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Study of MK-4830 as Monotherapy and in Combination With Pembrolizumab (MK-3475) in Participants With Advanced Solid Tumors (MK-4830-001)

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ClinicalTrials.gov Identifier: NCT03564691
Recruitment Status : Recruiting
First Posted : June 21, 2018
Last Update Posted : March 6, 2023
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme LLC

Tracking Information
First Submitted Date  ICMJE June 11, 2018
First Posted Date  ICMJE June 21, 2018
Last Update Posted Date March 6, 2023
Actual Study Start Date  ICMJE July 11, 2018
Estimated Primary Completion Date November 4, 2025   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 22, 2021)
  • Dose-Limiting Toxicities (DLTs) [ Time Frame: Cycle 1 (Up to 21 days) ]
    The occurrence of the following toxicities, if assessed by the investigator to be possibly, probably, or definitely related to study treatment administration:
    • Grade 4 nonhematologic toxicity (not laboratory)
    • Grade 4 hematologic toxicity lasting >=7 days, except thrombocytopenia:
    • Any nonhematologic AE >=Grade 3 in severity, with exceptions
    • Any Grade 3 or Grade 4 alanine aminotransferase, aspartate aminotransferase, and/or bilirubin laboratory value
    • Any other nonhematologic laboratory value if:
    Clinically significant medical intervention is required to treat the participant, OR The abnormality leads to hospitalization, OR The abnormality persists for >1 week, OR The abnormality results in a drug-induced liver injury
    • Febrile neutropenia Grade 3 or Grade 4
    • Prolonged delay (>2 weeks) in initiating Cycle 2 due to treatment-related toxicity.
    • Any treatment-related toxicity that causes the participant to discontinue treatment during Cycle 1.
    • Grade 5 toxicity
  • Number of Participants Who Experienced an Adverse Event (AE) [ Time Frame: Up to approximately 27 months ]
    An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. The number of participants who discontinued study treatment due to an AE will be presented.
  • Number of Participants Who Discontinued Study Treatment Due to an AE [ Time Frame: Up to approximately 24 months ]
    An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. The number of participants who discontinued study treatment due to an AE will be presented.
  • Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or Response Assessment in Neuro-Oncology (RANO) as Assessed by Investigator [ Time Frame: Up to approximately 24 months ]
    For Arms A, C-F, I, and K ORR is defined as the percentage of participants who have a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. For Arm B, ORR is defined as the percentage of participants who experience a PR or CR per RANO, determined by: disappearance or size reduction of lesions, and review of abnormalities on fluid-attenuated inversion recovery (T2/FLAIR) images; Clinical status based on age-adjusted performance; And whether daily steroid dose has changed since previous visit. The percentage of participants who experience a CR or PR based on modified RECIST 1.1 as assessed by investigator or based on RANO will be presented.
  • ORR per Modified RECIST (mRECIST) 1.1 as Assessed by Investigator [ Time Frame: Up to approximately 24 months ]
    Per protocol, ORR per mRECIST 1.1 will be reported for Arm L participants. ORR is defined as percentage of participants who have CR (disappearance of all pleural & non-pleural disease) or PR (summed measurement (SM) decrease by at least 30% from baseline scan SM) per mRECIST 1.1. The percentage of participants who experience CR or PR based on mRECIST 1.1 as assessed by investigator will be presented.
Original Primary Outcome Measures  ICMJE
 (submitted: June 11, 2018)
  • Dose-Limiting Toxicities (DLTs) [ Time Frame: Cycle 1 (Up to 21 days) ]
    The occurrence of the following toxicities, if assessed by the investigator to be possibly, probably, or definitely related to study treatment administration:
    • Grade 4 nonhematologic toxicity (not laboratory)
    • Grade 4 hematologic toxicity lasting >=7 days, except thrombocytopenia:
    • Any nonhematologic AE >=Grade 3 in severity, with exceptions
    • Any Grade 3 or Grade 4 alanine aminotransferase, aspartate aminotransferase, and/or bilirubin laboratory value
    • Any other nonhematologic laboratory value if:
    Clinically significant medical intervention is required to treat the participant, OR The abnormality leads to hospitalization, OR The abnormality persists for >1 week, OR The abnormality results in a drug-induced liver injury
