| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| advanced/unresectable (inoperable) or metastatic urothelial cancer of the renal pelvis, ureter, bladder, or urethra. |
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| E.1.1.1 | Medical condition in easily understood language |
| advanced/unresectable (inoperable) or metastatic urothelial cancer of the renal pelvis, ureter, bladder, or urethra. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10064467 |
| E.1.2 | Term | Urothelial carcinoma |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 1.Objective: To evaluate anti-tumor activity of pembrolizumab (MK-3475) as 1L therapy in subjects with advanced/unresectable (inoperable) or metastatic urothelial cancer who are 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 independent radiology review. |
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| E.2.2 | Secondary objectives of the trial |
1.Investigate association between PD-L1 protein expression and anti-tumor activity of pembrolizumab (MK-3475) as 1L therapy and establish a cut-point for PD-L1 positive status
2.Evaluate anti-tumor activity of pembrolizumab as 1L therapy:
•by ORR and by PFS based on RECIST 1.1/modified RECIST 1.1 as assessed by independent radiology review/in all subjects and PD-L1 positive subjects.
•by ORR based on RECIST 1.1 as assessed by the study site radiology review,in all subjects and PD-L1 positive subjects.
•based on OS, in all subjects and PD-L1 positive subjects
•based on response duration based on RECIST 1.1 as assessed by independent radiology review, in all subjects and PD-L1 positive subjects
•by proportions of PFS (based on RECIST 1.1 as assessed by independent radiology review) and OS at 6 & 12 months, in all subjects and PD-L1 positive subjects.
3.Determine the safety and tolerability of pembrolizumab as 1L therapy in subjects who are ineligible for cisplatin-based therapy . |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Merck will conduct Future Biomedical Research on DNA (blood) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding
of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time.
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| E.3 | Principal inclusion criteria |
In order to be eligible for participation in this trial, the subject must:
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 advanced/unresectable (inoperable) or metastatic urothelial cancer of the renal pelvis, ureter, bladder, or urethra. Both transitional cell and mixed transitional/non-transitional cell histologies are allowed. Subjects with non-urothelial cancer of the urinary tract are not allowed.
4. Be considered cisplatin-ineligible to receive cisplatin-based combination therapy, based on having at least one of the following criteria:
a. ECOG performance status of 2 (the proportion of ECOG 2 subjects will be limited to approximately 50% of the total population)
b. Creatinine clearance (calculated or measured) < 60 mL/min but >30 mL/min
Note: Subjects with a creatinine clearance (calculated or measured) < 30 mL/min or on dialysis are excluded from the trial.
c. CTCAE v.4, Grade >2 audiometric hearing loss (25dB in two consecutive wave ranges)
d. CTCAE v.4, Grade >2 peripheral neuropathy
e. NYHA Class III heart failure (Appendix 12.6)
Note: In the event that subjects are enrolled for the purposes of determining the biomarker cut-point prior to the start of the main body of this study, these subjects are not 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 available therapy or for which no effective standard therapy exists.
5. Have received no prior systemic chemotherapy for advanced/unresectable (inoperable) or metastatic urothelial cancer
a. Adjuvant platinum based chemotherapy, following radial cystectomy, with recurrence > 12 months from completion of therapy is permitted
b.Neoadjuvant platinum based chemotherapy, with recurrence > 12 months since completion of therapy is permitted.
6.Have provided tissue for biomarker analysis from a newly obtained core or excisional biopsy of a tumor lesion not previously irradiated (mandatory). Adequacy of the biopsy specimen for PD-L1 biomarker analysis must be confirmed by the central laboratory.
7.Have measureable disease based on RECIST 1.1 as determined by central review. 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.
9. Demonstrate adequate organ function as defined in Table 1. All screening labs should be performed within 10 days of treatment initiation.
10. Female subject 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 through 120 days after the last dose of study medication (Reference Section 5.7.2). Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for >1 year.
Note: Abstinence is acceptable if this is the established and preferred contraception for the subject.
12. Male subjects must agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy.
Note: Abstinence is acceptable if this is the established and preferred contraception for the subjec
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| E.4 | Principal exclusion criteria |
The subject must be excluded from participating in the trial if the subject:
1. Has disease that is suitable for local therapy administered with curative intent.
2. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks prior to the first dose of treatment.
3. Has had a prior anti-cancer monoclonal antibody (mAb) for direct anti-neoplastic treatment within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
4. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.
Note: Subjects with neuropathy or ≤ Grade 2 alopecia are an exception to this criterion and may qualify for the study.
Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
5. Has 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 that has undergone potentially curative therapy or in situ cervical cancer. A 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; and Gleason score ≤ 6, and undetectable PSA.
6. Has 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 (confirmed by CT scan if CT used at prior imaging, or confirmed by MRI if MRI was used at prior imaging) for at least four weeks prior to the first dose of trial treatment 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 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
7. Has an 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 (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
8. Has evidence of interstitial lung disease or active non-infectious pneumonitis.
9. Has an active infection requiring systemic therapy.
10. Has 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.
11. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
12. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment.
13. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, or with an agent directed to another co-inhibitory T-cell receptor (e.g. CTLA-4, OX-40, CD137).
14. Has a known history of Human Immunodeficiency Virus (HIV) (HIV-1/2 antibodies).
15. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
16. Has received a live virus vaccine within 30 days of planned start of trial treatment.
17. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or child) who is investigational site or sponsor staff directly involved with this trial, unless prospective IRB approval (by chair or designee) is given allowing exception to this criterion for a specific subject.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is overall response rate, defined as the proportion of subjects in the analysis population who have complete response (CR) or partial response (PR) using RECIST 1.1 criteria assessed by independent radiology review at any time during the study. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
•PD-L1 expression in tumor tissue will be characterized by immunohistochemistry to explore the relationship between tumor PD-L1 expression and response to treatment with pembrolizumab (MK-3475).
•Duration of response, defined as time from first RECIST 1.1 response to disease progression in subjects who achieve a PR or better.
•RECIST 1.1 ORR by study site radiology review.
•Modified RECIST 1.1 ORR by independent radiology review.
•Progression-free survival (PFS), defined as the time from Day 1 Cycle 1 treatment administration to the first documented disease progression according to RECIST 1.1 and modified RECIST 1.1, or death due to any cause, whichever occurs first.
•Overall survival (OS), defined as the time from Day 1 Cycle 1 treatment administration to death due to any cause.
•Proportions of PFS and OS at 6 months and 12 months.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 11 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| Denmark |
| Hungary |
| Israel |
| Italy |
| Puerto Rico |
| Spain |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| LVLS. The overall trial ends when the last subject completes the last trial visit, discontinues from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by the investigator). |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 36 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 36 |
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