In the Pipeline: Three Novel Drugs Hit Three Different Targets in CLL

ORLANDO – Three novel agents with three different targets cleared phase I hurdles in chronic lymphocytic leukemia.

These investigational agents, still known by their drug company labels, demonstrated varying degrees of activity in heavily pretreated patients. In all three presentations, investigators concluded that further trials are warranted.

PCI-32765 Hits Bruton’s Tyrosine Kinase

In the first presentation, PCI-32765 was described as a novel oral selective inhibitor of Bruton’s tyrosine kinase (Btk), a mediator of B-cell receptor signaling. Btk is not expressed in T cells or NK cells, which makes it "an ideal therapeutic target for B-cell malignancies dependent on BCR [gene] signaling," said Dr. Jan A. Burger of the University of Texas M.D. Anderson Cancer Center in Houston.

Dr. Burger presented pooled data from 54 patients (median age, 68 years), 47 of whom had chronic lymphocytic leukemia (CLL) and 7 of whom had small lymphocytic leukemia (SLL). Outcomes included 1 complete response and 16 partial responses in a population who had had a median of 3 previous therapies (range, 1-10). Nearly all (95%) had previously received a nucleoside analogue and anti-CD20 agents. In addition, 21% had prior bendamustine and 9% had alemtuzumab.

The trial divided these patients into the following two groups:

• Phase IA. Of 23 patients enrolled, 16 were treated in 28-day cycles with 7 days of rest. They received doses from 1.25 mg/kg per day to 12.5 mg/kg per day of the study drug. The other seven patients were treated for cycles of 35 days with no rest. In this group, six received 8.3 mg/kg per day, and one received a fixed dose of 560 mg/day. The median follow-up was 8 months.

Among the 13 evaluable patients in phase IA, 1 patient (8%) had a complete response, 8 (62%) had a partial response, and 2 (15%) had nodal response with lymphocytosis.

• Phase IB. Of 38 patients enrolled, 11 were treatment naive and 27 were relapsed or refractory patients. All received 420 mg/day in 28-day cycles. The median follow-up was 2 months.

Among the 32 evaluable patients in the phase IB group, none had complete response, 8 patients (25%) had a partial response, and 17 patients (53%) had nodal response with lymphocytosis.

All told, of 39 patients who were evaluated for changes in lymph node disease, 87% had a nodal response to PCI-32765. "Rapid lymph node responses are associated with a transient lymphocytosis, indicating a unique phenomenon of BCR-targeted therapy," Dr. Burger commented.

Overall, no renal or hepatic adverse events have been reported, and no evidence has been seen of cumulative toxicity in patients with at least 6 months of follow-up, Dr. Burger said. Reported adverse events included diarrhea, nausea, vomiting, headache, and rash.

Although the numbers are small and the results are preliminary, "the lack of drug-related myelosuppression or cumulative toxicity supports further investigation in various CLL treatment settings," Dr. Burger said.

Pharmacyclics sponsored the trial. Dr. Burger had no financial conflicts to disclose. Several coauthors reported serving as a consultant or receiving honoraria or research funding from the company; four were employees with equity ownership.

CAL-101 Blocks the PI3K-Delta Pathway

Novel CAL-101, an orally bioavailable small molecule, inhibits PI3K-delta activity, according to findings described in the second presentation.

"Constitutive activation of the PI3K-delta pathway drives proliferation, survival, and abnormal trafficking of malignant B-cells in chronic lymphocytic leukemia," said Dr. Richard R. Furman, director of the CLL and Waldenström’s macroglobulinemia programs at Cornell University in New York City.

In this study of patients with previously treated hematologic malignancies, 54 CLL patients received 50 mg to 150 mg of CAL-101 twice daily, with continuous oral dosing for an average of eight 28-day cycles. The median age of the patients was 63 years and 82% were male. All patients had been treated with fludarabine. In addition, 98% had received rituximab, 87% had received an alkylating agent, and 31% had received alemtuzumab.

The overall response rate was 26%, and the lymph node response rate was 80%. In addition, CAL-101 was associated with nodal shrinkage in all patients in an intent-to-treat analysis. Patients with baseline thrombocytopenia (defined as platelet counts less than 100,000/mcL) experienced sustained improvements in platelet count (that is, greater than 100,000/mcL, or greater than 50%), Dr. Furman said.