    • Febrile neutropenia Grade 3 or Grade 4
    • Prolonged delay (>2 weeks) in initiating Cycle 2 due to treatment-related toxicity.
    • Any treatment-related toxicity that causes the participant to discontinue treatment during Cycle 1.
    • Grade 5 toxicity
  • Adverse Events (AEs) [ Time Frame: Up to approximately 27 months ]
    Number of participants who experienced an AE. An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study.
  • Study Treatment Discontinuations Due to AEs [ Time Frame: Up to approximately 24 months ]
    Number of participants who discontinue from treatment due to an AE. An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 26, 2022)
  • Area Under the Curve (AUC) of Plasma MK-4830 [ Time Frame: At designated time points detailed in Description (Up to approximately 25 months) ]
    Pharmacokinetic (PK) parameter: area under the drug concentration/time curve. Samples will be drawn 24 hours pre-MK-4830 infusion and end of infusion on Day 1 of Cycles 1, 2, 4, 6, and 8, and every 4 cycles thereafter (plus cycle 3 for Dose Expansion Arms) and 2 hours post-infusion on Day 1 of Cycles 1, 2, 4, 6, and 8 (plus cycle 3 for Dose Expansion Arms); on Days 8 and 15 for cycle 1, and additionally in cycles 2-3 for Dose Escalation Arms only; and at time of drug Discontinuation and 30 days after last dose (Up to approximately 25 months). Dose Expansion Arm C additionally requires the above pre-, post-, and 2 hour post-dose samples on Day 3 of Cycle 1. Each cycle is 21 days.
  • Minimum Drug Concentration (Cmin) of Plasma MK-4830 [ Time Frame: At designated time points detailed in Description (Up to approximately 25 months) ]
    PK parameter: minimum drug concentration. Samples will be drawn 24 hours pre-MK-4830 infusion and end of infusion on Day 1 of Cycles 1, 2, 4, 6, and 8, and every 4 cycles thereafter (plus cycle 3 for Dose Expansion Arms) and 2 hours post-infusion on Day 1 of Cycles 1, 2, 4, 6, and 8 (plus cycle 3 for Dose Expansion Arms); on Days 8 and 15 for cycle 1, and additionally in cycles 2-3 for Dose Escalation Arms only; and at time of drug Discontinuation and 30 days after last dose (Up to approximately 25 months). Dose Expansion Arm C additionally requires the above pre-, post-, and 2 hour post-dose samples on Day 3 of Cycle 1. Each cycle is 21 days.
  • Maximum Drug Concentration (Cmax) of Plasma MK-4830 [ Time Frame: At designated time points detailed in Description (Up to approximately 25 months) ]
    PK parameter: maximum drug concentration. Samples will be drawn 24 hours pre-MK-4830 infusion and end of infusion on Day 1 of Cycles 1, 2, 4, 6, and 8, and every 4 cycles thereafter (plus cycle 3 for Dose Expansion Arms) and 2 hours post-infusion on Day 1 of Cycles 1, 2, 4, 6, and 8 (plus cycle 3 for Dose Expansion Arms); on Days 8 and 15 for cycle 1, and additionally in cycles 2-3 for Dose Escalation Arms only; and at time of drug Discontinuation and 30 days after last dose (Up to approximately 25 months). Dose Expansion Arm C additionally requires the above pre-, post-, and 2 hour post-dose samples on Day 3 of Cycle 1. Each cycle is 21 days.
  • Number of Participants Positive for Anti-Drug Antibodies (ADA) After MK-4830 plus Pembrolizumab Treatment [ Time Frame: At designated time points (Up to approximately 25 months) ]
    Serum samples from participants treated with MK-4830 plus pembrolizumab will be analyzed for ADA using a neutralizing antibody assay. The number of participants positive for ADA will be reported.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 11, 2018)
  • Area Under the Curve (AUC) of Plasma MK-4830 [ Time Frame: 24 hours pre-infusion and end of infusion on Day 1 of Cycles 1 to 4, 6, and 8, and every 4 cycles thereafter and 2 hours post-infusion on Day 1 of Cycles 1 to 4, 6, and 8 and on Days 8 and Day 15 in Cycles 1 to 3 (Up to approximately 24 months) ]
    Pharmacokinetic (PK) parameter: area under the drug concentration/time curve
  • Minimum Drug Concentration (Cmin) of Plasma MK-4830 [ Time Frame: 24 hours pre-infusion and end of infusion on Day 1 of Cycles 1 to 4, 6, and 8, and every 4 cycles thereafter and 2 hours post-infusion on Day 1 of Cycles 1 to 4, 6, and 8 and on Days 8 and Day 15 in Cycles 1 to 3 (Up to approximately 24 months) ]
    PK parameter: minimum drug concentration
