Study of Quavonlimab (MK-1308) in Combination With Pembrolizumab (MK-3475) in Advanced Solid Tumors (MK-1308-001)

Merck Sharp & Dohme LLC415 enrolled

Overview

This study will assess the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of escalating doses of quavonlimab when used in combination with pembrolizumab in participants with advanced solid tumors.

After screening, participants will be assigned to the Dose Escalation, Dose Confirmation, Efficacy Expansion, or Coformulation Phase. The Dose Escalation Phase will evaluate available PK and safety data including dose limiting toxicities (DLTs). The Dose Confirmation Phase will gather additional safety, tolerability, PK, and preliminary efficacy data of quavonlimab in combination with pembrolizumab, and will include first-line advanced/metastatic non-small cell lung cancer (NSCLC) and second line (and beyond) advanced/metastatic small cell lung cancer (SCLC). The purpose of the Efficacy Expansion Phase is to gather preliminary anti-tumor efficacy data for quavonlimab in combination with pembrolizumab as well as for quavonlimab monotherapy in the specific target population of programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) refractory melanoma. The Coformulation Phase will evaluate the safety and PK of a coformulated product of pembrolizumab/quavonlimab (MK-1308A) in comparison to that of the single, co-administered products given at the same dose and schedule, and include participants with advanced solid tumors and participants from mainland China.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

415

Conditions

Advanced Solid Tumors

Interventions

QuavonlimabBIOLOGICAL

Quavonlimab is administered intravenously (IV) during the Dose Escalation Phase and Dose Confirmation Phase at either DL1 or DL2, and is administered IV during the Efficacy Expansion Phase at DL2.

PembrolizumabBIOLOGICAL

Pembrolizumab is administered IV at PDL1 on Day 1 of each cycle starting Cycle 2 for the Dose Escalation Phase or starting Cycle 1 of the Dose Confirmation Phase. Pembrolizumab is administered IV at PDL2 on Day 1 of each cycle for the Efficacy Expansion Phase (Arm G).

Pembrolizumab/QuavonlimabDRUG

Pembrolizumab/Quavonlimab is a coformulated product composed of quavonlimab at DL1 in combination with pembrolizumab at dose level 2 (PDL2).