The most common grade 3/4 hematologic adverse event was neutropenia (24%), and the most common grade 3/4 nonhematologic event was pneumonia (24%). "Grade 3/4 adverse events were largely due to prior therapy or underlying CLL," said Dr. Furman. No pattern of drug-related symptomatic adverse events was observed, and patients showed no dose-limiting toxicities over periods of exposure beyond 1 year.

The results support further studies of CAL-101 at a dosage of 150 mg twice daily as a frontline therapy for CLL patients, or as a single agent or combined with chemoimmunotherapy for CLL patients, Dr. Furman added.

Calistoga Pharmaceuticals sponsored the trial. Dr. Furman had no financial conflicts to disclose. Several coauthors disclosed consultancy for, employment with, or research funding from Calistoga Pharmaceuticals; seven were employees and/or held equity ownership in the company.

TRU-016 Tackles CD37

Dr. Furman also presented results from a dose-escalation study of TRU-016, a novel humanized anti-CD37 small modular immunopharmaceutical (SMIP) protein.

Studies in mice have suggested that CD37 is involved in regulating B-cell function. TRU-016 offers direct apoptosis with greater cell-killing potential than rituximab and greater antibody-dependent cellular cytotoxicity than rituximab or alemtuzumab, he said.

In this dose-finding study, 57 patients with relapsed or refractory CLL or SLL received one of nine dosages, ranging from 0.03 mg/kg to 20 mg/kg, given intravenously once a week for 4-12 weekly doses. In a second dosing schedule, patients received 3, 6, or 10 mg/kg on days 1, 3, and 5 of the first week of treatment, followed by 3-11 weekly doses three times a week. The patients had no organ function problems, and their platelet counts were greater than 30,000/mcL.

The overall response rate was 13%, based on 1996 National Cancer Institute criteria. The overall median reduction in lymphocytes in the intent-to-treat population was 60%.

In the 16 patients with one to two prior therapies, the overall response rate was 40% and the clinical response rate was 44%. No clinical response was noted in patients with three or more prior therapies, but there was an overall median reduction in lymphocytes of 60% from baseline to the end of treatment, Dr. Furman said. The median progression-free survival for all patients was 134 days.

Neutropenia, the most common adverse event, was reported in nine patients (16%). There was no apparent relationship between drug dose and adverse events, and a maximum tolerated dose was not reached in this study.

"Given B-cell selective target, independent single agent activity, and synergy with CLL therapies, TRU-016 combination trials in CLL patients are planned," he said.

Trubion Pharmaceuticals (now Emergent Biosolutions) sponsored the trial. Dr. Furman had no financial conflicts to disclose. Several coinvestigators disclosed consultancy for, employment with equity ownership in, or research funding from Trubion.

ORLANDO – Three novel agents with three different targets cleared phase I hurdles in chronic lymphocytic leukemia.

These investigational agents, still known by their drug company labels, demonstrated varying degrees of activity in heavily pretreated patients. In all three presentations, investigators concluded that further trials are warranted.

PCI-32765 Hits Bruton’s Tyrosine Kinase

In the first presentation, PCI-32765 was described as a novel oral selective inhibitor of Bruton’s tyrosine kinase (Btk), a mediator of B-cell receptor signaling. Btk is not expressed in T cells or NK cells, which makes it "an ideal therapeutic target for B-cell malignancies dependent on BCR [gene] signaling," said Dr. Jan A. Burger of the University of Texas M.D. Anderson Cancer Center in Houston.

Dr. Burger presented pooled data from 54 patients (median age, 68 years), 47 of whom had chronic lymphocytic leukemia (CLL) and 7 of whom had small lymphocytic leukemia (SLL). Outcomes included 1 complete response and 16 partial responses in a population who had had a median of 3 previous therapies (range, 1-10). Nearly all (95%) had previously received a nucleoside analogue and anti-CD20 agents. In addition, 21% had prior bendamustine and 9% had alemtuzumab.

