Metastatic or locally advanced/unresectable urothelial cancer that has recurred or progressed following platinum-based chemotherapy MedDRA version: 20.0 Level: LLT Classification code 10046714 Term: Urothelial carcinoma bladder System Organ Class: 100000004864
Conditions
Sponsors
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Male and Female subjects of at least 18 years of age with recurrent/progressive metastatic urothelial cancer will be enrolled in this trial 1. Be willing and able to provide written informed consent/assent for the trial. The subject may also provide consent/assent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research 2. Be =18 years of age on day of signing informed consent 3. Have histologically or cytologically-confirmed diagnosis of urothelial cancer of the renal pelvis, ureter, bladder, or urethra. Both transitional cell and mixed transitional/non-transitional cell histologies are allowed, but transitional cell carcinoma must be the predominant histology. Subjects with non-urothelial cancer of the urinary tract are not allowed 4. Have had progression or recurrence of urothelial cancer following receipt of a first-line platinum-containing regimen (e.g cisplatin or carboplatin): a. Received a first-line platinum-containing regimen in the metastatic setting or for inoperable locally advanced disease OR b. Received adjuvant platinum-containing therapy following cystectomy for localized muscle-invasive urothelial cancer, with recurrence/progression =12 months following completion of therapy OR c. Received neoadjuvant platinum-containing therapy prior to cystectomy for localized muscle-invasive urothelial cancer, with recurrence =12 months following completion of therapy 5. Have received no more than two prior lines of systemic chemotherapy for metastatic urothelial cancer. Subjects for whom the most recent therapy has been a non-platinum-based regimen following progression/recurrence on platinum-based therapy (i.e. third-line patients) are eligible if they have progressed/recurred on their most recent therapy 6. Have provided tissue for biomarker analysis from an archival tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. A newly-obtained biopsy is strongly preferred but not required if archival tissue is adequate for analysis. Adequacy of the archived or freshly-obtained biopsy specimen must be confirmed by the central laboratory during the screening period prior to enrollment 7. Have measureable disease based on RECIST 1.1 as assessed by the investigator/site radiologist. Tumor lesions situated in a previously irradiated area are considered measureable if progression has been demonstrated in such lesions 8. Have a performance status of 0, 1 or 2 on the ECOG Performance Scale, as assessed within 10 days prior to treatment initiation. Subjects with an ECOG performance status of 2 must have a hemoglobin =10 g/dL, must not have liver metastases, and must have received the last dose of their last prior chemotherapy regimen =3 months (90 days) prior to enrollment 9. Demonstrate adequate organ function as defined in Table 1 of the protocol, all screening labs should be performed within 10 days of treatment initiation 10. Female subjects of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required 11. Female subjects of childbearing potential must be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through120 days aft
Exclusion criteria
Exclusion criteria: 1.Has disease suitable for local therapy administered with curative intent 2.Currently participating/has participated in a study of an investigational agent or using an investigational device within 4 weeks prior to first dose 3.Has diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7days prior to first dose. Use of physiologic doses of corticosteroids may be approved 4.Has had a prior anti-cancer mAb within 4weeks prior to study Day 1 or who has not recovered (i.e. = Grade 1 or at baseline) from AE due to agents administered more than 4 weeks earlier 5.Has had prior chemotherapy, targeted small molecule therapy or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered from AE due to previously administered agent Note: Subjects with = Grade 2 neuropathy or = Grade 2 alopecia may qualify for study Note: If subject received major surgery, they must have recovered adequately 6.Has a known additional malignancy progressing or requires active treatment. Exceptions include basal cell carcinoma of skin, squamous cell carcinoma of skin that has undergone potentially curative therapy or in situ cervical cancer. History of prostate cancer that was identified incidentally following cystoprostatectomy for bladder cancer is acceptable, provided that the following criteria are met:Stage T2N0M0 or lower; Gleason score = 6, PSA undetectable 7.Has known active CNS metastases and/or carcinomatous meningitis.Subjects with previously treated brain metastases may participate provided they are stable,have no evidence of new or enlarging brain metastases, are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability 8.Has active autoimmune disease requiring systemic treatment within past 3 months or documented history of clinically severe autoimmune disease or syndrome that requires systemic or immunosuppressive agents. Subjects with vitiligo, diabetes Type I or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators, inhaled steroids or local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjøgren’s syndrome will not be excluded from study. 