A Phase 1b, Open-Label, Dose Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of MK-0482 as Monotherapy and in Combination With Pembrolizumab in Participants With Advanced/Metastatic Solid Tumors.
Overview
- Phase
- Phase 1
- Intervention
- MK-0482
- Conditions
- Neoplasms
- Sponsor
- Merck Sharp & Dohme LLC
- Enrollment
- 222
- Locations
- 16
- Primary Endpoint
- Number of Participants Who Experience a Dose-Limiting Toxicity (DLT) Graded Using National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (Part 1 only)
- Status
- Completed
- Last Updated
- 10 months ago
Overview
Brief Summary
This is a 2 part study. Part 1 is a dose escalation to determine the safety and tolerability and to establish a preliminary recommended Phase 2 dose (RP2D) dose of MK-0482 administered as monotherapy and in combination with pembrolizumab (MK-3475) in participants with advanced solid tumors for which there is no available therapy which may convey clinical benefit. Part 2 is expansion cohort to determine safety and tolerability of MK-0482 in combination with pembrolizumab with and without chemotherapy in participants with advanced tumor specific cohorts.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Part 1 only: Has histologically-or cytologically-confirmed advanced/metastatic solid tumors and have received, been intolerant to, or been ineligible for, all treatments known to confer clinical benefit
- •Has measurable disease by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) or Response Assessment in Neuro-Oncology (RANO) for Cohort B as assessed by the local site investigator/radiology
- •Has provided an evaluable archival or newly obtained tumor tissue sample
- •Part 1, Arm 1 only: Has ≥1 discrete malignant lesions that are amenable to biopsy
- •Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
- •Male participants are eligible to participate if they agree to the following during the intervention period and for at least 95 days after the last dose of chemotherapy: refrain from donating sperm plus either be abstinent from heterosexual intercourse as their preferred and usual lifestyle and agree to remain abstinent or agree to use contraception unless confirmed to be azoospermic
- •A female participant is eligible to participate if she is not pregnant or breastfeeding, and ≥1 of the following conditions applies: is not a woman of childbearing potential (WOCBP) OR is using a contraceptive method that is highly effective or is abstinent from heterosexual intercourse as their preferred and usual lifestyle during the intervention period and for at least 180 days after the last dose of chemotherapy or 120 days after the last dose of MK-0482 or pembrolizumab, whichever occurs last
- •Part 2 Cohort A, C, and E only: WOCBP must also agree not to donate to others or freeze/store for her own use for the purpose of reproduction during and for at least 180 days after the last dose of chemotherapy
- •Has a negative highly sensitive pregnancy test within 72 hours before the first dose of study treatment
- •Human immunodeficiency virus (HIV) infected participants must have well controlled HIV on anti-retroviral therapy (ART)
Exclusion Criteria
- •Has a history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years
- •Has a known additional malignancy that is progressing or has required active treatment within the past 2 years; with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy
- •Has known active central nervous system metastases and/or carcinomatous meningitis
- •Has had a severe hypersensitivity reaction to treatment with a monoclonal antibody (mAb) and/or any component of pembrolizumab (MK-3475) or MK-0482
- •Has received any prior immunotherapy and was discontinued from that treatment due to a Grade 3 or higher immune-related adverse event (irAE)
- •Has an active infection requiring systemic therapy
- •Has a history of interstitial lung disease
- •Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
- •Has an active autoimmune disease that has required systemic treatment in the past 2 years
- •HIV-infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease
Arms & Interventions
Part 1: MK-0482 Monotherapy
Participants receive escalating doses of MK-0482 via intravenous (IV) infusion on Day 1 of each 21-day cycle (Q3W) for up to 35 administrations (up to approximately 2 years).
Intervention: MK-0482
Part 1: MK-0482 + Pembrolizumab Combination Therapy
Participants receive escalating doses of MK-0482 via IV infusion + pembrolizumab 200 mg via IV infusion on Day 1 of each 21-day cycle (Q3W) for up to 35 administrations (up to approximately 2 years).
Intervention: MK-0482
Part 1: MK-0482 + Pembrolizumab Combination Therapy
Participants receive escalating doses of MK-0482 via IV infusion + pembrolizumab 200 mg via IV infusion on Day 1 of each 21-day cycle (Q3W) for up to 35 administrations (up to approximately 2 years).
Intervention: pembrolizumab
Part 2: Cohort A
Participants with metastatic triple negative breast cancer (TNBC) first line treatment (1L) receive MK-0482 via IV infusion plus pembrolizumab 200 mg via IV infusion on Day 1 of each 21-day cycle (Q3W) up to 35 administrations (up to approximately 2 years) and paclitaxel 90 mg/m\^2 via IV infusion until PD or discontinuation.
Intervention: MK-0482
Part 2: Cohort A
Participants with metastatic triple negative breast cancer (TNBC) first line treatment (1L) receive MK-0482 via IV infusion plus pembrolizumab 200 mg via IV infusion on Day 1 of each 21-day cycle (Q3W) up to 35 administrations (up to approximately 2 years) and paclitaxel 90 mg/m\^2 via IV infusion until PD or discontinuation.
Intervention: pembrolizumab
Part 2: Cohort A
Participants with metastatic triple negative breast cancer (TNBC) first line treatment (1L) receive MK-0482 via IV infusion plus pembrolizumab 200 mg via IV infusion on Day 1 of each 21-day cycle (Q3W) up to 35 administrations (up to approximately 2 years) and paclitaxel 90 mg/m\^2 via IV infusion until PD or discontinuation.
Intervention: Paclitaxel
Part 2: Cohort B
Participants with recurrent non-operable glioblastoma (GBM) current treatment of second line (2L) receive MK-0482 via IV infusion plus pembrolizumab 200 mg via IV infusion on Day 1 of each 21-day cycle (Q3W) up to 35 administrations (up to approximately 2 years).
Intervention: MK-0482
Part 2: Cohort B
Participants with recurrent non-operable glioblastoma (GBM) current treatment of second line (2L) receive MK-0482 via IV infusion plus pembrolizumab 200 mg via IV infusion on Day 1 of each 21-day cycle (Q3W) up to 35 administrations (up to approximately 2 years).
Intervention: pembrolizumab
Part 2: Cohort C
Participants with metastatic pancreatic ductal adenocarcinoma (PDAC) (1L) receive MK-0482 via IV infusion plus pembrolizumab 200 mg via IV infusion on Day 1 of each 21-day cycle (Q3W) up to 35 administrations (up to approximately 2 years), Nab-Paclitaxel 125 mg/m\^2 via IV infusion and gemcitabine 1000 mg/m\^2 via IV infusion until PD or unacceptable toxicity that requires discontinuation.
Intervention: MK-0482
Part 2: Cohort C
Participants with metastatic pancreatic ductal adenocarcinoma (PDAC) (1L) receive MK-0482 via IV infusion plus pembrolizumab 200 mg via IV infusion on Day 1 of each 21-day cycle (Q3W) up to 35 administrations (up to approximately 2 years), Nab-Paclitaxel 125 mg/m\^2 via IV infusion and gemcitabine 1000 mg/m\^2 via IV infusion until PD or unacceptable toxicity that requires discontinuation.
Intervention: pembrolizumab
Part 2: Cohort C
Participants with metastatic pancreatic ductal adenocarcinoma (PDAC) (1L) receive MK-0482 via IV infusion plus pembrolizumab 200 mg via IV infusion on Day 1 of each 21-day cycle (Q3W) up to 35 administrations (up to approximately 2 years), Nab-Paclitaxel 125 mg/m\^2 via IV infusion and gemcitabine 1000 mg/m\^2 via IV infusion until PD or unacceptable toxicity that requires discontinuation.