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: For Dose Escalation Phase: * Have any histologically- or cytologically-confirmed advanced/metastatic solid tumor (except NSCLC for Cohorts 2 and 3) by pathology report and have received, been intolerant to, been ineligible for, or refused all treatment known to confer clinical benefit For Dose Confirmation Phase NSCLC Arms (A, B, C, and E): * Have newly diagnosed histologically or cytologically-confirmed stage IIIB/stage IV NSCLC. Epidermal growth factor receptor (EGFR)-and anaplastic lymphoma kinase (ALK) translocation-directed therapy is not indicated as primary therapy. Participant must not have received prior systemic treatment for advanced NSCLC or must have received previous neoadjuvant and adjuvant chemotherapies ≥6 months before dosing of study drug if prior systemic treatment was given for early stage disease For Dose Confirmation Phase SCLC Arm (Arm D): * Have histologically- or cytologically-confirmed metastatic (Stage III/IV) SCLC with progressive disease after ≥1 platinum-based chemotherapy regimen. Participants with platinum-sensitive disease are eligible * Have measurable disease by RECIST 1.1 as assessed by the local site investigator/radiology * Have Eastern Cooperative Oncology Group (ECOG) Performance Scale status of 0 or 1 * A female participant is eligible to participate if she is not pregnant or breastfeeding and at least 1 of the following conditions applies: * Is not a woman of child bearing potential (WOCBP) OR * Is a WOCBP and using a contraceptive method that is highly effective during the intervention period and for at least 120 days after the last dose of pembrolizumab or pembrolizumab/quavonlimab, whichever comes last * Female participants of childbearing potential must have negative urine or serum pregnancy test within 24 hours for urine and within 72 hours for serum prior to receiving the first dose of study treatment * Male participants with a female partner(s) of child-bearing potential must be willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of study medication and refrain from donating sperm during this period * Must submit an evaluable baseline tumor sample for analysis (either a recent or archival tumor sample) For Efficacy Expansion Phase Arms F and G: * Have histologically/cytologically-confirmed unresectable Stage III or Stage IV melanoma per American Joint Committee on Cancer (AJCC) staging system version 8, not amenable to local therapy * Have at least 1 measurable lesion by CT or MRI per RECIST 1.1 by BICR. Cutaneous lesions and other superficial lesions are not considered measurable lesions for the purposes of this protocol, but may be considered as non-target lesions * Participants with unresectable Stage III or IV disease must have progressed on treatment with an anti-PD-1/L1 monoclonal antibody (mAb) administered either as monotherapy, or in combination with other checkpoint inhibitors or other therapies (combinations with anti-cytotoxic T-lymphocyte associated protein 4 \[CTLA-4\] agents will not be allowed) * Participants who receive anti-PD-1 therapy as adjuvant treatment following complete resection of Stage III or IV melanoma and have disease recurrence (unresectable loco-regional disease or distant metastases) while on active treatment or within 6 months of stopping anti-PD-1 are eligible * Have submitted pre-trial imaging and provided a baseline tumor sample * Proto-oncogene B-raf (BRAF) V600 mutation-positive melanoma participants should have received targeted therapy for advanced or metastatic disease (eg, BRAF/MEK inhibitor, alone or in combination) prior to enrolling on this study; however, they are not required to progress on this treatment prior to enrollment * BRAF V600E mutation-positive melanoma participants who have NOT received a BRAF inhibitor (either as adjuvant therapy or in the metastatic disease setting) with lactate dehydrogenase (LDH) \< local upper limit of normal (ULN), no clinically significant tumor-related symptoms, and absence of rapidly progressing metastatic melanoma. Approximately 10 participants each from Arms F and G will have 2 mandatory biopsies For Dose Coformulation Phase Arm I: * Have 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 * Meet all requirements for Dose Escalation Phase and Dose Confirmation Phase For the Coformulation Phase - Arm K (China only): * Have 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 * Be a Chinese participant residing in China. Exclusion Criteria: * For all phases of the study: Has received previous treatment with another agent targeting cytotoxic T lymphocyte leukocyte antigen (CTLA)-4 For Dose Confirmation Phase: * Has received previous treatment with another agent targeting programmed cell death protein 1 (PD-1), programmed cell death ligand 1 (PD-L1), or anti PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor * 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 to Common Toxicity Criteria for Adverse Events (CTCAE) Grade 1 or better from any AEs that were due to cancer therapeutics administered more than 4 weeks earlier * Has received lung radiation therapy of \>30 Gray (Gy) within 6 months before the first dose of study treatment * 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 quavonlimab. * Has a history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 3 years For Dose Escalation Cohorts (1-3) and Dose Confirmation Arms (A-E): * Has known untreated central nervous system (CNS) metastases. Has known carcinomatous meningitis * Has received any prior immunotherapy and was discontinued from that treatment due to a Grade 3 or higher immune-related adverse events (irAE) * Has had a severe hypersensitivity reaction to treatment with any monoclonal antibody or components of the study drug * Has any active infection requiring therapy * Has a history of interstitial lung disease, history of noninfectious pneumonitis that required steroids (or has current pneumonitis), or history of inflammatory bowel disease * Has an active autoimmune disease that has required systemic treatment in the past 2 years * Has clinically significant cardiac disease * Has received a live or live attenuated vaccine within 28 days of planned treatment start * Has known history of human immunodeficiency virus (HIV) and/or known active Hepatitis B or C infections, and/or known to be positive for hepatitis B surface antigen (HBsAg)/ hepatitis B virus (HBV) DNA * Has known psychiatric or substance abuse disorders that would interfere with the participant's ability to cooperate with the requirements of the trial * Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with screening and for up to 120 days following cessation of pembrolizumab or pembrolizumab/quavonlimab * Has not fully recovered from any effects of major surgery without significant detectable infection For Arm F and G (Efficacy Expansion Phase) and Arm K (Coformulation Phase) ONLY: * Has known active CNS metastases and/or carcinomatous meningitis * Has not had resolution of anti-PD-1 antibody-related AEs, including immune-mediated AEs back to Grade ≤1 or baseline (not applicable to Arm K) * Has not discontinued steroid treatment for an irAE for at least 2 weeks prior to the first dose of study drug (not applicable to Arm K) * Has ocular melanoma (not applicable to Arm K) * Has mucosal melanoma (not applicable to Arm K) * Has had an allogenic tissue/solid organ transplant

