Phase 3 Study of Pembro with/without Epacadostat in 1L Urothelial Carcinoma

• Register: EUCTR
• Last refreshed on: 13 October 2020
• Main ID: EUCTR2017-002311-34-FR
• Date of registration: 01/03/2018
• Prospective Registration: No
• Primary sponsor: Incyte Corporation
• Public title: Phase 3 Study of Pembro with/without Epacadostat in 1L Urothelial Carcinoma
• Scientific title: A Phase 3 Randomized, Double-Blind Trial of Pembrolizumab (MK-3475) in Combination with Epacadostat (INCB024360) or Placebo in Participants with Cisplatin-ineligible Urothelial Carcinoma (KEYNOTE-672/ECHO-307) - Phase 3 Study of Pembro with/without Epacadostat in 1L Urothelial Carcinoma
• Date of first enrolment: 28/02/2018
• Target sample size: 650
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-002311-34
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Australia, Belgium, Brazil, France, Germany, Ireland, Israel, Italy, Japan, Korea, Republic of, Netherlands, Poland, Russian Federation, Spain, Taiwan, Ukraine, United Kingdom, United States

Contacts

• Name: Stephen
• Affiliation: Global Clinical Trial Operations

• Name: Stephen
• Affiliation: Global Clinical Trial Operations

Key inclusion & exclusion criteria

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.

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 150
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 500

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

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Cancer [C04]

Bladder cancer
MedDRA version: 20.0 Level: LLT Classification code 10046714 Term: Urothelial carcinoma bladder System Organ Class: 100000004864

Intervention(s)

Product Name: pembrolizumab
Product Code: MK-3475
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: PEMBROLIZUMAB
CAS Number: 1374853-91-4
Current Sponsor code: MK-3475
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 25-

Product Name: Epacadostat
Product Code: INCB024360
Pharmaceutical Form: Tablet
INN or Proposed INN: EPACADOSTAT
CAS Number: 1204669-58-8
Current Sponsor code: INCB024360
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Product Name: Epacadostat
Product Code: INCB024360
Pharmaceutical Form: Tablet
INN or Proposed INN: EPACADOSTAT
CAS Number: 1204669-58-8
Current Sponsor code: INCB024360
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 25-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: Two interim analyses and one final analysis are planned for the study ; timing of analyses is based on OS events; first interim analysis planned after all participants have been enrolled with at least 6 months of follow-up

Secondary Objective: - To evaluate the safety and tolerability of participants treated with pembrolizumab plus epacadostat to those treated with pembrolizumab plus placebo.
- To demonstrate the superiority of pembrolizumab and epacadostat versus pembrolizumab and placebo in objective response rate (ORR).
- To evaluate and compare mean change from baseline and time to true deterioration (TTD) in global health status/quality of life (QoL), in both treatment groups.

Main Objective: - To demonstrate the superiority of pembrolizumab and epacadostat versus pembrolizumab and placebo in progression-free survival (PFS).
- To demonstrate the superiority of pembrolizumab and epacadostat versus pembrolizumab and placebo in overall survival (OS).

Primary end point(s): - PFS, defined as the time from the date of randomization until disease progression by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or death from any cause, whichever occurs first.
- OS, defined as the time from the date of randomization to the date of death due to any cause.

Secondary Outcome(s)

Secondary end point(s): - Number of participants experiencing adverse events (AEs) and number of participants discontinuing study drug due to AEs.
- ORR, defined as the proportion of participants in the analysis population who have complete response (CR) or partial response (PR). Determination of response will be based on BICR per RECIST 1.1.
- Changes to the global health status/quality of life scales of the European Organisation for Research and Treatment of Cancer (EORTC) QoL questionnaire (QLQ)-C30 (items 29 and 30).
- TTD, defined as the time from baseline to first onset of patient-reported outcome(PRO) deterioration.

Timepoint(s) of evaluation of this end point: secondary endpoints will not be analyzed until the final analysis

Secondary ID(s)

MK-3475-672(INCB024360-307)

133,761

2017-002311-34-BE

Source(s) of Monetary Support

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

Incyte Corporation

Ethics review

Status: Approved
Approval date: 16/11/2017
Contact: