Efficacy and Safety Study of Navarixin (MK-7123) in Combination With Pembrolizumab (MK-3475) in Adults With Selected Advanced/Metastatic Solid Tumors (MK-7123-034)

A Phase II Study of Navarixin (MK-7123) in Combination With Pembrolizumab (MK-3475) in Participants With Selected Advanced/Metastatic Solid Tumors

The purpose of this study is to assess the efficacy and safety of navarixin (MK-7123) in combination with pembrolizumab (MK-3475) in adults with one of three types of solid tumors: Programmed Death-Ligand 1 (PD-L1) positive refractory non-small cell lung cancer (NSCLC), castration resistant prostate cancer (CRPC) or microsatellite stable (MSS) colorectal cancer (CRC).

Study Overview

• Status: Completed
• Conditions: Non-small Cell Lung Cancer; Solid Tumors; Castration Resistant Prostate Cancer; Microsatellite Stable Colorectal Cancer
• Intervention / Treatment: Biological: Pembrolizumab; Drug: Navarixin

• Study Type: Interventional
• Enrollment (Actual): 107
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Blacktown, New South Wales, Australia, 2148
      • Blacktown Hospital Western Sydney Local Health District ( Site 0024)
    • Randwick, New South Wales, Australia, 2031
      • Scientia Clinical Research ( Site 0021)
  • Victoria
    • Melbourne, Victoria, Australia, 3000
      • Peter MacCallum Cancer Centre ( Site 0023)
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Cancer Centre ( Site 0031)
  • Quebec
    • Montreal, Quebec, Canada, H3T 1E2
      • Jewish General Hospital ( Site 0032)
• Israel
  • Tel Aviv, Israel, 6423906
    • Sourasky Medical Center ( Site 0012)
• Korea, Republic of
  • Seoul, Korea, Republic of, 03080
    • Seoul National University Hospital ( Site 0042)
  • Seoul, Korea, Republic of, 03722
    • Severance Hospital Yonsei University Health System ( Site 0041)
  • Gyeonggi-do
    • Seongnam-si, Gyeonggi-do, Korea, Republic of, 13620
      • Seoul National University Bundang Hospital ( Site 0043)
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85258
      • Honor Health ( Site 0005)
  • Florida
    • Sarasota, Florida, United States, 34232
      • Florida Cancer Specialists ( Site 0003)
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland ( Site 0008)
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System ( Site 0006)
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center ( Site 0004)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

All Participants

• Has one of the following histologically- or cytologically-confirmed advanced/metastatic solid tumors: NSCLC, CRPC, or MSS CRC, by pathology report and has received, or been intolerant to, or has been ineligible for all treatment known to confer clinical benefit.
• Has Stage III or Stage IV disease that is not surgically resectable.
• Has measurable disease by RECIST 1.1 criteria as assessed by the local site investigator/radiology.
• Has supplied tumor tissue from either a newly obtained biopsy or an archival specimen for biomarker analysis.
• Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Male participants must agree to use contraception during the treatment period and for at least 120 days after the last dose of study treatment and refrain from donating sperm during this period.
• Female participants must agree to follow the contraceptive guidance during the treatment period and for at least 120 days after the last dose of study treatment.
• Demonstrates adequate organ function.

Non-small Cell Lung Cancer (NSCLC) Participants

• Has histologically or cytologically confirmed diagnosis of Stage IV metastatic NSCLC.
• Has progressed on treatment with an anti-Programmed Death-Ligand 1 (PD-L1) monoclonal antibody (mAb) administered either as monotherapy, or in combination with other checkpoint inhibitors or other therapies. PD-L1 treatment progression is defined by meeting all of the following criteria: a) Has received ≥2 doses of an approved anti-PD-L1 mAb; b) Has demonstrated disease progression after anti-PD-L1 as defined by RECIST 1.1; c) Progressive disease has been documented within 12 weeks from the last dose of anti-PD-L1 mAb.

Castration Resistant Prostate Cancer (CRPC) Participants

• Has histologically- or cytologically-confirmed adenocarcinoma of the prostate. Components of small cell prostate cancer are permitted.
• Has prostate cancer progression on the most recent treatment, as determined by the investigator, by means of one of the following: a) Prostate-Specific Antigen (PSA) progression using local laboratory values as defined by a minimum of 2 rising PSA levels with an interval of ≥1 week between each assessment where the PSA value at screening should be ≥2 ng/mL; b) Radiographic disease progression in soft tissue based on RECIST 1.1 criteria with or without PSA progression; c) Radiographic disease progression in bone defined as the appearance of 2 or more new bone lesions on bone scan with or without PSA progression.
• Has progressed on at least one second generation anti-androgen therapy (e.g., enzalutamide, abiraterone).
• Has ongoing androgen deprivation with serum testosterone <50 ng/dL (<2.0 nM).

Microsatellite Stable Colorectal Cancer (MSS-CRC) Participants

• Has a histologically proven locally advanced unresectable or metastatic (Stage IV) CRC.
• Has locally confirmed (MSS) CRC; participants with microsatellite instability-high (MSI-H) or microsatellite unstable CRC are not eligible.
• Has been previously treated with standard therapies, which must include fluoropyrimidine, oxaliplatin, and irinotecan.