Intervention: Nab-paclitaxel
Part 2: Cohort C
Participants with metastatic pancreatic ductal adenocarcinoma (PDAC) (1L) receive MK-0482 via IV infusion plus pembrolizumab 200 mg via IV infusion on Day 1 of each 21-day cycle (Q3W) up to 35 administrations (up to approximately 2 years), Nab-Paclitaxel 125 mg/m\^2 via IV infusion and gemcitabine 1000 mg/m\^2 via IV infusion until PD or unacceptable toxicity that requires discontinuation.
Intervention: Gemcitabine
Part 2: Cohort D
Participants with metastatic soft tissue sarcoma (STS) (2L) receive MK-0482 via IV infusion plus pembrolizumab 200 mg via IV infusion on Day 1 of each 21-day cycle (Q3W) up to 35 administrations (up to approximately 2 years).
Intervention: MK-0482
Part 2: Cohort D
Participants with metastatic soft tissue sarcoma (STS) (2L) receive MK-0482 via IV infusion plus pembrolizumab 200 mg via IV infusion on Day 1 of each 21-day cycle (Q3W) up to 35 administrations (up to approximately 2 years).
Intervention: pembrolizumab
Part 2: Cohort E
Participants with metastatic non-squamous non-small cell lung carcinoma (NSCLC) (1L) receive MK-0482 via IV infusion plus pembrolizumab 200 mg via IV infusion plus Pemetrexed 500 mg/m\^2 via IV infusion on Day 1 of each 21-day cycle (Q3W) up to 35 administrations (up to approximately 2 years) plus carboplatin with desired dose of area under the curve (AUC) 5 and pemetrexed 500 mg/m\^2, both administered via IV infusion, followed by maintenance therapy with pemetrexed 500 mg/m\^2 via IV infusion for up to a total of 35 administrations (up to approximately 2 years).
Intervention: MK-0482
Part 2: Cohort E
Participants with metastatic non-squamous non-small cell lung carcinoma (NSCLC) (1L) receive MK-0482 via IV infusion plus pembrolizumab 200 mg via IV infusion plus Pemetrexed 500 mg/m\^2 via IV infusion on Day 1 of each 21-day cycle (Q3W) up to 35 administrations (up to approximately 2 years) plus carboplatin with desired dose of area under the curve (AUC) 5 and pemetrexed 500 mg/m\^2, both administered via IV infusion, followed by maintenance therapy with pemetrexed 500 mg/m\^2 via IV infusion for up to a total of 35 administrations (up to approximately 2 years).
Intervention: pembrolizumab
Part 2: Cohort E
Participants with metastatic non-squamous non-small cell lung carcinoma (NSCLC) (1L) receive MK-0482 via IV infusion plus pembrolizumab 200 mg via IV infusion plus Pemetrexed 500 mg/m\^2 via IV infusion on Day 1 of each 21-day cycle (Q3W) up to 35 administrations (up to approximately 2 years) plus carboplatin with desired dose of area under the curve (AUC) 5 and pemetrexed 500 mg/m\^2, both administered via IV infusion, followed by maintenance therapy with pemetrexed 500 mg/m\^2 via IV infusion for up to a total of 35 administrations (up to approximately 2 years).
Intervention: Carboplatin
Part 2: Cohort E
Participants with metastatic non-squamous non-small cell lung carcinoma (NSCLC) (1L) receive MK-0482 via IV infusion plus pembrolizumab 200 mg via IV infusion plus Pemetrexed 500 mg/m\^2 via IV infusion on Day 1 of each 21-day cycle (Q3W) up to 35 administrations (up to approximately 2 years) plus carboplatin with desired dose of area under the curve (AUC) 5 and pemetrexed 500 mg/m\^2, both administered via IV infusion, followed by maintenance therapy with pemetrexed 500 mg/m\^2 via IV infusion for up to a total of 35 administrations (up to approximately 2 years).