9.Has active cardiac disease, defined as: A.Myocardial infarction or unstable angina pectoris within 6 months of the first date of study therapy; B.History of serious ventricular arrhythmia, high-grade AV block, or other cardiac arrhythmias requiring anti-arrhythmic medications (except for atrial fibrillation that is well controlled); history of QT interval prolongation; C.NYHA Class III or greater congestive heart failure, or left ventricular ejection fraction of < 40% 10.Has evidence of interstitial lung disease or active non-infectious pneumonitis 11.Has active infection requiring systemic therapy 12.Has history of severe hypersensitivity reaction to paclitaxel or other drugs formulated with polyoxyethylated castor oil, to docetaxel or other drugs formulated with polysorbate 80,or to vinflunine or other vinca alkaloids 13.Requires ongoing therapy with a medication that is a strong inhibitor or inducer of the CYP3A4 enzymes 14.Has history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial,
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: OS: The time from randomization to death due to any cause. Patients without documented death at the time of the final analysis will be censored at the date of the last follow-up. PFS: The time from randomization to the first documented disease progression per RECIST 1.1 based on blinded independent radiologists’ review or death due to any cause, whichever occurs first. ;Main Objective: -Evaluate PFS per RECIST 1.1 by blinded independent radiologists' review pf all subjects with recurrent/progressive metastatic urothelial cancer treated with pembrolizumab (MK-3475) compared to paclitaxel, Docetaxel or vinflunine. -Evaluate the OS of all subjects with metastatic or locally advanced /unresectable urothelial cancer that has recurred or progressed following platinum-based chemotherapy (recurrent/progressive metastatic urothelial cancer) when treated with MK3475 compared to paclitaxel, docetaxel or vinflumine. -Evaluate the PFS per RECIST1.1 by blinded independent radiologists' review of subjects with platinum-refractory recurrent/progressive metastatic PD-L1 positive urothelial cancer treated with MK3475 compared to paclitaxel, docetaxel or vinflumine. -Evaluate the OS of subjects with platinum-refractory metastatic or locally advanced/unresectable PD-L1 positive urothelial cancer, when treated with MK-3475 compared to paclitaxel, docetaxel or vinflumine. ;Secondary Objective: -Evaluate the safety and tolerability profile of pembrolizumab (MK-3475) in subjects with recurrent/progressive metastatic urothelial cancer. -Evaluate the ORR per RECIST 1.1 a by independent radiologists'review in PD-L1 strongly positive, PD-L1 positive and all subjects with recurrent/progressive metastatic urothelial cancer treated with MK3475 compared to paclitaxel, Docetaxel or vinflunine. -Evaluate PFS per modified RECIST by independent radiologists' review of PD-L1 strongly positive, PD-L1 positive and all subjects with recurrent/progressive met | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): -Objective Response Rate (ORR) -PFS/ORR -Response Duration;Timepoint(s) of evaluation of this end point: ORR:When the proportion of the subjects in the analysis population who have a complete response (CR) or partial response (PR). Responses are based upon blinded central radiologists'review per RECIST1.1. A supportive analysis of ORR will be conducted using site radiology review as defined in the Imaging Review Charter. PFS and ORR: When modified RECIST by blinded independent radiologists' review response duration: the time from first documented evidence of CR or PR until disease progression or death. Response duration will be calculated for RECIST1.1 based on blinded independent radiologists' review and site review. | — |
Countries
Australia, Austria, Belgium, Canada, Chile, Denmark, France, Germany, Hungary, Ireland, Israel, Italy, Korea, Republic of, Netherlands, New Zealand, Norway, Peru, Poland, Portugal, Puerto Rico, Romania, Singapore, Spain, Sweden, Taiwan, Turkey, United Kingdom, United States
Contacts
Public ContactGlobal Clinical Trials Operations
Merck Sharp & Dohme Corp., a subsidiary of Merck
Outcome results
None listed