Substudy 02C: Safety and Efficacy of Pembrolizumab in Combination With Investigational Agents or Pembrolizumab Alone in Participants With Stage III Melanoma Who Are Candidates for Neoadjuvant Therapy (MK-3475-02C/KEYMAKER-U02)

• ClinicalTrials.gov Identifier: NCT04303169
• Recruitment Status: Recruiting
• First Posted: March 10, 2020
• Last Update Posted: April 7, 2023
• Sponsor: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Merck Sharp & Dohme LLC

Tracking Information

• First Submitted Date: March 9, 2020
• First Posted Date: March 10, 2020
• Last Update Posted Date: April 7, 2023
• Actual Study Start Date: June 26, 2020
• Estimated Primary Completion Date: April 3, 2030 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 9, 2020)

• Percentage of participants who experience an adverse event (AE) [ Time Frame: Up to ~16 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 ~12 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.
• Pathological complete response (pCR) rate [ Time Frame: Up to ~1.5 months ]
  pCR rate is defined as the proportion of participants with complete absence of viable tumor in the treated tumor bed. Assessments are according to Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) by central review of the pathology results. 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: November 23, 2020)

• Near pathological complete response (near pCR) rate [ Time Frame: Up to ~1.5 months ]
  Near pCR is defined as the proportion of participants with >0% but ≤10% of viable tumor cells in the treated tumor bed. Assessments are according to RECIST 1.1 by central review of the pathology results. 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.
• Pathological partial response (pPR) rate [ Time Frame: Up to ~1.5 months ]
  pPR rate is defined as the proportion of participants with >10% but ≤50% of the treated tumor bed occupied by viable tumor cells. Assessments are according to RECIST 1.1 by central review of the pathology results. 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.
• Recurrence-free survival (RFS) [ Time Frame: Up to ~60 months ]
  RFS is defined as the time from the date of surgery to (1) any recurrence (local, regional, or distant) as assessed by the investigator or (2) death due to any cause (both cancer and noncancer causes of death). Assessments are according to RECIST 1.1 which 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 (submitted: March 9, 2020)

• Near pathological complete response (near pCR) rate [ Time Frame: Up to ~1.5 months ]
  Near pCR is defined as the proportion of participants with >0% but ≤10% of viable tumor cells in the treated tumor bed. Assessments are according to RECIST 1.1 by central review of the pathology results. 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.
• Pathological partial response (pPR) rate [ Time Frame: Up to ~1.5 months ]
  pPR rate is defined as the proportion of participants with >10% but ≤50% of the treated tumor bed occupied by viable tumor cells. Assessments are according to RECIST 1.1 by central review of the pathology results. 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.
• Recurrence-free survival (RFS) [ Time Frame: Up to ~65 months ]
  RFS is defined as the time from the date of surgery to (1) any recurrence (local, regional, or distant) as assessed by the investigator or (2) death due to any cause (both cancer and noncancer causes of death). Assessments are according to RECIST 1.1 which has been modified for this study to include a maximum of 10 target lesions and a maximum of 5 target lesions per organ.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Substudy 02C: Safety and Efficacy of Pembrolizumab in Combination With Investigational Agents or Pembrolizumab Alone in Participants With Stage III Melanoma Who Are Candidates for Neoadjuvant Therapy (MK-3475-02C/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 02C

Brief Summary

Substudy 02C 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 02C is to evaluate the safety and efficacy of investigational treatment arms in participants with Stage III melanoma who are candidates for neoadjuvant therapy 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: Vibostolimab
  Administered via IV infusion at a specified dose on specified days
  Other Name: MK-7684
• Biological: Gebasaxturev
  Administered via IT injection at a specified dose on specified days
  Other Names:

  • Coxsackievirus A21 (CVA21)
  • Formerly known as CAVATAK®
  • CAV21
  • V937
• Biological: MK-4830
  Administered via IV infusion at a specified dose on specified days
• Biological: Favezelimab + Pembrolizumab
  Administered via IV infusion at a specified dose on specified days
  Other Name: MK-4280A
• Drug: ATRA
  Administered via oral capsules at a specified dose on specified days
  Other Names:

  • Tretinoin
  • Vesanoid®

Study Arms

• Experimental: Pembrolizumab + Vibostolimab

  Prior to tumor resection surgery, in the neoadjuvant phase, participants will receive pembrolizumab intravenously (IV) plus vibostolimab IV at specified doses on specified days. After surgery, in the adjuvant phase, participants will receive pembrolizumab IV at a specified dose on specified days.

  Participants will receive treatments in the neoadjuvant and adjuvant phase for a total treatment duration of up to approximately 1 year.

  Interventions:

  • Biological: Pembrolizumab
  • Biological: Vibostolimab
• Experimental: Pembrolizumab + Gebasaxturev

  Prior to tumor resection surgery, in the neoadjuvant phase, participants will receive pembrolizumab IV plus gebasaxturev (V937) intratumorally (IT) at specified doses on specified days. After surgery, in the adjuvant phase, participants will receive pembrolizumab IV at a specified dose on specified days.

