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