  • Maximum Drug Concentration (Cmax) of Plasma MK-4830 [ Time Frame: 24 hours pre-infusion and end of infusion on Day 1 of Cycles 1 to 4, 6, and 8, and every 4 cycles thereafter and 2 hours post-infusion on Day 1 of Cycles 1 to 4, 6, and 8 and on Days 8 and Day 15 in Cycles 1 to 3 (Up to approximately 24 months) ]
    PK parameter: maximum drug concentration
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of MK-4830 as Monotherapy and in Combination With Pembrolizumab (MK-3475) in Participants With Advanced Solid Tumors (MK-4830-001)
Official Title  ICMJE A Phase 1 Open Label, Multi-Arm, Multicenter Study of MK-4830 as Monotherapy and in Combination With Pembrolizumab for Participants With Advanced Solid Tumors
Brief Summary This study consists of several parts: dose escalation, dose expansion, dose expansion in Chinese participants residing in China, and coformulation. Dose escalation is to evaluate the safety, tolerability, and preliminary efficacy of MK-4830 monotherapy administration (Arms A and B) and in combination with pembrolizumab (Arm C). Dose expansion is to evaluate the objective response rate (ORR) of MK-4830 in combination with pembrolizumab (Arms A-F); evaluate the safety and tolerability of MK-4830 administered in combination with pembrolizumab, carboplatin, and pemetrexed (Arm G) and of MK-4830 administered in combination with pembrolizumab and lenvatinib (Arm H); evaluate the safety, tolerability and ORR of MK-4830 in combination with pembrolizumab plus chemotherapy (Arms I-L); and evaluate the safety and tolerability of MK-4830 in combination with pembrolizumab in Chinese participants from China (Arm M). The coformulation part (Arm N) evaluates the safety and tolerability of MK-4830A (coformulation of MK-4830 800 mg + pembrolizumab 200 mg). There is no formal hypothesis testing in this study.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Arms are parallel, except that participants who progress by either clinical or radiographic evaluation on monotherapy with MK-4830 (Dose Escalation, Part B), may switch over into the combination therapy arm of MK-4830 and pembrolizumab (Dose Escalation, Part C), provided they meet eligibility criteria. All arms are non-randomized except Dose Expansion Arms E and F, with randomization of eligible participants between those two arms.
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Neoplasms
Intervention  ICMJE
  • Drug: MK-4830
    MK-4830 will be administered intravenously (IV) Q3W. In Part C, MK-4830 will be administered after completion of pembrolizumab infusion. Dose escalation will proceed based on emerging safety and tolerability data of MK-4830 as monotherapy (Part A and B) and as combination therapy with pembrolizumab (Part C). For each dose level, an assessment will be made of the safety and tolerability data in order to define the next dose level to be tested.
  • Drug: Pembrolizumab
    Pembrolizumab will be administered at 200 mg IV Q3W.
    Other Names:
    • MK-3475
    • SCH 900475
    • KEYTRUDA®
  • Drug: Carboplatin
    Carboplatin will be administered IV Q3W.
    Other Name: Paraplatin
  • Drug: Pemetrexed
    Pemetrexed will be administered IV Q3W.
    Other Names:
    • ALIMTA®
    • Pleumet
    • Pemecad
  • Drug: Lenvatinib
    Lenvatinib will be administered orally once daily.
    Other Names:
    • LENVIMA®
    • Lenvanix
  • Drug: Paclitaxel
    Paclitaxel will be administered IV QW on Days 1, 8, and 15 of each 21-day cycle until disease progression or prohibitive toxicity (Arm J) and on Days 1, 8, and 15 Q4W until disease progression or prohibitive toxicity (Arm K).
    Other Names:
    • Nov-Onxol
    • Onxol
    • Paclitaxel Novaplus
    • Taxol
  • Drug: Cisplatin
    Cisplatin will be administered IV Q3W.
    Other Names:
    • Platinol®
    • Platinol®-AQ
    • CDDP
  • Biological: MK-4830A
    MK-4830A, a coformulation of MK-4830 800 mg + pembrolizumab 200 mg, will be administered IV Q3W.
Study Arms  ICMJE
  • Experimental: Dose Escalation, Part A: MK-4830 Monotherapy
    MK-4830 monotherapy (with MK-4830 doses determined by an accelerated titration design [ATD]) will be administered intravenously (IV), every 3 weeks (Q3W), starting with Cycle 1, Day 1, for a maximum of 35 cycles (up to approximately 2 years). Each cycle is 21 days. Participants enroll with histologically or cytologically confirmed pancreatic adenocarcinoma.
    Intervention: Drug: MK-4830
  • Experimental: Dose Escalation, Part B: MK-4830 Monotherapy
    MK-4830 monotherapy (with MK 4830 doses determined by a modified toxicity probability interval [mTPI] method) will be administered IV, Q3W, starting with Cycle 1, Day 1, for a maximum of 35 cycles (up to approximately 2 years). Each cycle is 21 days. Participants enroll with histologically or cytologically confirmed pleural or peritoneal malignant mesothelioma, epithelial, sarcomatoid, or biphasic subtypes.