Exclusion Criteria:

• Has a known additional malignancy that is progressing or has required active treatment within the past 2 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e., without evidence of progression for at least 4 weeks by repeat imaging, clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment.
• Has had a severe hypersensitivity reaction to treatment with any mAb or components of the study treatment(s).
• Has an active autoimmune disease that has required systemic treatment in the past 2 years except vitiligo or resolved childhood asthma/atopy. Participants who have previously been permanently discontinued from PD-(L)1 therapy due to immune related side effects are not eligible for this study.
• Has an active infection requiring systemic therapy.
• Has symptomatic ascites or pleural effusion.
• Has interstitial lung disease that required oral or intravenous glucocorticoids to assist with management.
• Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
• Has undergone prior allogeneic hematopoietic stem cell transplantation within the last 5 years. Note: Participants who have had a stem cell transplant >5 years ago are eligible as long as there are no symptoms of graft-versus-host disease (GVHD).
• Has a known history of human immunodeficiency virus (HIV) infection.
• Has a known history of Hepatitis B or known active Hepatitis C virus infection.
• Has a history or current evidence of a gastrointestinal condition (e.g. inflammatory bowel disease, Crohn's disease, ulcerative colitis) or impaired liver function or diseases that in the opinion of the Investigator may significantly alter the absorption or metabolism of oral medications; any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, make administration of the study drugs hazardous, or make it difficult to monitor AEs such that it is not in the best interest of the participant to participate, in the opinion of the treating Investigator.
• Is pregnant or expecting to conceive or father children within the projected duration of the study.
• Has undergone major surgery and has not recovered adequately from any toxicity and/or complications from the intervention prior to starting study treatment.
• Has CRPC or MSS CRC and has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
• Has been treated with an agent directed to another stimulatory or co-inhibitory Tcell receptor (e.g. cytotoxic T-lymphocyte protein 4 [CTLA-4], tumor necrosis factor receptor superfamily, member 4 [OX 40], tumor necrosis factor receptor superfamily member 9 [CD137]).
• Has received prior systemic anti-cancer therapy including investigational agents or has used an investigational device within 28 days prior to the first dose of study treatment.
• Has received prior radiotherapy (not to target lesions) within 2 weeks of start of study treatment.
• Is expected to require any other form of antineoplastic therapy while on study.
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy in excess of replacement doses (prednisone ≤10 mg/day is acceptable), or on any other form of immunosuppressive medication.
• Has received a live-virus vaccine within 30 days prior to first dose of study treatment.
• Has been previously treated with a chemokine receptor 2 (CXCR2) inhibitor (e.g. AZD5069, reparixin, danirixin, LY3041658 Ab, HuMax-IL8, etc.).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Navarixin 30 mg + Pembrolizumab 200 mg; Participants received 30 mg navarixin via oral capsules once daily, plus 200 mg pembrolizumab via IV infusion on Day 1 of each 3-week cycle for up to 35 administrations (up to approximately 2 years	Biological: Pembrolizumab; Intravenous infusion; Other Names: MK-3475; Drug: Navarixin; Oral capsules; Other Names: MK-7123; SCH 527123
EXPERIMENTAL: Navarixin 100 mg + Pembrolizumab 200 mg; Participants received 100 mg navarixin via oral capsules once daily, plus 200 mg pembrolizumab via IV infusion on Day 1 of each 3-week cycle for up to 35 administrations (up to approximately 2 years).	Biological: Pembrolizumab; Intravenous infusion; Other Names: MK-3475; Drug: Navarixin; Oral capsules; Other Names: MK-7123; SCH 527123

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)	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. ORR was estimated using an exact method based on the binomial distribution, and the 95% confidence interval was estimated by the method of Clopper-Pearson.	Up to approximately 2 years
Number of Participants With Dose-limiting Toxicities (DLTs) During Treatment Cycle 1	The following toxicities are considered a DLT, assessed as related to study treatment: Grade 4 non-hematologic toxicity, Grade 4 anemia, Grade 3 anemia lasting >7 days or requiring transfusion, Grade 4 hematologic toxicity lasting ≥7 days, except thrombocytopenia, a) Grade 4 thrombocytopenia of any duration, b) Grade 3 thrombocytopenia associated with bleeding, Grade 3 non-hematologic toxicity lasting >3 days, any Grade 3 or Grade 4 non-hematologic laboratory value if: medical intervention is required or the abnormality leads to hospitalization or persists for >72 hours, Liver test abnormalities: Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3X Upper Limit of Normal (ULN) with total bilirubin (TBL) >2X ULN with no elevation in alkaline phosphatase (AP <2X ULN), Grade 3 or Grade 4 febrile neutropenia, inability to administer ≥75% of the planned navarixin dose due to drug-related tolerability, delay in Cycle 2 start by >2 weeks due to toxicity	Up to 21 days
Number of Participants Who Experience at Least One Adverse Event (AE)	An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study treatment.	Up to approximately 27 months
Number of Participants Who Discontinue Study Treatment Due to an AE	An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study treatment.	Up to approximately 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR) Per Modified RECIST 1.1 for Immune-based Therapeutics (iRECIST)	An objective response is defined as an immune-based Complete Response (iCR: Disappearance of all target lesions) or immune-based Partial Response (iPR: At least a 30% decrease in the sum of diameters of target lesions). ORR will be assessed by the investigator based on iRECIST following administration of navarixin in combination with pembrolizumab. The percentage of participants with progressive disease per RECIST 1.1 who experience an iCR or iPR are presented.	Up to approximately 2 years
Progression-free Survival (PFS) Per RECIST 1.1	PFS is defined as the time from the first dose of study treatment to the first confirmed documented disease progression, or death due to any cause, whichever occurs first. Per RECIST 1.1, progressive disease is defined as ≥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 ≥5 mm. Note: The appearance of one or more new lesions is also considered progression. Median PFS per RECIST 1.1 was assessed by the investigator from product-limit (Kaplan-Meier) method for censored data in participants with microsatellite stable colorectal cancer (CRC); with castration-resistant prostate cancer (CRPC), and with programmed cell death ligand 1 (PD-[L]1) refractory non-small cell lung cancer (NSCLC).	Up to approximately 2 years
PFS Per iRECIST	PFS is defined as the time from the first dose of study treatment to the first documented disease progression or death due to any cause, whichever occurs first. Per iRECIST, progressive disease (PD) is defined as ≥20% increase in the sum of diameters of target lesions. Disease progression is to be confirmed by a consecutive assessment at least 4-8 weeks after first documentation and will be assessed by the investigator. Median PFS per iRECIST was assessed by the investigator from product-limit (Kaplan-Meier) method for censored data in participants with microsatellite stable colorectal cancer (CRC); with castration-resistant prostate cancer (CRPC), and with programmed cell death ligand 1 (PD-[L]1) refractory non-small cell lung cancer (NSCLC).	Up to approximately 2 years
Overall Survival (OS)	OS is defined as the time from the first dose of study treatment to death due to any cause. Median OS was assessed from product-limit (Kaplan-Meier) method for censored data in participants with microsatellite stable colorectal cancer (CRC); with castration-resistant prostate cancer (CRPC), and with programmed cell death ligand 1 (PD-[L]1) refractory non-small cell lung cancer (NSCLC).	Up to approximately 2 years
Absolute Neutrophil Counts (ANC)	Peripheral blood neutrophil counts were performed at Cycle 1 Day 3: Predose, to determine the concentration of ANC.	Day 3: Predose
Navarixin Area Under the Plasma Concentration-Time Curve (AUC) From Time 0 to Infinity (AUC0-inf)	Plasma samples from participants with selected advanced/metastatic solid tumors were collected to determine the navarixin plasma AUC0-inf	Cycle 1 Day 1: Predose & 1, 2, 4, 6 & 8-12 hours postdose; Cycle 1 Days 3 & 8: Predose & 6-12 hours postdose; Cycle 2 Day 1: Predose & 1, 2, 4, 6 & 8-12 hours postdose (Up to approximately 23 days)
Navarixin Area Under the Plasma Concentration-Time Curve From Time 0 to Last (AUC0-last)	Plasma samples from participants with selected advanced/metastatic solid tumors were collected to determine the navarixin plasma AUC0-last.	Cycle 1 Day 1: Predose & 1, 2, 4, 6 & 8-12 hours postdose; Cycle 1 Days 3 & 8: Predose & 6-12 hours postdose; Cycle 2 Day 1: Predose & 1, 2, 4, 6 & 8-12 hours postdose(Up to approximately 23 days)
Navarixin Maximum Plasma Concentration (Cmax)	Plasma samples from participants with selected advanced/metastatic solid tumors were collected to determine the navarixin plasma Cmax.	Cycle 1 Day 1: Predose & 1, 2, 4, 6 & 8-12 hours postdose; Cycle 1 Days 3 & 8: Predose & 6-12 hours postdose; Cycle 2 Day 1: Predose & 1, 2, 4, 6 & 8-12 hours postdose (Up to approximately 23 days)
Navarixin Trough Plasma Concentration (Ctrough)	Plasma samples from participants with selected advanced/metastatic solid tumors were collected at steady state on Cycle 2 Day 21 to determine navarixin Ctrough. The Arithmetic Mean and CV% are presented.	Cycle 2 Day 21 (Up to approximately 43 days)

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 10, 2018
• Primary Completion (ACTUAL): May 19, 2021
• Study Completion (ACTUAL): May 19, 2021

Study Registration Dates

• First Submitted: March 8, 2018
• First Submitted That Met QC Criteria: March 15, 2018
• First Posted (ACTUAL): March 22, 2018

Study Record Updates

• Last Update Posted (ACTUAL): June 29, 2022
• Last Update Submitted That Met QC Criteria: June 28, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Colorectal Neoplasms; Antineoplastic Agents; Antineoplastic Agents, Immunological; Pembrolizumab
• Other Study ID Numbers: 7123-034; MK-7123-034 (OTHER: Merck Protocol Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No