M7824 in Subjects With HPV Associated Malignancies

Summary

Participation Requirements

Description

Background: Metastatic or refractory/recurrent HPV associated malignancies (cervical, anal, oropharyngeal cancers etc.) are often incurable and poorly palliated by standard therapies. TGF R1 pathway signaling and overexpression are significantly associated with HPV+ cancers. PD-1 inhibitors have pro...

Background: Metastatic or refractory/recurrent HPV associated malignancies (cervical, anal, oropharyngeal cancers etc.) are often incurable and poorly palliated by standard therapies. TGF R1 pathway signaling and overexpression are significantly associated with HPV+ cancers. PD-1 inhibitors have produced a 12-20% response rate for these diseases M7824 is a novel bifunctional fusion protein composed of monoclonal antibodies against human PD- L1 and soluble extracellular domain of human TGF- receptor II (TGF- RII), which functions as a TGF- "trap." Early data from a small cohort of patients with HPV associated malignancies in a phase I trial of M7824 has shown promising activity (NCT02517398). As of May 30, 2017, 4 of 9 patients (44%) with HPV associated malignancies have had preliminary evidence of clinical benefit including: Patient with metastatic cervical cancer with a 25% reduction in her disease at 3 months Patient with metastatic P16+ head and neck cancer with an unconfirmed partial response (PR) at 6 weeks Patient with metastatic anal cancer with a durable PR ongoing 9 months after starting treatment Patient with metastatic cervical cancer with a durable complete response (CR) ongoing 15 months after starting treatment. Notably, the P16+ head and neck cancer patient with unconfirmed PR, anal cancer patient with durable PR and cervical cancer patient with durable CR all have HPV+ disease. Immune related adverse events with M7824 in the phase I trial to date have been on par with other PD-1/PD-L1 inhibitors, suggesting a manageable safety profile. EMD Serono has an ongoing expansion cohort evaluating M7824 in patients with HNSCC as well as in cervical cancer excluding neuroendocrine cervical cancer. Objective: -To determine the objective response rate (ORR) according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) in subjects with recurrent or metastatic HPV associated malignancies. Eligibility: Age greater than or equal to 18 years old Subjects with cytologically or histologically confirmed locally advanced or metastatic HPV associated malignancies including: Non-Neuroendocrine Cervical cancers P16+ Oropharyngeal cancers Anal cancers Vulvar, vaginal, penile, squamous cell rectal and neuroendocrine cervical cancers Other locally advanced or metastatic solid tumors (e.g. lung, esophagus) that are known HPV+ Subjects must have measurable disease. Design: -This is a Phase II trial of M7824 in patients with recurrent or metastatic HPV associated malignancies. -Patients will be scheduled to receive 1,200 mg of M7824 IV every 2 weeks until off treatment criteria are met. -There will be six cohorts: (1) Patients with anal cancer whose disease is na"ve to checkpoint inhibition, (2) Patients with non-neuroendocrine cervical cancer na"ve to checkpoint inhibition, (3) Patients with P16+ oropharyngeal cancers na"ve to checkpoint inhibition, and (4) Patients with other rare HPV associated tumors (e.g. squamous cell rectal, vulvar, vaginal, penile cancer, neuroendocrine cervical) na"ve to checkpoint inhibition, (5) Patients with any HPV associated cancers whose disease is refractory to checkpoint inhibition. Patients who are determined to be HPV negative after enrolling will be taken off of their previously assigned cohort and reassigned to cohort 6 and their slot on their previously assigned cohort will be replaced. -Cohorts 1-5 of the trial will be conducted using a Simon two-stage phase II trial design.

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