Clinical trial NCT02500121: Testing the PD-1 Inhibitor Pembrolizumab as Maintenance Therapy After Initial Chemotherapy in Metastatic Bladder Cancer
Official title: A Randomized, Double-blinded, Phase II Study of Maintenance Pembrolizumab Versus Placebo After First-Line Chemotherapy in Patients With Metastatic Urothelial Cancer: Hoosier Cancer Research Network GU14-182
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Urothelial Carcinoma
Bladder Cancer
Keywords: Pembrolizumab
PD-1 Inhibitor
Lead sponsor: Hoosier Cancer Research Network
Sponsor class: OTHER
Collaborators: name: Hoosier Cancer Research Network
name: Merck Sharp & Dohme LLC
First posted: 2015-07-16
Enrollment: 108
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Progression-free Survival (PFS)
timeFrame: Calculated after a median follow-up time of 12.9 months
Secondary outcomes:
measure: 6-month PFS as Per irRECIST
timeFrame: Six months after randomization
measure: Number of Subjects With Adverse Events as a Measure of the Safety and Tolerability of Pembrolizumab
timeFrame: Every 3 weeks beginning with C1D1 for up to 24 months
measure: Objective Response Rate (ORR) Assessment of Subjects on Maintenance Pembrolizumab vs Placebo
timeFrame: Response assessed every 12 weeks from the date of randomization to the date of documented disease progression or date of death, whichever occurs first, assessed for up to a maximum of 104 weeks (24 months)
measure: ORR Assessment of Subjects Receiving Pembrolizumab After Progressing on Placebo
timeFrame: Every 12 weeks from the first treatment on the crossover to the date of documented disease progression, per irRECIST 1.1, assessed for up to a maximum of 104 weeks (24 months)
measure: Median Overall Survival (OS) Time in Subjects Treated With Pembrolizumab vs Placebo
timeFrame: From randomization until death from any cause. Reported after a median follow-up of 12.9 months.
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: University of Arizona at Dignity Health St. Joseph's
state: Arizona
city: Duarte
country: United States
facility: City of Hope Comprehensive Cancer Center
state: California
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: Washington
country: United States
facility: Georgetown University
state: District of Columbia
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Goshen
country: United States
facility: IU Health Goshen Center for Cancer Care
state: Indiana
city: Indianapolis
country: United States
facility: Indiana University Melvin and Bren Simon Cancer Center
state: Indiana
city: Indianapolis
country: United States
facility: IU Health Central Indiana Cancer Center
state: Indiana
city: Indianapolis
country: United States
facility: Community Regional Cancer Care
state: Indiana
city: Munster
country: United States
facility: Community Healthcare System
state: Indiana
city: Baltimore
country: United States
facility: University of Maryland
state: Maryland
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
state: Maryland
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University: Siteman Cancer Center
state: Missouri
city: Omaha
country: United States
facility: GU Cancer Research Network, LLC
state: Nebraska
city: Hackensack
country: United States
facility: The John Theuer Cancer Center at Hackensack University Medical Center
state: New Jersey
city: Albuquerque
country: United States
facility: University of New Mexico Cancer Center
state: New Mexico
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New York
country: United States
facility: Tisch Cancer Institute at Mount Sinai Medical Center
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina at Chapel Hill
state: North Carolina
city: Columbus
country: United States
facility: Ohio State University Comprehensive Cancer Center
state: Ohio
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt-Ingram Cancer Center
state: Tennessee
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute University of Utah
state: Utah
city: Norfolk
country: United States
facility: Virginia Oncology Associates
state: Virginia
Study officials:
affiliation: Hoosier Cancer Research Network
name: Matthew Galsky, M.D.
role: STUDY_CHAIR
References:
citation: 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.