Locations (53)

Outcomes

Primary Outcomes

Percentage of Participants With ≥1 Dose Limiting Toxicity (DLT)

DLT was defined as toxicity that is possibly, probably, or definitely related to study therapy and may result in a change in the given dose. DLTs include Grade (Gr)4 non-hematologic toxicity (not laboratory); Gr 4 hematologic toxicity lasting ≥7 days (except thrombocytopenia); most non-hematologic AEs ≥ Gr 3 in severity; any Gr 3 or Gr 4 non-hematologic laboratory value that requires clinically significant medical intervention, leads to hospitalization, persists for \>1 week, or results in a drug-induced liver injury; Gr 3 or Gr 4 febrile neutropenia; a prolonged delay in initiating Cycle 2 or 3 of Dose Escalation or Cycle 2 of Dose Confirmation due to treatment-related toxicity; any treatment-related toxicity that causes the participant to discontinue treatment during the DLT observation period, and Gr 5 toxicity.

Time frame: Up to 6 weeks

Number of Participants With ≥1 Adverse Event (AE)

An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product temporally associated with the use of study treatment, whether or not considered related to the study treatment. Per protocol, no analysis was planned for the cross over phase. The number of participants who experienced an AE are presented.

Time frame: Up to approximately 77 months

Number of Participants Discontinuing Study Treatment Due to an AE

Time frame: Up to approximately 26 months

Efficacy Expansion: Objective Response Rate (ORR) as Assessed by Blinded Independent Central Review (BICR) Based on Adjusted Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)

ORR is defined as the percentage of participants with Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions) per adjusted Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1). The percentage of participants who experience CR or PR in the concurrent randomized subset as assessed by Blinded Independent Central Review (BICR) will be presented. Per protocol, only data for arms F and G were presented for this endpoint.

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

Secondary Outcomes

Area Under the Plasma Concentration Time Curve (AUC) of Pembrolizumab

AUC was defined as a measure of pembrolizumab exposure that was calculated as the product of plasma drug concentration and time after drug administration. AUC determined by blood samples collected pre-dose and at designated timepoints post-dose are presented. Per protocol, no analysis was planned for participants in arm G and cross over phase. AUC of pembrolizumab is presented. Blood sampling was taken for Cohorts 1-3: Predose and Postdose on Days 1, 8, 15 on Cycles 2 and 3. Arms A, B, C, D, E: Predose and Postdose on Days 1, 8, 15 on Cycles 1, 2, 3. Arm F: Predose and Postdose on Day 1 and 21 on Cycles 1, 2, 3. Arm I: Predose and Postdose on Day 1 and 21 on Cycles 1, 2, 3. Arm K: Predose and Postdose on Days 1, 2, 8, 15, 21 on Cycles 1, 2; Days 1, 21 on Cycle 3. Each cycle is 21 days.

Time frame: At designated time points up to - Cohorts 1-3: Day 15 Cycle 3, Arms A, B, C, D, E: Day 15 Cycle 3, Arm F: Day 21 Cycle 3, Arm I: Day 21 Cycle 3, Arm K: Day 21 Cycle 3. Each cycle is 21 days.

Maximum Concentration (Cmax) of Pembrolizumab

Cmax was defined as the maximum concentration of pembrolizumab observed in plasma. Cmax determined by blood samples collected pre-dose and at designated timepoints post-dose are presented. Per protocol, no analysis was planned for participants in arm G and cross over phase. Cmax of pembrolizumab is presented. Blood sampling was taken for Cohorts 1-3: Predose and Postdose on Days 1, 8, 15 on Cycles 2 and 3. Arms A, B, C, D, E: Predose and Postdose on Days 1, 8, 15 on Cycles 1, 2, 3. Arm F: Predose and Postdose on Day 1 and 21 on Cycles 1, 2, 3. Arm I: Predose and Postdose on Day 1 and 21 on Cycles 1, 2, 3. Arm K: Predose and Postdose on Days 1, 2, 8, 15, 21 on Cycles 1, 2; Days 1, 21 on Cycle 3. Each cycle is 21 days.

