μg/m2/day dose.
Among patients who received the MTD, the ORR was 80% in FL patients, 71% in MCL patients, 55% in DLBCL patients, and 50% in the “other” category. There were 6 CR/CRus among FL patients, 3 CR/CRus among MCL patients, and 4 CR/CRus among DLBCL patients.
The median duration of response for patients who received the MTD was 404 days (95% CI, 207 to 1129). The median duration of CR/CRu was 508 days (95% CI, 213 to not estimable). And the median duration of partial response was 185 days (95% CI, 28 to 754).
Nine patients were still in remission at the time of the analysis, and 12 patients had remissions lasting more than 1 year.
“Blinatumomab continues to demonstrate a long duration of response in heavily pretreated non-Hodgkin lymphoma patients,” Dr Bargou said. “Results of the expanded phase 1 experience suggest that blinatumomab has the potential to alter the clinical course of disease in patients with a variety of NHL subtypes.”
Blinatumomab, a CD19/CD3 bispecific T-cell engager antibody construct, can produce durable responses in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL), according to a phase 1 study.
Among patients who received the maximum-tolerated dose (MTD) of blinatumomab, the overall response rate (ORR) was nearly 70%, and the median duration of response was more than 400 days.
However, there was a high rate of neurologic events, particularly among patients who received higher doses of the drug.
Ralph Bargou, MD, of Wuerzburg University Hospital in Germany, and his colleagues conducted this study and reported the results in the Journal of Clinical Oncology.
The study was supported by Amgen (and Micromet before its acquisition by Amgen), the companies developing blinatumomab.
The study enrolled 76 patients with relapsed/refractory NHL. Most patients (n=52) had indolent NHL. Subtypes included follicular lymphoma (FL, n=28), mantle cell lymphoma (MCL, n=24), diffuse large B-cell lymphoma (DLBCL, n=14), and “other” (n=10).
The “other” category included lymphoplasmacytic lymphoma (n=2), small lymphoplasmacytic lymphoma (n=1), immunocytoma (n=1), Waldenstrom’s macroglobulinemia (n=1), marginal zone NHL (n=1), marginal zone B-cell lymphoma (n=1), marginal zone lymphoma (n=1), chronic lymphocytic leukemia (n=1), and small lymphoplasmacytic lymphoma/chronic lymphocytic leukemia (n=1).
The patients’ median age was 65 (range, 20-80), and the median number of prior treatment regimens was 3 (range, 1-10).
Dosing, toxicity, and discontinuation
This phase 1, dose-escalation study had a 3 + 3 design. Blinatumomab was given over 4 or 8 weeks at 7 different dose levels, ranging from 0.5 μg/m2/day to 90 μg/m2/day.
The researchers found that neurologic events were dose-limiting, and 60 μg/m2/day was the MTD.
Five patients experienced dose-limiting toxicities, including a grade 2 mental disorder (15 μg/m2/day), a case of grade 4 metabolic acidosis due to grand mal seizure (30 μg/m2/day), 2 cases of grade 3 encephalopathy (90 μg/m2/day), and 1 case of grade 3 seizure and aphasia (90 μg/m2/day).
Forty-two patients received treatment in the formal dose-escalation phase. Thirty-four additional patients were recruited to evaluate the antilymphoma activity of blinatumomab and test strategies for mitigating neurologic events at the MTD.
The researchers found that stepwise dosing (5 μg/m2/day to 60 μg/m2/day) plus pentosan polysulfate SP54 (n=3) prompted no treatment discontinuations.
However, single-step (n=5) dosing led to 2 discontinuations, and double-step (n=24) dosing led to 7 discontinuations. All were due to neurologic events.
The most clinically relevant adverse events were neurologic in nature. The overall incidence of these events, regardless of causality, was 71%. The incidence of grade 3 neurologic events was 22%.
Twenty percent of patients experienced serious neurologic events, including encephalopathy (8%), aphasia (4%), and headache (3%). There were no grade 4 or 5 neurologic events.
Response
Among patients treated at the MTD (60 μg/m2/day), the ORR was 69% (24/35). The ORR was 50% at 90 μg/m2/day (2/4), 20% at 15 μg/m2/day (3/15), and 17% at 30 μg/m2/day (1/6).
Complete responses (CRs) occurred in 1 patient at the 15 μg/m2/day dose, 1 at the 30 μg/m2/day dose, 1 at the 90 μg/m2/day dose, and 8 at the 60 μg/m2/day dose. Unconfirmed CRs (CRus) occurred in 5 patients at the 60 μg/m2/day dose.
Among patients who received the MTD, the ORR was 80% in FL patients, 71% in MCL patients, 55% in DLBCL patients, and 50% in the “other” category. There were 6 CR/CRus among FL patients, 3 CR/CRus among MCL patients, and 4 CR/CRus among DLBCL patients.
The median duration of response for patients who received the MTD was 404 days (95% CI, 207 to 1129). The median duration of CR/CRu was 508 days (95% CI, 213 to not estimable). And the median duration of partial response was 185 days (95% CI, 28 to 754).
Nine patients were still in remission at the time of the analysis, and 12 patients had remissions lasting more than 1 year.
“Blinatumomab continues to demonstrate a long duration of response in heavily pretreated non-Hodgkin lymphoma patients,” Dr Bargou said. “Results of the expanded phase 1 experience suggest that blinatumomab has the potential to alter the clinical course of disease in patients with a variety of NHL subtypes.”
Blinatumomab, a CD19/CD3 bispecific T-cell engager antibody construct, can produce durable responses in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL), according to a phase 1 study.
Among patients who received the maximum-tolerated dose (MTD) of blinatumomab, the overall response rate (ORR) was nearly 70%, and the median duration of response was more than 400 days.
However, there was a high rate of neurologic events, particularly among patients who received higher doses of the drug.
Ralph Bargou, MD, of Wuerzburg University Hospital in Germany, and his colleagues conducted this study and reported the results in the Journal of Clinical Oncology.
The study was supported by Amgen (and Micromet before its acquisition by Amgen), the companies developing blinatumomab.
The study enrolled 76 patients with relapsed/refractory NHL. Most patients (n=52) had indolent NHL. Subtypes included follicular lymphoma (FL, n=28), mantle cell lymphoma (MCL, n=24), diffuse large B-cell lymphoma (DLBCL, n=14), and “other” (n=10).
