Testing the PD-1 Inhibitor Pembrolizumab as Maintenance Therapy After Initial Chemotherapy in Metastatic Bladder Cancer
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
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:
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Absolute neutrophil count (ANC) ≥1,500 /mcL
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Platelets ≥100,000 / mcL
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Hemoglobin ≥8.5 g/dL
Renal:
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Creatinine ≤1.5x ULN OR
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Measured or calculated creatinine clearance ≥30 mL/min for subject with creatinine levels >1.5x institutional ULN
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GFR can also be used in place of creatinine or CrCl
Hepatic:
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Serum total bilirubin ≤ 1.5 X ULN OR
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Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN
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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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Placebo Comparator: 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. |
Other: Placebo
Normal saline
|
| Experimental: 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. |
Drug: Pembrolizumab
Pembrolizumab, 200mg IV every 3 weeks until progressive disease, unacceptable toxicity, or for up to 24 months
|
Outcome Measures
Primary Outcome Measures
- Six-month progression-free survival (PFS) disease assessment among subjects treated with pembrolizumab versus placebo as maintenance therapy after up to 8 cycles of first-line chemotherapy. [Assessed at six months, calculated from the date of randomization]
Percentage of subjects still alive and progression-free at six months, as per immune-related RECIST (irRECIST).
Secondary Outcome Measures
- Six-month PFS rates among the subsets of subjects with PD-L1 positive and PD-L1 negative tumors treated with pembrolizumab versus placebo. [Assessed at six months, calculated from the date of randomization]
Percentage of subjects in these subsets still alive and progression-free, as per immune-related RECIST (irRECIST).
- PFS rates among subjects treated with pembrolizumab versus placebo [Every 3 weeks beginning with C1D1 for up to 24 months]
Percentage of subjects still alive and progression-free, as per immune-related RECIST (irRECIST).
- PFS rates among the subsets of subjects with PD-L1 positive and PD-L1 negative tumors treated with pembrolizumab versus placebo. [Every 3 weeks beginning with C1D1 for up to 24 months]
Percentage of subjects still alive and progression-free, as per immune-related RECIST (irRECIST).
- PFS rates among subjects with metastatic urothelial cancer, treated with pembrolizumab versus placebo as maintenance therapy, after up to 8 cycles of first-line therapy [Every 3 weeks beginning with C1D1, assessed for up to 6 months]
Percentage of subjects still alive and progression-free, as per RECIST 1.1
- Number of subjects with adverse events as a measure of the safety and tolerability of pembrolizumab [Every 3 weeks beginning with C1D1 for up to 24 months]
Proportion of subjects with treatment-related toxicities, as per Common Terminology Criteria for Adverse Events (CTCAE) v 4.0
- Objective response rate (ORR) assessment of subjects on maintenance pembrolizumab vs placebo with measurable [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 104 weeks (24 months)]
ORR as per irRECIST and RECIST 1.1
- ORR assessment of subjects receiving pembrolizumab after progressing on placebo [Every 12 weeks from the date of randomization to the date of documented disease progression, per irRECIST and RECIST 1.1, assessed for up to 104 weeks (24 months)]
ORR per irRECIST and RECIST 1.1
- Overall survival (OS) rates in subjects treated with pembrolizumab vs placebo [Every 12 weeks from the date of randomization to the date of death, assessed for up to 24 months]
Proportion of subjects still alive at the end of study treatment
- Hazard ratios (HR) with respect to both PFS and OS, comparing subjects treated with pembrolizumab vs placebo [From the date of randomization to documented progression or death, whichever occurs first, assessed for up to 24 months]
HRs will be evaluated using Cox proportional hazard models
- Restricted mean survival time (RMST) of subjects treated with pembrolizumab vs placebo [Every 12 weeks from the date of randomization to the date of death or documented disease progression, whichever occurs first, assessed for up to 24 months]
RMST in subjects treated with pembrolizumab versus placebo using Kaplan-Meier estimates of survival functions
- Durations of response in subjects treated with pembrolizumab versus placebo [Every 12 weeks from date of randomization to the date of documented disease progression or date of death, whichever occurs first, assessed for up to 24 months]
Durations of response will be summarized by median and compared using Wilcoxon rank sum test
Eligibility Criteria
Criteria
Inclusion Criteria:
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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.
