FDA Advisory Committee Meeting

SILVER SPRING, MD. – Three experimental agents currently being developed as treatments for various cancers in adults – ganetespib, etirinotecan pegol, and a still-unnamed MDM2 (murine double-minute 2) antagonist – should be studied in pediatric patients, according to a Food and Drug Administration advisory panel.

The manufacturers of the three agents presented information on their development and clinical trials for oncology indications in adults, at a meeting of the FDA’s Pediatric Oncology Subcommittee of the Oncologic Drugs Advisory Committee. The meeting was held to allow the manufacturers to provide information about the adult studies and plans for pediatric development and for the expert panelists to discuss the pediatric development of the agents, to help guide the agency’s decisions regarding written requests to companies, which outline the types of pediatric studies, study design, objectives, and age groups that should be studied.

Ganetespib is an inhibitor of heat shock protein 90 (Hsp90), in an injectable formulation, which has been evaluated in phase I, II, and II/III studies of adults with non–small cell lung cancer (NSCLC), breast cancer, ovarian cancer, and acute myeloid leukemia (AML), according to the manufacturer, Synta Pharmaceuticals. It is currently being evaluated in combination with docetaxel, vs. docetaxel alone, as second-line treatment in patients with advanced non–small cell lung adenocarcinoma in an ongoing phase III study (GALAXY-2). To date, several patients have been enrolled in a phase I/II study (SARC023) evaluating ganetespib plus sirolimus for patients with refractory sarcomas, including unresectable or metastatic malignant peripheral nerve sheath tumors, a type of aggressive soft tissue sarcoma, in patients aged 18 years and above. The drug has evidence of antimetastatic effects in clinical studies, and GI toxicity, notably diarrhea, is the most common adverse event.

Panelists agreed that further studies of this agent in pediatric populations should be conducted, evaluating its effect on pediatric malignancies, such as neuroblastoma and sarcomas, and that the age of patients enrolled in the SARC023 study could be lowered to age 12 years. Other recommendations included studies evaluating ganetespib in combination with other agents, because studies to date do not support its use as a single agent; and studies of longterm adverse effects of treatment.

The second drug on the agenda was a prodrug of irinotecan, etirinotecan pegol, a long-acting topoisomerase I inhibitor, which has been studied in more than 1,000 patients, but not in any pediatric patients, according to the manufacturer, Nektar Therapeutics. Efficacy of etirinotecan has been demonstrated against multiple types of tumors, “some of which are pertinent to pediatric oncology,” such as primary brain cancer, and the company has received two proposals from pediatric oncologists to conduct phase I studies in patients with solid tumors, Dr. Alison Hannah, a consultant to the company, said at the meeting.

Etirinotecan has been or is being evaluated in phase I studies of advanced solid tumors, phase II studies of platinum-resistant ovarian cancer, metastatic breast cancer, colorectal cancer with KRAS mutations (as second-line therapy), and in NSCLC (as second- and third-line treatments). The one phase III study is the BEACON study, comparing etirinotecan vs. Treatment of Physicians Choice in 852 women with locally recurrent and metastatic breast cancer. Diarrhea has been the most common toxicity associated with the agent, which has been associated with a low rate of neutropenia (about 5%) and a relatively low rate of alopecia (11%), Dr. Hannah said.

Panelists agreed that etirinotecan was a good candidate for pediatric studies, for treatment of malignancies that included neuroblastoma, Ewing sarcoma and rhabdomyosarcoma, and also recommended that studies evaluate pediatric pharmacokinetics, and treatment with the agent in relapsed patients, as front-line therapy, and as part of combination treatments.

Earlier in the development process is RO5503781 (Hoffmann-La Roche), an orally administered antagonist of murine double minute 2 (MDM2), which binds tumor suppressor protein 53 (p53). Some tumors are thought to “overproduce MDM2 which causes inhibition of p53 activity and promotes tumorigenesis,” according to the FDA.

To date, there is “early evidence of efficacy” of this agent in cancers in adults, particularly AML, and it is being evaluated in phase I studies, according to the manufacturer. Challenges for pediatric studies include identifying the appropriate patients to treat with this agent and developing a formulation suitable for all pediatric age groups, according to the company, which is planning a study evaluating the pharmacokinetics, toxicity, safety, and activity of the agent in children with a solid tumor or acute leukemia.

The panelists expressed interest in pediatric studies, particularly regarding the promising early AML data, and were interested in studies of solid tumors, although which populations of patients to treat, what combinations of treatments, and at what disease stage to study were unclear.

FDA panelists were cleared of potential conflicts.

