A Study of the Safety and Efficacy of Pembrolizumab (MK-3475) in Combination With Trametinib and Dabrafenib in Participants With Advanced Melanoma (MK-3475-022/KEYNOTE-022)

Merck Sharp & Dohme (MSD)

Status and phase

Completed

Phase 2

Phase 1

Conditions

Melanoma

Solid Tumors

Treatments

Drug: Dabrafenib

Biological: Pembrolizumab

Drug: Trametinib

Drug: Placebo

Study type

Interventional

Funder types

Industry

Identifiers

NCT02130466

MK-3475-022 (Other Identifier)

2015-000681-55 (EudraCT Number)

3475-022

KEYNOTE-022 (Other Identifier)

Details and patient eligibility

About

This is a 5-part dose-finding and preliminary efficacy study of pembrolizumab (Pembro) + dabrafenib (D) + trametinib (T) for participants with advanced melanoma and solid tumors.

Parts 1 and 2 are open-label to find and confirm the maximum tolerated dose (MTD)/maximum administered dose (MAD) for Pembro+D+T. The primary hypothesis (Parts 1 and 2) is that Pembro+D+T is sufficiently well-tolerated to permit clinical investigation.

Part 3 is a double-blind study of Pembro+D+T versus placebo+D+T. The primary study hypothesis (Part 3 only) is that the Pembro+D+T improves progression-free survival (PFS) compared with placebo+D+T.

Part 4 is nonrandomized and open-label and is designed to evaluate the safety and tolerability and identify the MTD or MAD of Pembro+T in participants who have v-raf murine sarcoma viral oncogene homolog B1 [BRAF] mutation-negative (without V600 E or K) melanoma or solid tumors [irrespective of BRAF status]. The primary hypothesis (Part 4) is that Pembro+T is sufficiently well-tolerated to permit clinical investigation.

Part 5 will confirm the dose(s) identified in Part 4 in participants BRAF wild type [without V600E or K] melanoma or solid tumors [irrespective of BRAF status] and will further evaluate the safety and preliminary efficacy (Objective Response Rate [ORR]) of Pembro+T in participants who have BRAF wild type [without V600E or K] melanoma or solid tumors [irrespective of BRAF status]. The primary hypotheses (Part 5) are that Pembro+T is sufficiently well-tolerated at the MTD/MAD to permit further clinical investigation and is effective in attaining objective responses based upon Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by Investigator review in participants who have melanoma without BRAF V600 E or K mutations. With Amendment 5 (21-Mar-2019), the Part 5 expansion cohort will not be pursued following the completion of Part 5 dose confirmation.

Parts 1 and 2 of the study may also explore, if needed based on tolerability, the backup combinations of open-label Pembro+T (for BRAF mutation-negative participants) or Pembro+D (for BRAF mutation-positive participants). These will run concurrently with the Pembro+D+T arm.

Enrollment

184 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion criteria

Histologically-confirmed diagnosis of advanced (unresectable Stage III) or metastatic (Stage IV) melanoma excluding mucosal, or ocular melanoma (or a histologically or cytologically-documented locally-advanced or metastatic solid malignancy in Parts 4 and 5)
At least 1 measurable lesion as defined by RECIST 1.1 on imaging studies (computed tomography [CT] or magnetic resonance imaging [MRI])
For solid tumors other than melanoma, (in Part 4 or 5 [dose confirmation only]), participants must 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 participants and treating physician. There is no limit to the number of prior treatment regimens, but prior treatment(s) should not include compounds targeting programmed cell death 1 (PD-1), programmed cell death ligand 1 (PD-L1), BRAF, or mitogen-activated protein kinase (MEK). Treatment must end at least 4 weeks prior to randomization
BRAF mutation-positive (V600 E or K) melanoma for Parts 1, 2 and 3, or for Parts 1, 2, 4 and 5 only BRAF mutation-negative (wild type) melanoma with documented progression of ≥1 measurable lesion after prior therapy (if prior therapy was received). The inclusion criterion does not apply to participants with solid tumors in Parts 4 and 5 (dose confirmation only)
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
Anticipated life expectancy of at least 3 months
Able to swallow and retain oral medication and no clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels
Adequate organ function
Provide 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
Female participants of non-childbearing potential must be willing to use highly effective contraceptive measures from the Screening Visit (Visit 1) through 120 days after the last dose of study drug; male participants must agree to use an adequate method of contraception starting with the first dose of study drug through 120 days after the last dose of study drug
Female participants of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study drug

Exclusion criteria

Currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of study drug
Prior systemic therapy (for participants who are BRAF mutation-positive), or BRAF mutation-negative and has received >1 prior systemic therapy for metastatic melanoma
Prior therapy with compounds targeting PD-1, PD-L1, BRAF, MEK or other molecules in the mitogen-activated protein kinase (MAPK) pathway
BRAF mutation-positive and has received prior systemic therapy with ipilimumab or other anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) blocking antibodies. The BRAF exclusion criterion does not apply to participants with solid tumor in Parts 4 and 5 (dose confirmation only)
Chemotherapy, radioactive, or biological cancer therapy within 4 weeks prior to the first dose of study drug, or not recovered from clinically significant adverse events due to cancer therapeutics administered more than 4 weeks prior to the first dose of study drug
Expected to require any other form of systemic or localized antineoplastic therapy while in this study
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
Active central nervous system (CNS) metastases and/or carcinomatous meningitis
Active infection requiring systemic therapy
Active autoimmune disease, or documented history of autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents
Previous severe hypersensitivity reaction to treatment with another monoclonal antibody (mAb)
On chronic systemic steroid therapy (>10 mg/day prednisone or equivalent) within 2 weeks prior to first dose of study drug or on any other form of immunosuppressive medication
History or evidence of cardiovascular risk
Uncorrectable electrolyte abnormalities, long QT syndrome or taking medications known to prolong the QT interval
History of prior or current retinal vein occlusion (RVO)
Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study drugs, their excipients, and/or dimethyl sulfoxide (DMSO)
Has had an allogeneic tissue/solid organ transplant, prior stem cell or bone marrow transplant
History of (non-infectious) pneumonitis that required steroids or current pneumonitis
Human immunodeficiency virus (HIV)
Hepatitis B or C
Received a live vaccine within 30 days prior to first dose of study drug
Pregnant or breastfeeding or expecting to conceive or father children from the Screening Visit (Visit 1) through 120 days after last dose of study drug

