Details
Title A Phase II Trial of Pembrolizumab (MK-3475) in Subjets with Advanced / Unresectable or Metastatic Urothelial Cancer.
IRB MRK 2814
CC 15-500
Hospital Main Campus
Phase Phase 2
Disease Bladder
Drug Pembrolizumab
Description
To evaluate anti-tumor activity of pembrolizumab (MK-3475) as 1L therapyin subjects with advanced/unresectable (inoperable) or metastatic urothelial cancer whoare ineligible for cisplatin-based therapy and whose tumors express PD-L1 protein (IHC),by overall response rate (ORR) based on RECIST 1.1 as assessed by independentradiology review.
Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
- Be willing and able to provide written informed consent/assent for the trial. Thesubject may also provide consent/assent for Future Biomedical Research. However,the subject may participate in the main trial without participating in FutureBiomedical Research.
- Be ≥ 18 years of age on day of signing informed consent.
- Have histologically or cytologically-confirmed diagnosis of advanced/unresectable(inoperable) or metastatic urothelial cancer of the renal pelvis, ureter, bladder, orurethra. Both transitional cell and mixed transitional/non-transitional cell histologiesare allowed. Subjects with non-urothelial cancer of the urinary tract are not allowed.
- Be considered cisplatin-ineligible to receive cisplatin-based combination therapy,based on having at least one of the following criteria:
- ECOG performance status of 2 (the proportion of ECOG 2 subjects will belimited to approximately 50% of the total population)
- Creatinine clearance (calculated or measured) < 60 mL/min but ≥ 30 mL/min Note: Subjects with a creatinine clearance (calculated or measured) < 30mL/min or on dialysis are excluded from the trial.
- CTCAE v.4, Grade ≥ 2 audiometric hearing loss (25dB in two consecutivewave ranges)
- CTCAE v.4, Grade ≥ 2 peripheral neuropathy
- NYHA Class III heart failure (Appendix 12.6)
- Have received no prior systemic chemotherapy for advanced/unresectable(inoperable) or metastatic urothelial cancer
- Adjuvant platinum based chemotherapy, following radial cystectomy, withrecurrence > 12 months from completion of therapy is permitted
- Neoadjuvant platinum based chemotherapy, with recurrence > 12 monthssince completion of therapy is permitted.
- Have provided tissue for biomarker analysis from a newly obtained core or excisionalbiopsy of a tumor lesion not previously irradiated (mandatory). Adequacy of thebiopsy specimen for PD-L1 biomarker analysis must be confirmed by the centrallaboratory.
- Have measureable disease based on RECIST 1.1 as determined by central review.Tumor lesions situated in a previously irradiated area are considered measureable ifprogression has been demonstrated in such lesions.
- Have a performance status of 0, 1 or 2 on the ECOG Performance Scale, as assessedwithin 10 days prior to treatment initiation.
- Demonstrate adequate organ function as defined in Table 1. All screening labs shouldbe performed within 10 days of treatment initiation.
Note: In the event that subjects are enrolled for the purposes of determining thebiomarker cut-point prior to the start of the main body of this study, these subjects arenot required to be cisplatin-ineligible and the above criteria does not apply. However,such subjects are required to have bladder cancer which is refractory to availabletherapy or for which no effective standard therapy exists.
Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
- Has disease that is suitable for local therapy administered with curative intent.
- Is currently participating and receiving study therapy or has participated in a study ofan investigational agent and received study therapy or used an investigational devicewithin 4 weeks prior to the first dose of treatment.
- Has had a prior anti-cancer monoclonal antibody (mAb) for direct anti-neoplastictreatment within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade1 or at baseline) from adverse events due to agents administered more than 4 weeksearlier.
- Has had prior chemotherapy, targeted small molecule therapy, or radiation therapywithin 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or atbaseline) from adverse events due to a previously administered agent.
Note: Subjects with neuropathy or ≤ Grade 2 alopecia are an exception to thiscriterion and may qualify for the study.
Note: If subject received major surgery, they must have recovered adequately fromthe toxicity and/or complications from the intervention prior to starting therapy.
- Has a known additional malignancy that is progressing or requires active treatment.Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of theskin that has undergone potentially curative therapy or in situ cervical cancer. Ahistory of prostate cancer that was identified incidentally followingcystoprostatectomy for bladder cancer is acceptable, provided that the followingcriteria are met: stage T2N0M0 or lower; and Gleason score ≤ 6, and undetectablePSA.
- Has known active central nervous system (CNS) metastases and/or carcinomatousmeningitis. Subjects with previously treated brain metastases may participateprovided they are stable [without evidence of progression by imaging (confirmed byCT scan if CT used at prior imaging, or confirmed by MRI if MRI was used at priorimaging) for at least four weeks prior to the first dose of trial treatment and anyneurologic symptoms have returned to baseline], have no evidence of new orenlarging brain metastases, and are not using steroids for at least 7 days prior to trialtreatment. This exception does not include carcinomatous meningitis which isexcluded regardless of clinical stability.
- Has an active autoimmune disease that has required systemic treatment in past 2 years(i.e. with use of disease modifying agents, corticosteroids or immunosuppressivedrugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroidreplacement therapy for adrenal or pituitary insufficiency, etc.) is not considered aform of systemic treatment.
- Has evidence of interstitial lung disease or active non-infectious pneumonitis.
- Has an active infection requiring systemic therapy.
- Has a history or current evidence of any condition, therapy, or laboratory abnormalitythat might confound the results of the trial, interfere with the subject’s participationfor the full duration of the trial, or is not in the best interest of the subject toparticipate, in the opinion of the treating investigator.
- Has known psychiatric or substance abuse disorders that would interfere withcooperation with the requirements of the trial.
- Is pregnant or breastfeeding, or expecting to conceive or father children within theprojected duration of the trial, starting with the screening visit through 120 days afterthe last dose of trial treatment.
- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, orwith an agent directed to another co-inhibitory T-cell receptor (e.g. CTLA-4, OX-40,CD137).
- Has a known history of Human Immunodeficiency Virus (HIV) (HIV-1/2 antibodies).
- Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA[qualitative] is detected).
- Has received a live virus vaccine within 30 days of planned start of trial treatment.
- Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling orchild) who is investigational site or sponsor staff directly involved with this trial,unless prospective IRB approval (by chair or designee) is given allowing exception tothis criterion for a specific subject.