Clinical Trials /

Bintrafusp Alfa (M7824) in Checkpoint Inhibitor Na(SqrRoot) ve and Refractory Subjects With Urothelial Carcinoma

NCT04501094

Description:

Background: Metastatic urothelial carcinoma is lethal and has no cure. Response rates to current treatments are modest. Researchers want to find new strategies to treat the disease. In this study, they will test a drug called M7824. The drug is a new immunotherapy that blocks the pathways that cancer cells use to stop the immune system from fighting cancer. Objective: To learn if M7824 can help the immune system s ability to fight urothelial cancer. Eligibility: People age 18 and older who have urothelial cancer that has spread to other parts of their body and they have been previously treated with chemotherapy or immunotherapy Design: Participants will be screened with a medical history and physical exam. They will have blood and urine tests. They will have imaging scans. They will have an electrocardiogram to measure heart function. Their ability to perform their normal activities will be evaluated. They may have a tumor biopsy. They will take a pregnancy test if needed. Participants will repeat some of the screening tests during the study. Treatment will be given in a series of 28-day cycles. Participants will get M7824 once every 2 weeks. It is given through an intravenous infusion. For this, a small plastic tube is put into an arm vein. They will get M7824 until their disease gets worse, they have unacceptable side effects, or they decide to stop treatment. Participants will have a follow-up visit 30 days after treatment ends. Then they will be followed every 12 weeks in the clinic or by telephone/email. Follow-up will last indefinitely.

Related Conditions:
  • Urothelial Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Bintrafusp Alfa (M7824) in Checkpoint Inhibitor Na(SqrRoot) ve and Refractory Subjects With Urothelial Carcinoma
  • Official Title: A Phase II Study of Bintrafusp Alfa (M7824) in Checkpoint Inhibitor Naive and Refractory Subjects With Urothelial Carcinoma

Clinical Trial IDs

  • ORG STUDY ID: 200142
  • SECONDARY ID: 20-C-0142
  • NCT ID: NCT04501094

Conditions

  • Urothelial Cancer

Interventions

DrugSynonymsArms
Bintrafusp alfa (M7824)1/Arm 1

Purpose

Background: Metastatic urothelial carcinoma is lethal and has no cure. Response rates to current treatments are modest. Researchers want to find new strategies to treat the disease. In this study, they will test a drug called M7824. The drug is a new immunotherapy that blocks the pathways that cancer cells use to stop the immune system from fighting cancer. Objective: To learn if M7824 can help the immune system s ability to fight urothelial cancer. Eligibility: People age 18 and older who have urothelial cancer that has spread to other parts of their body and they have been previously treated with chemotherapy or immunotherapy Design: Participants will be screened with a medical history and physical exam. They will have blood and urine tests. They will have imaging scans. They will have an electrocardiogram to measure heart function. Their ability to perform their normal activities will be evaluated. They may have a tumor biopsy. They will take a pregnancy test if needed. Participants will repeat some of the screening tests during the study. Treatment will be given in a series of 28-day cycles. Participants will get M7824 once every 2 weeks. It is given through an intravenous infusion. For this, a small plastic tube is put into an arm vein. They will get M7824 until their disease gets worse, they have unacceptable side effects, or they decide to stop treatment. Participants will have a follow-up visit 30 days after treatment ends. Then they will be followed every 12 weeks in the clinic or by telephone/email. Follow-up will last indefinitely.

Detailed Description

      Background:

        -  Metastatic urothelial carcinoma is lethal and incurable with a median overall survival
           of 14 months from diagnosis.

        -  Immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have greatly changed
           clinical management of metastatic urothelial carcinoma (mUC) improving survival by 3
           months in the second-line setting.

        -  Five PD-1/PD-L1 inhibitors are FDA-approved for for second-line mUC, two agents for
           first-line cisplatin-ineligible mUC. However, response rates are modest, ranging from15-
           20% in the second-line and 24% in the first-line cisplatin-ineligible.

        -  Therefore, novel strategies are needed to extend benefit of immunotherapy to the
           remaining approximately 75% of non-responders.

        -  Higher levels of transforming growth factor-beta (TGF-beta) are associated with immune
           escape, therapy resistance and poor outcomes in advanced malignancies. Non-responders to
           anti-PD-1/PD-L1 antibodies have also been found to have increased TGF-beta in the tumor
           microenvironment.

        -  Bintrafusp alfa (M7824) is a novel first-in-class bifunctional fusion protein composed
           of a monoclonal antibody against PD-L1 fused to the extracellular domain of human
           TGF-beta receptor II (TGFbetaRII), which effectively functions to sequester or "trap"
           all three TGF-beta isoforms. A phase I study of M7824 (NCT02517398) demonstrated a
           manageable safety profile and clinical efficacy among patients with heavily pre-treated
           advanced solid tumors.

        -  We hypothesize that M7824 is safe and improves outcomes in patients with checkpoint
           naive or refractory urothelial carcinoma.