The “other” category included lymphoplasmacytic lymphoma (n=2), small lymphoplasmacytic lymphoma (n=1), immunocytoma (n=1), Waldenstrom’s macroglobulinemia (n=1), marginal zone NHL (n=1), marginal zone B-cell lymphoma (n=1), marginal zone lymphoma (n=1), chronic lymphocytic leukemia (n=1), and small lymphoplasmacytic lymphoma/chronic lymphocytic leukemia (n=1).
The patients’ median age was 65 (range, 20-80), and the median number of prior treatment regimens was 3 (range, 1-10).
Dosing, toxicity, and discontinuation
This phase 1, dose-escalation study had a 3 + 3 design. Blinatumomab was given over 4 or 8 weeks at 7 different dose levels, ranging from 0.5 μg/m2/day to 90 μg/m2/day.
The researchers found that neurologic events were dose-limiting, and 60 μg/m2/day was the MTD.
Five patients experienced dose-limiting toxicities, including a grade 2 mental disorder (15 μg/m2/day), a case of grade 4 metabolic acidosis due to grand mal seizure (30 μg/m2/day), 2 cases of grade 3 encephalopathy (90 μg/m2/day), and 1 case of grade 3 seizure and aphasia (90 μg/m2/day).
Forty-two patients received treatment in the formal dose-escalation phase. Thirty-four additional patients were recruited to evaluate the antilymphoma activity of blinatumomab and test strategies for mitigating neurologic events at the MTD.
The researchers found that stepwise dosing (5 μg/m2/day to 60 μg/m2/day) plus pentosan polysulfate SP54 (n=3) prompted no treatment discontinuations.
However, single-step (n=5) dosing led to 2 discontinuations, and double-step (n=24) dosing led to 7 discontinuations. All were due to neurologic events.
The most clinically relevant adverse events were neurologic in nature. The overall incidence of these events, regardless of causality, was 71%. The incidence of grade 3 neurologic events was 22%.
Twenty percent of patients experienced serious neurologic events, including encephalopathy (8%), aphasia (4%), and headache (3%). There were no grade 4 or 5 neurologic events.
Response
Among patients treated at the MTD (60 μg/m2/day), the ORR was 69% (24/35). The ORR was 50% at 90 μg/m2/day (2/4), 20% at 15 μg/m2/day (3/15), and 17% at 30 μg/m2/day (1/6).
Complete responses (CRs) occurred in 1 patient at the 15 μg/m2/day dose, 1 at the 30 μg/m2/day dose, 1 at the 90 μg/m2/day dose, and 8 at the 60 μg/m2/day dose. Unconfirmed CRs (CRus) occurred in 5 patients at the 60 μg/m2/day dose.
Among patients who received the MTD, the ORR was 80% in FL patients, 71% in MCL patients, 55% in DLBCL patients, and 50% in the “other” category. There were 6 CR/CRus among FL patients, 3 CR/CRus among MCL patients, and 4 CR/CRus among DLBCL patients.
The median duration of response for patients who received the MTD was 404 days (95% CI, 207 to 1129). The median duration of CR/CRu was 508 days (95% CI, 213 to not estimable). And the median duration of partial response was 185 days (95% CI, 28 to 754).
Nine patients were still in remission at the time of the analysis, and 12 patients had remissions lasting more than 1 year.
“Blinatumomab continues to demonstrate a long duration of response in heavily pretreated non-Hodgkin lymphoma patients,” Dr Bargou said. “Results of the expanded phase 1 experience suggest that blinatumomab has the potential to alter the clinical course of disease in patients with a variety of NHL subtypes.”
Studies explain how mutations promote lymphoma
New research suggests there are 4 different “locks” that keep the CARD11 protein in check.
Researchers say these locks, also known as “repressive elements,” work together to prevent unwarranted CARD11 signaling.
But mutations in CARD11 can perturb or bypass the action of the repressive elements, which leads to a level of hyperactive CARD11 signaling that supports lymphoma growth.
Joel Pomerantz, PhD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland, and his colleagues reported these findings in 2 articles published in The Journal of Biological Chemistry.1,2
The researchers noted that mutated CARD11 proteins are sometimes found in patients with lymphoma, particularly diffuse large B-cell lymphoma. But none of the mutations exist in the “lock region” of CARD11, known as the autoinhibitory domain.
To find out why, the team conducted experiments with T cells. They first genetically deleted CARD11’s autoinhibitory domain so that the protein was always “on” and signaling.
Then, to figure out which region of the autoinhibitory domain accounted for its function, the researchers systematically deleted 6 different segments of it one at a time, rather than deleting the whole thing.
They expected most of the deletions to keep CARD11 inactive and 1 or 2 to “unlock” it. However, none of the deletions unlocked it, which suggested there was more than 1 repressive element within the autoinhibitory domain.
To see if that was the case and to find out how many repressive elements there might be, the researchers deleted the full autoinhibitory domain again, then added back small regions of it.
In this way, they pieced together the presence of 4 different biochemical regions, or repressive elements, that are each capable of locking CARD11 on their own.
“Having 4 redundant repressive elements seems to explain why patients with lymphoma don’t have mutations in CARD11’s autoinhibitory domain,” Dr Pomerantz said. “A mutation in any one of the repressive elements would only unlock 1 of the 4 locks, keeping CARD11’s signaling under the control of the other 3.”
So where do the lymphoma-associated mutations occur, and how do they circumvent CARD11’s quadruple locks? Clinical data show that the mutations occur in 3 other regions of CARD11—the CARD, LATCH, and coiled-coil regions.
Dr Pomerantz and his colleagues conducted biochemical tests on T cells and found that those 3 regions clasp the autoinhibitory domain to keep CARD11’s activity on lockdown. This makes sense, Dr Pomerantz said, because CARD11 uses those same regions to connect with other signaling proteins to send its message.
“When they are interacting with the autoinhibitory domain, they can’t be interacting with other proteins,” he said.
According to Dr Pomerantz, single mutations in the CARD, LATCH, or coiled-coil regions appear to be sufficient to disable the 4 repressive elements. And the ultimate goal is to advance the development of therapies that rein in hyperactive CARD11 in patients with lymphoma.
