M7824 in Subjects With HPV Associated Malignancies

Background:

• Metastatic or refractory/recurrent human papillomavirus (HPV) associated malignancies (cervical, anal, oropharyngeal cancers etc.) are often incurable and poorly palliated by standard therapies.

• Transforming growth factor receptor type 1 (TGF R1) pathway signaling and overexpression are significantly associated with HPV+ cancers.
• Programmed cell death protein 1 (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 programmed death-ligand 1 (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 positive (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 head and neck squamous cell carcinoma (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 intravenous (IV) every 2 weeks until off treatment criteria are met.
• There will be six cohorts: (1) Patients with anal cancer whose disease is naive to checkpoint inhibition, (2) Patients with non-neuroendocrine cervical cancer naive to checkpoint inhibition,

(3) Patients with P16+ oropharyngeal cancers naive to checkpoint inhibition, and (4) Patients with other rare HPV associated tumors (e.g. squamous cell rectal, vulvar, vaginal, penile cancer, neuroendocrine cervical) naive 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.

• INCLUSION CRITIERIA:
• Age greater than or equal to 18 years.
• Ability of subject to understand and the willingness to sign a written informed consent document.
• Subjects with cytologically or histologically confirmed locally advanced or metastatic human papillomavirus (HPV) associated malignancies including:

• Non-Neuroendocrine Cervical cancers
• P16 positive (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+
• Patients must have disease that is not amenable to potentially curative resection
• Subjects must have measurable disease
• Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2
• Adequate hematologic function at screening, as follows:

• Absolute neutrophil count (ANC) greater than or equal to 1 x 109/L
• Hemoglobin greater than or equal to 9 g/dL
• Platelets greater than or equal to 75,000/microliter.
• Adequate renal and hepatic function at screening, as follows:

• Serum creatinine less than or equal to 1.5 x upper limit of normal (ULN) OR creatinine clearance (CrCl) greater than or equal to 40 mL/min per institutional standard
• Bilirubin less than or equal to 1.5 x ULN OR in subjects with Gilbert's syndrome, a total bilirubin less than or equal to 3.0 x ULN
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal to 2.5 x ULN, unless liver metastases are present, then values must be less than or equal to 3 x ULN)
• The effects of M7824 on the developing human fetus are unknown; thus, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and up to 60 days after the last dose of the drug. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
• Patients serologically positive for human immunodeficiency virus (HIV), Hep B, Hep C are eligible as long as the viral loads are undetectable by quantitative polymerase chain reaction (PCR). HIV positive patients must have cluster of differentiation 4 (CD4) count greater than or equal to 300 cells per cubic millimeter at enrollment, be on stable antiretroviral therapy and have no reported opportunistic infections within 12 months prior to enrollment.
• EXCLUSION CRITERIA:
• Pregnant women are excluded from this study because this drug has not been tested in pregnant women and there is potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to

treatment of the mother with M7824, breastfeeding should be discontinued if the mother is treated with M7824.

• Patients with prior investigational drug, chemotherapy, immunotherapy or any prior radiotherapy (except for palliative bone directed therapy) within the past 28 days prior to the first drug administration except if the investigator has assessed that all residual treatment-related toxicities have resolved or are minimal and feel the patient is otherwise suitable for enrollment. Patients may continue adjuvant hormonal therapy in the setting of a definitively treated cancer (e.g., breast).
• Major surgery within 28 days prior to the first drug administration (minimally invasive procedures such as diagnostic biopsies are permitted).
• Known intolerance to or life-threatening side effects resulting from prior checkpoint inhibitor therapy.
• Known active brain or central nervous system metastasis (less than 1 month out from definitive radiotherapy or surgery), seizures requiring anticonvulsant treatment (<3 months) or clinically significant cerebrovascular accident (<3 months). In order to be eligible patients must have repeat central nervous system (CNS) imaging at least two months after definitive treatment showing stable CNS disease. Patients with evidence of intra-tumoral or peritumoral hemorrhage on baseline imaging are also excluded unless the hemorrhage is grade less than or equal to 1 and has been shown to be stable on two consecutive imaging scans.
• Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent with exception of:

• diabetes type I, eczema, vitiligo, alopecia, psoriasis, hypo- or hyperthyroid disease or other mild autoimmune disorders not requiring immunosuppressive treatment;
• Subjects requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses less than or equal to 10 mg of prednisone or equivalent per day;
• Administration of steroids for other conditions through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) is acceptable;
• Subjects on systemic intravenous or oral corticosteroid therapy with the exception of physiologic doses of corticosteroids (less than or equal to the equivalent of prednisone 10 mg/day) or other immunosuppressives such as azathioprine or cyclosporin A are excluded on the basis of potential immune suppression. For these subjects these excluded treatments must be discontinued at least 1 weeks prior to enrollment for recent short course use (less than or equal to 14 days) or discontinued at least 4 weeks prior to enrollment for long term use (>14 days). In addition, the use of corticosteroids as premedication for contrast enhanced studies is allowed prior to enrollment and on study.
• Subjects with a history of serious intercurrent chronic or acute illness, such as cardiac or pulmonary disease, hepatic disease, bleeding diathesis or recent (within 3 months) clinically significant bleeding events, or other illness considered by the Investigator as high risk for investigational drug treatment.
• History of non-HPV associated second malignancy within 3 years of enrollment except localized malignancy which has been adequately treated or malignancy which does not require active systemic treatment (e.g., low risk chronic lymphocytic leukemia (CLL).
• Known severe hypersensitivity reactions to monoclonal antibodies (Grade greater than or equal to 3 National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v4.03)
• Receipt of any organ transplantation requiring ongoing immunosuppression.
• Patients with vulvar cancer originating from differentiated vulvar intraepithelial neoplasia (d-VIN), as opposed to vulvar intraepithelial neoplasia of usual type, are excluded. Vulvar squamous cell carcinoma originating from differentiated VIN (d-VIN) is HPV negative; however, rare cases of HPV positive d-VIN can occur. Patients are not excluded if their tumor has tested positive for HPV or there is no documentation of prior VIN type.
• Patients with known HPV negative malignancies based on comprehensive laboratory testing (e.g. PCR based assay evaluating for HPV 16, 18, 31, 33, 35, 39, 51, 52, 56, 58, 59, 66, 68). Patients with HPV associated malignancies and unknown HPV status prior to enrollment are eligible.