Phase I/II Study of MK-3475 in Combination with Trametinib and Dabrafenib

Phase 1

• Conditions: advanced or metastatic melanoma - all parts of the trialadvanced (unresectable and/or metastatic) solid tumours - Parts 4 and 5; MedDRA version: 21.1Level: LLTClassification code 10053571Term: MelanomaSystem Organ Class: 100000004864; MedDRA version: 21.1Level: LLTClassification code 10065252Term: Solid tumorSystem Organ Class: 100000004864; Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2015-000681-55-IT
• Lead Sponsor: MERCK SHARP & DOHME CORP. UNA SUSSIDIARIA DI MERCK & CO. INC.

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2021-01-22
• Last Update Posted: 17 August 2021

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 219

Inclusion Criteria

1. Have a histologically confirmed diagnosis of advanced (unresectable Stage III) or metastatic (Stage IV) melanoma or a histologically or cytologically-documented locallyadvanced 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 nontarget 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 FBR. However, the subject may participate in the main trial without participating in FBR
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 pembrolizumab+trametinib+dabrafenib, trametinib+dabrafenib or pembrolizumab+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 mutationpositive,
the subject meets this eligibility criterion.
b. Have a BRAF mutation-negative (wild type) tumor to be eligible for treatment with pembrolizumab+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 ECOG Performance Scale
.........
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, 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.
Please refer to protocol for the rest of inclusion crite

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.

Please refer to protocol for the rest of exclusion criteria

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified