Substudy 02D: Safety and Efficacy of Pembrolizumab in Combination With Investigational Agents or Pembrolizumab Alone in Participants With Melanoma Brain Metastasis (MK-3475-02D/KEYMAKER-U02)

Phase 1

Active, not recruiting

• Conditions: Melanoma
• Interventions: Biological: Pembrolizumab; Biological: Pembrolizumab/Quavonlimab; Drug: Lenvatinib

• Registration Number: NCT04700072
• Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary

Substudy 02D is part of a larger research study that is testing experimental treatments for melanoma, a type of skin cancer. The larger study is the umbrella study.

The goal of substudy 02D is to evaluate the safety and efficacy of investigational treatment arms in programmed cell-death 1 (PD-1) naïve or PD-1 exposed participants with melanoma brain metastasis (MBM) and to identify the investigational agent(s) that, when used in combination, are superior to the current treatment options/historical control available.

As of amendment 2 (effective 01DEC2022) enrollment into the treatment arm of pembrolizumab and lenvatinib has been discontinued.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2021-01-05
• Study First Submitted QC: 2021-01-05
• Study First Posted: 2021-01-07
• Study Start: 2021-05-03
• Status Verified: 2025-07
• Last Update Submitted: 2025-07-10
• Last Update Posted: 2025-07-14
• Primary Completion: 2030-04-03
• Study Completion: 2030-04-03

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 300

Inclusion Criteria

• Has American Joint Committee on Cancer (AJCC) Stage IV, M1D melanoma
• Is neurologically asymptomatic from brain metastases and has not received systemic corticosteroid therapy in the 10 days prior to beginning study intervention
• If capable of producing sperm, male participants agree to the following during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention. The length of time required to continue contraception for each study intervention is:
• Lenvatinib: 7 days
• Abstains from penile-vaginal intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agrees to remain abstinent. OR
• Uses contraception unless confirmed to be azoospermic
• Female participants are not pregnant or breastfeeding and are either not a woman of child-bearing potential (WOCBP) OR use a contraceptive method that is highly effective or are abstinent from heterosexual intercourse during the intervention period and for at least 120 days after the last dose of pembrolizumab or pembrolizumab/quavonlimab, or 30 days after the last dose of lenvatinib, whichever occurs last
• Has adequate organ function
• Female participants agree to abstain from breastfeeding during the study intervention period and for at least the time needed to eliminate study intervention after the last dose of study intervention. The length of time required for each study intervention is:
• MK-1308A: 120 days
• MK-3475: 120 days
• Lenvatinib: 30 days

Exclusion Criteria

• Has a diagnosis of immunodeficiency or is receiving immunosuppressive therapy within 10 days before the first dose of study intervention
• Has current or history of known leptomeningeal involvement
• Has received stereotactic or highly conformal radiotherapy within 2 weeks before the start of dosing
• Has clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the first dose of study drug
• Has untreated or unresolved intracranial hemorrhage from central nervous system (CNS) metastasis
• Has an active infection requiring systemic therapy
• Has a known additional malignancy that is progressing or requires active treatment within the past 2 years
• Has ocular melanoma
• Has an active autoimmune disease that has required systemic treatment in the past 2 years
• Has known history of immunodeficiency virus (HIV)
• Has known history of hepatitis B or known hepatitis C virus
• Has a history of (noninfectious) pneumonitis that required steroids or current pneumonitis
• Has received prior systemic anticancer therapy within 4 weeks prior to randomization/allocation
• Has a history of whole brain irradiation
• Has received prior radiotherapy within 2 weeks of first dose of study intervention
• Has had major surgery <3 weeks prior to first dose of study intervention
• Has received a live or live attenuated vaccine within 30 days prior to the first dose of study intervention
• Has had an allogeneic tissue/solid organ transplant

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Coformulation Pembrolizumab/Quavonlimab + Lenvatinib	Pembrolizumab	Participants will receive pembrolizumab/quavonlimab (coformulation of pembrolizumab and quavonlimab) intravenously (IV) plus lenvatinib orally at specified doses on specified days for a total treatment duration of up to approximately 2 years.
Coformulation Pembrolizumab/Quavonlimab + Lenvatinib	Pembrolizumab/Quavonlimab	Participants will receive pembrolizumab/quavonlimab (coformulation of pembrolizumab and quavonlimab) intravenously (IV) plus lenvatinib orally at specified doses on specified days for a total treatment duration of up to approximately 2 years.
Pembrolizumab + Lenvatinib	Pembrolizumab	Participants will receive pembrolizumab IV plus lenvatinib orally at specified doses on specified days for a total treatment duration of up to approximately 2 years.
Pembrolizumab + Lenvatinib	Lenvatinib	Participants will receive pembrolizumab IV plus lenvatinib orally at specified doses on specified days for a total treatment duration of up to approximately 2 years.
Coformulation Pembrolizumab/Quavonlimab + Lenvatinib	Lenvatinib	Participants will receive pembrolizumab/quavonlimab (coformulation of pembrolizumab and quavonlimab) intravenously (IV) plus lenvatinib orally at specified doses on specified days for a total treatment duration of up to approximately 2 years.

