M7824 in Subjects With HPV Associated Malignancies

Study Overview
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Brief Summary
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Background: In the United States, each year there are more than 30,000 cases of human papillomavirus (HPV) associated cancers. Some of these cancers are often incurable and are not improved by standard therapies. Researchers want to see if a new drug M7824, which targets and blocks a pathway that prevents the immune system from effectively fighting the cancer can shrink tumors in people with some HPV cancers. Objectives: To see if the drug M7824 causes tumors to shrink. Eligibility: Adults age 18 and older who have a cancer associated with HPV infection. Design: Participants will be screened with medical history and physical exam. They will review their symptoms and how they perform normal activities. They will have body scans. They will give blood and urine samples. They will have a sample of their tumor tissue taken if one is not available. Participants will have an electrocardiogram to evaluate their heart. Then they will get the study drug through a thin tube in an arm vein. Participants will get the drug every 2 weeks for 26 times (1 year). This is 1 course. After the course, participants will be monitored but will not take the study drug. If their condition gets worse, they will start another course with the drug. This process can be repeated as many times as needed. Treatment will stop if the participant has bad side effects or the drug stops working. Throughout the study, participants will repeat some or all the screening tests. After participants stop taking the drug, they will have a follow-up visit and repeat some screening tests. They will get periodic follow-up phone calls.

Detailed Description
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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.

Official Title
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Phase II Trial of M7824 in Subjects With HPV Associated Malignancies

Conditions
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Cervical Cancer, Human Papilloma Virus, Oropharyngeal Cancer, Anal Cancer, Vaginal or Penile Cancer

Intervention / Treatment
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* Drug: M7824


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1/Arm 1-M7824 1,200 mg intravenous (IV) once every 2 weeks<br>M7824 at a flat dose of 1,200 mg intravenous (IV) once every 2 weeks | Drug: M7824<br>* Flat dose of 1,200 mg of M7824 intravenous (IV) once every 2 weeks<br>* Other names: MSB0011359C;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants That Achieved an Objective Confirmed Complete or Partial Overall Tumor Response | The percentage of participants that achieved an objective confirmed complete or partial overall tumor response was measured using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Complete response is disappearance of all target lesions. Partial response is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. | Every six weeks for up to one year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival Time (PFS) | PFS is defined as the time from the date of first treatment to the date of disease progression or death. Progression was measured using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and is defined as at least a 20% increase in the sum of diameters of target lesions, or appearance of one or more new lesions. | Time from the date of first treatment to the date of disease progression or death, up to 12 months | 
| Percentage of Participants With Disease Control Who Achieved a Complete Response, Partial Response and Stable Disease Defined by the Response Evaluation Criteria in Solid Tumors (RECIST)Version 1.1 Lasting at Least 6 Months | The percentage of participants with disease control who achieved a complete response, partial response and stable disease lasting at least 6 months was measured by the response evaluation criteria in solid tumors (RECIST)version 1.1. Complete response (CR) is disappearance of all target lesions. Partial response (PR) is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD) (at least a 20% increase in the sum of diameters of target lesions, or appearance of one or more new lesions). | 6 months | 
| Overall Survival (OS) | OS is defined as the time from the date of first treatment to the date of death and was measured by Kaplan-Meier analysis. | Time from the date of first treatment to the date of death, up to 3 years. | 
| Number of Participants With Serious Grade ≥3 Adverse Events Considered Related to Study Treatment of M7824 | Adverse events were assessed by the Common Terminology Criteria for Adverse Events version 5.0. A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. Grade 1 is mild. Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening, and Grade 5 is death related to adverse event. | 28 days after treatment | 
| Number of Checkpoint Inhibitor Naive Participants With Response Based on Adequate Similarity (Defined as P-value > 0.2 With Fisher's Exact Test) of Results in Cohorts 1 and 2 | Response based on adequate similarity defined as P-value > 0.2 with Fisher's exact test of results in cohorts 1 and 2 was compared with a two-sided Fishers exact test, and response was measured by the response evaluation criteria in solid tumors (RECIST)version 1.1. Complete response (CR) is disappearance of all target lesions. Partial response (PR) is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive disease is at least a 20% increase in the sum of diameters of target lesions, or appearance of one or more new lesions. Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD). | median of 2 years | 
| Percentage of Participants That Were Hospitalized Because of Adverse Events Attributed to Disease Progression | Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. Disease progression is at least a 20% increase in the sum of diameters of target lesions, or appearance of one or more new lesions measured by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. | Up to 30 days from last treatment | 
| Duration of Response (Complete Response or Partial Response) | Duration of response is defined as the time from complete response or partial response (whichever is first recorded) until the first date that recurrent or progressive disease (PD) is objectively documented. Response was measured by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Complete response is disappearance of all target lesions. Partial response is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progression is at least a 20% increase in the sum of diameters of target lesions, or appearance of one or more new lesions. | Time from complete response or partial response (whichever is first recorded) until the first date that recurrent or progressive disease (PD) is objectively documented, up to 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TGFR1 pathway signaling and overexpression, PD-1 inhibitors, Manageable Safety Profile, Bifunctional Fusion Protein, Refractory/Recurrent HPV Associated Malignancies