M7824 in Subjects With HPV Associated Malignancies
Condition: Human Papilloma Virus; Cervical Cancer; Oropharyngeal Cancer; Anal Cancer; Vaginal or Penile Cancer
MeSH terms: Neoplasms; Papilloma; Anus Neoplasms; Oropharyngeal Neoplasms; Penile Neoplasms
Intervention: M7824
Intervention description: Flat dose of 1,200 mg of M7824 intravenous (IV) once every 2 weeks
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 57.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: TGFR1 pathway signaling and overexpression; PD-1 inhibitors; Manageable Safety Profile; Bifunctional Fusion Protein; Refractory/Recurrent HPV Associated Malignancies

Summary:

      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.
    

Eligibility criteria:

        -  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.