      Objectives:

      -To evaluate the activity of M7824 as determined by objective response rate (ORR) in two
      metastatic urothelial carcinoma cohorts:

        -  Cohort 1: Checkpoint inhibitor naive

             -  Cohort 1A: cisplatin ineligible

             -  Cohort 1B: refractory post-platinum therapy

        -  Cohort 2: Checkpoint inhibitor previously treated patients

             -  Cohort 2A: previously achieved a CR/PR

             -  Cohort 2B: previously had SD/PD

      Eligibility:

        -  Patients must have a histologically confirmed diagnosis of metastatic urothelial cancer.

        -  Patients may have been previously treated with prior cytotoxic chemotherapy regimen or
           targeted agent. Patients may have received any number of prior cytotoxic agents.

        -  18 years of age or older

      Design:

        -  This is an open label, non-randomized, single arm phase II trial of M7824 in checkpoint
           inhibitor naive and previously treated patients with urothelial carcinoma of the
           bladder.

        -  M7824 (intravenous 1200 mg fixed dose) will be delivered every 2 weeks

        -  Patients will receive treatment in cycles consisting of 4 weeks.

        -  A maximum of 75 subjects will be enrolled in this trial.
    

Trial Arms

NameTypeDescriptionInterventions
1/Arm 1ExperimentalTreatment with Bintrafusp alfa (M7824)
  • Bintrafusp alfa (M7824)

Eligibility Criteria

        -  INCLUSION CRITERIA:

          -  Ability to understand the purpose of the study, provide signed and dated informed
             consent, and able to comply with all procedures.

          -  Male or female patients aged greater than or equal to 18 years of age at time of
             consent.

          -  Patients with histologically confirmed diagnosis of urothelial carcinoma of the
             urinary tract, including the renal pelvis, ureter, bladder, or urethra.
             Differentiation with variant histologies (e.g. squamous cell differentiated) will be
             permitted. Mixed histologies are required to have a dominant urothelial/transitional
             cell pattern.

          -  Patients must have metastatic disease defined as new or progressive lesions on cross-
             sectional imaging. Radiological evaluation should occur within 21 days prior to
             enrollment.

          -  Patient must have evaluable and measurable disease, per RECIST 1.1.

          -  Patients may have been previously treated with prior cytotoxic chemotherapy regimen or
             targeted agent. Patients may have received any number of prior cytotoxic agents.

          -  Patients may have had prior immunomodulating therapy including therapy targeting the
             PD-1/PDL-1 axis (cohort 2A and B) but excluding prior treatment with M7824.

          -  Pre-treatment tissue biopsy and/or archival tissue availability for PD-L1 expression
             testing is mandatory for enrollment.

          -  Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2

          -  Required laboratory values reflective of organ function are listed below:

               -  Absolute neutrophil count greater than or equal to 1000/microliter

               -  Platelets greater than or equal to 75,000 microliter

               -  Hemoglobin greater than or equal to 9 g/dL (erythrocyte tranfusions are allowed
                  to achieve acceptable Hgb)

               -  AST(SGOT)/ALT(SGPT) less than or equal to 1.5 (SqrRoot) institutional upper limit
                  of normal (ULN) with the following exception:

                  ---Patients with liver involvement who have AST and ALT less than or equal to 5
                  (SqrRoot) ULN may be enrolled.

               -  Total bilirubin within normal limits with the following exceptions:

                    -  Patients with known Gilbert disease who have serum bilirubin level less than
                       or equal to 3 ULN may be enrolled.

                    -  Patients with tumor liver involvement bilirubin with less than or equal to
                       3.0 (SqrRoot) ULN.

               -  INR and aPTT less than or equal to 1.5 (SqrRoot) ULN

                  ---This applies only to patients who are not receiving therapeutic
                  anticoagulation; patients receiving therapeutic anticoagulation (such as
                  low-molecular-weight heparin or warfarin) should be on a stable dose.

               -  Creatinine clearance (CrCl) greater than or equal to 30 mL/min/1.73 m^2 (GFR may
                  be used in place of CrCl. Creatinine clearance or eGFR should be calculated per
                  institutional standard)

          -  The effects of M7824 on the developing human fetus are unknown. For this reason, women
             of child-bearing potential and men must agree to use strict and effective
             contraception (hormonal or barrier method of birth control; abstinence) during
             treatment and for at least 65 days for women and 125 days for men, after the last dose
             of M7824 administration. 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.

          -  Human immunodeficiency virus (HIV) positive patients are eligible if on stable dose of
             highly active antiretroviral therapy (HAART), CD4 counts are greater than 350
             cells/mm3 and viral load is undetectable.

          -  Patients with previously treated brain or central nervous system (CNS) metastases are
             eligible provided that the subjects have recovered from any acute effects of
             radiotherapy and is not requiring steroids, and any whole brain radiation therapy or
             any stereotactic radiosurgery was completed at least 2 weeks prior to M7824
             administration.

          -  Hepatitis B virus (HBV) positive patients are eligible-they must have been treated and
             on a stable dose of antivirals (eg, entecavir, tenofovir, or lamivudine; adefovir or
             interferon are not allowed) at study entry and with planned monitoring and management
             according to appropriate labeling guidance.

