| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
advanced or metastatic melanoma - all parts of the trial
advanced (unresectable and/or metastatic) solid tumours - Parts 4 and 5 |
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| E.1.1.1 | Medical condition in easily understood language |
advanced or metastatic melanoma - all parts of the trial
advanced (unresectable and/or metastatic) solid tumours - Parts 4 and 5 |
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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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065252 |
| E.1.2 | Term | Solid tumor |
| 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 |
Parts 1/2: To evaluate the safety/tolerability and identify the MTD/MAD of: (1a) MK-3475 +D/T in subjects with adv. melanoma with BRAF V600E/K mutations (1b) MK-3475 +T in subjects with adv. melanoma without BRAF V600E/K mutations (1c) MK-3475 +D in subjects with adv. melanoma with BRAF V600E mutations. (only if (1a) is not tolerated).
Part 2: To confirm the safety/tolerability of the preliminary MTD/MAD of:(2) MK-3475 + D/T in subjects with adv. melanoma with BRAF V600E/K mutations (3) MK-3475 + T in subjects with adv. melanoma without BRAF V600E/K mutations (4) To evaluate the efficacy of MK-3475+T in subjects with adv. melanoma without BRAF V600E/K mutations with respect to Objective Response Rate
Part 3: (5) To evaluate the efficacy with respect to PFS of MK-3475 in combination with D/T in subjects with adv. melanoma with BRAF V600E/K mutations, compared with placebo + D/T alone D/T: dabrafenib/tremetinib; T: trametinib; D: dabrafenib
Part 4/5:refer to protocol for details |
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| E.2.2 | Secondary objectives of the trial |
Part 1 and 2:
(1) Objective: To evaluate the efficacy of MK-3475 administered intravenously in combination with oral dabrafenib and trametinib in subjects with advanced (unresectable or metastatic) melanoma with BRAF V600 E or K mutations with respect to Objective Response Rate (ORR).
Parts 1, 2, 3, 4 and 5:
(2) Objective: To evaluate the pharmacokinetics (PK) of MK-3475, dabrafenib, and/or trametinib when MK-3475 is administered intravenously in combination with oral dabrafenib and/or trametinib.
Part 3:
(3) Objective: To evaluate the efficacy of MK-3475 administered intravenously in combination with oral dabrafenib and trametinib in subjects with advanced (unresectable or metastatic) melanoma with BRAF V600 E or K mutations with respect to Objective Response Rate (ORR), Response Duration, and overall survival (OS), compared with oral dabrafenib and trametinib alone.
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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 |
| Merck will conduct Future Biomedical Research on DNA (blood and tissue) 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 |
The Subject must:
1.Have a histologically confirmed diagnosis of advanced (unresectable Stage III) or metastatic (Stage IV) melanoma or a histologically or cytologically-documented locally-advanced or metastatic solid malignancy,and have at least one measurable lesion as defined by RECIST 1.1 on imaging studies (CT or MRI). Cutaneous lesions and other superficial lesions that are detectable only by physical examination and subcutaneous lesions detectable by CT are not considered measurable lesions for the purposes of this protocol, but may be considered as non-target lesions.
• Mucosal or ocular melanoma are excluded.
• For solid tumors other than melanoma, the subject must be a participant in Part 4 or 5 (dose confirmation only), have a malignancy that is incurable and has either: (a) failed prior standard therapy, (b) for which no standard therapy exists, or (c) standard therapy is not considered appropriate by the patient and treating physician. There is no limit to the number of prior treatment regimens, but prior treatment(s) should not include compounds targeting PD-1, PD-L1, BRAF, or MEK. Treatment must end at least 4 weeks prior to randomization.
2.Be willing and able to provide written informed consent for the trial. The subject may also provide consent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research.
3.Be ≥ 18 years of age on day of signing the informed consent.
4.Have BRAF mutation testing as determined at a local laboratory and either:
a.Have a BRAF mutation-positive (V600 E or K) tumor to be eligible for treatment with MK-3475+trametinib+dabrafenib, trametinib+dabrafenib or MK-3475+dabrafenib (if this part of the study is performed). If a subject’s initial specimen does not test BRAF mutation-positive, a newly obtained specimen (different from the sample previously submitted) may be submitted for testing. If the newer specimen tests BRAF mutation-positive, the subject meets this eligibility criterion.
b.Have a BRAF mutation-negative (wild type) tumor to be eligible for treatment with MK-3475+trametinib.
• Criterion 4a is applicable only to enrollment of melanoma subjects in Parts 1, 2, and 3 of the trial design. Criterion 4b is applicable only to enrollment of melanoma subjects in Parts 1, 2, 4, and 5 of the trial design. The inclusion criterion does not apply to solid tumor subjects in Parts 4 and 5 (dose confirmation only).
5.For BRAF mutation-negative (wild type) subjects who have received prior therapy for metastatic or advanced melanoma, must have documented progression of at least one measurable lesion by RECIST 1.1 on imaging studies (CT or MRI).
6.Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.
7.Have an anticipated life expectancy of at least 3 months.
8.Be able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels.
9.Have adequate organ function as defined in Table 6 of the protocol.
10.Have provided tissue for biomarker analysis from a newly or recently-obtained biopsy (within 90 days of Study Day 1) of a tumor lesion not previously irradiated.
11.Female subjects of childbearing potential should 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. The serum pregnancy test must be negative for the subject to be eligible.
12.A female participant is eligible to participate if she is not pregnant (see Appendix 12.14), not breastfeeding, and at least one of the following conditions applies:
a. Not a woman of childbearing potential (WOCBP) as defined in Appendix 12.14
OR
b. A WOCBP who agrees to follow the contraceptive guidance in Appendix 12.14 during the treatment period and for at least 120 days after the last dose of study treatment.