    Intervention: Drug: MK-4830
  • Experimental: Dose Escalation, Part C: MK-4830 and Pembrolizumab
    Combination therapy with MK-4830 and pembrolizumab (with MK-4830 doses determined by an mTPI design). MK-4830 will be administered IV following pembrolizumab infusion, Q3W, starting with Cycle 1, Day 1, for a maximum of 35 cycles. Each cycle is 21 days. Pembrolizumab will be administered by IV, Q3W, starting with Cycle 1, Day 1. Each cycle is 21 days. The combination may be administered for a maximum of 35 cycles (up to approximately 2 years).
    Interventions:
    • Drug: MK-4830
    • Drug: Pembrolizumab
  • Experimental: Dose Expansion, Arm A: Pancreatic Adenocarcinoma
    Combination therapy with the preliminary recommended phase 2 dose (RP2D) A of MK-4830, and pembrolizumab, in participants with histologically or cytologically confirmed pancreatic adenocarcinoma. MK-4830 will be administered IV following pembrolizumab infusion, Q3W, starting with Cycle 1, Day 1, for a maximum of 35 cycles. Each cycle is 21 days. Pembrolizumab will be administered by IV, Q3W, starting with Cycle 1, Day 1. Each cycle is 21 days. The combination may be administered for a maximum of 35 cycles (up to approximately 2 years).
    Interventions:
    • Drug: MK-4830
    • Drug: Pembrolizumab
  • Experimental: Dose Expansion, Arm B: Glioblastoma (GBM)
    Combination therapy with the preliminary RP2D A of MK-4830, and pembrolizumab, in participants with histologically or cytologically confirmed GBM. MK-4830 will be administered IV following pembrolizumab infusion, Q3W, starting with Cycle 1, Day 1, for a maximum of 35 cycles. Each cycle is 21 days. Pembrolizumab will be administered by IV, Q3W, starting with Cycle 1, Day 1. Each cycle is 21 days. The combination may be administered for a maximum of 35 cycles (up to approximately 2 years).
    Interventions:
    • Drug: MK-4830
    • Drug: Pembrolizumab
  • Experimental: Dose Expansion, Arm C: R/M HNSCC
    Combination therapy with the preliminary RP2D A of MK-4830, and pembrolizumab, in participants who have histologically or cytologically-confirmed recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) whose disease progressed on an anti-programmed cell death 1/programmed cell death ligand 1 (PD1/L1) therapy. MK-4830 will be administered IV following pembrolizumab infusion, Q3W, starting with Cycle 1, Day 1, for a maximum of 35 cycles. Each cycle is 21 days. Pembrolizumab will be administered by IV, Q3W, starting with Cycle 1, Day 1. Each cycle is 21 days. The combination may be administered for a maximum of 35 cycles (up to approximately 2 years).
    Interventions:
    • Drug: MK-4830
    • Drug: Pembrolizumab
  • Experimental: Dose Expansion, Arm D: PD-L1 positive HNSCC, Dose A
    Combination therapy with the preliminary RP2D A of MK-4830, and pembrolizumab, in participants who have histologically or cytologically-confirmed advanced programmed death-ligand 1 (PD-L1) positive head and neck squamous cell carcinoma (HNSCC). MK-4830 will be administered IV following pembrolizumab infusion, Q3W, starting with Cycle 1, Day 1, for a maximum of 35 cycles. Each cycle is 21 days. Pembrolizumab will be administered by IV, Q3W, starting with Cycle 1, Day 1. Each cycle is 21 days. The combination may be administered for a maximum of 35 cycles (up to approximately 2 years).
    Interventions:
    • Drug: MK-4830
    • Drug: Pembrolizumab
  • Experimental: Dose Expansion, Arm E: First-Line Advanced NSCLC, Dose A
    Combination therapy with the preliminary RP2D A of MK-4830, and pembrolizumab, in participants who have histologically-confirmed, first-line treatment advanced non-small-cell-lung-cancer (NSCLC) (Stage IIIB or IV). MK-4830 will be administered IV following pembrolizumab infusion, Q3W, starting with Cycle 1, Day 1, for a maximum of 35 cycles. Each cycle is 21 days. Pembrolizumab will be administered by IV, Q3W, starting with Cycle 1, Day 1. Each cycle is 21 days. The combination may be administered for a maximum of 35 cycles (up to approximately 2 years).
    Interventions:
    • Drug: MK-4830
    • Drug: Pembrolizumab
  • Experimental: Dose Expansion, Arm F: First-Line Advanced NSCLC, Dose B