Trial design

Primary purpose

Treatment

Allocation

Randomized

Interventional model

Parallel Assignment

Masking

Double Blind

184 participants in 14 patient groups, including a placebo group

Part 1:pembrolizumab 2 mg/kg+dabrafenib150 mg+trametinib 2 mg

Experimental group

Description:

Participants with BRAF mutant melanoma received 2 mg/kg pembrolizumab administered by intravenous (IV) infusion on Days 1 and 22 of each 6-week cycle (Q6W); 150 mg/day total dabrafenib orally, in a divided dose, twice a day (BID) starting on Day 1 and continuing up until study treatment discontinuation; and 2 mg trametinib orally once a day (QD) starting on Day 1 and continuing up until study treatment discontinuation.

Treatment:

Drug: Trametinib

Biological: Pembrolizumab

Drug: Dabrafenib

Part 1:pembrolizumab 2 mg/kg+trametinib 2 mg

Experimental group

Description:

Participants with BRAF wild-type melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W and 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.

Treatment:

Drug: Trametinib

Biological: Pembrolizumab

Part 1:pembrolizumab 2 mg/kg+trametinib 1.5 mg

Experimental group

Description:

Participants with BRAF wild-type melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W and 1.5 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.

Treatment:

Drug: Trametinib

Biological: Pembrolizumab

Part 2:pembrolizumab 2 mg/kg+dabrafenib 150 mg+trametinib 2 mg

Experimental group

Description:

Participants with BRAF mutant melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W; 150 mg/day total dabrafenib orally, in a divided dose, BID starting on Day 1 and continuing up until study treatment discontinuation; and 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.

Treatment:

Drug: Trametinib

Biological: Pembrolizumab

Drug: Dabrafenib

Part 2:pembrolizumab 2 mg/kg+trametinib 1.5 mg

Experimental group

Description:

Treatment:

Drug: Trametinib

Biological: Pembrolizumab

Part 3:pembrolizumab 2 mg/kg+dabrafenib 150 mg+trametinib 2 mg

Experimental group

Description:

Treatment:

Drug: Trametinib

Biological: Pembrolizumab

Drug: Dabrafenib

Part 3:placebo+dabrafenib 150 mg+trametinib 2 mg

Placebo Comparator group

Description:

Participants with BRAF mutant melanoma received saline placebo administered by IV infusion on Days 1 and 22 Q6W; 150 mg/day total dabrafenib orally, in a divided dose, BID starting on Day 1 and continuing up until study treatment discontinuation; and 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.

Treatment:

Drug: Trametinib

Drug: Placebo

Drug: Dabrafenib

Part 4:trametinib 2 mg for 4 weeks+pembrolizumab 200 mg+trametinib 2 mg concurrent dosing

Experimental group

Description:

Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 2 mg trametinib orally QD for 4 weeks. Starting with Week 5, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 of each 3-week cycle (Q3W) and a concurrent dosing schedule of 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.

Treatment:

Drug: Trametinib

Biological: Pembrolizumab

Part 4:trametinib 1.5 mg for 2 weeks+pembrolizumab 200 mg+trametinib 1.5 mg concurrent dosing

Experimental group

Description:

Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 1.5 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and a concurrent dosing schedule of 1.5 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.

Treatment:

Drug: Trametinib

Biological: Pembrolizumab

Part 4:trametinib 1.5 mg for 4 weeks+pembrolizumab 200 mg+trametinib 1.5 mg concurrent dosing

Experimental group

Description:

Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 1.5 mg trametinib orally QD for 4 weeks. Starting with Week 5, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and a concurrent dosing schedule of 1.5 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.

Treatment:

Drug: Trametinib

Biological: Pembrolizumab

Part 4:trametinib 2 mg for 2 weeks+pembrolizumab 200 mg+trametinib 2 mg intermittent dosing

Experimental group

Description:

Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 2 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent dose schedule of 2 mg trametinib orally QD with 1 week OFF trametinib and 2 weeks ON trametinib continuing up until study treatment discontinuation.

Treatment:

Drug: Trametinib

Biological: Pembrolizumab

Part 4:trametinib 1.5 mg for 2 weeks+pembrolizumab 200 mg+trametinib 1.5 mg intermittent dosing

Experimental group

Description:

Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 1.5 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent dose schedule of 1.5 mg trametinib orally QD with 1 week OFF trametinib and 2 weeks ON trametinib continuing up until study treatment discontinuation.

Treatment:

Drug: Trametinib

Biological: Pembrolizumab

Part 5:trametinib 1.5 mg for 2 weeks+pembrolizumab 200 mg+trametinib 1.5 mg concurrent dosing

Experimental group

Description:

Treatment:

Drug: Trametinib

Biological: Pembrolizumab

Part 5:trametinib 2 mg for 2 weeks+pembrolizumab 200 mg+trametinib 2 mg intermittent dosing

Experimental group

Description: