M7824 in Treating Participants with HPV Associated Locally Advanced or Metastatic Cancer

Status: Active

Description

This phase II trial studies how well M7824 works in treating participants with human papillomavirus (HPV) associated cancer that has spread to nearby tissues or lymph nodes, or that has spread to other parts of the body. Biological therapies, such as M7824, use substances made from living organisms that may target and block a pathway that prevents the immune system from effectively fighting the cancer.

Eligibility Criteria

Inclusion Criteria

  • 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
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 1
  • Absolute neutrophil count (ANC) >= 1 x 10^9/L
  • Hemoglobin >= 9 g/dL
  • Platelets >= 75,000/microliter
  • Serum creatinine =< 1.5 x upper limit of normal (ULN) OR creatinine clearance (CrCl) >= 40 mL/min according to the Cockcroft-Gault formula
  • Bilirubin =< 1.5 x ULN OR in subjects with Gilbert’s syndrome, a total bilirubin =< 3.0 x ULN
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN, unless liver metastases are present, then values must be =< 3 x ULN
  • 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 120 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), hepatitis (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 CD4 count >= 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; 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
  • 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 2 months 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 intratumoral or peritumoral hemorrhage on baseline imaging are also excluded unless the hemorrhage is grade =< 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 =< 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 (=< 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 (=< 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, or other illness considered by the investigator as high risk for investigational drug treatment
  • History of second malignancy within 3 years of enrollment except for the following: adequately treated non-melanoma skin cancer, cervical carcinoma in situ, superficial bladder cancer or other localized malignancy which has been adequately treated
  • Known severe hypersensitivity reactions to monoclonal antibodies (grade >= 3 National Cancer Institute [NCI]-Common Terminology Criteria for Adverse Events [CTCAE] version [v]5.0)
  • 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

Locations & Contacts

Maryland

Bethesda
National Institutes of Health Clinical Center
Status: Active
Contact: Julius Y. Strauss
Phone: 301-480-0202 Email: julius.strauss@nih.gov

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. 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.

SECONDARY OBJECTIVES:

I. To determine the safety and tolerability of M7824.

II. To determine disease control rate (DCR) - confirmed response or stable disease (SD) lasting for at least 6 months.

III. To assess progression-free survival time (PFS) according to RECIST 1.1.

IV. To assess overall survival (OS) time.

V. To assess duration of response.

VI. To combine checkpoint inhibitor naive subjects if permitted based on adequate similarity of results in the cohorts 1, 2, 3, and 4.

EXPLORATORY OBJECTIVES:

I. To conduct exploratory immunologic studies to understand and improve the administered treatment, including peripheral immune subset analysis before and on treatment; soluble factors circulation (e.g. sCD27 and sCD40 ligand) before and on treatment; antigen specific T cell responses to E6/E7 oncoproteins before and on treatment; tumor tissue immune infiltration before and after treatment.

II. To assess circulating tumor deoxyribonucleic acid (DNA) before and after treatment.

III. To perform HPV typing.

IV. To assess responses to M7824 in patients with HPV associated tumors using (immune related RECIST [irRECIST]).

V. To assess responses to M7824 in patients with HPV negative tumors by RECIST 1.1 and irRECIST.

VI. To assess response rate to M7824 by RECIST 1.1 and iRECIST in two sub populations: (1) patients who have previously received lymphodepleting chemotherapy regimens (e.g. fludarabine/cyclophosphamide) and (2) patients who have not previously received lymphodepleting chemotherapy regimens.

OUTLINE:

Participants receive anti-PD-L1/TGFbetaRII fusion protein MSB0011359C intravenously (IV) over 1 hour every 2 weeks for 1 year. Participants may continue treatment for an additional year at the time of disease progression and in the absence of unacceptable toxicities at the discretion of the treating physician. Participants with disease progression after second year may receive additional treatment with anti-PD-L1/TGFbetaRII fusion protein MSB0011359C at the discretion of the treating physician.

After completion of study treatment, participants are followed up every 3 months for a year followed by every 6 months thereafter.

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
NCI - Center for Cancer Research

Principal Investigator
Julius Y. Strauss

Trial IDs

Primary ID 18-C-0056
Secondary IDs NCI-2018-00265
Clinicaltrials.gov ID NCT03427411