“If we can understand how CARD11 is normally kept off, we might be able to mimic that with a drug,” he said. “We also hope to shed light on how different mutations in CARD11 affect its function and a patient’s prognosis.”
New research suggests there are 4 different “locks” that keep the CARD11 protein in check.
Researchers say these locks, also known as “repressive elements,” work together to prevent unwarranted CARD11 signaling.
But mutations in CARD11 can perturb or bypass the action of the repressive elements, which leads to a level of hyperactive CARD11 signaling that supports lymphoma growth.
Joel Pomerantz, PhD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland, and his colleagues reported these findings in 2 articles published in The Journal of Biological Chemistry.1,2
The researchers noted that mutated CARD11 proteins are sometimes found in patients with lymphoma, particularly diffuse large B-cell lymphoma. But none of the mutations exist in the “lock region” of CARD11, known as the autoinhibitory domain.
To find out why, the team conducted experiments with T cells. They first genetically deleted CARD11’s autoinhibitory domain so that the protein was always “on” and signaling.
Then, to figure out which region of the autoinhibitory domain accounted for its function, the researchers systematically deleted 6 different segments of it one at a time, rather than deleting the whole thing.
They expected most of the deletions to keep CARD11 inactive and 1 or 2 to “unlock” it. However, none of the deletions unlocked it, which suggested there was more than 1 repressive element within the autoinhibitory domain.
To see if that was the case and to find out how many repressive elements there might be, the researchers deleted the full autoinhibitory domain again, then added back small regions of it.
In this way, they pieced together the presence of 4 different biochemical regions, or repressive elements, that are each capable of locking CARD11 on their own.
“Having 4 redundant repressive elements seems to explain why patients with lymphoma don’t have mutations in CARD11’s autoinhibitory domain,” Dr Pomerantz said. “A mutation in any one of the repressive elements would only unlock 1 of the 4 locks, keeping CARD11’s signaling under the control of the other 3.”
So where do the lymphoma-associated mutations occur, and how do they circumvent CARD11’s quadruple locks? Clinical data show that the mutations occur in 3 other regions of CARD11—the CARD, LATCH, and coiled-coil regions.
Dr Pomerantz and his colleagues conducted biochemical tests on T cells and found that those 3 regions clasp the autoinhibitory domain to keep CARD11’s activity on lockdown. This makes sense, Dr Pomerantz said, because CARD11 uses those same regions to connect with other signaling proteins to send its message.
“When they are interacting with the autoinhibitory domain, they can’t be interacting with other proteins,” he said.
According to Dr Pomerantz, single mutations in the CARD, LATCH, or coiled-coil regions appear to be sufficient to disable the 4 repressive elements. And the ultimate goal is to advance the development of therapies that rein in hyperactive CARD11 in patients with lymphoma.
“If we can understand how CARD11 is normally kept off, we might be able to mimic that with a drug,” he said. “We also hope to shed light on how different mutations in CARD11 affect its function and a patient’s prognosis.”
New research suggests there are 4 different “locks” that keep the CARD11 protein in check.
Researchers say these locks, also known as “repressive elements,” work together to prevent unwarranted CARD11 signaling.
But mutations in CARD11 can perturb or bypass the action of the repressive elements, which leads to a level of hyperactive CARD11 signaling that supports lymphoma growth.
Joel Pomerantz, PhD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland, and his colleagues reported these findings in 2 articles published in The Journal of Biological Chemistry.1,2
The researchers noted that mutated CARD11 proteins are sometimes found in patients with lymphoma, particularly diffuse large B-cell lymphoma. But none of the mutations exist in the “lock region” of CARD11, known as the autoinhibitory domain.
To find out why, the team conducted experiments with T cells. They first genetically deleted CARD11’s autoinhibitory domain so that the protein was always “on” and signaling.
Then, to figure out which region of the autoinhibitory domain accounted for its function, the researchers systematically deleted 6 different segments of it one at a time, rather than deleting the whole thing.
They expected most of the deletions to keep CARD11 inactive and 1 or 2 to “unlock” it. However, none of the deletions unlocked it, which suggested there was more than 1 repressive element within the autoinhibitory domain.
To see if that was the case and to find out how many repressive elements there might be, the researchers deleted the full autoinhibitory domain again, then added back small regions of it.
In this way, they pieced together the presence of 4 different biochemical regions, or repressive elements, that are each capable of locking CARD11 on their own.
“Having 4 redundant repressive elements seems to explain why patients with lymphoma don’t have mutations in CARD11’s autoinhibitory domain,” Dr Pomerantz said. “A mutation in any one of the repressive elements would only unlock 1 of the 4 locks, keeping CARD11’s signaling under the control of the other 3.”
So where do the lymphoma-associated mutations occur, and how do they circumvent CARD11’s quadruple locks? Clinical data show that the mutations occur in 3 other regions of CARD11—the CARD, LATCH, and coiled-coil regions.
Dr Pomerantz and his colleagues conducted biochemical tests on T cells and found that those 3 regions clasp the autoinhibitory domain to keep CARD11’s activity on lockdown. This makes sense, Dr Pomerantz said, because CARD11 uses those same regions to connect with other signaling proteins to send its message.
“When they are interacting with the autoinhibitory domain, they can’t be interacting with other proteins,” he said.
According to Dr Pomerantz, single mutations in the CARD, LATCH, or coiled-coil regions appear to be sufficient to disable the 4 repressive elements. And the ultimate goal is to advance the development of therapies that rein in hyperactive CARD11 in patients with lymphoma.
“If we can understand how CARD11 is normally kept off, we might be able to mimic that with a drug,” he said. “We also hope to shed light on how different mutations in CARD11 affect its function and a patient’s prognosis.”
EMA recommends safety measures for idelalisib
Photo courtesy of
Gilead Sciences, Inc.
In light of recently reported safety concerns, the European Medicines Agency’s (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) has issued provisional advice for doctors and patients using idelalisib (Zydelig).
The EMA recently began reviewing the safety of idelalisib because of serious adverse events, most of which were infection-related, that were reported in 3 clinical trials investigating idelalisib in combination with other drugs.
These trials have since been stopped.
Now, the PRAC is making provisional recommendations to ensure idelalisib is used as safely as possible outside of clinical trials.
These recommendations will be forwarded to the European Commission, which will issue a provisional legally binding decision applicable in all European Union (EU) member states.
In the EU, idelalisib is approved as monotherapy for adults with follicular lymphoma that is refractory to 2 prior lines of treatment.
Idelalisib is also approved for use in combination with rituximab to treat adults with chronic lymphocytic leukemia (CLL) who have received at least 1 prior therapy or as first-line treatment in the presence of 17p deletion or TP53 mutation in CLL patients considered unsuitable for chemo-immunotherapy.
Recommendations
The PRAC is recommending that previously untreated CLL patients with 17p deletion or TP53 mutation do not begin treatment with idelalisib. In addition, doctors should re-evaluate each patient taking idelalisib as first-line treatment for CLL and only continue treatment if the benefits outweigh the risks.
Idelalisib can continue to be used in combination, only with rituximab, in CLL patients who have received at least 1 prior therapy and as monotherapy in patients with follicular lymphoma that is refractory to 2 lines of treatment.
Patients with any evidence of ongoing systemic infection should not be started on treatment with idelalisib.
And patients should be informed about the risk of serious infections with idelalisib.
All patients who do receive idelalisib should take antibiotics to prevent Pneumocystis jirovecii pneumonia, and they should be monitored for respiratory signs and symptoms. Regular clinical and laboratory monitoring for cytomegalovirus infection is also recommended.
Patients should have regular blood tests to detect neutropenia. In case a patient has moderate or severe neutropenia, treatment with idelalisib may have to be interrupted, in line with the updated summary of product characteristics.
The EMA said further details on these provisional measures will be provided in writing to healthcare professionals, and the product information will be updated accordingly.
Likewise, further information on the review of idelalisib will be provided as necessary and once the review is finished.
About the review
The EMA’s review of idelalisib started after a higher rate of serious adverse events, including deaths, was seen in 3 clinical trials evaluating the addition of idelalisib to standard therapy in first-line CLL and relapsed indolent non-Hodgkin lymphoma (NHL).
Most of the deaths were related to infections such as Pneumocystis jirovecii pneumonia and cytomegalovirus infection. Other excess deaths were related mainly to respiratory events.
The NHL studies (NCT01732926 and NCT01732913) included patients with disease characteristics different from those covered by the currently approved indication for idelalisib and investigated combinations of drugs that are not currently approved in the EU—idelalisib plus rituximab for NHL and idelalisib plus bendamustine and rituximab for NHL.
The CLL trial (NCT01980888) involved patients who had not received previous treatment, some of whom had the 17p deletion or TP53 mutation. However, the trial also investigated a combination of drugs not currently approved in the EU—idelalisib plus bendamustine and rituximab.
At present, the PRAC is conducting the review. Once the PRAC is finished, its recommendations will be forwarded to the EMA’s Committee for Medicinal Products for Human Use, which will adopt a final opinion.
The European Commission will take this opinion into account and adopt a legally binding decision that is applicable in all EU member states.
Photo courtesy of
Gilead Sciences, Inc.
In light of recently reported safety concerns, the European Medicines Agency’s (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) has issued provisional advice for doctors and patients using idelalisib (Zydelig).
The EMA recently began reviewing the safety of idelalisib because of serious adverse events, most of which were infection-related, that were reported in 3 clinical trials investigating idelalisib in combination with other drugs.
These trials have since been stopped.
Now, the PRAC is making provisional recommendations to ensure idelalisib is used as safely as possible outside of clinical trials.
These recommendations will be forwarded to the European Commission, which will issue a provisional legally binding decision applicable in all European Union (EU) member states.
In the EU, idelalisib is approved as monotherapy for adults with follicular lymphoma that is refractory to 2 prior lines of treatment.
Idelalisib is also approved for use in combination with rituximab to treat adults with chronic lymphocytic leukemia (CLL) who have received at least 1 prior therapy or as first-line treatment in the presence of 17p deletion or TP53 mutation in CLL patients considered unsuitable for chemo-immunotherapy.
Recommendations
The PRAC is recommending that previously untreated CLL patients with 17p deletion or TP53 mutation do not begin treatment with idelalisib. In addition, doctors should re-evaluate each patient taking idelalisib as first-line treatment for CLL and only continue treatment if the benefits outweigh the risks.
Idelalisib can continue to be used in combination, only with rituximab, in CLL patients who have received at least 1 prior therapy and as monotherapy in patients with follicular lymphoma that is refractory to 2 lines of treatment.
Patients with any evidence of ongoing systemic infection should not be started on treatment with idelalisib.
And patients should be informed about the risk of serious infections with idelalisib.
All patients who do receive idelalisib should take antibiotics to prevent Pneumocystis jirovecii pneumonia, and they should be monitored for respiratory signs and symptoms. Regular clinical and laboratory monitoring for cytomegalovirus infection is also recommended.
Patients should have regular blood tests to detect neutropenia. In case a patient has moderate or severe neutropenia, treatment with idelalisib may have to be interrupted, in line with the updated summary of product characteristics.
The EMA said further details on these provisional measures will be provided in writing to healthcare professionals, and the product information will be updated accordingly.
Likewise, further information on the review of idelalisib will be provided as necessary and once the review is finished.
About the review
The EMA’s review of idelalisib started after a higher rate of serious adverse events, including deaths, was seen in 3 clinical trials evaluating the addition of idelalisib to standard therapy in first-line CLL and relapsed indolent non-Hodgkin lymphoma (NHL).
Most of the deaths were related to infections such as Pneumocystis jirovecii pneumonia and cytomegalovirus infection. Other excess deaths were related mainly to respiratory events.
The NHL studies (NCT01732926 and NCT01732913) included patients with disease characteristics different from those covered by the currently approved indication for idelalisib and investigated combinations of drugs that are not currently approved in the EU—idelalisib plus rituximab for NHL and idelalisib plus bendamustine and rituximab for NHL.
The CLL trial (NCT01980888) involved patients who had not received previous treatment, some of whom had the 17p deletion or TP53 mutation. However, the trial also investigated a combination of drugs not currently approved in the EU—idelalisib plus bendamustine and rituximab.