    Combination therapy with the preliminary RP2D B of MK-4830, and pembrolizumab, in participants who have histologically-confirmed, first-line treatment advanced non-small-cell-lung-cancer (NSCLC) (Stage IIIB or IV). MK-4830 will be administered IV following pembrolizumab infusion, Q3W, starting with Cycle 1, Day 1, for a maximum of 35 cycles. Each cycle is 21 days. Pembrolizumab will be administered by IV, Q3W, starting with Cycle 1, Day 1. Each cycle is 21 days. The combination may be administered for a maximum of 35 cycles (up to approximately 2 years).
    Interventions:
    • Drug: MK-4830
    • Drug: Pembrolizumab
  • Experimental: Dose Expansion, Arm G: NSCLC, +Carboplatin/Pemetrexed
    Combination therapy with the preliminary RP2D A of MK-4830, pembrolizumab, and carboplatin/pemetrexed in participants with advanced non-squamous non-small-cell-lung-cancer (NSCLC) (Stage IIIB or IV). MK-4830 will be administered IV following pembrolizumab infusion, Q3W, starting with Cycle 1, Day 1, for a maximum of 35 cycles. Each cycle is 21 days. Pembrolizumab will be administered by IV, Q3W, starting with Cycle 1, Day 1. Each cycle is 21 days. The combination may be administered for a maximum of 35 cycles. Carboplatin and pemetrexed will be administered IV Q3W, starting with Cycle 1, Day 1, for 4 cycles, followed by pemetrexed Q3W continuous with MK-4830 and pembrolizumab, up to 35 cycles. Each cycle is 21 days (up to approximately 2 years).
    Interventions:
    • Drug: MK-4830
    • Drug: Pembrolizumab
    • Drug: Carboplatin
    • Drug: Pemetrexed
  • Experimental: Dose Expansion, Arm H: RCC, +Lenvatinib
    Combination therapy with the preliminary RP2D A of MK-4830, pembrolizumab, and lenvatinib in participants with advanced renal cell carcinoma (RCC). MK-4830 will be administered IV, Q3W, starting with Cycle 1 following pembrolizumab infusion, Day 1, for a maximum of 35 cycles. Each cycle is 21 days. Pembrolizumab will be administered by IV, Q3W, starting with Cycle 1, Day 1. Each cycle is 21 days. The combination may be administered for a maximum of 35 cycles (up to approximately 2 years). Lenvatinib will be administered orally once daily for up to 35 cycles of 21 days (up to approximately 2 years).
    Interventions:
    • Drug: MK-4830
    • Drug: Pembrolizumab
    • Drug: Lenvatinib
  • Experimental: Dose Expansion, Arm I: R/M Gastric/GE Junction Adenocarcinoma
    Combination therapy with the preliminary RP2D A of MK-4830, and pembrolizumab, in participants who have histologically or cytologically-confirmed recurrent or metastatic (R/M) gastric or gastroesophageal (GE) junction adenocarcinoma and who have been previously treated with at least 2 prior lines of therapy. MK-4830 will be administered IV following pembrolizumab infusion, Q3W, starting with Cycle 1, Day 1, for a maximum of 35 cycles. Each cycle is 21 days. Pembrolizumab will be administered by IV, Q3W, starting with Cycle 1, Day 1. Each cycle is 21 days. The combination may be administered for a maximum of 35 cycles (up to approximately 2 years).
    Interventions:
    • Drug: MK-4830
    • Drug: Pembrolizumab
  • Experimental: Dose Expansion, Arm J: Ovarian Cancer
    Triple combination therapy with pembrolizumab plus preliminary RP2D A of MK-4830 plus paclitaxel in participants who have histologically confirmed, ovarian cancer. MK-4830 will be administered IV following pembrolizumab infusion, Q3W, starting with Cycle 1, Day 1, for a maximum of 35 cycles. Each cycle is 21 days. Pembrolizumab will be administered by IV, Q3W, starting with Cycle 1, Day 1 for a maximum of 35 cycles (up to approximately 2 years). Each cycle is 21 days. Paclitaxel will be administered by IV, once every week (QW) on Days 1, 8, and 15 of each 21-day cycle until disease progression or prohibitive toxicity.
    Interventions:
    • Drug: MK-4830
    • Drug: Pembrolizumab
    • Drug: Paclitaxel
  • Experimental: Dose Expansion, Arm K: Triple negative Breast Cancer (TNBC)
    Triple combination therapy with pembrolizumab plus preliminary RP2D A of MK-4830 plus paclitaxel in participants who have histologically confirmed TNBC. MK-4830 will be administered IV following pembrolizumab infusion, Q3W, starting with Cycle 1, Day 1, for a maximum of 35 cycles. Each cycle is 21 days. Pembrolizumab will be administered by IV, Q3W, starting with Cycle 1, Day 1 for a maximum of 35 cycles (up to approximately 2 years). Each cycle is 21 days. Paclitaxel will be administered by IV on Days 1, 8, and 15 every 4 weeks (Q4W) until disease progression or prohibitive toxicity.
    Interventions:
    • Drug: MK-4830
    • Drug: Pembrolizumab
    • Drug: Paclitaxel
  • Experimental: Dose Expansion, Arm L: Mesothelioma