Primary Outcome Measures

Name	Time	Method
Percentage of participants who experience an adverse event (AE)	Up to ~28 months	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The percentage of participants who experience an AE will be reported.
Percentage of participants who discontinue study treatment due to an AE	Up to ~24 months	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The percentage of participants who discontinue study treatment due to an AE will be reported.
Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1)	Up to ~30 months	ORR is defined as the percentage of participants in the analysis population who have a complete response (CR: disappearance of all target lesions) or partial response (PR: at ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters). Responses are according to RECIST 1.1 as assessed by blinded independent central review (BICR). RECIST 1.1 has been modified for this study to include a maximum of 10 target lesions and a maximum of 5 target lesions per organ.

Secondary Outcome Measures

Name	Time	Method
Duration of Response (DOR) per RECIST 1.1	Up to ~30 months	For participants in the analysis population who demonstrate a confirmed CR (disappearance of all target lesions) or confirmed PR (≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters), DOR is defined as the time from first documented CR or PR until progressive disease (PD) or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of ≥1 new lesion is also considered PD. Responses are according to RECIST 1.1 as assessed by BICR. RECIST 1.1 has been modified for this study to include a maximum of 10 target lesions and a maximum of 5 target lesions per organ.
Brain metastasis response rate (BMRR) per Response Assessment in Neuro- Oncology Brain Metastases (RANO-BM)	Up to ~30 months	BMRR is defined as the percentage of participants in the analysis population who achieve a confirmed intracranial CR (disappearance of all lesions, no usage of corticosteroids and stable or improved clinical status) or PR (≥30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters, no progression of non-target lesions or new lesions, stable or decreased corticosteroid use, or stable or improved clinical status). Responses are according to RANO-BM as assessed by BICR. RANO-BM uses a combination of RECIST 1.1 and clinical data to assess response to treatment in brain metastases.
Brain metastasis duration of response (BM-DOR) per RANO-BM	Up to ~30 months	For participants in the analysis population who demonstrate a confirmed intracranial CR (disappearance of all lesions, no usage of corticosteroids, stable or improved clinical status) or PR (≥30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters, no progression of non-target lesions or new lesions, stable or decreased corticosteroid use, or stable or improved clinical status), DOR is defined as the time from first documented CR or PR until PD or death due to any cause, whichever occurs first. Per RANO-BM, PD is defined as ≥20% increase in the sum of diameters of target lesions and an absolute increase of ≥5 mm in ≥1 lesion. Unequivocal increase in non-target lesions, the appearance of ≥1 new lesion or worsening of clinical status is also considered PD. Responses are according to RANO-BM as assessed by BICR. RANO-BM uses a combination of RECIST 1.1 and clinical data to assess response to treatment in brain metastases.
Progression-free survival (PFS) per RECIST 1.1	Up to ~30 months	PFS is defined as the time from randomization to the first documented PD or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions is also considered PD. Responses are according to RECIST 1.1 as assessed by BICR. RECIST 1.1 has been modified for this study to include a maximum of 10 target lesions and a maximum of 5 target lesions per organ.

Trial Locations

Locations (36)

HOSPITAL CLÍNIC DE BARCELONA-ICHMO- Clinic Institut of Haematological and Oncological diseases ( Site 4801); 🇪🇸 Barcelona, Cataluna, Spain

The Angeles Clinic and Research Institute ( Site 4009); 🇺🇸 Los Angeles, California, United States

UCLA Hematology & Oncology ( Site 4004); 🇺🇸 Los Angeles, California, United States

Providence Saint John's Health Center ( Site 4010); 🇺🇸 Santa Monica, California, United States

University of Colorado, Anschutz Cancer Pavilion ( Site 4012); 🇺🇸 Aurora, Colorado, United States

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins ( Site 4022); 🇺🇸 Baltimore, Maryland, United States

NYU Clinical Cancer Center ( Site 4002); 🇺🇸 New York, New York, United States

Duke Cancer Institute ( Site 4005); 🇺🇸 Durham, North Carolina, United States

Martha Morehouse Tower ( Site 4020); 🇺🇸 Columbus, Ohio, United States

Inova Schar Cancer Institute ( Site 4011); 🇺🇸 Fairfax, Virginia, United States

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