[email protected]

SILVER SPRING, MD. – Three experimental agents currently being developed as treatments for various cancers in adults – ganetespib, etirinotecan pegol, and a still-unnamed MDM2 (murine double-minute 2) antagonist – should be studied in pediatric patients, according to a Food and Drug Administration advisory panel.

The manufacturers of the three agents presented information on their development and clinical trials for oncology indications in adults, at a meeting of the FDA’s Pediatric Oncology Subcommittee of the Oncologic Drugs Advisory Committee. The meeting was held to allow the manufacturers to provide information about the adult studies and plans for pediatric development and for the expert panelists to discuss the pediatric development of the agents, to help guide the agency’s decisions regarding written requests to companies, which outline the types of pediatric studies, study design, objectives, and age groups that should be studied.

Ganetespib is an inhibitor of heat shock protein 90 (Hsp90), in an injectable formulation, which has been evaluated in phase I, II, and II/III studies of adults with non–small cell lung cancer (NSCLC), breast cancer, ovarian cancer, and acute myeloid leukemia (AML), according to the manufacturer, Synta Pharmaceuticals. It is currently being evaluated in combination with docetaxel, vs. docetaxel alone, as second-line treatment in patients with advanced non–small cell lung adenocarcinoma in an ongoing phase III study (GALAXY-2). To date, several patients have been enrolled in a phase I/II study (SARC023) evaluating ganetespib plus sirolimus for patients with refractory sarcomas, including unresectable or metastatic malignant peripheral nerve sheath tumors, a type of aggressive soft tissue sarcoma, in patients aged 18 years and above. The drug has evidence of antimetastatic effects in clinical studies, and GI toxicity, notably diarrhea, is the most common adverse event.

Panelists agreed that further studies of this agent in pediatric populations should be conducted, evaluating its effect on pediatric malignancies, such as neuroblastoma and sarcomas, and that the age of patients enrolled in the SARC023 study could be lowered to age 12 years. Other recommendations included studies evaluating ganetespib in combination with other agents, because studies to date do not support its use as a single agent; and studies of longterm adverse effects of treatment.

The second drug on the agenda was a prodrug of irinotecan, etirinotecan pegol, a long-acting topoisomerase I inhibitor, which has been studied in more than 1,000 patients, but not in any pediatric patients, according to the manufacturer, Nektar Therapeutics. Efficacy of etirinotecan has been demonstrated against multiple types of tumors, “some of which are pertinent to pediatric oncology,” such as primary brain cancer, and the company has received two proposals from pediatric oncologists to conduct phase I studies in patients with solid tumors, Dr. Alison Hannah, a consultant to the company, said at the meeting.

Etirinotecan has been or is being evaluated in phase I studies of advanced solid tumors, phase II studies of platinum-resistant ovarian cancer, metastatic breast cancer, colorectal cancer with KRAS mutations (as second-line therapy), and in NSCLC (as second- and third-line treatments). The one phase III study is the BEACON study, comparing etirinotecan vs. Treatment of Physicians Choice in 852 women with locally recurrent and metastatic breast cancer. Diarrhea has been the most common toxicity associated with the agent, which has been associated with a low rate of neutropenia (about 5%) and a relatively low rate of alopecia (11%), Dr. Hannah said.

Panelists agreed that etirinotecan was a good candidate for pediatric studies, for treatment of malignancies that included neuroblastoma, Ewing sarcoma and rhabdomyosarcoma, and also recommended that studies evaluate pediatric pharmacokinetics, and treatment with the agent in relapsed patients, as front-line therapy, and as part of combination treatments.

Earlier in the development process is RO5503781 (Hoffmann-La Roche), an orally administered antagonist of murine double minute 2 (MDM2), which binds tumor suppressor protein 53 (p53). Some tumors are thought to “overproduce MDM2 which causes inhibition of p53 activity and promotes tumorigenesis,” according to the FDA.

To date, there is “early evidence of efficacy” of this agent in cancers in adults, particularly AML, and it is being evaluated in phase I studies, according to the manufacturer. Challenges for pediatric studies include identifying the appropriate patients to treat with this agent and developing a formulation suitable for all pediatric age groups, according to the company, which is planning a study evaluating the pharmacokinetics, toxicity, safety, and activity of the agent in children with a solid tumor or acute leukemia.

The panelists expressed interest in pediatric studies, particularly regarding the promising early AML data, and were interested in studies of solid tumors, although which populations of patients to treat, what combinations of treatments, and at what disease stage to study were unclear.

FDA panelists were cleared of potential conflicts.

