A Phase II Study of Bintrafusp Alfa (M7824) in Checkpoint Inhibitor Naive and Refractory Subjects With Urothelial Carcinoma

Phase 2

Terminated

Conditions: Urothelial Cancer

Interventions: Drug: Bintrafusp alfa (M7824)

Registration Number: NCT04501094

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: 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 Bintrafusp alfa (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 Programmed death-1 (PD-1)/programmed death-ligand 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 Food and Drug Administration (FDA)-approved for for second-line metastatic urothelial carcinoma (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 Complete Response (CR)/Partial Response (PR)

* Cohort 2B: previously had Stable Disease (SD)/Progressive Disease (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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 2

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 response by Response Evaluation Criteria in Solid Tumors (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.
Subjects unwilling to accept blood products as medically indicated
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 (with the exception of diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment) 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 a currently active second malignancy other than non-melanoma skin cancers or cervical carcinoma in situ or incidental organ-confined prostate cancer found on cystoprostatectomy (provided that the following criteria are met: Stage T2N0M0 or lower; Gleason score <= 3+4, prostate-specific antigen (PSA) undetectable). Patients are not considered to have a currently active malignancy if they have completed therapy and are free of disease for >= 2 years and currently do not require systemic therapy.
Patients who have received or will receive a live vaccine within 30 days prior to the first administration of study intervention. Seasonal flu vaccines that do not contain a live virus are permitted. Locally approved COVID vaccines are permitted.
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)

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
1/Arm 1-Treatment with Bintrafusp alfa (M7824)	Bintrafusp alfa (M7824)	Treatment with Bintrafusp alfa (M7824)

Primary Outcome Measures

Name	Time	Method
Proportion of Participants With an Objective Response Rate (ORR)	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, approximately 3 months.	The proportion of evaluable patients with objective response rate (ORR) defined as a partial response (PR) or complete response (CR) at the end of treatment with Bintrafusp alfa (M7824). Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST)v1.1. Partial response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Complete response is disappearance of all target lesions.

Secondary Outcome Measures

Name	Time	Method
Number of Participants That Survived	Time from treatment to the date of death from any cause, approximately 11 months.	Here is the number of participants that survived.
Number of Participants With Toxicity Grade >1	Until confirmed progression, unacceptable toxicity or trial withdrawal, approximately 4 months and 3 days for cohort 1B and 11 months and 17 days for cohort B.	The number of participants with toxicity grade \>1 assessed by the Common Terminology Criteria for Adverse Events (CTCAE)v5.0. Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening, and Grade 5 is death related to adverse events.
Number of Participants With Progression Free Survival (PFS)	From start of treatment to time of progression or death, approximately 6 weeks (first scheduled restaging scan)	PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. Progression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST)v1.1 and is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study; and the appearance of one or more new lesions.