    Triple combination therapy with pembrolizumab plus preliminary RP2D A of MK-4830 plus pemetrexed plus cisplatin in participants who have histologically confirmed advanced mesothelioma. MK-4830 will be administered IV following pembrolizumab infusion, Q3W, starting with Cycle 1, Day 1, for a maximum of 35 cycles. Each cycle is 21 days. Pembrolizumab will be administered by IV, Q3W, starting with Cycle 1, Day 1 for a maximum of 35 cycles (up to approximately 2 years). Each cycle is 21 days. Pemetrexed will be administered by IV, on Day 1 of each Q3W cycle for a maximum of 6 cycles. Each cycle is 21 days. Cisplatin will be administered by IV, on Day 1 of each Q3W cycle for a maximum of 6 cycles. Each cycle is 21 days.
    Interventions:
    • Drug: MK-4830
    • Drug: Pembrolizumab
    • Drug: Pemetrexed
    • Drug: Cisplatin
  • Experimental: Dose Expansion, Arm M: Advanced Solid Tumor in Chinese Participants In China
    Combination therapy with the preliminary RP2D A of MK-4830, and pembrolizumab, in Chinese participants, who reside in China, have histologically or cytologically-confirmed advanced/metastatic solid tumor, and who have been previously treated with at least 2 prior lines of therapy. MK-4830 will be administered IV following pembrolizumab infusion, Q3W, starting with Cycle 1, Day 1, for a maximum of 35 cycles. Each cycle is 21 days. Pembrolizumab will be administered by IV, Q3W, starting with Cycle 1, Day 1. Each cycle is 21 days. The combination may be administered for a maximum of 35 cycles (up to approximately 2 years).
    Interventions:
    • Drug: MK-4830
    • Drug: Pembrolizumab
  • Experimental: Coformulation Phase, Arm N: MK-4830A (Coformulation of MK-4830 + pembrolizumab)
    Monotherapy with MK-4830A, a coformulation of MK-4830 800 mg + pembrolizumab 200 mg, in participants with histologically or cytologically-confirmed advanced/metastatic solid tumor, and who and have received, been intolerant to, been ineligible for, or refused all treatment known to confer clinical benefit. MK-4830A will be administered IV, Q3W, starting with Cycle 1, Day 1, for a maximum of 35 cycles (up to approximately 2 years). Each cycle is 21 days.
    Intervention: Biological: MK-4830A
Publications * Siu LL, Wang D, Hilton J, Geva R, Rasco D, Perets R, Abraham AK, Wilson DC, Markensohn JF, Lunceford J, Suttner L, Siddiqi S, Altura RA, Maurice-Dror C. First-in-Class Anti-immunoglobulin-like Transcript 4 Myeloid-Specific Antibody MK-4830 Abrogates a PD-1 Resistance Mechanism in Patients with Advanced Solid Tumors. Clin Cancer Res. 2022 Jan 1;28(1):57-70. doi: 10.1158/1078-0432.CCR-21-2160. Epub 2021 Oct 1. Erratum In: Clin Cancer Res. 2022 Apr 14;28(8):1734. Clin Cancer Res. 2022 Sep 15;28(18):4158.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 26, 2022)		 442
Original Estimated Enrollment  ICMJE
 (submitted: June 11, 2018)		 70
Estimated Study Completion Date  ICMJE November 4, 2025
Estimated Primary Completion Date November 4, 2025   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Dose escalation participants: Has any histologically- or cytologically-confirmed advanced/metastatic solid tumor by pathology report and has received, has been intolerant to, or has been ineligible for all treatment known to confer clinical benefit. Solid tumors of any type are eligible for enrollment
  • Has measurable disease by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1), Response Assessment in Neuro-Oncology (RANO), or modified RECIST (mRECIST) as assessed by the local site investigator/radiology
  • Submits an evaluable baseline tumor sample for analysis (either a recent or archival tumor sample). This inclusion criterion does not apply to Expansion phase Arm M
  • Dose Escalation Part C and Back-fill participants: Has 1 or more discrete malignant lesions that are amenable to biopsy
  • Has a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale. This inclusion criterion does not apply to Expansion phase Arm B
  • Demonstrates adequate organ function
  • A male participant must agree to use an approved contraception(s) during the treatment period and for at least 180 days after the last dose of study treatment and refrain from donating sperm during this period
  • A female participant is eligible to participate if she is not pregnant, not breastfeeding, and either not a woman of childbearing potential (WOCBP) OR if a WOCBP agrees to follow the study contraceptive guidance during the treatment period and for at least 180 days after the last dose of study treatment