The trial divided these patients into the following two groups:

• Phase IA. Of 23 patients enrolled, 16 were treated in 28-day cycles with 7 days of rest. They received doses from 1.25 mg/kg per day to 12.5 mg/kg per day of the study drug. The other seven patients were treated for cycles of 35 days with no rest. In this group, six received 8.3 mg/kg per day, and one received a fixed dose of 560 mg/day. The median follow-up was 8 months.

Among the 13 evaluable patients in phase IA, 1 patient (8%) had a complete response, 8 (62%) had a partial response, and 2 (15%) had nodal response with lymphocytosis.

• Phase IB. Of 38 patients enrolled, 11 were treatment naive and 27 were relapsed or refractory patients. All received 420 mg/day in 28-day cycles. The median follow-up was 2 months.

Among the 32 evaluable patients in the phase IB group, none had complete response, 8 patients (25%) had a partial response, and 17 patients (53%) had nodal response with lymphocytosis.

All told, of 39 patients who were evaluated for changes in lymph node disease, 87% had a nodal response to PCI-32765. "Rapid lymph node responses are associated with a transient lymphocytosis, indicating a unique phenomenon of BCR-targeted therapy," Dr. Burger commented.

Overall, no renal or hepatic adverse events have been reported, and no evidence has been seen of cumulative toxicity in patients with at least 6 months of follow-up, Dr. Burger said. Reported adverse events included diarrhea, nausea, vomiting, headache, and rash.

Although the numbers are small and the results are preliminary, "the lack of drug-related myelosuppression or cumulative toxicity supports further investigation in various CLL treatment settings," Dr. Burger said.

Pharmacyclics sponsored the trial. Dr. Burger had no financial conflicts to disclose. Several coauthors reported serving as a consultant or receiving honoraria or research funding from the company; four were employees with equity ownership.

CAL-101 Blocks the PI3K-Delta Pathway

Novel CAL-101, an orally bioavailable small molecule, inhibits PI3K-delta activity, according to findings described in the second presentation.

"Constitutive activation of the PI3K-delta pathway drives proliferation, survival, and abnormal trafficking of malignant B-cells in chronic lymphocytic leukemia," said Dr. Richard R. Furman, director of the CLL and Waldenström’s macroglobulinemia programs at Cornell University in New York City.

In this study of patients with previously treated hematologic malignancies, 54 CLL patients received 50 mg to 150 mg of CAL-101 twice daily, with continuous oral dosing for an average of eight 28-day cycles. The median age of the patients was 63 years and 82% were male. All patients had been treated with fludarabine. In addition, 98% had received rituximab, 87% had received an alkylating agent, and 31% had received alemtuzumab.

The overall response rate was 26%, and the lymph node response rate was 80%. In addition, CAL-101 was associated with nodal shrinkage in all patients in an intent-to-treat analysis. Patients with baseline thrombocytopenia (defined as platelet counts less than 100,000/mcL) experienced sustained improvements in platelet count (that is, greater than 100,000/mcL, or greater than 50%), Dr. Furman said.

The most common grade 3/4 hematologic adverse event was neutropenia (24%), and the most common grade 3/4 nonhematologic event was pneumonia (24%). "Grade 3/4 adverse events were largely due to prior therapy or underlying CLL," said Dr. Furman. No pattern of drug-related symptomatic adverse events was observed, and patients showed no dose-limiting toxicities over periods of exposure beyond 1 year.

The results support further studies of CAL-101 at a dosage of 150 mg twice daily as a frontline therapy for CLL patients, or as a single agent or combined with chemoimmunotherapy for CLL patients, Dr. Furman added.

Calistoga Pharmaceuticals sponsored the trial. Dr. Furman had no financial conflicts to disclose. Several coauthors disclosed consultancy for, employment with, or research funding from Calistoga Pharmaceuticals; seven were employees and/or held equity ownership in the company.

TRU-016 Tackles CD37

Dr. Furman also presented results from a dose-escalation study of TRU-016, a novel humanized anti-CD37 small modular immunopharmaceutical (SMIP) protein.

Studies in mice have suggested that CD37 is involved in regulating B-cell function. TRU-016 offers direct apoptosis with greater cell-killing potential than rituximab and greater antibody-dependent cellular cytotoxicity than rituximab or alemtuzumab, he said.

