| 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 | 10027481 |
| E.1.2 | Term | Metastatic melanoma |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10053571 |
| E.1.2 | Term | Melanoma |
| 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 compare the progression-free survival (PFS) of the combination of pembrolizumab and epacadostat versus pembrolizumab and placebo (i.e. 2 treatment groups) based on RECIST 1.1 by independent central review; and To compare overall survival (OS) of the 2 treatment groups. |
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| E.2.2 | Secondary objectives of the trial |
| To compare the objective response rate (ORR) of the 2 treatment groups based on RECIST 1.1 by independent central review; To evaluate the safety and tolerability of the 2 treatment groups; To evaluate the duration of response (DOR) of the 2 treatment groups based on RECIST 1.1 by independent central review; and To evaluate the pharmacokinetics (PK) and anti-pembrolizumab antibodies of pembrolizumab and epacadostat administered concomitantly.**Samples for PK and antidrug antibody (ADA) assessments are no longer being collected** |
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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 |
| Future Biomedical Research will be conducted 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 |
1. Have histologically or cytologically confirmed melanoma.
2. Have unresectable Stage III or Stage IV melanoma, as per AJCC staging system not amenable to local therapy.
3. Have been untreated for advanced or metastatic disease except as follows.
a. BRAF V600 mutant melanoma may have received standard of care targeted therapy (e.g. BRAF/MEK inhibitor, alone or in combination) and be eligible for this study
Note: Targeted therapy is not required for eligibility.
b. Prior adjuvant or neoadjuvant melanoma therapy is permitted if it was completed at least 4 weeks before randomization and all related adverse events have either returned to baseline or stabilized (resolution of toxic effect(s) of the most recent prior therapy to Grade 1 or less (except alopecia).
c. Prior adjuvant therapy containing immunotherapy such as interferon or anti-CTLA-4 therapy will only be permitted if relapse did not occur during treatment or within 6 months of treatment discontinuation.
d. Prior anti-PD-1, anti-PD-L1, or IDO1 inhibitors are excluded.
4. Have documentation of V600-activating BRAF mutation status or consent to BRAF V600 mutation testing during the screening period.
5. Have laboratory parameters within Protocol-defined range. The screening laboratory tests below must be ≤ 7 days before treatment initiation.
6. Have the presence of at least one measurable lesion by CT or MRI per RECIST 1.1 criteria as determined by the local site investigator/radiology assessment. Cutaneous lesions and other superficial lesions are not considered measurable lesions for the purposes of this protocol, but may be considered as non-target lesions.
a. If subjects have only 1 measurable lesion per RECIST 1.1, the biopsy specimen should be obtained from the non-target lesion or archival tissue.
b. If subjects have only 1 measurable lesion per RECIST 1.1, this lesion should not have been in the field of prior irradiation unless there is documented progression of the lesion(s).
7. Provide a baseline tumour biopsy
a. Subjects must submit the tumour sample during screening for PD-L1 expression
testing at a central pathology laboratory. Subjects will be eligible to participate regardless of the level of PD-L1 expression, but will be stratified by PD-L1 expression level. Subjects who do not submit a sample adequate for PD-L1 determination will not be randomized. The biopsy may not be obtained from a lone target lesion.
b. Newly-obtained tissue is preferred (no intervening treatment [local or systemic] involving the site of tissue biopsy once tissue biopsy is obtained at time of study enrollment). THe only exception to this is a sample that was collected prior to BRAF +/-MEK targeted treatment where the subject progressed on this targeted treatment, in cases where 1) fresh tissue or 2) archival tissue with no intervening local or systemic therapy is not possible to provide.
8. Have resolution of toxic effect(s) of the most recent prior therapy to Grade 1 or less (except alopecia). If subject received major surgery or radiation therapy of > 30 Gy, they must have recovered from the toxicity and/or complications from the intervention.
9. Be male or female subjects, age 18 years or older on day of signing consent.
10. Provide written informed consent/assent for the study. 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.
11. Have an Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1.
12. If female of childbearing potential (Section 5.7.2), 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.
13. If female of childbearing potential (Section 5.7.2), must be willing to use an adequate method of contraception as outlined in Section 5.7.2 – Contraception, for the course of the study through 120 days after the last dose of study medication.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
14. If male of childbearing potential (Section 5.7.2), must agree to use an adequate method of contraception as outlined in Section 5.7.2- Contraception, and not to donate sperm 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 usual lifestyle and preferred contraception for the subject.