Minimum Concentration (Cmin) of Pembrolizumab

Cmin was defined as the minimum or "trough" concentration of pembrolizumab observed after its administration and just prior to the administration of a subsequent dose. Cmin determined by blood samples collected pre-dose and at designated timepoints post-dose are presented. Per protocol, no analysis was planned for participants in arm G and cross over phase. Cmin of pembrolizumab is presented. Blood sampling was taken for Cohorts 1-3: Predose and Postdose on Days 1, 8, 15 on Cycles 2 and 3, Day 1 on Cycle 4. Arms A, B, C, D, E: Predose and Postdose on Days 1, 8, 15 on Cycles 1, 2, 3. Arm F: Predose and Postdose on Day 1 and 21 on Cycles 1, 2, 3. Arm I: Predose and Postdose on Day 1 and 21 on Cycles 1, 2, 3. Arm K: Predose and Postdose on Days 1, 2, 8, 15, 21 on Cycles 1, 2; Days 1, 21 on Cycle 3. Each cycle is 21 days.

Time frame: At designated time points up to - Cohorts 1-3: Day 1 Cycle 4, Arms A, B, C, D, E: Day 15 Cycle 3, Arm F: Day 21 Cycle 3, Arm I: Day 21 Cycle 3, Arm K: Day 21 Cycle 3. Each cycle is 21 days.

Area Under the Plasma Concentration Time Curve (AUC) of Quavonlimab (MK-1308)

AUC was defined as a measure of quavonlimab exposure that was calculated as the product of plasma drug concentration and time after drug administration. AUC determined by blood samples collected pre-dose and at designated timepoints post-dose are presented. Per protocol, no analysis was planned for the cross over phase. AUC of quavonlimab is presented. Blood sampling was taken for Cohorts 1-3: Predose and Postdose on Days 1, 8, 15 on Cycles 1, 2 and 3. Arms A, B, C, D, E: Days 1, 8, 15 on Cycles 1, 2, 3. Arms F, G and I: Predose and Postdose on Day 1 and 21 on Cycles 1, 2, 3. Arm K: Days 1, 2, 8, 15, 21 on Cycles 1, 2; Days 1, 21 on Cycle 3. Each cycle is 21 days.

Time frame: At designated time points up to - Cohorts 1-3: Day 15 Cycle 3, Arms A, B, C, D, E: Day 15 Cycle 3, Arm F, G, I: Day 21 Cycle 3, Arm K: Day 21 Cycle 3. Each cycle is 21 days.

Maximum Concentration (Cmax) of Quavonlimab

Cmax was defined as the maximum concentration of quavonlimab observed in plasma. Cmax determined by blood samples collected pre-dose and at designated timepoints post-dose are presented. Per protocol, no analysis was planned for the cross over phase. Cmax of quavonlimab is presented. Blood sampling was taken for Cohorts 1-3: Predose and Postdose on Days 1, 8, 15 on Cycles 1, 2 and 3. Arms A, B, C, D, E: Days 1, 8, 15 on Cycles 1, 2, 3. Arms F, G and I: Predose and Postdose on Day 1 and 21 on Cycles 1, 2, 3. Arm K: Days 1, 2, 8, 15, 21 on Cycles 1, 2; Days 1, 21 on Cycle 3. Each cycle is 21 days.

Time frame: At designated time points up to - Cohorts 1-3: Day 15 Cycle 3, Arms A, B, C, D, E: Day 15 Cycle 3, Arm F, G, I: Day 21 Cycle 3, Arm K: Day 21 Cycle 3. Each cycle is 21 days.

Minimum Concentration (Cmin) of Quavonlimab

Cmin was defined as the minimum or "trough" concentration of quavonlimab observed after its administration and just prior to the administration of a subsequent dose. Cmin determined by blood samples collected pre-dose and at designated timepoints post-dose are presented. Per protocol, no analysis was planned for the cross over phase. Cmin of quavonlimab is presented. Blood sampling was taken for Cohorts 1-3: Predose and Postdose on Days 1, 8, 15 on Cycles 1, 2 and 3. Arms A, B, C, D, E: Days 1, 8, 15 on Cycles 1, 2, 3. Arms F, G and I: Predose and Postdose on Day 1 and 21 on Cycles 1, 2, 3. Arm K: Days 1, 2, 8, 15, 21 on Cycles 1, 2; Days 1, 21 on Cycle 3. Each cycle is 21 days.

Time frame: At designated time points up to - Cohorts 1-3: Day 15 Cycle 3, Arms A, B, C, D, E: Day 15 Cycle 3, Arm F, G, I: Day 21 Cycle 3, Arm K: Day 21 Cycle 3. Each cycle is 21 days.

Number of Participants With Pembrolizumab Anti-drug Antibodies (ADAs)

Non-Treatment emergent (TE) ADA refers to presence of ADAs (as determined by assay) in the absence of treatment with pembrolizumab (i.e., at predose). Evaluable participants (used as the denominator for analysis) are the total number of negative, inconclusive, and positive participants (non-treatment emergent, treatment emergent and treatment boosted). Inconclusive participants are the number of participants with no positive ADA samples present and the drug concentration in the last sample above the drug tolerance level. ADA determined by blood samples collected pre-dose and at designated timepoints post-dose are presented. Per protocol, no analysis was planned for arm G and cross over phase.

Time frame: Cohorts 1-3: Predose and day 1 of cycles 2, 3, 5, 6, 7, 9 and every 4 cycles up to 35 cycles. Arms A-E: Predose and day 1 of cycles 1-5, 6, 8 and every 4 cycles up to 35 cycles. Arms F, I, K: Predose and day 1 of cycles 1, 2, 3, 4. Each cycle is 21 days.

Number of Participants With Quavonlimab Anti-drug Antibodies (ADAs)

Non-Treatment emergent (TE) ADA refers to presence of ADAs (as determined by assay) in the absence of treatment with quavonlimab (i.e., at predose). Evaluable participants (used as the denominator for analysis) are the total number of negative, inconclusive, and positive participants (non-treatment emergent, treatment emergent and treatment boosted (TB)). Inconclusive participants are the number of participants with no positive ADA samples present and the drug concentration in the last sample above the drug tolerance level. ADA determined by blood samples collected pre-dose and at designated timepoints post-dose are presented. Per protocol, no analysis was planned for the cross over phase.

Time frame: Cohort 1-3: Predose and day 1 of cycles 2, 3, 5, 6, 7, 9 and every 4 cycles up to 35 cycles. Arms A-E: Predose and day 1 of cycle 1-5, 6, 8 and every 4 cycles up to 35 cycles. Arms F, G, I, K: Predose and day 1 of cycles 1, 2, 3, 4. Each cycle is 21 days.

Dose Escalation, Dose Confirmation, Coformulation: ORR as Assessed by Investigator Based on Adjusted RECIST v1.1

ORR is defined as the percentage of participants with Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions) per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1). The percentage of participants who experience CR or PR as assessed by Blinded Independent Central Review (BICR) will be presented. Per protocol, no analysis was planned for the cross over phase.

Time frame: Up to approximately 72 months

Efficacy Expansion: Duration of Response (DOR) as Assessed by BICR Based on Adjusted RECIST v1.1

DOR was defined as the time from first documented evidence of complete response (CR: Disappearance of all target lesions) or confirmed partial response (PR: At least a 30% decrease in the sum of diameters of target lesions) until progressive disease (PD) or death. Per RECIST 1.1, PD is defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD. DOR as assessed by Blinded Independent Central Review (BICR) will be presented. Per protocol, only data for arms F and G were presented for this endpoint.

Time frame: Up to approximately 72 months