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Age ≥ 18 years at the time of consent.
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ECOG Performance Status (PS) of ≤ 1 within fourteen days of registration for protocol therapy.
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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.
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Metastatic and/or unresectable (cT4b) disease
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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.
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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.
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Female subjects of childbearing potential must have a negative serum pregnancy within three days prior to registration for protocol therapy
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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.
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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:
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More than one line of prior chemotherapy for metastatic or locally advanced disease, with the following exception:
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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.
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Current or past participation in a study of an investigational agent or using an investigational device within four weeks of registration for protocol therapy.
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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.
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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.
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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.
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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.
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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.
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Has evidence of active, non-infectious pneumonitis.
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Has a history of interstitial lung disease.
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An active infection requiring systemic therapy.
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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.
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Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
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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.
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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.
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A known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
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A known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
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Receipt of a live vaccine within 30 days prior to registration for protocol therapy.
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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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Arizona at Dignity Health St. Joseph's | Phoenix | Arizona | United States | 85004 |
| 2 | City of Hope Comprehensive Cancer Center | Duarte | California | United States | 91010 |
| 3 | University of Southern California | Los Angeles | California | United States | 90033 |
| 4 | Georgetown University | Washington | District of Columbia | United States | 20057 |
| 5 | University of Florida | Gainesville | Florida | United States | 32610 |
| 6 | IU Health Goshen Center for Cancer Care | Goshen | Indiana | United States | 46526 |
| 7 | Indiana University Melvin and Bren Simon Cancer Center | Indianapolis | Indiana | United States | 46202 |
| 8 | IU Health Central Indiana Cancer Center | Indianapolis | Indiana | United States | 46219 |
| 9 | Community Regional Cancer Care | Indianapolis | Indiana | United States | 46256 |
| 10 | Community Healthcare System | Munster | Indiana | United States | 46321 |
| 11 | University of Maryland | Baltimore | Maryland | United States | 21201 |
| 12 | Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Baltimore | Maryland | United States | 21231 |
| 13 | Henry Ford Health System | Detroit | Michigan | United States | 48202 |
| 14 | University of Minnesota | Minneapolis | Minnesota | United States | 55455 |
| 15 | Washington University: Siteman Cancer Center | Saint Louis | Missouri | United States | 63110 |
| 16 | GU Cancer Research Network, LLC | Omaha | Nebraska | United States | 68130 |
| 17 | The John Theuer Cancer Center at Hackensack University Medical Center | Hackensack | New Jersey | United States | 07601 |
| 18 | University of New Mexico Cancer Center | Albuquerque | New Mexico | United States | 87106 |
| 19 | Roswell Park Cancer Institute | Buffalo | New York | United States | 14263 |
| 20 | Tisch Cancer Institute at Mount Sinai Medical Center | New York | New York | United States | 10029 |
| 21 | University of Rochester Medical Center | Rochester | New York | United States | 14642 |
| 22 | University of North Carolina at Chapel Hill | Chapel Hill | North Carolina | United States | 27514 |
| 23 | Ohio State University Comprehensive Cancer Center | Columbus | Ohio | United States | 43210 |
| 24 | Fox Chase Cancer Center | Philadelphia | Pennsylvania | United States | 19111 |
| 25 | Medical University of South Carolina | Charleston | South Carolina | United States | 29425 |
| 26 | Vanderbilt-Ingram Cancer Center | Nashville | Tennessee | United States | 37232 |
| 27 | Huntsman Cancer Institute University of Utah | Salt Lake City | Utah | United States | 84112 |
| 28 | Virginia Oncology Associates | Norfolk | Virginia | United States | 23502 |
Sponsors and Collaborators
- Matthew Galsky
- Hoosier Cancer Research Network
- Merck Sharp & Dohme LLC
Investigators
- Study Chair: Matthew Galsky, M.D., Hoosier Cancer Research Network
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- HCRN GU14-182