[email protected]

SILVER SPRING, MD. – Three experimental agents currently being developed as treatments for various cancers in adults – ganetespib, etirinotecan pegol, and a still-unnamed MDM2 (murine double-minute 2) antagonist – should be studied in pediatric patients, according to a Food and Drug Administration advisory panel.

The manufacturers of the three agents presented information on their development and clinical trials for oncology indications in adults, at a meeting of the FDA’s Pediatric Oncology Subcommittee of the Oncologic Drugs Advisory Committee. The meeting was held to allow the manufacturers to provide information about the adult studies and plans for pediatric development and for the expert panelists to discuss the pediatric development of the agents, to help guide the agency’s decisions regarding written requests to companies, which outline the types of pediatric studies, study design, objectives, and age groups that should be studied.

Ganetespib is an inhibitor of heat shock protein 90 (Hsp90), in an injectable formulation, which has been evaluated in phase I, II, and II/III studies of adults with non–small cell lung cancer (NSCLC), breast cancer, ovarian cancer, and acute myeloid leukemia (AML), according to the manufacturer, Synta Pharmaceuticals. It is currently being evaluated in combination with docetaxel, vs. docetaxel alone, as second-line treatment in patients with advanced non–small cell lung adenocarcinoma in an ongoing phase III study (GALAXY-2). To date, several patients have been enrolled in a phase I/II study (SARC023) evaluating ganetespib plus sirolimus for patients with refractory sarcomas, including unresectable or metastatic malignant peripheral nerve sheath tumors, a type of aggressive soft tissue sarcoma, in patients aged 18 years and above. The drug has evidence of antimetastatic effects in clinical studies, and GI toxicity, notably diarrhea, is the most common adverse event.

Panelists agreed that further studies of this agent in pediatric populations should be conducted, evaluating its effect on pediatric malignancies, such as neuroblastoma and sarcomas, and that the age of patients enrolled in the SARC023 study could be lowered to age 12 years. Other recommendations included studies evaluating ganetespib in combination with other agents, because studies to date do not support its use as a single agent; and studies of longterm adverse effects of treatment.

The second drug on the agenda was a prodrug of irinotecan, etirinotecan pegol, a long-acting topoisomerase I inhibitor, which has been studied in more than 1,000 patients, but not in any pediatric patients, according to the manufacturer, Nektar Therapeutics. Efficacy of etirinotecan has been demonstrated against multiple types of tumors, “some of which are pertinent to pediatric oncology,” such as primary brain cancer, and the company has received two proposals from pediatric oncologists to conduct phase I studies in patients with solid tumors, Dr. Alison Hannah, a consultant to the company, said at the meeting.

Etirinotecan has been or is being evaluated in phase I studies of advanced solid tumors, phase II studies of platinum-resistant ovarian cancer, metastatic breast cancer, colorectal cancer with KRAS mutations (as second-line therapy), and in NSCLC (as second- and third-line treatments). The one phase III study is the BEACON study, comparing etirinotecan vs. Treatment of Physicians Choice in 852 women with locally recurrent and metastatic breast cancer. Diarrhea has been the most common toxicity associated with the agent, which has been associated with a low rate of neutropenia (about 5%) and a relatively low rate of alopecia (11%), Dr. Hannah said.

Panelists agreed that etirinotecan was a good candidate for pediatric studies, for treatment of malignancies that included neuroblastoma, Ewing sarcoma and rhabdomyosarcoma, and also recommended that studies evaluate pediatric pharmacokinetics, and treatment with the agent in relapsed patients, as front-line therapy, and as part of combination treatments.

Earlier in the development process is RO5503781 (Hoffmann-La Roche), an orally administered antagonist of murine double minute 2 (MDM2), which binds tumor suppressor protein 53 (p53). Some tumors are thought to “overproduce MDM2 which causes inhibition of p53 activity and promotes tumorigenesis,” according to the FDA.

To date, there is “early evidence of efficacy” of this agent in cancers in adults, particularly AML, and it is being evaluated in phase I studies, according to the manufacturer. Challenges for pediatric studies include identifying the appropriate patients to treat with this agent and developing a formulation suitable for all pediatric age groups, according to the company, which is planning a study evaluating the pharmacokinetics, toxicity, safety, and activity of the agent in children with a solid tumor or acute leukemia.

The panelists expressed interest in pediatric studies, particularly regarding the promising early AML data, and were interested in studies of solid tumors, although which populations of patients to treat, what combinations of treatments, and at what disease stage to study were unclear.

FDA panelists were cleared of potential conflicts.

[email protected]