In this dose-finding study, 57 patients with relapsed or refractory CLL or SLL received one of nine dosages, ranging from 0.03 mg/kg to 20 mg/kg, given intravenously once a week for 4-12 weekly doses. In a second dosing schedule, patients received 3, 6, or 10 mg/kg on days 1, 3, and 5 of the first week of treatment, followed by 3-11 weekly doses three times a week. The patients had no organ function problems, and their platelet counts were greater than 30,000/mcL.

The overall response rate was 13%, based on 1996 National Cancer Institute criteria. The overall median reduction in lymphocytes in the intent-to-treat population was 60%.

In the 16 patients with one to two prior therapies, the overall response rate was 40% and the clinical response rate was 44%. No clinical response was noted in patients with three or more prior therapies, but there was an overall median reduction in lymphocytes of 60% from baseline to the end of treatment, Dr. Furman said. The median progression-free survival for all patients was 134 days.

Neutropenia, the most common adverse event, was reported in nine patients (16%). There was no apparent relationship between drug dose and adverse events, and a maximum tolerated dose was not reached in this study.

"Given B-cell selective target, independent single agent activity, and synergy with CLL therapies, TRU-016 combination trials in CLL patients are planned," he said.

Trubion Pharmaceuticals (now Emergent Biosolutions) sponsored the trial. Dr. Furman had no financial conflicts to disclose. Several coinvestigators disclosed consultancy for, employment with equity ownership in, or research funding from Trubion.

ORLANDO – Three novel agents with three different targets cleared phase I hurdles in chronic lymphocytic leukemia.

These investigational agents, still known by their drug company labels, demonstrated varying degrees of activity in heavily pretreated patients. In all three presentations, investigators concluded that further trials are warranted.

PCI-32765 Hits Bruton’s Tyrosine Kinase

In the first presentation, PCI-32765 was described as a novel oral selective inhibitor of Bruton’s tyrosine kinase (Btk), a mediator of B-cell receptor signaling. Btk is not expressed in T cells or NK cells, which makes it "an ideal therapeutic target for B-cell malignancies dependent on BCR [gene] signaling," said Dr. Jan A. Burger of the University of Texas M.D. Anderson Cancer Center in Houston.

Dr. Burger presented pooled data from 54 patients (median age, 68 years), 47 of whom had chronic lymphocytic leukemia (CLL) and 7 of whom had small lymphocytic leukemia (SLL). Outcomes included 1 complete response and 16 partial responses in a population who had had a median of 3 previous therapies (range, 1-10). Nearly all (95%) had previously received a nucleoside analogue and anti-CD20 agents. In addition, 21% had prior bendamustine and 9% had alemtuzumab.

The trial divided these patients into the following two groups:

• Phase IA. Of 23 patients enrolled, 16 were treated in 28-day cycles with 7 days of rest. They received doses from 1.25 mg/kg per day to 12.5 mg/kg per day of the study drug. The other seven patients were treated for cycles of 35 days with no rest. In this group, six received 8.3 mg/kg per day, and one received a fixed dose of 560 mg/day. The median follow-up was 8 months.

Among the 13 evaluable patients in phase IA, 1 patient (8%) had a complete response, 8 (62%) had a partial response, and 2 (15%) had nodal response with lymphocytosis.

• Phase IB. Of 38 patients enrolled, 11 were treatment naive and 27 were relapsed or refractory patients. All received 420 mg/day in 28-day cycles. The median follow-up was 2 months.

Among the 32 evaluable patients in the phase IB group, none had complete response, 8 patients (25%) had a partial response, and 17 patients (53%) had nodal response with lymphocytosis.

All told, of 39 patients who were evaluated for changes in lymph node disease, 87% had a nodal response to PCI-32765. "Rapid lymph node responses are associated with a transient lymphocytosis, indicating a unique phenomenon of BCR-targeted therapy," Dr. Burger commented.

Overall, no renal or hepatic adverse events have been reported, and no evidence has been seen of cumulative toxicity in patients with at least 6 months of follow-up, Dr. Burger said. Reported adverse events included diarrhea, nausea, vomiting, headache, and rash.

Although the numbers are small and the results are preliminary, "the lack of drug-related myelosuppression or cumulative toxicity supports further investigation in various CLL treatment settings," Dr. Burger said.