          -  Hepatitis C virus (HCV) positive patients are eligible if participants are on active
             HCV therapy at study entry and on a stable dose without documented clinically
             significant impaired liver function test or hematologic abnormalities and with planned
             monitoring and management according to appropriate labeling guidance.

          -  Cohort 1A Cisplatin Ineligible Specific Inclusion Criteria (first-line for metastatic
             cisplatin-ineligible):

               -  No prior chemotherapy for inoperable locally advanced or metastatic or recurrent
                  UC

                  ---For patients who received prior adjuvant/neoadjuvant chemotherapy or
                  chemoradiation for UC, a treatment-free interval > 12 months between the last
                  treatment administration and the date of recurrence is required in order to be
                  considered treatment naive in the metastatic setting. Prior local intravesical
                  chemotherapy or immunotherapy is allowed if completed at least 4 weeks prior to
                  the initiation of study treatment.

               -  Ineligible ("unfit") for chemotherapy or cisplatin-based chemotherapy as defined
                  by any one of the following criteria:

                    -  Impaired renal function (CrCl > 30 but < 60 mL/min); GFR should be
                       calculated per institutional standard.

                    -  A hearing loss (measured by audiometry) of 25 dB at two contiguous
                       frequencies

                    -  Grade greater than or equal to 2 peripheral neuropathy (i.e., sensory
                       alteration or paresthesias including tingling)

                    -  ECOG performance score of 2

                    -  Patient declines chemotherapy after informed discussion with the study
                       doctor

          -  Cohort 1B Refractory Post-platinum Therapy Specific Inclusion Criteria (second-line
             for metastatic disease):

             --Disease progression during or following treatment with a platinum-containing regimen
             for inoperable locally advanced or metastatic urothelial carcinoma or disease
             recurrence. Examples of regimens include cisplatin + gemcitabine (GC), methotrexate +
             vinblastine sulfate + doxorubicin + cisplatin (MVAC), and carboplatin + gemcitabine
             (CarboGem).

             ---Patients who received prior adjuvant/neoadjuvant chemotherapy and progressed within
             12 months of treatment with a platinum-containing adjuvant/neoadjuvant regimen will be
             considered as second-line patients.

          -  Cohort 2A Checkpoint Inhibitor Previously Treated Patients that Previously Achieved a
             Complete Response (CR) or Partial Respsonse (PR) Specific Inclusion Criteria:

             --Patients must have been treated with at least one treatment of a PD-1/PD-L1
             checkpoint inhibitor for advance or metastatic UC and achieved a complete response or
             partial respsonse by RECIST 1.1 criteria.

          -  Cohort 2B Checkpoint inhibitor previously treated patients that previously had stable
             disease (SD) or progressive disease (PD)

          -  Specific Inclusion Criteria:

               -  Patients must have been treated with at least one treatment of a PD-1/PD-L1
                  checkpoint inhibitor for advance or metastatic UC and had stable disease or a
                  progressive disease by RECIST 1.1 criteria.

        EXCLUSION CRITERIA:

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to M7824 investigational agents used in the study.

          -  Uncontrolled intercurrent illness including, but not limited to, symptomatic
             congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric
             illness/social situations that would limit compliance with study requirements.

          -  Symptomatic central nervous system metastasis.

          -  Pregnant women are excluded from this study because M7824 is an agent with the
             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
             these agents.

          -  Patients with any active or recent history of a known or suspected autoimmune disease
             or recent history of a syndrome that required treatment with either systemic
             corticosteroids (>10 mg daily prednisone equivalent) or immunosuppressive medications.
             Inhaled steroids and adrenal replacement steroid doses up to 10 mg daily prednisone
             equivalents are permitted in the absence of active autoimmune disease.

          -  Patients with prior malignancy active within the previous 3 years except for locally
             curable cancers that have been apparently cured such as basal or squamous cell skin
             cancer, superficial bladder cancer, or carcinoma in situ of the cervix, breast or low
             risk Gleason 6 prostate cancer.

          -  Patients having tumor lesion(s) in the liver or chest which are 10 cm or larger.

          -  Patients previously treated with M7824.

          -  Patients previously treated with PD-1/PD-L1 checkpoint inhibitors (for Cohorts 1A and
             1B only)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate (ORR)
Time Frame:From time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented
Safety Issue:
Description:the fraction of evaluable patients with a PR or CR at the end of treatment with Bintrafusp alfa (M7824)

Secondary Outcome Measures

Measure:safety of Bintrafusp alfa (M7824)
Time Frame:until confirmed progression, unacceptable toxicity or trial withdrawal
Safety Issue:
Description:The fraction of patients with toxicity will be reported by grade and type of toxicity identified.
Measure:Progression free survival (PFS)
Time Frame:From start of treatment to time of progression or death, whichever occurs first
Safety Issue:
Description:duration of time from start of treatment to time of progression or death, whichever occurs first
Measure:Overall Survival (OS)
Time Frame:Time from treatment to the date of death from any cause
Safety Issue:
Description:Time from the start of treatment that patients are still alive.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • TGF-Beta
  • Immune Therapy
  • PD-L1
  • Immunocytokine

Last Updated

August 12, 2020