At present, the PRAC is conducting the review. Once the PRAC is finished, its recommendations will be forwarded to the EMA’s Committee for Medicinal Products for Human Use, which will adopt a final opinion.
The European Commission will take this opinion into account and adopt a legally binding decision that is applicable in all EU member states.
Photo courtesy of
Gilead Sciences, Inc.
In light of recently reported safety concerns, the European Medicines Agency’s (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) has issued provisional advice for doctors and patients using idelalisib (Zydelig).
The EMA recently began reviewing the safety of idelalisib because of serious adverse events, most of which were infection-related, that were reported in 3 clinical trials investigating idelalisib in combination with other drugs.
These trials have since been stopped.
Now, the PRAC is making provisional recommendations to ensure idelalisib is used as safely as possible outside of clinical trials.
These recommendations will be forwarded to the European Commission, which will issue a provisional legally binding decision applicable in all European Union (EU) member states.
In the EU, idelalisib is approved as monotherapy for adults with follicular lymphoma that is refractory to 2 prior lines of treatment.
Idelalisib is also approved for use in combination with rituximab to treat adults with chronic lymphocytic leukemia (CLL) who have received at least 1 prior therapy or as first-line treatment in the presence of 17p deletion or TP53 mutation in CLL patients considered unsuitable for chemo-immunotherapy.
Recommendations
The PRAC is recommending that previously untreated CLL patients with 17p deletion or TP53 mutation do not begin treatment with idelalisib. In addition, doctors should re-evaluate each patient taking idelalisib as first-line treatment for CLL and only continue treatment if the benefits outweigh the risks.
Idelalisib can continue to be used in combination, only with rituximab, in CLL patients who have received at least 1 prior therapy and as monotherapy in patients with follicular lymphoma that is refractory to 2 lines of treatment.
Patients with any evidence of ongoing systemic infection should not be started on treatment with idelalisib.
And patients should be informed about the risk of serious infections with idelalisib.
All patients who do receive idelalisib should take antibiotics to prevent Pneumocystis jirovecii pneumonia, and they should be monitored for respiratory signs and symptoms. Regular clinical and laboratory monitoring for cytomegalovirus infection is also recommended.
Patients should have regular blood tests to detect neutropenia. In case a patient has moderate or severe neutropenia, treatment with idelalisib may have to be interrupted, in line with the updated summary of product characteristics.
The EMA said further details on these provisional measures will be provided in writing to healthcare professionals, and the product information will be updated accordingly.
Likewise, further information on the review of idelalisib will be provided as necessary and once the review is finished.
About the review
The EMA’s review of idelalisib started after a higher rate of serious adverse events, including deaths, was seen in 3 clinical trials evaluating the addition of idelalisib to standard therapy in first-line CLL and relapsed indolent non-Hodgkin lymphoma (NHL).
Most of the deaths were related to infections such as Pneumocystis jirovecii pneumonia and cytomegalovirus infection. Other excess deaths were related mainly to respiratory events.
The NHL studies (NCT01732926 and NCT01732913) included patients with disease characteristics different from those covered by the currently approved indication for idelalisib and investigated combinations of drugs that are not currently approved in the EU—idelalisib plus rituximab for NHL and idelalisib plus bendamustine and rituximab for NHL.
The CLL trial (NCT01980888) involved patients who had not received previous treatment, some of whom had the 17p deletion or TP53 mutation. However, the trial also investigated a combination of drugs not currently approved in the EU—idelalisib plus bendamustine and rituximab.
At present, the PRAC is conducting the review. Once the PRAC is finished, its recommendations will be forwarded to the EMA’s Committee for Medicinal Products for Human Use, which will adopt a final opinion.
The European Commission will take this opinion into account and adopt a legally binding decision that is applicable in all EU member states.
Idelalisib trials stopped due to AEs
Photo courtesy of
Gilead Sciences
The US Food and Drug Administration (FDA) has reported that Gilead Sciences, Inc., is stopping 6 clinical trials of idelalisib (Zydelig) due to adverse events (AEs) observed in patients receiving idelalisib in combination with other drugs.
The AEs, which include deaths, were mostly related to infections.
The trials include patients with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma, and indolent non-Hodgkin lymphomas.
The FDA said it is reviewing the findings of these trials and will communicate new information as necessary.
A few days ago, the European Medicines Agency (EMA) announced its decision to review the safety of idelalisib due to the aforementioned AEs. The EMA said it is reviewing data from 3 idelalisib trials.
While this review is underway, the EMA advised that patients starting or already on treatment with idelalisib be carefully monitored for signs of infection. If the drug is well tolerated, treatment should not be stopped.
The FDA has not made any recommendations about treatment with idelalisib.
About idelalisib
Idelalisib is currently approved by the FDA for use in combination with rituximab to treat patients with relapsed CLL who cannot receive rituximab alone.
Idelalisib also has accelerated approval from the FDA to treat patients with relapsed follicular lymphoma who have received at least 2 prior systemic therapies and patients with relapsed small lymphocytic lymphoma who have received at least 2 prior systemic therapies.
In the European Union, idelalisib is approved for use in combination with rituximab to treat adults with CLL who have received at least 1 prior therapy or as first-line treatment in the presence of 17p deletion or TP53 mutation in CLL patients deemed unsuitable for chemo-immunotherapy.
Idelalisib is also approved in the European Union as monotherapy for adults with follicular lymphoma that is refractory to 2 prior lines of treatment.
Photo courtesy of
Gilead Sciences
The US Food and Drug Administration (FDA) has reported that Gilead Sciences, Inc., is stopping 6 clinical trials of idelalisib (Zydelig) due to adverse events (AEs) observed in patients receiving idelalisib in combination with other drugs.
The AEs, which include deaths, were mostly related to infections.
The trials include patients with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma, and indolent non-Hodgkin lymphomas.
The FDA said it is reviewing the findings of these trials and will communicate new information as necessary.
A few days ago, the European Medicines Agency (EMA) announced its decision to review the safety of idelalisib due to the aforementioned AEs. The EMA said it is reviewing data from 3 idelalisib trials.
