| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10046714 |
| E.1.2 | Term | Urothelial carcinoma bladder |
| 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 |
| - To estimate the ORR of pembrolizumab plus epacadostat and pembrolizumab plus placebo based on RECIST 1.1 by investigator determination. |
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| E.2.2 | Secondary objectives of the trial |
- To evaluate the safety and tolerability of pembrolizumab plus epacadostat versus pembrolizumab plus placebo.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. 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 (predominantly transitional) cell histologies are allowed. Participants with non-urothelial cancer of the urinary tract are not allowed.
2. Have measureable disease based on RECIST 1.1 as assessed by the local site investigator/radiology. Tumor lesions situated in a previously irradiated area are considered measureable if progression has been demonstrated in such lesions.
3. Be considered ineligible to receive cisplatin-based combination therapy, based on having at least one of the following criteria:
a. ECOG PS of 2 within 14 days prior to randomization (the proportion of participants with an ECOG PS of 2 will be limited to approximately 50% of the total population)
b. CrCl (calculated or measured) <60 mL/min but ≥30 mL/min
c. CTCAE v.4.0, Grade ≥2 audiometric hearing loss (25 dB in two consecutive wave ranges)
d. CTCAE v.4.0, Grade ≥2 peripheral neuropathy
e. New York Heart Association (NYHA) Class III heart failure
4. Have provided tissue for PD-L1 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. If submitting unstained cut slides, freshly cut slides should be submitted to the central laboratory within 14 days from when the slides are cut. PD-L1 status (CPS ≥10 or CPS <10) must be determined by the central laboratory prior to randomization. Participants will be excluded if PD-L1 status cannot be determined.
5. Have received no prior systemic chemotherapy for advanced/unresectable (inoperable) or metastatic urothelial cancer
a. Adjuvant platinum based chemotherapy, following radical cystectomy, with recurrence >12 months from completion of therapy is permitted.
OR
b. Neoadjuvant platinum based chemotherapy, with recurrence >12 months since completion of therapy is permitted.
6. Be ≥18 years of age on day of signing informed consent.
7. Have a PS of 0, 1 or 2 within 14 days prior to randomization on the ECOG Performance Scale.
8. A male participant must agree to use a contraception as detailed in the protocol during the treatment period and for at least 120 days after the last dose of study treatment and refrain from donating sperm during this period.
9. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
a.) Not a woman of childbearing potential (WOCBP) OR
b.) A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 120 days (corresponding to time needed to eliminate any study treatments (MK-3475 and epacadostat) after the last dose of study treatment.
10. The participant (or legally acceptable representative if applicable) provides written informed consent for the trial.
11. Demonstrate adequate organ function as defined in the protocol. All screening labs must be collected within 14 days prior to randomization.
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| E.4 | Principal exclusion criteria |
1. Has disease that is suitable for local therapy administered with curative intent.
2. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.
3. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
4. Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, 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) is not considered a form of systemic treatment and is allowed.
5. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study treatment.
6. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
7. Has an active infection requiring systemic therapy.
8. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority.
9. Has known history of or is positive for active Hepatitis B (Hepatitis B surface antigen [HBsAg] reactive) or has active Hepatitis C (HCV RNA).
10. Has a history of a gastrointestinal condition or procedure that in the opinion of the Investigator may affect oral drug absorption.
11. Has a history or presence of an abnormal electrocardiogram (ECG) that, in the investigator's opinion, is clinically meaningful. Screening corrected QT interval (QTc) interval >480 milliseconds is excluded (corrected by Fridericia or Bazett formula). In the event that a single QTc is >480 milliseconds, the participant may enroll if the average QTc for the 3 ECGs is <480 milliseconds.
12. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the participant's participation for the full duration of the trial, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
13. Has known psychiatric or substance abuse disorders that would interfere with cooperating with the requirements of the study.
14. A WOCBP who has a positive urine pregnancy test within 72 hours before randomization. If the urine test cannot be confirmed as negative, a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
15. 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 pembrolizumab and epacadostat/matching placebo.
16. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti PD-L2 agent, IDO1 inhibitor, or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137), or any other antibody or drug targeting T-cell costimulatory pathways in the adjuvant or advanced/metastatic setting.
17. Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to randomization.
18. Has received prior radiotherapy within 2 weeks of start of trial treatment. Participants must have recovered from all radiation-related toxicities, and not require corticosteroids. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non- CNS disease.
19. Has received a live vaccine within 30 days prior to the first dose of trial drug. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines are live attenuated vaccines and are not allowed.
20. Has received therapy with a MAOI, or UGT1A9 inhibitor within 21 days prior to starting treatment, or anticipates requiring one of these prohibited medications during the treatment phase.
21. Has any history of Serotonin Syndrome after receiving serotonergic drugs.
22. Has severe hypersensitivity (≥Grade 3) to study treatment (pembrolizumab and epacadostat) and/or any of its excipients.
23. Is currently participating in or has participated in a trial of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of trial treatment.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| - ORR - defined as the proportion of participants in the analysis population who have a best response of complete response (CR) or partial response (PR) |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
There is no interim analysis. During the course of the study, DMC will perform 1 safety review based on the DMC charter.
The final analysis will be performed after the last participant completes the Week 9 imaging assessment. |
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| E.5.2 | Secondary end point(s) |
- Adverse events (AEs)
- Study drug discontinuations due to AEs |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
There is no interim analysis. During the course of the study, DMC will perform 1 safety review based on the DMC charter.
The final analysis will be performed after the last participant completes the Week 9 imaging assessment. |
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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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Unblinded after the last participant completes Week 9 imaging assessment for efficacy analysis |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 60 |
| 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 |
| Belgium |
| Brazil |
| France |
| Germany |
| Ireland |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Netherlands |
| Poland |
| Russian Federation |
| Spain |
| Taiwan |
| Ukraine |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
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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 | 32 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
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