  • Expansion phase Arm A participants:

    • Has histologically or cytologically confirmed metastatic pancreatic adenocarcinoma
    • Received at least 1 prior line of therapy and no more than 3 prior lines of systemic therapy

  • Expansion phase Arm B participants:

    • Has histologically or cytologically confirmed unresectable glioblastoma multiforme (GBM) or its variants
    • Has a Karnofsky performance status (KPS) ≥ 70
    • Has had no more than 1 prior line of therapy for GBM. Radiation with or without chemotherapy is acceptable as the prior treatment
    • Has shown unequivocal evidence for tumor progression by magnetic resonance imaging (MRI) or computed tomography (CT) scan by contrast within 2 weeks prior to randomization
    • Has an interval of at least 3 weeks (to randomization) between prior surgical resection (one week for stereotactic biopsy)
    • Has an interval of at least 12 weeks from the completion of radiation therapy to randomization unless there is unequivocal histologic confirmation of tumor progression or radiographic progression outside of the prior radiation field
    • Is neurologically stable (eg, without a progression of neurologic symptoms or requiring escalating doses of systemic steroid therapy within last 2 weeks) and clinically stable

  • Expansion phase Arm C participants:

    • Has histologically confirmed recurrent or metastatic head and neck squamous cell cancer (HNSCC) of the oral cavity, oropharynx, hypopharynx, and/or larynx that is considered incurable by local therapies
    • Has experienced disease progression at any time during or after treatment with a platinum-containing (eg, carboplatin or cisplatin) regimen with or without cetuximab

  • Expansion phase Arm D participants:

    • Has histologically confirmed advanced or metastatic HNSCC of the oral cavity, oropharynx, hypopharynx, and/or larynx that is considered incurable by local therapies
    • Has not had any prior programmed cell death 1 (PD-1)/ programmed cell death ligand 1 (PD-L1) therapy

  • Expansion phase Arms E and F participants:

    • Has a histologically or cytologically confirmed diagnosis of advanced (Stage IIIb) or Stage IV metastatic non-small-cell lung cancer (NSCLC)
    • Has received no prior systemic therapy for chemotherapy or other targeted or biological antineoplastic therapy treatment for Stage IIIb or Stage IV metastatic NSCLC. Treatment with chemotherapy and/or radiation as part of neoadjuvant/adjuvant therapy is allowed if therapy was completed at least 6 months prior to the diagnosis of advanced disease. Participants with prior treatment with an anti-PD-1 or PD-L1 agent are not eligible

  • Expansion phase Arm G participants:

    • Has a histologically or cytologically confirmed diagnosis of advanced (Stage IIIb) or Stage IV metastatic nonsquamous NSCLC (American Joint Committee on Cancer (AJCC) version 8)
    • Is able to tolerate chemotherapy with carboplatin and pemetrexed
    • Has received no prior systemic therapy for advanced NSCLC

  • Expansion phase Arm H participants:

    • Has histologically confirmed diagnosis of renal cell cancer (RCC) with clear cell component with or without sarcomatoid features
    • Has locally advanced/metastatic disease or has recurrent disease
    • Has received no prior systemic therapy for advanced RCC

  • Expansion phase Arm I participants:

    • Has histologically confirmed diagnosis of recurrent and/or metastatic gastric or gastroesophageal junction adenocarcinoma that is considered incurable by local therapies
    • Has received and progressed on at least two prior chemotherapy regimens
    • If tumor was if human epidermal growth factor receptor 2 (HER2/neu) positive, participant must have previously received treatment with trastuzumab

  • Expansion phase Arm J participants

    • Has histologically confirmed high-grade epithelial ovarian, fallopian tube or primary peritoneal carcinoma
    • Has received prior systemic therapy
    • Has radiographic evidence of disease progression
    • Is a candidate for paclitaxel chemotherapy

  • Expansion phase Arm K participants:

    • Has locally recurrent inoperable breast cancer OR have metastatic breast cancer not previously treated
    • Has confirmed triple-negative breast cancer (TNBC)
    • Has completed treatment for Stage I-III breast cancer, if indicated, and ≥6 months elapsed between the completion of treatment and first documented local or distant disease recurrence
    • Has been treated with (neo)adjuvant anthracycline

  • Expansion phase Arm L participants:

    • Has histologically confirmed diagnosis of recurrent and/or advanced mesothelioma that is considered incurable by standard therapies
    • Is eligible to receive standard chemotherapy

  • Expansion phase Arm M participants

    • Has any histologically or cytologically confirmed advanced/metastatic solid tumor by pathology report and have received, been intolerant of, been ineligible for, or refused all treatment known to confer clinical benefit
    • Has received up to 2 prior systemic regimens for the treatment of advanced/metastatic solid tumor
    • Is a Chinese participant residing in China

  • Coformulation Arm N participants

    • Has any histologically- or cytologically-confirmed advanced/metastatic solid tumor by pathology report and have received, been intolerant to, been ineligible for, or refused all treatment known to confer clinical benefit

Exclusion Criteria:

