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)

• ClinicalTrials.gov Identifier: NCT04700072
• Recruitment Status: Recruiting
• First Posted: January 7, 2021
• Last Update Posted: March 16, 2023
• Sponsor: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Merck Sharp & Dohme LLC

Tracking Information

• First Submitted Date: January 5, 2021
• First Posted Date: January 7, 2021
• Last Update Posted Date: March 16, 2023
• Actual Study Start Date: May 3, 2021
• Estimated Primary Completion Date: April 3, 2030 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 5, 2021)

• 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.
• 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.
• 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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: January 5, 2021)

• 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.
• 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.
• 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.
• 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.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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)
• Official 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

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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Melanoma

Intervention

• Biological: Pembrolizumab
  Administered via IV infusion at a specified dose on specified days
  Other Names:

  • MK-3475
  • KEYTRUDA®
• Biological: Pembrolizumab/Quavonlimab
  Administered via IV infusion at a specified dose on specified days
  Other Name: MK-1308A
• Drug: Lenvatinib
  Administered via oral capsule at a specified dose on specified days
  Other Names:

  • MK-7902
  • E7080
  • LENVIMA®

Study Arms

• Experimental: Coformulation Pembrolizumab/Quavonlimab + 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.
  Interventions:

  • Biological: Pembrolizumab
  • Biological: Pembrolizumab/Quavonlimab
  • Drug: Lenvatinib
• Experimental: Pembrolizumab + 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.
  Interventions:

  • Biological: Pembrolizumab
  • Drug: Lenvatinib

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: January 5, 2021): 300
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: April 3, 2030
• Estimated Primary Completion Date: April 3, 2030 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 120 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Toll Free Number; 1-888-577-8839; Trialsites@merck.com

• Listed Location Countries: Australia, France, Israel, Italy, South Africa, Spain, Switzerland, United States

Administrative Information

• NCT Number: NCT04700072
• Other Study ID Numbers: 3475-02D; MK-3475-02D ( Other Identifier: Merck ); KEYMAKER-U02 ( Other Identifier: Merck ); 2020-003742-36 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
• URL: http://engagezone.msd.com/ds_documentation.php

• Current Responsible Party: Merck Sharp & Dohme LLC
• Original Responsible Party: Same as current
• Current Study Sponsor: Merck Sharp & Dohme LLC
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme LLC

• PRS Account: Merck Sharp & Dohme LLC
• Verification Date: March 2023