  Participants will receive treatments in the neoadjuvant and adjuvant phase for a total treatment duration of up to approximately 1 year.

  Interventions:

  • Biological: Pembrolizumab
  • Biological: Gebasaxturev
• Experimental: Pembrolizumab

  Prior to tumor resection surgery, in the neoadjuvant phase, participants will receive pembrolizumab IV at a specified dose on specified days. After surgery, in the adjuvant phase, participants will receive pembrolizumab IV at a specified dose on specified days.

  Participants will receive treatments in the neoadjuvant and adjuvant phase for a total treatment duration of up to approximately 1 year.

  Intervention: Biological: Pembrolizumab
• Experimental: Pembrolizumab + MK-4830

  Prior to tumor resection surgery, in the neoadjuvant phase, participants will receive pembrolizumab IV plus MK-4830 IV at specified doses on specified days. After surgery, in the adjuvant phase, participants will receive pembrolizumab IV at a specified dose on specified days.

  Participants will receive treatments in the neoadjuvant and adjuvant phase for a total treatment duration of up to approximately 1 year.

  Interventions:

  • Biological: Pembrolizumab
  • Biological: MK-4830
• Experimental: Favezelimab + Pembrolizumab

  Prior to tumor resection surgery, in the neoadjuvant phase, participants will receive MK-4280A (favezelimab and pembrolizumab administered as a co-formulation) IV at specified doses on specified days. After surgery, in the adjuvant phase, participants will receive pembrolizumab IV at a specified dose on specified days.

  Participants will receive treatments in the neoadjuvant and adjuvant phase for a total treatment duration of up to approximately 1 year.

  Intervention: Biological: Favezelimab + Pembrolizumab
• Experimental: Pembrolizumab + all-trans retinoic acid (ATRA)

  Prior to tumor resection surgery, in the neoadjuvant phase, participants will receive pembrolizumab IV plus ATRA orally at specified doses on specified days. After surgery, in the adjuvant phase, participants will receive pembrolizumab IV at a specified dose on specified days.

  Participants will receive treatments in the neoadjuvant and adjuvant phase for a total treatment duration of up to approximately 1 year.

  Interventions:

  • Biological: Pembrolizumab
  • Drug: ATRA

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: December 27, 2021): 90
• Original Estimated Enrollment (submitted: March 9, 2020): 65
• 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 histologically or cytologically confirmed melanoma
• Has clinically detectable and resectable Stage IIIB or IIIC or IIID melanoma amenable to surgery

• Has been untreated for Stage IIIB, IIIC or IIID melanoma

  • surgical resection of primary melanoma is allowed
  • prior radiotherapy to the primary melanoma is allowed
• Has provided a baseline tumor biopsy
• Male participants who receive gebasaxturev are abstinent from heterosexual intercourse or agree to use contraception during the intervention period and for at least 120 days after the last dose of gebasaxturev
• Male participants who receive ATRA are abstinent from heterosexual intercourse or agree to use contraception during the intervention period and for at least 7 days after the last dose of ATRA
• 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, vibostolimab, gebasaxturev, or MK-4830, favezelimab + pembrolizumab, or 30 days after the last dose of ATRA, whichever occurs last
• Has adequate organ function
• Has resolution of toxic effect(s) of the most recent prior therapy to Grade 1 or less (except alopecia)

Exclusion Criteria:

• Has a diagnosis of immunodeficiency or is receiving immunosuppressive therapy within 7 days before the first dose of study intervention
• Has a known additional malignancy that is progressing or requires active treatment within the past 2 years
• Has known central nervous system (CNS) metastases and/or carcinomatous meningitis
• Has ocular or mucosal melanoma
• Has known hypersensitivity including previous clinically significant hypersensitivity reaction to treatment with another monoclonal antibody (mAb)
• Has an active autoimmune disease that has required systemic treatment in the past 2 years
• Has an active infection requiring systemic therapy
• Has known history of human immunodeficiency virus (HIV)
• Has known history of hepatitis B
• Has a history of (noninfectious) pneumonitis
• Has a history of active tuberculosis (TB)
• Has received prior systemic anticancer therapy within 4 weeks prior to randomization
• 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 before the first dose of study intervention
• Has participated in a study of an investigational agent within 4 weeks prior to the first dose of study intervention
• Has had an allogeneic tissue/solid organ transplant
• Has only mucosal lesions
• Is not naïve to Talimogene laherparepvec (TVEC) and other oncolytic viruses

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, Switzerland, United States

Administrative Information

• NCT Number: NCT04303169
• Other Study ID Numbers: 3475-02C; MK-3475-02C ( Other Identifier: Merck ); KEYMAKER-U02 ( Other Identifier: Merck ); 2019-003978-22 ( 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: April 2023