Phase I/II Study of MK-3475 in Combination with Trametinib and Dabrafenib
- Conditions
- advanced or metastatic melanoma - all parts of the trialadvanced (unresectable and/or metastatic) solid tumours - Parts 4 and 5Therapeutic area: Diseases [C] - Cancer [C04]MedDRA version: 21.1Level: LLTClassification code 10065252Term: Solid tumorSystem Organ Class: 100000004864MedDRA version: 21.1Level: LLTClassification code 10053571Term: MelanomaSystem Organ Class: 100000004864
- Registration Number
- EUCTR2015-000681-55-DK
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 190
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 medica
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 excipie
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method