| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Locally advanced or metastatic renal cell cancer (mRCC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced or Spreading Renal cell cancer |
|
| 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 | 10038407 |
| E.1.2 | Term | Renal cell cancer |
| E.1.2 | System Organ Class | 100000072939 |
|
| 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 |
Objective: To compare the progression-free survival (PFS) of pembrolizumab plus epacadostat versus standard of care (SOC) (sunitinib or pazopanib)
Objective: To compare the overall survival (OS) of pembrolizumab plus epacadostat versus SOC
|
|
| E.2.2 | Secondary objectives of the trial |
Objective: To compare the objective response rate (ORR) of pembrolizumab plus epacadostat versus SOC
Objective: To compare the duration of response (DOR) of pembrolizumab plus epacadostat versus SOC
Objective: To compare the safety and tolerability of pembrolizumab plus epacadostat versus SOC
Objective: To compare change from baseline in the Health Related Quality of Life (HRQoL) outcomes of pembrolizumab plus epacadostat versus SOC |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Has histologic confirmation of locally advanced or metastatic RCC (Stage IV per American Joint Committee on Cancer) with a clear cell component with or without sarcomatoid features.
2. Must not have received any prior systemic therapy for their mRCC.
3. Have measurable disease per RECIST 1.1 as determined by the site. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
4. Have provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. The tumor tissue must have been obtained prior to randomization and after the latest systemic treatment for RCC.
5. Have a Karnofsky performance status of ≥ 70 within 14 days prior to randomization.
6. Male/female participants who are at least 18 years of age on the day of signing the informed consent.
7. A male participant must agree to use contraception, during the treatment period and for at least 120 days after the last dose of pembrolizumab and epacadostat and up to 180 days after last dose of SOC agents and refrain from donating sperm during this period.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the participant.
8. 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 after the last dose of pembrolizumab and epacadostat and up to 180 days after last dose of SOC agents. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the participant.
9. The participant (or legally acceptable representative if applicable) provides written
informed consent for the trial
10. Have adequate organ function. Specimens must be collected within 14 days prior to randomization. |
|
| E.4 | Principal exclusion criteria |
1. Has a history of severe hypersensitivity reaction (eg, generalized rash/erythema, hypotension, bronchospasm, angioedema or anaphylaxis) to study treatments or their excipients.
2. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (doses exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study treatment . Corticosteroid use as premedication for IV contrast prophylaxis is permitted.
3. 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, etc.) is not considered systemic treatment .
4. Has a known additional malignancy that has progressed or has required active systemic treatment in the last 3 years. Note: participants with curatively treated basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, curatively resected in situ cervical cancer and curatively resected in situ breast cancer are
not excluded.
5. Has known active central nervous system metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable (without evidence of progression by imaging for at least 4 weeks prior to the first dose of study treatment), clinically stable, and have not required steroids for at least 14 days before 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 a known history of or is positive for active Hepatitis B (HBsAg reactive) or has active Hepatitis C (HCV RNA). Note: Testing must be performed to determine eligibility.
10. Has any history of serotonin syndrome after receiving serotonergic drugs.
11. Has a history of a gastrointestinal condition or procedure that in the opinion of the Investigator may affect oral drug absorption.
12. Has a history of any of the following cardiovascular conditions within 12 months prior to randomization: myocardial infarction, unstable angina pectoris, cardiac angioplasty or stenting, coronary/peripheral artery bypass graft, Class III or IV congestive heart failure per New York Heart Association (NYHA), cerebrovascular accident or transient ischemic attack, or NYHA Class III or IV congestive heart failure (CHF). Medically controlled arrhythmia stable on medication is permitted.
13. Has a history of deep vein thrombosis or pulmonary embolism within 6 months of screening.
14. Poorly controlled hypertension (defined as systolic BP ≥ 150 mm Hg or diastolic BP ≥ 90 mm Hg). Initiation or adjustment of antihypertensive medication(s) is permitted prior to randomization.
15. Has a history or presence of an abnormal electrocardiogram (ECG) that, in the Investigator's opinion, is clinically meaningful. Screening QTc interval > 480 msec is excluded (corrected by Fridericia or Bazett formula). In the event that a single QTc is > 480 msec, the participant may enroll if the average QTc for 3 ECGs is < 480 msec.
16. WOCBP who has a positive urine pregnancy test within 72 hours before the first dose of study treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
17. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of pembrolizumab and epacadostat and up to 180 days after last dose of chemotherapeutic agents. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Progression-Free Survival (PFS) (defined as the time from randomization until the first documented disease progression per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) by blinded independent central review (BICR), or death due to any cause, whichever occurs first)
2. Overall Survival (OS) (defined as the time from randomization to death due to any cause) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| PFS at Interim analysis 1 (IA1), IA2; OS at IA2,, IA3 and Final analysis |
|
| E.5.2 | Secondary end point(s) |
1. Overall Response Rate (ORR) (defined as the proportion of participants who have a best response of complete response (CR) or partial response (PR) as measured per RECIST 1.1 by BICR)
2. Duration of Response (DOR) (defined as the time from the earliest date of qualifying response, until earliest date of disease progression (per RECIST 1.1 by BICR) or death due to any cause, whichever occurs first)
3. Safety and tolerability of the treatment regimens as measured by the following:
o Number of participants experiencing adverse events (AEs)
o Number of participants discontinuing study treatment due to AEs
4. Time to deterioration (TTD) from baseline based on the Functional Assessment of Cancer Therapy Kidney Symptom Index–15 (FKSI-15) and based on subset of items designated in disease-related symptoms (Functional Assessment of Cancer Therapy Kidney Symptom Index–Disease-Related Symptoms [FKSI-DRS])
5. Changes in longitudinal score from baseline to 42 weeks as measured by the European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) global health status/quality of life scale |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| ORR at IA1, DOR at Final analysis, Safety and tolerability (through out the study), Health Related Quality of Life (HRQoL) at Final Analysis |
|
| 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 | No |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| 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 | 58 |
| 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 |
|
| 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
|
| The overall study ends when the last participant completes the last study-related phone-call or visit, withdraws from the study or is lost to follow-up (ie, the participant is unable to be contacted by the investigator). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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