A STUDY OF ENCORAFENIB AND BINIMETINIB PLUS PEMBROLIZUMAB VERSUS PLACEBO PLUS PEMBROLIZUMAB IN PARTICIPANTS WITH IN PARTICIPANTS WITH MELANOMA THAT HAVE A GENETIC ABNORMALITY IN THE BRAF GENE.

Phase 1

• Conditions: Metastatic or unresectable locally advanced BRAF V600E/K mutation positive melanoma; MedDRA version: 20.0Level: HLTClassification code 10027156Term: Skin melanomas (excl ocular)System Organ Class: 100000004858; MedDRA version: 21.1Level: PTClassification code 10025671Term: Malignant melanoma stage IVSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 21.1Level: PTClassification code 10025650Term: Malignant melanomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 20.0Level: PTClassification code 10066600Term: Melanoma recurrentSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 21.1Level: PTClassification code 10025670Term: Malignant melanoma stage IIISystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 21.1Level: PTClassification code 10027480Term: Metastatic malignant melanomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 20.0Level: LLTClassification code 10027150Term: Melanoma malignantSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 20.0Level: LLTClassification code 10027155Term: Melanoma skinSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 21.1Level: LLTClassification code 10025665Term: Malignant melanoma of skin stage unspecifiedSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

• Registration Number: EUCTR2020-004850-31-HU
• Lead Sponsor: Pfizer Inc.

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2021-03-05
• Last Update Posted: 24 June 2024

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 624

Inclusion Criteria

1. Male or female participants = 18 years at the time of informed consent. Refer to protocol appendix 4 for reproductive criteria for male (protocol section 10.4.1) and female (protocol section 10.4.2) participants.
2. Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures.
3. Histologically confirmed unresectable (Stage IIIB, IIIC, or IIID) or metastatic (Stage IV) cutaneous melanoma, according to the AJCC 8th edition.
Note: Locally advanced disease must not be amenable for treatment with curative intent.
4. Presence of at least 1 measurable lesion as detected by radiological and/or photographic methods according to RECIST v1.1.
Note: Tumor lesions situated in a previously irradiated area, or in an area subjected to other locoregional therapy, are not considered measurable unless there has been documented progression of the lesion.
Note: If baseline scans from an institution other than the investigational site are used, the site must obtain copies of the scans prior to enrolment of the participant, or the scans must be repeated at the investigational site and submitted for independent review (Phase 3 only).
Note: Clinical lesions will only be considered measurable when they are superficial and = 10 mm diameter as assessed using calipers (eg, skin nodules). When lesions can be evaluated by both clinical exam and imaging, imaging evaluation should be performed and submitted for independent review (Phase 3 only).
5. ECOG performance status 0 or 1.
6. Documented evidence of a BRAF V600E or V600K mutation in melanoma tumor tissue as previously determined by either PCR or NGS-based local laboratory assay (eg, US FDA-approved test, CE-marked [European conformity] in vitro diagnostic in EU countries, or equivalent), obtained during the course of normal clinical care, in a CLIA- or similarly certified laboratory.
Note: During Phase 3, if at any time BRAF V600E/K mutation confirmation cannot be determined in tissue samples provided to the central laboratory in a total of 6% of the planned number of randomized participants or there is discordance between the local laboratory result and the central laboratory result in a total of 3% of the planned number of randomized participants, all subsequent participants will be required to have BRAF V600E/K mutation status determined by the central laboratory prior to randomization (ie, local BRAF testing will no longer be accepted to determine participant eligibility). This will be communicated to the investigative sites via an administrative letter.
7. Submission of adequate tumor tissue (archival or newly obtained; block or slides; see protocol section 8.7.2) to the sponsor central laboratory(ies) during the screening period and prior to enrollment (SLI)/randomization (Phase 3).
Note: Whenever possible, the archival sample should be from the same tumor block that was used for local BRAF V600E/K mutation testing.
Note: A newly obtained tumour tissue biopsy must be provided prior to enrolment (SLI)/ randomization (Phase 3) for participants unable to provide adequate archival tumour tissue. If a newly obtained biopsy is taken, the biopsy should be taken from a nontarget lesion when possible.
Note: Confirmation of the BRAF V600E/K mutation from the central laboratory is required (see protocol section 8.7.2). If results from the central laboratory are indeterminate or indicate insufficient tissue, addit

Exclusion Criteria

1. Other medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator’s judgment, make the participant inappropriate for the study.
2. Mucosal or ocular melanoma.
3. Diagnosis of immunodeficiency or an active autoimmune disease that required systemic treatment in the past 2 years (ie, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs).
Note: Participants with diabetes type I, vitiligo, psoriasis, controlled asthma, Graves’ disease, Hashimoto’s disease or hypo- or hyperthyroid disease are exceptions and may participate.
Note: Replacement and symptomatic therapies (eg, levothyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) are not considered a form of immunosuppressive agents and are permitted.
4. Clinically significant multiple or severe drug allergies, intolerance to topical corticosteroids, or severe post-treatment hypersensitivity reactions (including, but not limited to, erythema multiforme major, linear IgA dermatosis, toxic epidermal necrolysis, and exfoliative dermatitis).
5. Unable to swallow, retain, and absorb oral medications.
6. Impairment of GI function or disease which may significantly alter the absorption of oral study intervention (eg, uncontrolled nausea, vomiting or diarrhea, malabsorption syndrome, including malabsorption syndrome secondary to prior GI surgery).
7. Clinically significant cardiovascular diseases, including any of the following:
a. History of acute myocardial infarction, acute coronary syndromes (including unstable angina, coronary artery bypass graft, coronary angioplasty or stenting) = 6 months prior to enrollment (SLI)/randomization (Phase 3);
b. Congestive heart failure requiring treatment (New York Heart Association Grade = 2);
c. LVEF < 50% as determined by ECHO or MUGA scan;
d. Uncontrolled hypertension, defined as persistent systolic blood pressure = 150 mmHg or diastolic blood pressure = 100 mmHg, despite optimal therapy;
e. History or presence of clinically significant cardiac arrhythmias (including uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventricular tachycardia);
f. Triplicate average baseline QTcF interval = 480 ms or a history of prolonged QT syndrome.
8. History of thromboembolic or cerebrovascular events = 12 weeks prior to enrollment (SLI)/randomization (Phase 3). Examples include transient ischemic attacks, cerebrovascular accidents, hemodynamically significant (ie, massive or sub-massive) deep vein thrombosis or pulmonary emboli.
9. History or current evidence of RVO or current risk factors for RVO (eg, uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes); history of retinal degenerative disease.
10. Concurrent neuromuscular disorder that is associated with the potential of elevated CK (eg, inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy).
11. Current noninfectious pneumonitis or history of noninfectious pneumonitis requiring steroids.
12. Evidence of HBV or HCV infection.
13. Known history of a positive test for HIV or known AIDS. Testing for HIV must be performed at sites where mandated locally.
14. Any active infection requiring systemic therapeutic treatment within 2 weeks prior to enrollment (SLI)/ randomization (Ph

Study & Design

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