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Completed

NCT Number: NCT04700072

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)

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.

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Key information

Conditions

Melanoma Neoplasms Neoplasms by Histologic Type Neoplasms by Site Neoplasms, Germ Cell and Embryonal Neoplasms, Nerve Tissue Neuroectodermal Tumors Neuroendocrine Tumors Nevi and Melanomas Parkinson Disease 4, Autosomal Dominant Lewy Body Skin Diseases Skin Neoplasms Skin and Connective Tissue Diseases

Age range

18 year–120 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1 / Phase 2

Primary location

Calvary Mater Newcastle ( Site 4404), Waratah, New South Wales, Australia

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Pembrolizumab

Biological

Administered via IV infusion at a specified dose on specified days

Other names: MK-3475, KEYTRUDA®

Pembrolizumab/Quavonlimab

Biological

Administered via IV infusion at a specified dose on specified days

Other names: MK-1308A

Lenvatinib

Drug

Administered via oral capsule at a specified dose on specified days

Other names: MK-7902, E7080, LENVIMA®

Primary outcomes

  1. Percentage of participants who experience an adverse event (AE)

    Time frame: 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.

  2. Percentage of participants who discontinue study treatment due to an AE

    Time frame: 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.

  3. Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1)

    Time frame: 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 outcomes

  1. Duration of Response (DOR) per RECIST 1.1

    Time frame: 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.

  2. Brain metastasis response rate (BMRR) per Response Assessment in Neuro- Oncology Brain Metastases (RANO-BM)

    Time frame: 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.

  3. Brain metastasis duration of response (BM-DOR) per RANO-BM

    Time frame: 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.

  4. Progression-free survival (PFS) per RECIST 1.1

    Time frame: 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.

Sponsors and collaborators

Lead sponsor

Merck Sharp & Dohme LLC

Industry

Registry information

Official study title

A Phase 1/2 Open-Label Rolling-Arm Umbrella Platform Design of Investigational Agents With or Without Pembrolizumab or Pembrolizumab Alone in Participants With Melanoma (KEYMAKER-U02): Substudy 02D

Important dates

Study start
2021
Primary completion
2025
Study completion
2025
First posted
Jan 7, 2021
Registry last updated
Oct 28, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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