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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 : September 17, 2021
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Brief Summary:
This study has dose escalation (Part A, B, C) and dose expansion (Cohorts A-L) parts. Dose escalation is to evaluate the safety, tolerability, and preliminary efficacy of MK-4830 monotherapy administration (Parts A and B) and in combination with pembrolizumab (Part C). Dose expansion is to evaluate the objective response rate (ORR) of MK-4830 in combination with pembrolizumab and evaluate the safety, tolerability and ORR of MK-4830 administered in combination with pembrolizumab and chemotherapy. There is no formal hypothesis testing in this study.

Condition or disease Intervention/treatment Phase
Neoplasms Drug: MK-4830 Drug: Pembrolizumab Drug: Carboplatin Drug: Pemetrexed Drug: Lenvatinib Drug: Paclitaxel Drug: Cisplatin Phase 1

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 410 participants
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 cross 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
Official Title: 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
Actual Study Start Date : July 11, 2018
Estimated Primary Completion Date : November 18, 2024
Estimated Study Completion Date : November 18, 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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. Each cycle is 21 days. Participants enroll with histologically or cytologically confirmed pancreatic adenocarcinoma.
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.

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. Each cycle is 21 days. Participants enroll with histologically or cytologically confirmed pleural or peritoneal malignant mesothelioma, epithelial, sarcomatoid, or biphasic subtypes,
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.

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.
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 dosed at 200 mg IV Q3W.
Other Names:
  • MK-3475
  • SCH 900475
  • KEYTRUDA®

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.
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 dosed at 200 mg IV Q3W.
Other Names:
  • MK-3475
  • SCH 900475
  • KEYTRUDA®

Experimental: Dose Expansion, Arm B: Glioblastoma (GBM)
Combination therapy with the preliminary recommended phase 2 dose (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.
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 dosed at 200 mg IV Q3W.
Other Names:
  • MK-3475
  • SCH 900475
  • KEYTRUDA®

Experimental: Dose Expansion, Arm C: R/M HNSCC
Combination therapy with the preliminary recommended phase 2 dose (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.
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 dosed at 200 mg IV Q3W.
Other Names:
  • MK-3475
  • SCH 900475
  • KEYTRUDA®

Experimental: Dose Expansion, Arm D: PD-L1 positive HNSCC, Dose A
Combination therapy with the preliminary recommended phase 2 dose (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.
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 dosed at 200 mg IV Q3W.
Other Names:
  • MK-3475
  • SCH 900475
  • KEYTRUDA®

Experimental: Dose Expansion, Arm E: First-Line Advanced NSCLC, Dose A
Combination therapy with the preliminary recommended phase 2 dose (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.
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 dosed at 200 mg IV Q3W.
Other Names:
  • MK-3475
  • SCH 900475
  • KEYTRUDA®

Experimental: Dose Expansion, Arm F: First-Line Advanced NSCLC, Dose B
Combination therapy with the preliminary recommended phase 2 dose (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.
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 dosed at 200 mg IV Q3W.
Other Names:
  • MK-3475
  • SCH 900475
  • KEYTRUDA®

Experimental: Dose Expansion, Arm G: NSCLC, +Carboplatin/Pemetrexed
Combination therapy with the preliminary recommended phase 2 dose (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.
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 dosed at 200 mg IV Q3W.
Other Names:
  • MK-3475
  • SCH 900475
  • KEYTRUDA®

Drug: Carboplatin
Carboplatin will be administered intravenously (IV) Q3W.
Other Name: Paraplatin

Drug: Pemetrexed
Pemetrexed will be administered intravenously (IV) Q3W.
Other Names:
  • ALIMTA®
  • Pleumet
  • Pemecad

Experimental: Dose Expansion, Arm H: RCC, +Lenvatinib
Combination therapy with the preliminary recommended phase 2 dose (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. Lenvatinib will be administered orally once daily for up to 35 cycles of 21 days.
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 dosed at 200 mg IV Q3W.
Other Names:
  • MK-3475
  • SCH 900475
  • KEYTRUDA®

Drug: Lenvatinib
Lenvatinib will be administered orally once daily.
Other Names:
  • LENVIMA®
  • Lenvanix

Experimental: Dose Expansion, Arm I: R/M Gastric/GE Junction Adenocarcinoma
Combination therapy with the preliminary recommended phase 2 dose (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.
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 dosed at 200 mg IV Q3W.
Other Names:
  • MK-3475
  • SCH 900475
  • KEYTRUDA®

Experimental: Dose Expansion, Arm J: Ovarian Cancer
Triple combination therapy with pembrolizumab plus preliminary recommended phase 2 dose (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. 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.
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 dosed at 200 mg IV Q3W.
Other Names:
  • MK-3475
  • SCH 900475
  • KEYTRUDA®

Drug: Paclitaxel
Paclitaxel will be administered intravenously (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

Experimental: Dose Expansion, Arm K: Triple negative Breast Cancer (TNBC)
Triple combination therapy with pembrolizumab plus preliminary recommended phase 2 dose (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. 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.
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 dosed at 200 mg IV Q3W.
Other Names:
  • MK-3475
  • SCH 900475
  • KEYTRUDA®

Drug: Paclitaxel
Paclitaxel will be administered intravenously (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

Experimental: Dose Expansion, Arm L: Mesothelioma
Triple combination therapy with pembrolizumab plus preliminary recommended phase 2 dose (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. 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.
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 dosed at 200 mg IV Q3W.
Other Names:
  • MK-3475
  • SCH 900475
  • KEYTRUDA®

Drug: Pemetrexed
Pemetrexed will be administered intravenously (IV) Q3W.
Other Names:
  • ALIMTA®
  • Pleumet
  • Pemecad

Drug: Cisplatin
Cisplatin will be administered intravenously (IV) Q3W.
Other Names:
  • Platinol®
  • Platinol®-AQ
  • CDDP




Primary Outcome Measures :
  1. 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

  2. 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.

  3. 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.

  4. 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.

  5. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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)
  • 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
    • Should not have 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 non-squamous 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

    • Must have 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:

    • Have locally recurrent inoperable breast cancer OR have metastatic breast cancer not previously treated
    • Have centrally confirmed triple-negative breast cancer (TNBC)
    • Have 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
    • Have been treated with (neo)adjuvant anthracycline
  • Expansion phase Arm L participants:

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

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
  • 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
  • Known history of human immunodeficiency virus (HIV)
  • 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 non-squamous 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03564691


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

Locations
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Sponsors and Collaborators
Merck Sharp & Dohme Corp.
Investigators
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Study Director: Medical Director Merck Sharp & Dohme Corp.
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Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT03564691    
Other Study ID Numbers: 4830-001
MK-4830-001 ( Other Identifier: Merck Protocol Number )
2019-003164-53 ( EudraCT Number )
First Posted: June 21, 2018    Key Record Dates
Last Update Posted: September 17, 2021
Last Verified: September 2021
Individual Participant Data (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

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Merck Sharp & Dohme Corp.:
PD1
PD-1
PDL1
PD-L1
Additional relevant MeSH terms:
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Paclitaxel
Albumin-Bound Paclitaxel
Cisplatin
Carboplatin
Pembrolizumab
Pemetrexed
Lenvatinib
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Immunological
Enzyme Inhibitors
Folic Acid Antagonists
Nucleic Acid Synthesis Inhibitors
Protein Kinase Inhibitors