While this review is underway, the EMA advised that patients starting or already on treatment with idelalisib be carefully monitored for signs of infection. If the drug is well tolerated, treatment should not be stopped.
The FDA has not made any recommendations about treatment with idelalisib.
About idelalisib
Idelalisib is currently approved by the FDA for use in combination with rituximab to treat patients with relapsed CLL who cannot receive rituximab alone.
Idelalisib also has accelerated approval from the FDA to treat patients with relapsed follicular lymphoma who have received at least 2 prior systemic therapies and patients with relapsed small lymphocytic lymphoma who have received at least 2 prior systemic therapies.
In the European Union, idelalisib is approved for use in combination with rituximab to treat adults with CLL who have received at least 1 prior therapy or as first-line treatment in the presence of 17p deletion or TP53 mutation in CLL patients deemed unsuitable for chemo-immunotherapy.
Idelalisib is also approved in the European Union as monotherapy for adults with follicular lymphoma that is refractory to 2 prior lines of treatment.
Photo courtesy of
Gilead Sciences
The US Food and Drug Administration (FDA) has reported that Gilead Sciences, Inc., is stopping 6 clinical trials of idelalisib (Zydelig) due to adverse events (AEs) observed in patients receiving idelalisib in combination with other drugs.
The AEs, which include deaths, were mostly related to infections.
The trials include patients with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma, and indolent non-Hodgkin lymphomas.
The FDA said it is reviewing the findings of these trials and will communicate new information as necessary.
A few days ago, the European Medicines Agency (EMA) announced its decision to review the safety of idelalisib due to the aforementioned AEs. The EMA said it is reviewing data from 3 idelalisib trials.
While this review is underway, the EMA advised that patients starting or already on treatment with idelalisib be carefully monitored for signs of infection. If the drug is well tolerated, treatment should not be stopped.
The FDA has not made any recommendations about treatment with idelalisib.
About idelalisib
Idelalisib is currently approved by the FDA for use in combination with rituximab to treat patients with relapsed CLL who cannot receive rituximab alone.
Idelalisib also has accelerated approval from the FDA to treat patients with relapsed follicular lymphoma who have received at least 2 prior systemic therapies and patients with relapsed small lymphocytic lymphoma who have received at least 2 prior systemic therapies.
In the European Union, idelalisib is approved for use in combination with rituximab to treat adults with CLL who have received at least 1 prior therapy or as first-line treatment in the presence of 17p deletion or TP53 mutation in CLL patients deemed unsuitable for chemo-immunotherapy.
Idelalisib is also approved in the European Union as monotherapy for adults with follicular lymphoma that is refractory to 2 prior lines of treatment.
Drug granted orphan designation for DLBCL
The US Food and Drug Administration (FDA) has granted orphan designation to the oncology drug candidate PNT2258 for the treatment of diffuse large B-cell lymphoma (DLBCL).
The FDA grants orphan designation to drugs intended to treat conditions affecting fewer than 200,000 patients in the US.
The designation provides the drug’s sponsor with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.
About PNT2258
PNT2258 is designed to target cancers that overexpress BCL2, and BCL2 overexpression is thought to be a key driver of DLBCL.
PNT2258 consists of a single-stranded, 24-base DNAi oligonucleotide known as PNT100 that is encapsulated in lipid nanoparticles (LNPs).
The DNAi technology platform is based on a discovery that single-stranded DNA oligonucleotides can interact with genomic DNA to interfere with oncogenes. PNT100 DNAi is designed to target a genetic regulatory region associated with BCL2.
The LNPs are designed to provide enhanced serum stability and optimized pharmacokinetic properties to facilitate broad systemic distribution after intravenous infusion. Within the acidic environment found in tumors, the LNPs become positively charged and therefore more amenable to cellular uptake and cytoplasmic release of their payloads.
Trials of PNT2258
PNT2258 is being developed by ProNAi Therapeutics, Inc. The company has completed 2 trials of PNT2258 to date—a phase 1 trial of patients with solid tumors and a phase 2 trial of patients with non-Hodgkin lymphoma.
The phase 1 trial enrolled 22 patients with relapsed or refractory solid tumor malignancies. Results were published in Cancer Chemotherapy and Pharmacology in February 2014.
PNT2258 was deemed well-tolerated in this trial. There was no evidence of a systemic immune response to the LNPs or PNT100. There were no significant changes in immune-stimulatory cytokines or clinical signs of anaphylaxis following PNT2258 administration.
The phase 2 trial enrolled 13 patients with relapsed or refractory non-Hodgkin lymphoma. Results were presented at ASH 2014 (abstract 1716).
Six patients responded to PNT2258—4 with complete responses and 2 with partial responses. Five patients had stable disease, and 2 progressed. All 4 of the DLBCL patients in this trial responded—3 with complete responses and 1 with a partial response.
Adverse events reported in this trial include nausea (n=11), pain (n=9), chills (n=7), diarrhea (n=7), vomiting (n=7), fatigue (n=6), fever (n=6), headache (n=6), dyspnea (n=5), generalized aching (n=4), anorexia (n=4), back pain (n=4), sensory neuropathy (n=4), hypophosphatemia (n=4), anemia (n=3), hypokalemia (n=3), hyperuricemia (n=2), neutropenia (n=2), thrombocytopenia (n=4), and elevated AST/ALT (n=1).
ProNAi Therapeutics is now enrolling patients in “Wolverine,” a phase 2 trial evaluating PNT2258 in patients with relapsed or refractory DLBCL, and in “Brighton,” a phase 2 trial evaluating PNT2258 for the treatment of Richter’s transformation.
The US Food and Drug Administration (FDA) has granted orphan designation to the oncology drug candidate PNT2258 for the treatment of diffuse large B-cell lymphoma (DLBCL).
The FDA grants orphan designation to drugs intended to treat conditions affecting fewer than 200,000 patients in the US.
The designation provides the drug’s sponsor with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.
About PNT2258
PNT2258 is designed to target cancers that overexpress BCL2, and BCL2 overexpression is thought to be a key driver of DLBCL.
PNT2258 consists of a single-stranded, 24-base DNAi oligonucleotide known as PNT100 that is encapsulated in lipid nanoparticles (LNPs).
