FDA
17th October 2017

FDA Committee Discusses Potential Pediatric Applications for Adult Cancer Products Currently Under Development

On June 21st & 22nd, the Oncologic Drugs Advisory Committee (ODAC) explored pediatric development plans, to gauge investigator interest, for multiple products currently under development for adult cancer indications.

FDA Committee Discusses Potential Pediatric Applications for Adult Cancer Products Currently Under Development

On June 21st & 22nd, the Oncologic Drugs Advisory Committee (ODAC) explored pediatric development plans, to gauge investigator interest, for multiple products currently under development for adult cancer indications. The products (5 total) which were being considered included: APX-005M (Apexigen, Inc), PM01183 (PharmaMar USA, Inc), ASP2215 (Astellas Pharma Global Development, Inc), olaratumab, and prexasertib (Eli Lilly). As these products were being explored for pediatric use, only the Pediatric Subcommittee of the ODAC was called to order.

APX-005M is a monoclonal anti-body (MAB) serving as a potent CD40 agonist, which is essential for the activation of antigen presenting cells (APCs). These APCs play a central role in thebody’s fight against cancer. APX-005M is at the forefront of Apexigen’s growing immuno-oncology program. After the completion of Apexigen’s presentation, the panel discussed potential issues surrounding the application of APX-005M in pediatric populations. When discussing safety concerns, regarding immune activator agents, the committee was unclear on what mitigation strategies will be implemented for the APX-005M product. Additionally, the committee was puzzled with Apexigen’s choice in selecting primary CNS tumors as the first target pediatric solid tumor to be studied. This is due to the difficulty antibodies have crossing the blood-brain-barrier, given their large size. Ultimately, the committee stated that the success or failure of the proposed plan would depend on the biologic correlative studies and suggested focusing on non-brain tumors before pursuing CNS-based development plans in the pediatric population.

PM01183 or lurbinectedin, is intended for the treatment of Ewing’s Sarcoma and neuroblastoma. Lurbinectedin triggers the destruction of RNA polymerase II via ubiquitin tagging and subsequent proteasome degradation, which prevents further DNA replication within the cancerous cell. The committee was given four discussion points to cover. The first of which, prompted members to discuss the preliminary pediatric development plan proposed by PharmaMar. Members suggested developing additional pre-clinical efficacy data, regarding specific pediatric tumors and recommended lowering the age of their trial in Ewing’s Sarcoma to 12 years. Additionally, the committee suggested pursuing a leukemia-based trial in pediatric populations when asked if other cancers can be explored with lurbinectedin. Lastly, when asked to address any safety concerns, the committee identified this product as a myelotoxic drug, which should be taken into consideration when the sponsor is designing extended exposure studies.

ASP2215, or gilteritinib, intended for the treatment of Acute Myeloid Leukemia (AML – FLT3/ITD mutation +), is a highly potent tyrosine-kinase inhibitor in oral form. Gilteritinib acts on either or both FLT3-ITD/FLT3-D835 mutations, subsequently inhibiting the growth of cells carrying these mutations. When asked to discuss the current preliminary pediatric development plan, the committee members agreed with the sponsor’s proposal – that the trial should only be conducted in patients with the specific mutation described above. Additionally, the committee agreed that plans for the pediatric study are contingent upon oral formulation availability, which the sponsor is currently addressing. When discussing safety, the committee pointed out that the study would need to be designed to monitor long-term effects of ASP2215 in pediatric populations, but saw no reason to enforce age restrictions in treatment groups.

Olaratumab, in combination with doxorubicin, is a MAB intended for adult patients with soft tissue sarcoma (STS). Olaratumab prevents the growth of solid tumor cells via the inhibition of platelet-derived growth factor receptor (PDGF-R). Lilly’s other drug for discussion, prexasertib, is a potent competitive inhibitor of checkpoint kinase 1 (CHK1), which regulates the cell cycle, DNA replication, and DNA damage repair in cancer cells. Prexasertib is intended for use in patients with head and neck cancer, as well as small cell lung cancer, but is still in phase 1 trials and is not approved for use in any country.

Highlights from the olaratumab discussion included suggestions for: the generation of additional pre-clinical data; the development plan to include exploration in hepatic tumors in addition to sarcoma; and recommendation that a trial in rhabdomyosarcoma patients be pursued, as opposed to a placebo controlled trial, with progression free survival as the primary endpoint. The prexasertib discussion led the committee to encourage exploring the use of this product in different applications, such as Ewing’s sarcoma, hematologic malignancies, and osteosarcoma, in addition to the sponsor’s proposed plan in neuroblastoma and rhabdomyosarcoma patients. Although the committee strongly supported the evaluation of this product in neuroblastoma and rhabdomyosarcoma patients, they suggested a smaller study inthe pediatric population.

Overall, the discussion between the various sponsors and the ODAC pediatric sub-committee was largely positive over the course of the two-day advisory committee meeting. Sponsors gained valuable insight into how experts in the pediatric oncologic setting would design a trial, if given the opportunity with each drug reviewed. Discussions such as this benefit sponsors as gaps are identified prior to the initiation of clinical trials, maximizing the efficacy of the trial while minimizing potential safety concerns to patients.

ISS has almost two decades of experience in developing regulatory strategies including support for FDA Advisory Committee meetings. We are involved in more FDA AdComms per year than even the largest pharmaceutical companies. For more information on how ISS can help you prepare for your next meeting, contact info@innovativescience.net.

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