M7824 in Subjects With HPV Associated Malignancies
M7824 in Subjects With HPV Associated Malignancies
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.

 ...
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.
-  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
 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+

 -  Patients must have disease that is not amenable to potentially curative resection

 -  Subjects must have measurable disease

 -  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 HIV, Hep B, Hep C are eligible as long as the
 viral loads are undetectable by quantitative PCR. HIV positive patients must have 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 CNS imaging at least two months after definitive
 treatment showing stable CNS disease. Patients with evidence of intratumoral 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
 contrastenhanced 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 CLL).

 -  Known severe hypersensitivity reactions to monoclonal antibodies (Grade greater than
 or equal to 3 NCI 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.