The DNAi technology platform is based on a discovery that single-stranded DNA oligonucleotides can interact with genomic DNA to interfere with oncogenes. PNT100 DNAi is designed to target a genetic regulatory region associated with BCL2.
The LNPs are designed to provide enhanced serum stability and optimized pharmacokinetic properties to facilitate broad systemic distribution after intravenous infusion. Within the acidic environment found in tumors, the LNPs become positively charged and therefore more amenable to cellular uptake and cytoplasmic release of their payloads.
Trials of PNT2258
PNT2258 is being developed by ProNAi Therapeutics, Inc. The company has completed 2 trials of PNT2258 to date—a phase 1 trial of patients with solid tumors and a phase 2 trial of patients with non-Hodgkin lymphoma.
The phase 1 trial enrolled 22 patients with relapsed or refractory solid tumor malignancies. Results were published in Cancer Chemotherapy and Pharmacology in February 2014.
PNT2258 was deemed well-tolerated in this trial. There was no evidence of a systemic immune response to the LNPs or PNT100. There were no significant changes in immune-stimulatory cytokines or clinical signs of anaphylaxis following PNT2258 administration.
The phase 2 trial enrolled 13 patients with relapsed or refractory non-Hodgkin lymphoma. Results were presented at ASH 2014 (abstract 1716).
Six patients responded to PNT2258—4 with complete responses and 2 with partial responses. Five patients had stable disease, and 2 progressed. All 4 of the DLBCL patients in this trial responded—3 with complete responses and 1 with a partial response.
Adverse events reported in this trial include nausea (n=11), pain (n=9), chills (n=7), diarrhea (n=7), vomiting (n=7), fatigue (n=6), fever (n=6), headache (n=6), dyspnea (n=5), generalized aching (n=4), anorexia (n=4), back pain (n=4), sensory neuropathy (n=4), hypophosphatemia (n=4), anemia (n=3), hypokalemia (n=3), hyperuricemia (n=2), neutropenia (n=2), thrombocytopenia (n=4), and elevated AST/ALT (n=1).
ProNAi Therapeutics is now enrolling patients in “Wolverine,” a phase 2 trial evaluating PNT2258 in patients with relapsed or refractory DLBCL, and in “Brighton,” a phase 2 trial evaluating PNT2258 for the treatment of Richter’s transformation.
The US Food and Drug Administration (FDA) has granted orphan designation to the oncology drug candidate PNT2258 for the treatment of diffuse large B-cell lymphoma (DLBCL).
The FDA grants orphan designation to drugs intended to treat conditions affecting fewer than 200,000 patients in the US.
The designation provides the drug’s sponsor with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.
About PNT2258
PNT2258 is designed to target cancers that overexpress BCL2, and BCL2 overexpression is thought to be a key driver of DLBCL.
PNT2258 consists of a single-stranded, 24-base DNAi oligonucleotide known as PNT100 that is encapsulated in lipid nanoparticles (LNPs).
The DNAi technology platform is based on a discovery that single-stranded DNA oligonucleotides can interact with genomic DNA to interfere with oncogenes. PNT100 DNAi is designed to target a genetic regulatory region associated with BCL2.
The LNPs are designed to provide enhanced serum stability and optimized pharmacokinetic properties to facilitate broad systemic distribution after intravenous infusion. Within the acidic environment found in tumors, the LNPs become positively charged and therefore more amenable to cellular uptake and cytoplasmic release of their payloads.
Trials of PNT2258
PNT2258 is being developed by ProNAi Therapeutics, Inc. The company has completed 2 trials of PNT2258 to date—a phase 1 trial of patients with solid tumors and a phase 2 trial of patients with non-Hodgkin lymphoma.
The phase 1 trial enrolled 22 patients with relapsed or refractory solid tumor malignancies. Results were published in Cancer Chemotherapy and Pharmacology in February 2014.
PNT2258 was deemed well-tolerated in this trial. There was no evidence of a systemic immune response to the LNPs or PNT100. There were no significant changes in immune-stimulatory cytokines or clinical signs of anaphylaxis following PNT2258 administration.
The phase 2 trial enrolled 13 patients with relapsed or refractory non-Hodgkin lymphoma. Results were presented at ASH 2014 (abstract 1716).
Six patients responded to PNT2258—4 with complete responses and 2 with partial responses. Five patients had stable disease, and 2 progressed. All 4 of the DLBCL patients in this trial responded—3 with complete responses and 1 with a partial response.
Adverse events reported in this trial include nausea (n=11), pain (n=9), chills (n=7), diarrhea (n=7), vomiting (n=7), fatigue (n=6), fever (n=6), headache (n=6), dyspnea (n=5), generalized aching (n=4), anorexia (n=4), back pain (n=4), sensory neuropathy (n=4), hypophosphatemia (n=4), anemia (n=3), hypokalemia (n=3), hyperuricemia (n=2), neutropenia (n=2), thrombocytopenia (n=4), and elevated AST/ALT (n=1).
ProNAi Therapeutics is now enrolling patients in “Wolverine,” a phase 2 trial evaluating PNT2258 in patients with relapsed or refractory DLBCL, and in “Brighton,” a phase 2 trial evaluating PNT2258 for the treatment of Richter’s transformation.
AEs prompt EMA review of idelalisib
Photo courtesy of
Gilead Sciences, Inc.
The European Medicines Agency (EMA) is reviewing the safety of idelalisib (Zydelig), a drug approved to treat chronic lymphocytic leukemia (CLL) and follicular lymphoma in the European Union (EU).
The European Commission (EC) requested the review because of serious adverse events (AEs), including deaths, reported in 3 clinical trials investigating idelalisib in combination with other drugs.
The AEs were mostly infection-related.
The EMA is reviewing data from these studies to assess whether the findings have any consequences for the authorized uses of idelalisib.
In the meantime, the EMA advises that patients starting or already on treatment with idelalisib be carefully monitored for signs of infections. If the drug is well tolerated, treatment should not be stopped.
The EMA is considering whether any other immediate measures are necessary during the review period. The agency said it will communicate further and keep doctors and patients informed as appropriate.
About idelalisib
In the EU, idelalisib is approved for use in combination with rituximab to treat adults with CLL who have received at least 1 prior therapy or as first-line treatment in the presence of 17p deletion or TP53 mutation in CLL patients unsuitable for chemo-immunotherapy.
