| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic NSCLC with high PD-L1 expression |
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| E.1.1.1 | Medical condition in easily understood language |
| Non-small cell lung cancer |
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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 | PT |
| E.1.2 | Classification code | 10029522 |
| E.1.2 | Term | Non-small cell lung cancer stage IV |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 compare objective response rate (ORR) of the combination of pembrolizumab plus epacadostat versus pembrolizumab plus placebo.
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| E.2.2 | Secondary objectives of the trial |
- To compare progression-free survival (PFS) of the combination of pembrolizumab plus epacadostat versus pembrolizumab plus placebo.
-To compare overall survival (OS) of pembrolizumab plus epacadostat versus pembrolizumab plus placebo.
- To evaluate duration of response (DOR) of the combinations of pembrolizumab plus epacadostat and pembrolizumab plus placebo.
- To evaluate the safety and tolerability of the combinations of pembrolizumab plus epacadostat and pembrolizumab plus placebo.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Have a histologically or cytologically confirmed diagnosis of stage IV (AJCC version 8 or current version as applicable) NSCLC
2. Have confirmation that EGFR, ALK, or ROS1 directed therapy is not indicated as primary therapy (documentation of absence of tumor activating EGFR mutations AND absence of ALK and ROS1 gene rearrangements OR presence of a KRAS mutation)
a. If participant’s tumor is known to have a predominantly squamous histology, molecular testing for EGFR mutation and ALK and ROS1 translocations will not be required, as this is not part of current diagnostic guidelines
3. Have measurable disease based on RECIST 1.1 as determined by the local site
a. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions
4. Tumor tissue that demonstrates PD-L1 expression in ≥50% of tumor cells (TPS ≥50%) as assessed by IHC at a central laboratory
a. Assessment of PD-L1 expression must be made from provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffin-embedded tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue
5. Be ≥18 years of age on the day of signing informed consent
6. Have a life expectancy of at least 3 months
7. Have an ECOG performance status of 0 or 1 within 7 days prior to the first dose of study treatment but before randomization
8. A male participant must agree to use 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 after the last dose of study treatment
10. The participant (or legally acceptable representative if applicable) provides written informed consent for the study
11. Have adequate organ function as indicated by the laboratory values in the protocol. |
|
| E.4 | Principal exclusion criteria |
1. Has known untreated central nervous system (CNS) metastases and/or carcinomatous meningitis.
2. Has a history of (non-infectious) pneumonitis that required systemic steroids or current pneumonitis/interstitial lung disease.
3. Has symptomatic ascites or pleural effusion. A participant who is clinically stable following treatment for these conditions (including therapeutic thoraco- or paracentesis) is eligible.
4. Has a known history of an additional malignancy, except if the participant has undergone potentially curative therapy with no evidence of that disease recurrence for 5 years since initiation of that therapy.
5. Has an active autoimmune disease that has required systemic treatment in past 2 years. Replacement therapy is allowed.
6. 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.
7. Has had an allogeneic tissue/solid organ transplant.
8. Has a known history of human immunodeficiency virus (HIV) infection. HIV testing is not required unless mandated by the local health authority.
9. Has known history of or is positive for active Hepatitis B (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 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.
12. Has clinically significant cardiac disease, including unstable angina, acute myocardial infarction within 6 months from Day 1 of study drug administration, or New York Heart Association Class III or IV congestive heart failure. Medically controlled arrhythmia stable on medication is permitted.
13. Has a known history of active tuberculosis (TB; Bacillus tuberculosis).
14. Has an active infection requiring systemic therapy.
15. Has known psychiatric or substance abuse disorders that would interfere with the participant’s cooperation for the requirements of the study.
16. Previously had a severe hypersensitivity reaction to treatment with a monoclonal antibody or has a known sensitivity to any component of epacadostat or pembrolizumab.
17. 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.
18. 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 study treatment.
19. Has received prior systemic chemotherapy or other targeted or biological anti-neoplastic therapy for their metastatic NSCLC.
20. Has received prior treatment with pembrolizumab or any other anti-PD-1, anti-PD-L1, anti-PD-L2 agent, with epacadostat or any anti-IDO1 agent, or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137, GITR).
21. Has received radiotherapy within 14 days before the first dose of study treatment or received lung radiation therapy of >30 Gy within 6 months before the first dose of study treatment.
22. Is receiving systemic steroid therapy ≤7 days prior to the first dose of study treatment or receiving any other form of immunosuppressive medication.
23. Has received a live vaccine within 30 days prior to the first dose of study treatment.
24. Has any history of Serotonin Syndrome after receiving serotonergic drugs.
25. Has received therapy with an MAOI, or UGT1A9 inhibitor within 21 days prior to starting treatment, or anticipates requiring one of these prohibited medications during the treatment phase.
26. 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 of the first dose of study treatment.
27. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's ability to participate for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating Investigator.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Original protocol
- Objective response rate (ORR), is defined as the proportion of participants who have a confirmed complete response (CR) or partial response (PR) per RECIST 1.1 based on blinded independent central review (BICR).
Under amendment 5 the study will stop collecting efficacy endpoints. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Original protocol
- Objective Response Rate: imaging (CT and/or MRI) every 9 weeks through 54 weeks then every 12 weeks until disease progression or starting a new therapy
Under amendment 5 the timing of imaging during the treatment phase is according to the site’s SOC for tumor assessment until PD or initiation of a new anticancer regimen. |
|
| E.5.2 | Secondary end point(s) |
Original protocol
- PFS is defined as the time from randomization to the first documented progressive disease (PD) per RECIST 1.1 based on blinded independent central review (BICR) or death due to any cause, whichever occurs first.
-OS is defined as the time from randomization to death due to any cause.
- Duration of response (DOR), defined as the time from the earliest date of qualifying response until earliest date of disease progression or death from any cause, whichever comes first, per RECIST 1.1 based on BICR.
- Safety and tolerability: Number of participants experiencing AEs and number of participants discontinuing study drug due to AEs.
Under amendment 5 the study will stop collecting efficacy endpoints. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Original protocol
- PFS: imaging (CT and/or MRI) every 9 weeks through 54 weeks then every 12 weeks until PD or starting a new therapy
- OS: telephone contacts every 3 mo after PD or starting a new therapy. Additional updated survival status may be requested by the Sponsor.
- Duration of Response: imaging every 9 weeks through 54 weeks then every 12 weeks until PD or starting a new therapy
- Safety: AE/SAE from Screening through 30/90 days after the last dose. AEs assessed at every visit (every 3 weeks)
Under amendment 5 the timing of imaging during the treatment phase is according to the site’s SOC for tumor assessment until PD or initiation of a new anticancer regimen. The last study visit is the Safety Follow-up Visit and there will be no follow-up for survival status. |
|
| 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 | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Patient-reported outcomes |
|
| 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 | 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 |
| As of amendment 05:unblinded, open-label, single arm (pembrolizumab) |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| 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
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 85 |
| 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 |
| Brazil |
| Canada |
| Denmark |
| Estonia |
| France |
| Germany |
| Ireland |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Malaysia |
| New Zealand |
| Poland |
| Romania |
| Russian Federation |
| Spain |
| Switzerland |
| Turkey |
| Ukraine |
| United Kingdom |
| United States |
|
| 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 | |
| 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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