Testing the PD-1 Inhibitor Pembrolizumab as Maintenance Therapy After Initial Chemotherapy in Metastatic Bladder Cancer

NCT ID: NCT02500121

Last Updated: 2022-09-30

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 108 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-11-11
• Study Completion Date: 2021-01-01

Brief Summary

This is a multi-institutional, randomized, placebo controlled, double-blinded phase II trial of maintenance pembrolizumab versus placebo after first-line chemotherapy in patients with metastatic urothelial cancer who have achieved at least stable disease on first-line chemotherapy.

Detailed Description

OUTLINE: This is a multi-center trial.

Eligible subjects will be 1:1 randomized to placebo (Control Arm A) and pembrolizumab (Experimental Arm B). Stratification factors for randomization: presence of visceral metastatic disease (lung, liver, or bone or other organs vs. lymph node only) at the time of initiation of first-line chemotherapy, and response to first-line chemotherapy (CR/PR vs. SD. Subjects who progress on placebo will be assessed to determine if they are eligible to cross over to unblinded treatment with pembrolizumab.

INVESTIGATIONAL TREATMENT:

For Control Arm A, commercially available normal saline will be used as the placebo. No active placebo drug will be mixed with the normal saline.

For Experimental Arm B, pembrolizumab (or placebo), 200 mg intravenous infusion (IV) every 3 weeks for up to 12 months, or until progressive disease (PD) or unacceptable toxicity.

The following required laboratory values must be obtained within fourteen days prior to registration for protocol therapy:

Hematopoietic:

• Absolute neutrophil count (ANC) ≥1,500 /mcL
• Platelets ≥100,000 / mcL
• Hemoglobin ≥8.5 g/dL

Renal:

• Creatinine ≤1.5x ULN OR
• Measured or calculated creatinine clearance ≥30 mL/min for subject with creatinine levels >1.5x institutional ULN
• GFR can also be used in place of creatinine or CrCl

Hepatic:

• Serum total bilirubin ≤ 1.5 X ULN OR
• Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN
• AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subject with liver metastases

Coagulation:

• International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN. If subject is on anticoagulant therapy, PT or PTT must be within therapeutic range of intended use of anticoagulants.

Conditions

Urothelial Carcinoma; Bladder Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Control Arm A

Commercially available normal saline will be used as the placebo. No active placebo drug will be mixed with the normal saline. Treatment will continue, in the absence of prohibitive toxicities or disease progression, for up to 24 months.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

Normal saline

Experimental Arm B

Pembrolizumab, 200mg IV every 3 weeks. Treatment will continue, in the absence of prohibitive toxicities or disease progression, for up to 24 months.

Group Type: EXPERIMENTAL

Pembrolizumab

Intervention Type: DRUG

Pembrolizumab, 200mg IV every 3 weeks until progressive disease, unacceptable toxicity, or for up to 24 months

Interventions

Placebo

Normal saline

Intervention Type: OTHER

Pembrolizumab

Pembrolizumab, 200mg IV every 3 weeks until progressive disease, unacceptable toxicity, or for up to 24 months

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Written informed consent and HIPAA authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
• Age ≥ 18 years at the time of consent.
• ECOG Performance Status (PS) of ≤ 1 within fourteen days of registration for protocol therapy.
• Histological or cytological evidence of urothelial cancer of the bladder, urethra, ureter, or renal pelvis. Differentiation with variant histologies (e.g., squamous cell differentiated) will be permitted provided that the predominant histology is urothelial carcinoma.
• Metastatic and/or unresectable (cT4b) disease
• Must have achieved an objective response (CR/PR) or stable disease (SD) after 4 to 6 cycles of standard first-line platinum-based chemotherapy for mUC (e.g., as per NCCN guidelines). Able to commence study treatment within 2 to 6 weeks of receiving last dose of first-line chemotherapy.
• All subjects must have adequate archival tissue available prior to registration (i.e., at least 20 unstained slides or paraffin block). If acceptable archival tissue is not available, the subject must be willing to consent to providing a core or excisional biopsy for research prior to registration for protocol therapy. If archival tissue is not available and there are no sites amenable to biopsy, enrollment must be discussed with the sponsor-investigator on a case by case basis.
• Female subjects of childbearing potential must have a negative serum pregnancy within three days prior to registration for protocol therapy
• Sexually active, pre-menopausal women of childbearing potential must be willing to use an adequate method of contraception or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study drug. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > one year.
• Male subjects of childbearing potential must agree to use an adequate method of contraception starting with the first dose of study drug through 120 days after the last dose of study drug.