Intervention: Pemetrexed
Outcomes
Primary Outcomes
Number of Participants Who Experience a Dose-Limiting Toxicity (DLT) Graded Using National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (Part 1 only)
Time Frame: Cycle 1 (Up to 21 days)
DLTs defined as any of the following assessed as treatment (Tx)-related by investigator: Grade (Gr)4 nonhematologic toxicity (T); Gr4 hematologic T lasting ≥7 days, except thrombocytopenia (TCP); Gr4 TCP of any duration; Gr3 TCP associated with clinically-significant bleeding; nonhematologic adverse event (AE) ≥Gr3 in severity, with exceptions; Gr3/4 alanine transaminase (ALT), aspartate transaminase (AST), and/or bilirubin (bili) with exceptions; a protocol-defined elevation of ALT, AST, and bili; Gr3/4 nonhematologic laboratory abnormality if: clinically significant medical intervention is required, leads to hospitalization, persists for \>1 week, or results in liver injury with exceptions; Gr3/4 febrile neutropenia; \>2 week-delay in starting Cycle 2 due to Tx-related T; Tx-related T resulting in Tx discontinuation during DLT evaluation period; missing \>25% of the MK-0482 or any combination component during DLT evaluation period resulting from Tx-related AE; or Gr5 toxicity.
Number of Participants Who Experience at Least One Adverse Event (AE)
Time Frame: Up to approximately 27 months
An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who experience at least one AE will be presented.
Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE)
Time Frame: Up to approximately 24 months
The number of participants who discontinue study treatment due to an AE will be presented.
Number of Participants Who Experience a Dose-Limiting Toxicity (DLT) Graded Using National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (Part 2 only)
Time Frame: Up to approximately 28 days from the start of study intervention
DLTs defined as any of the following assessed as treatment (Tx)-related by investigator: Grade (Gr)4 nonhematologic toxicity (T); Gr4 hematologic T lasting ≥7 days, except thrombocytopenia (TCP); Gr4 TCP of any duration; Gr3 TCP associated with clinically-significant bleeding; nonhematologic adverse event (AE) ≥Gr3 in severity, with exceptions; Gr3/4 alanine transaminase (ALT), aspartate transaminase (AST), and/or bilirubin (bili) with exceptions; a protocol-defined elevation of ALT, AST, and bili; Gr3/4 nonhematologic laboratory abnormality if: clinically significant medical intervention is required, leads to hospitalization, persists for \>1 week, or results in liver injury with exceptions; Gr3/4 febrile neutropenia; \>2 week-delay in starting Cycle 2 due to Tx-related T; Tx-related T resulting in Tx discontinuation during DLT evaluation period; missing \>25% of the MK-0482 or any combination component during DLT evaluation period resulting from Tx-related AE; or Gr5 toxicity.
Secondary Outcomes
- Area Under the Concentration-Time Curve (AUC) of MK-0482 When Administered as Monotherapy (Part 1 only)(At designated time points (Up to approximately 25 months))
- Cmin of MK-0482 When Administered in Combination with Pembrolizumab (Part 1 only)(At designated time points (Up to approximately 25 months))
- Maximum Serum Concentration (Cmax) of MK-0482 When Administered as Monotherapy (Part 1 only)(At designated time points (Up to approximately 25 months))
- ORR As Assessed by Investigator per Response Assessment in Neuro-Oncology (RANO) (Part 2 only)(Up to approximately 25 months)
- Minimum Serum Concentration (Cmin) of MK-0482 When Administered as Monotherapy (Part 1 only)(At designated time points (Up to approximately 25 months))
- Cmax of MK-0482 When Administered in Combination with Pembrolizumab (Part 1 only)(At designated time points (Up to approximately 25 months))
- AUC of MK-0482 When Administered in Combination with Pembrolizumab (Part 1 only)(At designated time points (Up to approximately 25 months))
- Objective Response Rate (ORR) As Assessed by Investigator per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) (Part 2 only)(Up to approximately 25 months)