Idelalisib is also approved as monotherapy for adults with follicular lymphoma that is refractory to 2 prior lines of treatment.
About the trials
The trials in which patients have experienced serious AEs involve patients with CLL and indolent non-Hodgkin lymphoma (NHL).
In one trial (NCT01732926), researchers are evaluating idelalisib in combination with bendamustine and rituximab for previously treated indolent NHL.
In another (NCT01732913), researchers are testing idelalisib in combination with rituximab for previously treated indolent NHL.
And in the third (NCT01980888), researchers are evaluating idelalisib in combination with bendamustine and rituximab in patients with previously untreated CLL.
The EMA noted that these studies are investigating combinations of drugs that are currently not approved in the EU and include patients with disease characteristics different from those covered by the approved indications for idelalisib.
About the review
The EMA has begun the review of idelalisib at the request of the EC, under Article 20 of Directive 2001/83/EC.
The review is being carried out by the EMA’s Pharmacovigilance Risk Assessment Committee, the committee responsible for the evaluation of safety issues for human medicines, which will make a set of recommendations.
Those recommendations will then be forwarded to the Committee for Medicinal Products for Human Use, which is responsible for questions concerning medicines for human use and will adopt a final opinion on the safety of idelalisib.
The final stage of the review procedure is the EC’s adoption of a legally binding decision that is applicable in all EU member states.
Photo courtesy of
Gilead Sciences, Inc.
The European Medicines Agency (EMA) is reviewing the safety of idelalisib (Zydelig), a drug approved to treat chronic lymphocytic leukemia (CLL) and follicular lymphoma in the European Union (EU).
The European Commission (EC) requested the review because of serious adverse events (AEs), including deaths, reported in 3 clinical trials investigating idelalisib in combination with other drugs.
The AEs were mostly infection-related.
The EMA is reviewing data from these studies to assess whether the findings have any consequences for the authorized uses of idelalisib.
In the meantime, the EMA advises that patients starting or already on treatment with idelalisib be carefully monitored for signs of infections. If the drug is well tolerated, treatment should not be stopped.
The EMA is considering whether any other immediate measures are necessary during the review period. The agency said it will communicate further and keep doctors and patients informed as appropriate.
About idelalisib
In the EU, idelalisib is approved for use in combination with rituximab to treat adults with CLL who have received at least 1 prior therapy or as first-line treatment in the presence of 17p deletion or TP53 mutation in CLL patients unsuitable for chemo-immunotherapy.
Idelalisib is also approved as monotherapy for adults with follicular lymphoma that is refractory to 2 prior lines of treatment.
About the trials
The trials in which patients have experienced serious AEs involve patients with CLL and indolent non-Hodgkin lymphoma (NHL).
In one trial (NCT01732926), researchers are evaluating idelalisib in combination with bendamustine and rituximab for previously treated indolent NHL.
In another (NCT01732913), researchers are testing idelalisib in combination with rituximab for previously treated indolent NHL.
And in the third (NCT01980888), researchers are evaluating idelalisib in combination with bendamustine and rituximab in patients with previously untreated CLL.
The EMA noted that these studies are investigating combinations of drugs that are currently not approved in the EU and include patients with disease characteristics different from those covered by the approved indications for idelalisib.
About the review
The EMA has begun the review of idelalisib at the request of the EC, under Article 20 of Directive 2001/83/EC.
The review is being carried out by the EMA’s Pharmacovigilance Risk Assessment Committee, the committee responsible for the evaluation of safety issues for human medicines, which will make a set of recommendations.
Those recommendations will then be forwarded to the Committee for Medicinal Products for Human Use, which is responsible for questions concerning medicines for human use and will adopt a final opinion on the safety of idelalisib.
The final stage of the review procedure is the EC’s adoption of a legally binding decision that is applicable in all EU member states.
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The European Medicines Agency (EMA) is reviewing the safety of idelalisib (Zydelig), a drug approved to treat chronic lymphocytic leukemia (CLL) and follicular lymphoma in the European Union (EU).
The European Commission (EC) requested the review because of serious adverse events (AEs), including deaths, reported in 3 clinical trials investigating idelalisib in combination with other drugs.
The AEs were mostly infection-related.
The EMA is reviewing data from these studies to assess whether the findings have any consequences for the authorized uses of idelalisib.
In the meantime, the EMA advises that patients starting or already on treatment with idelalisib be carefully monitored for signs of infections. If the drug is well tolerated, treatment should not be stopped.
The EMA is considering whether any other immediate measures are necessary during the review period. The agency said it will communicate further and keep doctors and patients informed as appropriate.
About idelalisib
In the EU, idelalisib is approved for use in combination with rituximab to treat adults with CLL who have received at least 1 prior therapy or as first-line treatment in the presence of 17p deletion or TP53 mutation in CLL patients unsuitable for chemo-immunotherapy.
Idelalisib is also approved as monotherapy for adults with follicular lymphoma that is refractory to 2 prior lines of treatment.
About the trials
The trials in which patients have experienced serious AEs involve patients with CLL and indolent non-Hodgkin lymphoma (NHL).
In one trial (NCT01732926), researchers are evaluating idelalisib in combination with bendamustine and rituximab for previously treated indolent NHL.
In another (NCT01732913), researchers are testing idelalisib in combination with rituximab for previously treated indolent NHL.
And in the third (NCT01980888), researchers are evaluating idelalisib in combination with bendamustine and rituximab in patients with previously untreated CLL.
The EMA noted that these studies are investigating combinations of drugs that are currently not approved in the EU and include patients with disease characteristics different from those covered by the approved indications for idelalisib.
About the review
The EMA has begun the review of idelalisib at the request of the EC, under Article 20 of Directive 2001/83/EC.
The review is being carried out by the EMA’s Pharmacovigilance Risk Assessment Committee, the committee responsible for the evaluation of safety issues for human medicines, which will make a set of recommendations.
Those recommendations will then be forwarded to the Committee for Medicinal Products for Human Use, which is responsible for questions concerning medicines for human use and will adopt a final opinion on the safety of idelalisib.
The final stage of the review procedure is the EC’s adoption of a legally binding decision that is applicable in all EU member states.