Exclusion Criteria

• More than one line of prior chemotherapy for metastatic or locally advanced disease, with the following exception:

• Prior neoadjuvant/adjuvant chemotherapy will not count as line of therapy if completed greater than 12 months prior to initiation of chemotherapy regimen for metastatic or unresectable disease.
• Current or past participation in a study of an investigational agent or using an investigational device within four weeks of registration for protocol therapy.
• A diagnosis of immunodeficiency or is receiving treatment with systemic steroid therapy or any other form of immunosuppressive therapy within seven days prior to registration for protocol therapy.
• Prior chemotherapy, targeted small molecule therapy, or radiation therapy within two weeks prior to registration for protocol therapy. Note: If the subjects have undergone major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting protocol therapy.
• A known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy.
• A known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to registration for protocol therapy and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least seven days prior to registration for protocol therapy.
• Active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Has evidence of active, non-infectious pneumonitis.
• Has a history of interstitial lung disease.
• An active infection requiring systemic therapy.
• A history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating Investigator.
• Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening period through 120 days after the last dose of protocol therapy.
• Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways). Examples include nivolumab, MPDL3280, etc.
• A known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
• A known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
• Receipt of a live vaccine within 30 days prior to registration for protocol therapy.
• Unresolved toxicity (i.e., > Grade 1 or above baseline) due to previously administered agents. Exception includes: subjects with ≤ Grade 2 neuropathy are eligible for the study.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Hoosier Cancer Research Network

OTHER

Sponsor Role: collaborator

Merck Sharp & Dohme LLC

INDUSTRY

Sponsor Role: collaborator

Matthew Galsky

OTHER

Sponsor Role: lead

Responsible Party

Matthew Galsky

Sponsor-Investigator

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Matthew Galsky, M.D.

Role: STUDY_CHAIR

Hoosier Cancer Research Network

Locations

University of Arizona at Dignity Health St. Joseph's

Phoenix, Arizona, United States

City of Hope Comprehensive Cancer Center

Duarte, California, United States

University of Southern California

Los Angeles, California, United States

Georgetown University

Washington D.C., District of Columbia, United States

University of Florida

Gainesville, Florida, United States

IU Health Goshen Center for Cancer Care

Goshen, Indiana, United States

Indiana University Melvin and Bren Simon Cancer Center

Indianapolis, Indiana, United States

IU Health Central Indiana Cancer Center

Indianapolis, Indiana, United States

Community Regional Cancer Care

Indianapolis, Indiana, United States

Community Healthcare System

Munster, Indiana, United States

University of Maryland

Baltimore, Maryland, United States

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Baltimore, Maryland, United States

Henry Ford Health System

Detroit, Michigan, United States

University of Minnesota

Minneapolis, Minnesota, United States

Washington University: Siteman Cancer Center

St Louis, Missouri, United States

GU Cancer Research Network, LLC

Omaha, Nebraska, United States

The John Theuer Cancer Center at Hackensack University Medical Center

Hackensack, New Jersey, United States

University of New Mexico Cancer Center

Albuquerque, New Mexico, United States

Roswell Park Cancer Institute

Buffalo, New York, United States

Tisch Cancer Institute at Mount Sinai Medical Center

New York, New York, United States

University of Rochester Medical Center

Rochester, New York, United States

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, United States

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, United States

Fox Chase Cancer Center

Philadelphia, Pennsylvania, United States

Medical University of South Carolina

Charleston, South Carolina, United States

Vanderbilt-Ingram Cancer Center

Nashville, Tennessee, United States

Huntsman Cancer Institute University of Utah

Salt Lake City, Utah, United States

Virginia Oncology Associates

Norfolk, Virginia, United States

Countries

United States

References

Galsky MD, Mortazavi A, Milowsky MI, George S, Gupta S, Fleming MT, Dang LH, Geynisman DM, Walling R, Alter RS, Kassar M, Wang J, Gupta S, Davis N, Picus J, Philips G, Quinn DI, Haines GK 3rd, Hahn NM, Zhao Q, Yu M, Pal SK. Randomized Double-Blind Phase II Study of Maintenance Pembrolizumab Versus Placebo After First-Line Chemotherapy in Patients With Metastatic Urothelial Cancer. J Clin Oncol. 2020 Jun 1;38(16):1797-1806. doi: 10.1200/JCO.19.03091. Epub 2020 Apr 9.

Reference Type: DERIVED

PMID: 32271672 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Related Links

http://www.hoosiercancer.org

Hoosier Cancer Research Network Website

Other Identifiers

HCRN GU14-182

Identifier Type: -

Identifier Source: org_study_id