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| E.4 | Principal exclusion criteria |
1. Has received prior systemic treatment for unresectable or metastatic melanoma (except BRAF directed therapy as noted in inclusion criteria #3).
2. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or IDO1 inhibitor or any other antibody or drug specifically targeting checkpoint pathways other than anti-CTLA-4 which is permitted in the adjuvant setting.
3. Has received prior adjuvant therapy, monoclonal antibody, chemotherapy, or an investigational agent or device within 4 weeks or 5 half-lives (whichever is longer) before administration of study drug or not recovered (≤ Grade 1 or at baseline) from AEs due to previously administered agents. Exception to this rule would be use of denosumab, which is not excluded.
Note: Subjects with ≤ Grade 2 neuropathy are an exception and may enroll.
4. 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 before the first dose of study treatment.
5. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include early stage cancers (carcinoma in situ or stage 1) treated with curative intent, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, in situ cervical cancer, or in situ breast cancer that has undergone potentially curative therapy.
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 for at least 4 weeks before the first dose of study treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases confirmed by repeat imaging, and have not required steroids for at least 14 days before study treatment.
7. Has ocular melanoma.
8. Has known hypersensitivity to active substances or any of their excipients including previous clinically significant hypersensitivity reaction to treatment with another monoclonal antibody. For a list of excipients, refer to the respective Investigator Brochure (Section 3.3).
9. 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.
10. Has an active infection requiring systemic therapy.
11. Has known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).
12. Has known history of or is positive for Hepatitis B (HBsAg reactive) or Hepatitis C (HCV RNA [qualitative] is detected).
13. Has history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
14. Has received prior radiotherapy within 2 weeks of therapy. Subjects must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤ 2 weeks of RT) to non-CNS disease.
15. 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.
16. Has received live vaccine within 30 days before the first dose of study treatment.
17. Has received monoamine oxidase inhibitors within 21 days prior to starting study treatment.
18. Has any history of Serotonin Syndrome after receiving serotonergic drugs.
19. Has presence of a gastrointestinal condition that may affect drug absorption.
20. 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 Fredericia or Bazett formula). In the event that a single QTc is > 480 milliseconds, the subject may enroll if the average QTc for the 3 ECGs is < 480 milliseconds.
21. Has clinically significant cardiac disease, including unstable angina, acute myocardial infarction within 6 months from Day 1 of study drug administration, New York Heart Association Class III or IV congestive heart failure, and arrhythmia requiring therapy. Medically controlled arrhythmia would be permitted.
22. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
23. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirement of the study.
Refer to protocol f |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The dual primary endpoints are PFS and OS.
• Progression-free survival, defined as the time from date of randomization until the earliest date of disease progression, as determined by independent central review of objective radiographic disease assessments per RECIST 1.1, or death from any cause, whichever comes first.
• Overall survival, defined as the time from date of randomization to date of death due to any cause.
The study is considered to have met its study objective if the combination is superior to pembrolizumab and placebo in either PFS or OS.
*NOTE: As of Amendment 10, central imaging vendor assessment will no longer be required. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Two interim analyses (IA1, IA2) will be performed in this study:
• IA1 to be performed when ~331 PFS events have been observed
• IA 2 to be performed when ~420 PFS events have been observed
• Final Analysis to be performed when ~293 OS events have occurred
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| E.5.2 | Secondary end point(s) |
• Objective response rate, defined as the proportion of subjects who have best response as complete response (CR) or partial response (PR). Responses are based on independent central review using RECIST 1.1.
• Duration of response (DOR) determined by disease assessment 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. Response will be determined by independent central review using RECIST 1.1.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Two interim analyses (IA1, IA2) will be performed in this study:
• IA1 to be performed when ~331 PFS events have been observed
• IA 2 to be performed when ~420 PFS events have been observed
• Final Analysis to be performed when ~293 OS events have occurred
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| 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 | No |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 44 |
| 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 |
| Canada |
| Chile |
| Denmark |
| France |
| Germany |
| Ireland |
| Israel |
| Italy |
| Korea, Republic of |
| Mexico |
| Netherlands |
| New Zealand |
| Poland |
| Russian Federation |
| South Africa |
| Spain |
| Sweden |
| Switzerland |
| 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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| The overall trial ends when the last subject completes the last study-related phone-call or 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 | 4 |
| 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 | 4 |
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