Clinical Trials /

M7824 in Subjects With HPV Associated Malignancies

NCT03427411

Description:

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. ...

Related Conditions:
  • Malignant Solid Tumor
  • Oropharyngeal Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: M7824 in Subjects With HPV Associated Malignancies
  • Official Title: M7824 in Subjects With HPV Associated Malignancies

Clinical Trial IDs

  • ORG STUDY ID: 180056
  • SECONDARY ID: 18-C-0056
  • NCT ID: NCT03427411

Conditions

  • Human Papilloma Virus
  • Cervical Cancer
  • Oropharyngeal Cancer
  • Anal Cancer
  • Vaginal or Penile Cancer

Interventions

DrugSynonymsArms
M7824Arm 1

Purpose

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

      Background:

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

        -  TGF-betaR1 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-beta receptor II (TGF-beta
           RII) which functions as a TGF-beta "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 three cohorts: (1) Patients with anal cancer whose disease is na(SqrRoot)
           ve to checkpoint inhibition, (2) Patients with other rare HPV associated tumors
           (squamous cell rectal, vulvar, vaginal, penile cancer, neuroendocrine cervical)
           na(SqrRoot) ve to checkpoint inhibition (3) Patients with any HPV associated cancers
           whose disease is refractory to checkpoint inhibition.

        -  All 3 cohorts of the trial will be conducted using a Simon two-stage phase II trial
           design.
    

Trial Arms

NameTypeDescriptionInterventions
Arm 1ExperimentalHPV associated cancer
  • M7824

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
             HPV associated malignancies including:

               -  Non-Neuroendocrine Cervical cancers

               -  P16+ Oropharyngeal cancers

               -  Anal cancers

               -  Vulvar, vaginal, penile, squamous cell rectal and neuroendocrine cervical cancers

          -  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 1

          -  Adequate hematologic function at screening, as follows:

               -  Absolute neutrophil count (ANC) greater than or equal to 1 x 10^9/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 according to the
                  Cockcroft-Gault formula: CrCl= ((140-age) x (weight in kg) x (0.85, if
                  female))/72 x Serum Creatinine (mg.dL)

               -  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 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 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 oer 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 f 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.

          -  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 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, 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 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.
      
Maximum Eligible Age:99 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate (ORR)
Time Frame:Every Six weeks
Safety Issue:
Description:The percentage of subjects that achieve an objective confirmed complete or partial overall tumor response using RECIST Version 1.1

Secondary Outcome Measures

Measure:duration of response
Time Frame:disease progression
Safety Issue:
Description:The time from CR or PR (whichever is first recorded) until the first date that recurrent or PD is objectively documented
Measure:overall survival (OS)
Time Frame:death
Safety Issue:
Description:The time from the date of first treatment to the date of death
Measure:progression-free survival time (PFS)
Time Frame:disease progression or death
Safety Issue:
Description:The time from the date of first treatment to the date of disease progression or death
Measure:disease control rate (DCR)
Time Frame:6 month
Safety Issue:
Description:The percentage of subjects that achieve an objective confirmed complete or partial overall tumor response using RECIST Version 1.1
Measure:safety and tolerability of M7824
Time Frame:30 days after treatment
Safety Issue:
Description:List of adverse event frequency

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • TGFR1 pathway signaling and overexpression
  • PD-1 inhibitors
  • Manageable Safety Profile
  • Bifunctional Fusion Protein
  • Refractory/Recurrent HPV Associated Malignancies

Last Updated

April 27, 2018