Pharmacyclics sponsored the trial. Dr. Burger had no financial conflicts to disclose. Several coauthors reported serving as a consultant or receiving honoraria or research funding from the company; four were employees with equity ownership.

CAL-101 Blocks the PI3K-Delta Pathway

Novel CAL-101, an orally bioavailable small molecule, inhibits PI3K-delta activity, according to findings described in the second presentation.

"Constitutive activation of the PI3K-delta pathway drives proliferation, survival, and abnormal trafficking of malignant B-cells in chronic lymphocytic leukemia," said Dr. Richard R. Furman, director of the CLL and Waldenström’s macroglobulinemia programs at Cornell University in New York City.

In this study of patients with previously treated hematologic malignancies, 54 CLL patients received 50 mg to 150 mg of CAL-101 twice daily, with continuous oral dosing for an average of eight 28-day cycles. The median age of the patients was 63 years and 82% were male. All patients had been treated with fludarabine. In addition, 98% had received rituximab, 87% had received an alkylating agent, and 31% had received alemtuzumab.

The overall response rate was 26%, and the lymph node response rate was 80%. In addition, CAL-101 was associated with nodal shrinkage in all patients in an intent-to-treat analysis. Patients with baseline thrombocytopenia (defined as platelet counts less than 100,000/mcL) experienced sustained improvements in platelet count (that is, greater than 100,000/mcL, or greater than 50%), Dr. Furman said.

The most common grade 3/4 hematologic adverse event was neutropenia (24%), and the most common grade 3/4 nonhematologic event was pneumonia (24%). "Grade 3/4 adverse events were largely due to prior therapy or underlying CLL," said Dr. Furman. No pattern of drug-related symptomatic adverse events was observed, and patients showed no dose-limiting toxicities over periods of exposure beyond 1 year.

The results support further studies of CAL-101 at a dosage of 150 mg twice daily as a frontline therapy for CLL patients, or as a single agent or combined with chemoimmunotherapy for CLL patients, Dr. Furman added.

Calistoga Pharmaceuticals sponsored the trial. Dr. Furman had no financial conflicts to disclose. Several coauthors disclosed consultancy for, employment with, or research funding from Calistoga Pharmaceuticals; seven were employees and/or held equity ownership in the company.

TRU-016 Tackles CD37

Dr. Furman also presented results from a dose-escalation study of TRU-016, a novel humanized anti-CD37 small modular immunopharmaceutical (SMIP) protein.

Studies in mice have suggested that CD37 is involved in regulating B-cell function. TRU-016 offers direct apoptosis with greater cell-killing potential than rituximab and greater antibody-dependent cellular cytotoxicity than rituximab or alemtuzumab, he said.

In this dose-finding study, 57 patients with relapsed or refractory CLL or SLL received one of nine dosages, ranging from 0.03 mg/kg to 20 mg/kg, given intravenously once a week for 4-12 weekly doses. In a second dosing schedule, patients received 3, 6, or 10 mg/kg on days 1, 3, and 5 of the first week of treatment, followed by 3-11 weekly doses three times a week. The patients had no organ function problems, and their platelet counts were greater than 30,000/mcL.

The overall response rate was 13%, based on 1996 National Cancer Institute criteria. The overall median reduction in lymphocytes in the intent-to-treat population was 60%.

In the 16 patients with one to two prior therapies, the overall response rate was 40% and the clinical response rate was 44%. No clinical response was noted in patients with three or more prior therapies, but there was an overall median reduction in lymphocytes of 60% from baseline to the end of treatment, Dr. Furman said. The median progression-free survival for all patients was 134 days.

Neutropenia, the most common adverse event, was reported in nine patients (16%). There was no apparent relationship between drug dose and adverse events, and a maximum tolerated dose was not reached in this study.

"Given B-cell selective target, independent single agent activity, and synergy with CLL therapies, TRU-016 combination trials in CLL patients are planned," he said.

Trubion Pharmaceuticals (now Emergent Biosolutions) sponsored the trial. Dr. Furman had no financial conflicts to disclose. Several coinvestigators disclosed consultancy for, employment with equity ownership in, or research funding from Trubion.