13.Male subjects should agree to use an adequate method of contraception as outlined in Appendix 12.14 starting with the first dose of study medication through 120 days after the last dose of study medication.
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| E.4 | Principal exclusion criteria |
1. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigation device within 4 weeks of the first dose of treatment.
2. Is either:
1) BRAF mutation-positive and has received prior systemic therapy for metastatic or advanced melanoma or
2) BRAF mutation-negative and has received >1 prior systemic therapy for metastatic melanoma. The BRAF exclusion criterion does not apply to solid tumour subjects in Parts 4 and 5 (dose confirmation only).
3. Has received prior therapy with compounds targeting the PD-1, PD-L1, BRAF, MEK or other molecules in the MAPK pathway.
4. Is BRAF mutation-positive and has received prior systemic therapy with ipilimumab or other CTLA-4 blocking antibodies.
5. Has had chemotherapy, radioactive, or biological cancer therapy within four weeks prior to the first dose of trial treatment, or who has not recovered to CTCAE Grade 1 or better from the clinically significant AEs due to cancer therapeutics administered more than four weeks prior to the first dose of trial treatment.
6. Is expected to require any other form of systemic or localized antineoplastic therapy while in study.
7. 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. For dabrafenib-containing treatment regimens in this study, subjects with any malignancy with confirmed activating RAS mutation are excluded.
8. Has known active central nervous metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by MRI for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are off systemic steroids for at least two weeks.
9. Has an active infection requiring systemic therapy.
10. Has an active autoimmune disease, or a documented history of autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or resolved childhood asthma/atopy would be exception to this rule.
Subjects that require intermittent use of bronchodilators or local steroid injections are not excluded from the study. Subjects with hypothyroidism stable on hormone replacement are not excluded from the study.
11. Has previously had a severe hypersensitivity reaction to treatment with another monoclonal antibody.
12. Is on chronic systemic steroid therapy (>10 mg/day prednisone or equivalent) within two weeks before the planned date for first dose of study treatment or on any other form of immunosuppressive medication.
13. Currently uses a prohibited medication as described in Section 5.5.2.
14. Has history or evidence of cardiovascular risk. Refer to protocol for the complete list
15. Has uncorrectable electrolyte abnormalities long QT syndrome or taking medicinal products known to prolong the QT interval.
16. Has known history of prior or current retinal vein occlusion.
17. Has known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide.
18. Has had an allogeneic tissue/solid organ transplant, prior stem cell or bone marrow transplant.
19. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
20. Has known history of Human Immunodeficiency Virus
21. Has a known history of or is positive for Hepatitis B or Hepatitis C
22. Has received a live vaccine within 30 days prior to first dose.
23. Has known psychiatric or substance abuse disorders that would interfere with the subjects ability to cooperate with the requirements of the trial.
24. Has a clinical history suggestive of a condition which could impact the safety or efficacy of the subject in the study. Is, at the time of signing informed consent, a regular user of any illicit drugs or had a recent history of substance abuse.
25. Is, at the time of signing informed consent, a regular user of any illicit drugs or had a recent history of substance abuse.
26. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, from Visit 1 through 120 days after the last dose of trial treatment.
27. Is or has an immediate family member who is investigational site or sponsor staff directly involved with this trial, unless prospective IRB approval is given allowing exception to this criterion for a specific subject.
Refer to protocol for additional details
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary safety endpoint in Parts 1, 2, 4, and 5 of the study is DLT. In Part 3, there will be no Tier 1 safety endpoints; Tier 2 and Tier 3 safety endpoints will be evaluated as described in 8.2.5.4. Safety will be monitored by cumulative data reviews throughout the trial. The toxicities and grades experienced by subjects who have received study treatment, including adverse events (AEs), serious adverse events (SAEs) and events of clinical interest (ECIs) will be summarized. Other safety measures evaluated in all parts of the study include laboratory safety assessments, ECGs, vital signs, and physical examinations.
The primary efficacy endpoint in Part 3 will be progression-free survival (PFS), and defined as the time from randomization in Part 3 (or the start of treatment in other Parts) to progressive disease (PD) or death, whichever occurs earlier, based upon RECIST 1.1 by the investigator review. Subjects without documented PD/death will be censored at the last disease assessment date.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At each cycle, and as clinically deemed. |
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| E.5.2 | Secondary end point(s) |
Secondary endpoints include objective response rate (ORR) per RECIST 1.1, response duration per RECIST 1.1, overall survival (time to death), and the evaluation of pharmacokinetic properties of MK-3475, dabrafenib, and/or trametinib, when used in combination.
Objective Response Rate (ORR) is defined as the percentage of subjects who have achieved confirmed complete response (CR) or partial response (PR) according to RECIST 1.1 by the investigator review. Subjects with missing outcome on objective response will be considered non-responders.
Response Duration: is defined as the time interval between the date of the first confirmed response (CR/PR) (the response prior to confirmation) and the date of first documented disease progression based upon RECIST 1.1 by the investigator review. Response duration will be only determined for confirmed responses.
Overall survival (OS): is defined as the time from randomization (or the start of treatment when there is no randomization) to death due to any cause. Subjects without documented death at the time of analysis will be censored at the date last known to be alive.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At each cycle, and as clinically deemed. |
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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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Parts 1,2,4,5 of the study are Phase I dose confirmation and dose expansion of combination treatment |
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| 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 | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Part 1, 2 (non-EU) 4, 5 (all) non-randomized, open-label; Part3-unblinded |
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| 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
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 8 |
| 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 |
| Canada |
| Israel |
| New Zealand |
| United States |
| Denmark |
| Italy |
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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 | 7 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 27 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 27 |
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