  • Has had chemotherapy, definitive radiation, or biological cancer therapy within 4 weeks (2 weeks for palliative radiation) prior to the first dose of study therapy, or has not recovered from any adverse events (AEs) that were due to cancer therapeutics administered more than 4 weeks earlier
  • Has not recovered from all radiation-related toxicities to Grade 1 or less, requires corticosteroids, and had radiation pneumonitis
  • Has a history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years
  • Has known untreated central nervous system metastases or known carcinomatous meningitis. This exclusion criterion does not apply to Expansion phase Arm B
  • Has received any prior immunotherapy and was discontinued from that treatment due to a Grade 3 or higher immune-related AEs
  • Has previously had a severe hypersensitivity reaction to treatment with a monoclonal antibody or has a known sensitivity to any component of pembrolizumab and/or chemotherapy agents
  • Has an active infection requiring therapy
  • Has a history or current interstitial lung disease
  • Has a history of noninfectious pneumonitis that required steroids or current pneumonitis
  • Has an active autoimmune disease that has required systemic treatment in the past 2 years except vitiligo or resolved childhood asthma/atopy
  • Has clinically significant cardiac disease, including unstable angina, acute myocardial infarction within 6 months from Day 1 of study drug administration, or New York Heart Association Class III or IV congestive heart failure
  • Has a known history of human immunodeficiency virus (HIV)
  • Has a known active hepatitis B or C
  • Is taking chronic systemic steroids in doses >10 mg daily of prednisone or equivalent within 7 days prior to the first dose of trial treatment
  • Has not fully recovered from any effects of major surgery without significant detectable infection. Surgical proceduress that required general anesthesia must be completed at least 2 weeks before first study treatment administration. Surgery requiring regional/epidural anesthesia must be completed at least 72 hours before first study treatment administration and participants should be recovered
  • Has received a live or live-attenuated virus vaccine within 30 days prior to first dose of study intervention
  • Is currently participating and receiving study therapy in a study of an investigational agent or has participated and received study therapy in a study of an investigational agent or has used an investigational device within 28 days of administration of MK-4830

  • All Expansion phase participants:

    • Tumor types with known MSI-high status are not eligible

  • Expansion phase Arm A participants:

    • Has received more than 3 lines of prior therapy for advanced disease (pancreatic cancer)

  • Expansion phase Arm B participants:

    • Has tumor primarily localized to the brainstem or spinal cord
    • Has presence of diffuse leptomeningeal disease or extracranial disease
    • Has recurrent tumor greater than 6 cm in maximum diameter
    • Requires treatment with moderate or high dose systemic corticosteroids for at least 3 days within 2 weeks of randomization

  • Expansion phase Arm D participants:

    • Has received prior systemic chemotherapy or other targeted or biological antineoplastic therapy treatment for their advanced metastatic HNSCC

  • Expansion phase Arm E and F participants:

    • Has received prior systemic chemotherapy or other targeted or biological antineoplastic therapy treatment for their Stage IIIb or Stage IV metastatic NSCLC
    • Has had prior treatment with any anti-PD-1, PD-L1, or programmed cell death-ligand 2 (PD-L2) agent

  • Expansion phase Arm G participants:

    • Has received prior systemic chemotherapy or other targeted or biological antineoplastic therapy treatment for their Stage IIIb or Stage IV nonsquamous NSCLC
    • Has had prior treatment with any anti-PD-1, PD-L1, or PD-L2 agent

  • Expansion phase Arm H participants:

    • Has received prior systemic anticancer therapy for advanced RCC with a tyrosine kinase inhibitor
    • Has a clinically significant gastrointestinal (GI) abnormality
    • Has a history of untreated deep vein thrombosis or pulmonary embolism within 6 months prior to screening
    • Has poorly controlled hypertension
    • Has active GI bleeding
    • Has evidence of inadequate wound healing
    • Has active bleeding disorder or other history of significant bleeding episodes within 30 days prior to randomization
    • Has hemoptysis within 6 weeks prior to randomization
    • Has radiographic evidence of encasement or invasion of a major blood vessel, or of intratumoral cavitation

  • Expansion phase Arm I participants:

    • Has experienced weight loss > 10 % over 2 months prior to first dose of study therapy
    • Has clinical evidence of ascites
    • Has peritoneal metastases

  • Expansion phase Arm J participants:

    • Has non-epithelial cancers, including borderline, malignant Müllerian mixed mucinous, malignant Brenner's tumor and undifferentiated carcinoma and/or germ cell tumors and/or sex cord - stromal tumors
    • Has received more than 2 prior lines of systemic therapy for ovarian cancer

  • Expansion phase Arm K participants:

    • Has a known history of hypersensitivity or allergy to the study chemotherapies and/or any of their components

  • Expansion phase Arm L participants:

    • Has a known history of hypersensitivity or allergy to the study chemotherapies and/or any of their components
    • Is receiving any medication prohibited in combination with study chemotherapies as described in the respective product labels, unless medication was stopped within 7 days prior to randomization

  • All Participants (Arms A through N)

    • Has symptomatic pleural effusion (eg, cough, dyspnea, pleuritic chest pain)
    • Has had an allogenic tissue/solid organ transplant.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Toll Free Number 1-888-577-8839 Trialsites@merck.com
Listed Location Countries  ICMJE Australia,   Canada,   China,   Greece,   Israel,   Japan,   Korea, Republic of,   Poland,   South Africa,   Spain,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03564691
Other Study ID Numbers  ICMJE 4830-001
MK-4830-001 ( Other Identifier: Merck )
2019-003164-53 ( 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  ICMJE
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  ICMJE Merck Sharp & Dohme LLC
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Director Merck Sharp & Dohme LLC
PRS Account Merck Sharp & Dohme LLC
Verification Date March 2023

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP