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Study of MK-1454 Alone or in Combination With Pembrolizumab in Participants With Advanced/Metastatic Solid Tumors or Lymphomas (MK-1454-001)

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ClinicalTrials.gov Identifier: NCT03010176
Recruitment Status : Recruiting
First Posted : January 4, 2017
Last Update Posted : March 15, 2019
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Brief Summary:

The purpose of this study is to identify a maximum tolerated dose (MTD) or maximum administered dose (MAD) of MK-1454 alone and of MK-1454 in combination with pembrolizumab (MK-3475) in participants with advanced/metastatic solid tumors or lymphomas in Part 1, and to evaluate the safety and efficacy of MK-1454 via intratumoral (IT) injection in combination with pembrolizumab in selected solid tumors in Part 2.

MK-1454 will be administered IT; pembrolizumab (pembro) will be administered via intravenous (IV) infuison. In Part 1, participants will be allocated to one of three treatment arms: MK-1454 monotherapy (cutaneous/subcutaneous [cut/subcut] lesions), MK-1454+pembro (cut/subcut lesions), or MK-1454+pembro (visceral lesions).

In Part 2, participants with head and neck squamous cell carcinoma (HNSCC) who are anti-programmed cell death-protein 1 or anti-programmed cell death-ligand 1 (anti-PD-1/PD-L1) refractory or with anti-PD-1/PD-L1 treatment-naïve triple-negative breast cancer (TNBC) or with anti-PD-1/PD-L1 treatment-naïve solid tumors with liver metastases/lesions will receive MK-1454 via IT injection at the RP2D determined in Part 1 PLUS pembrolizumab via IV infusion for up 35 cycles (up approximately 2 years).


Condition or disease Intervention/treatment Phase
Solid Tumors Lymphoma Drug: MK-1454 Biological: Pembrolizumab Phase 1

Detailed Description:
Participants will receive either MK-1454 monotherapy or MK-1454 in combination with pembrolizumab for up to 35 cycles (approximately 2 years). Participants will undergo at least a 24-hour observation period following the first dose administration of MK-1454 on Cycle 1, Day 1.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 235 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1 Open Label, Multicenter Study of MK-1454 Administered by Intratumoral Injection as Monotherapy and in Combination With Pembrolizumab for Patients With Advanced/Metastatic Solid Tumors or Lymphomas
Actual Study Start Date : February 3, 2017
Estimated Primary Completion Date : October 22, 2021
Estimated Study Completion Date : October 22, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma

Arm Intervention/treatment
Experimental: Part 1 Arm 1: MK-1454 (cut/subcut lesions)
Participants with cutaneous (cut) or subcutaneous (subcut) lesions receive escalating doses of MK-1454 monotherapy via IT injection on Days 1, 8 and 15 of each 21-day cycle for Cycles 1, 2 and 3 and then on Day 1 of each 21-day cycle for Cycles 4 and beyond for up to 35 cycles (up to approximately 2 years).
Drug: MK-1454
IT injection

Experimental: Part 1 Arm 2: MK-1454+pembro (cut/subcut lesions)
Participants with cut or subcut lesions receive escalating doses of MK-1454 via IT injection on Days 1, 8 and 15 of each 21-day cycle for Cycles 1, 2 and 3 and then on Day 1 of each 21-day cycle for Cycles 4 and beyond PLUS pembrolizumab (pembro) 200 mg via IV infusion on Day 1 of each 21-day cycle for up to 35 cycles (up to approximately 2 years).
Drug: MK-1454
IT injection

Biological: Pembrolizumab
IV infusion
Other Name: MK-3475

Experimental: Part 1 Arm 3: MK-1454+pembro (visceral lesions)
Participants with visceral lesions receive escalating dose frequencies of MK-1454 via IT injection at escalating dose frequencies (Day 1 of each 21-day cycle for up to 35 cycles, then Days 1 and 8 of each 21-day cycle for two cycles, then Day 1 of each 21 day cycle up to 35 cycles, then Days 1, 8 and 15 of each 21-day cycle for two cycles followed by Day 1 of each 21-day cycle up to 35 cycles, PLUS pembrolizumab 200 mg via IV infusion on Day 1 of each 21-day cycle for up to 35 cycles (approximately 2 years).
Drug: MK-1454
IT injection

Biological: Pembrolizumab
IV infusion
Other Name: MK-3475

Experimental: Part 2 Cohort A: Head & Neck Squamous Cell Carcinoma (HNSCC)
Participants with HNSCC who are anti-programmed cell death-1 or anti-programmed cell death-ligand 1 refractory receive MK-1454 at the preliminary Recommended Phase 2 Dose (RP2D) determined by dose escalation in Part 1 Arm 1 and 2 via IT injection on Days 1, 8, and 15 of Cycles 1 and 2 and on Day 1 of each 21-day cycle from Cycle 3 onward (up to a total of 35 cycles) PLUS pembrolizumab 200 mg via IV infusion on Day 1 of each 21-day cycle for up to 35 cycles (up to approximately 2 years)
Drug: MK-1454
IT injection

Biological: Pembrolizumab
IV infusion
Other Name: MK-3475

Experimental: Part 2 Cohort B: Triple-Negative Breast Cancer (TNBC)
Participants with TNBC who are anti-PD-1/PD-L1 treatment-naïve receive MK-1454 at the preliminary RP2D determined by dose escalation in Part 1 via IT injection on Days 1, 8, and 15 of Cycles 1 and 2 and on Day 1 of each 21-day cycle from Cycle 3 onward (up to a total of 35 cycles) PLUS pembrolizumab 200 mg via IV infusion on Day 1 of each 21-day cycle for up to 35 cycles (up to approximately 2 years)
Drug: MK-1454
IT injection

Biological: Pembrolizumab
IV infusion
Other Name: MK-3475

Experimental: Part 2 Cohort C: Solid Tumors with Liver Metastases/Lesions
Participants with solid tumors with liver metastases/lesions who are anti-PD-1/PD-L1 treatment-naïve receive MK-1454 at the preliminary RP2D based on Part 1: MK-1454+pembro (visceral lesions) treatment arm via IT injection in a to-be-determined dose and frequency, based on data from Arm 3, PLUS pembrolizumab 200 mg via IV infusion on Day 1 of each 21-day cycle for up to 35 cycles (up to approximately 2 years).
Drug: MK-1454
IT injection

Biological: Pembrolizumab
IV infusion
Other Name: MK-3475




Primary Outcome Measures :
  1. Part 1: Percentage of Participants Who Experience a Dose-limiting Toxicity (DLT) Per Common Terminology Criteria for Adverse Events, Version 4.0 (CTCAE 4.0) [ Time Frame: Up to 3 weeks at each dose level ]
    DLTs will be assessed during the first cycle (21 days) & are defined as: Grade (Gr) 4 nonhematologic toxicity; Gr 4 hematologic toxicity lasting ≥7 days, except thrombocytopenia, Gr 4 thrombocytopenia, Gr 3 thrombocytopenia (if associated with clinically significant bleeding); nonhematologic adverse event (AE) ≥ Gr 3 (with exceptions); Gr 3 or 4 nonhematologic lab abnormality (if medical intervention is required, leads to hospitalization, or persists for >1 week); Gr 3 or 4 febrile neutropenia; drug-related toxicity that causes treatment discontinuation or dose delay >7 days between consecutive doses during Cycle 1; drug-related toxicity that causes a >2 week delay in Cycle 2 initiation; elevated aspartate aminotransferase or alanine aminotransferase lab value that is ≥3× upper limit of normal (ULN) & an elevated total bilirubin value ≥2× ULN & an alkaline phosphatase value <2× ULN, in which no alternative reasons can be found; ≥Gr 2 immune-mediated uveitis; or Gr 5 toxicity.

  2. Parts 1 and 2: Percentage of Participants Who Discontinue Study Drug Due to an Adverse Event (AE) [ Time Frame: Up to 2 years ]
    AEs are defined as any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of study treatment or protocol-specified procedure, whether or not considered related to the study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that is temporally associated with the use of the study treatment, is also an AE. The percentage of participants who discontinue study treatment due to an AE will be presented.


Secondary Outcome Measures :
  1. Parts 1 and 2: Area Under the Plasma Drug Concentration-Time Curve from 0 to 24 hours (AUC0-24h) of MK-1454 When Administered as Monotherapy and as Combination Therapy With Pembrolizumab [ Time Frame: Cycle 1 Day 1: Predose, at end of IT injection and 0.5, 1, 1.5, 4, 6, 12 and 24 hours postdose; Cycle 2 Day 1: Predose, at end of IT injection and 0.5, 1, 1.5, 4 and 6 hours postdose; Each cycle is 21 days ]
    AUC0-24h is the area under the plasma drug concentration curve during the first 24 hours after study treatment administration. The AUC0-24h of MK-1454 when administered as monotherapy and as combination therapy with pembrolizumab will be presented.

  2. Parts 1 and 2: AUC0-24h of Pembrolizumab When Administered as Combination Therapy With MK-1454 [ Time Frame: Cycle 1 Day 1: Predose, at end of IT injection and 0.5, 1, 1.5, 4, 6, 12 and 24 hours postdose; Cycle 2 Day 1: Predose, at end of IT injection and 0.5, 1, 1.5, 4 and 6 hours postdose; Each cycle is 21 days ]
    AUC0-24h is the area under the plasma drug concentration curve during the first 24 hours after study treatment administration. The AUC0-24h of pembrolizumab when administered as combination therapy with MK-1454 will be presented.

  3. Part 2: Objective Response Rate (ORR) As Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) [ Time Frame: Up to 2 years ]
    ORR is defined as the percentage of participants in the analysis population 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, taking as reference the baseline sum diameters) per RECIST 1.1. The ORR of MK-1454 at the preliminary RP2D in combination with pembrolizumab will be assessed by RECIST 1.1 modified to follow a maximum of 10 target lesions with a maximum of 5 target lesions per organ. ORR for the three Part 2 cohorts will be presented.



Information from the National Library of Medicine

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

Inclusion Criteria:

  • All Arms and Cohorts (Parts 1 and 2):
  • Has ≥1 injectable lesion which is measurable and amenable to injection and biopsy.
  • Has ≥1 distant, discrete non-injected lesion which is amenable to biopsy. This lesion must be measurable as defined by the response criteria used to assess the participant (RECIST 1.1 for solid tumors or revised International Working Group [IWG] criteria for lymphomas).
  • Has an Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1.
  • Demonstrates adequate organ function within 7 days prior to treatment initiation.
  • Female participants of childbearing potential must be willing to use a highly effective method of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study drug through 130 days after last dose of study treatment. Male participants of reproductive potential must agree to use a highly effective method of contraception during sexual contact with females of childbearing potential starting with the first dose of study treatment through 130 days after the last dose of study treatment.
  • Human Immunodeficiency (HIV)-infected participants must meet these additional criteria: a) Has laboratory-test-documented HIV-1 infection; b) Has well-controlled HIV on anti-retroviral therapy (ART), defined as: 1) must have a cluster of differentiation (CD4+) T-cell count >350 cells/mm^3 at time of screening; 2) must have achieved and maintained virologic suppression defined as confirmed HIV ribonucleic acid (RNA) level below 50 or the lower limit of quantification (LLOQ) using the locally available assay at the time of screening and for ≥12 weeks prior to screening; and, 3) must have been on a stable regimen, without changes in drugs or dose modification, for ≥4 weeks prior to study entry (Day 1).
  • Part 1, MK-1454 (cut/subcut lesions) and Part 1, MK-1454+pembro (cut/subcut lesions) Arms:
  • Has a histologically- or cytologically-confirmed advanced/metastatic solid tumor or lymphoma by pathology report and who has received, or been intolerant to, all treatment known to confer clinical benefit. Solid tumors and lymphomas of any type are eligible for enrollment.
  • Has stage III or stage IV disease that is not surgically resectable. Stage IIB (T3N0M0B0-1) cutaneous T cell lymphoma (CTCL) participants are eligible.
  • Part 1, MK-1454+pembro (visceral lesions) Arm:
  • Has stage III or stage IV disease that is not surgically resectable.
  • Has metastatic liver involvement that does not exceed one third of the total liver volume in participants to be treated by liver IT injection. Hepatocellular carcinoma participants are excluded from eligibility of IT liver injection.
  • Part 2, All Cohorts:
  • In participants to be treated by liver IT injection, has metastatic liver involvement that does not exceed one third of the total liver volume.
  • Part 2: HNSCC Cohort:
  • Has HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx; anti-PD-1/PD-L1 refractory metastatic or recurrent. Participants may not have a primary tumor site of the nasopharynx (any histology).
  • Has histologically confirmed Stage III, IVa, or IVb disease per TNM (Tumor, Nodes, Metastasis) staging, American Joint Committee on Cancer (AJCC, 8th edition), with recurrent or persistent disease after definitive chemoradiation, deemed unresectable and considered refractory to both platinum-based combination chemotherapy and anti-programmed cell death-ligand 1 (anti-PD-1/PD-L1) antibody therapy.

OR

  • Has histologically confirmed Stage IVc disease per TNM staging, AJCC 8th edition, considered refractory to platinum-based combination chemotherapy and anti-PD-1/PD-L1 antibody therapy.
  • Part 2: TNBC Cohort:
  • Has confirmed metastatic TNBC as locally determined according to the American Society of Clinical Oncology-College of American Pathologists (ASCO-CAP) guidelines on a newly obtained core or excisional biopsy from a metastatic, not previously irradiated, tumor lesion.
  • Has received either 1 or 2 prior systemic treatments for metastatic breast cancer and has intolerance to, or documented disease progression on or after their most recent therapy.
  • Has been previously treated with an anthracycline and/or taxane in the (neo)adjuvant or metastatic setting.
  • Part 2: Solid tumors with liver metastases including pancreatic cancer, non-microsatellite instability-high (MSI-H) colorectal cancer CRC, and other solid tumors
  • Has histologically or cytologically confirmed Stage IV solid tumor that is not surgically resectable.
  • Complete resolution of toxic effect(s) of the most recent prior chemotherapy to Grade 1 or baseline (except alopecia). If participant received major surgery or radiation therapy of >30 Gray (Gy), they must have recovered from the toxicity and/or complications from the intervention.

Exclusion Criteria:

  • All Arms and Cohorts (Parts 1 and 2):
  • Has had chemotherapy, definitive radiation, or biological cancer therapy within 4 weeks prior to the first dose of study drug, or has not recovered to Baseline or Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 from the adverse events due to cancer therapeutics administered >4 weeks earlier.
  • Is currently participating and receiving study therapy or has participated in a study of an investigational agent and has received study therapy or has used an investigational device within 28 days of administration of MK-1454. Note: Prior exposure to immunotherapeutics is allowed, including PD-1 and PD-L1 inhibitors
  • Is expected to require any other form of antineoplastic therapy while on study.
  • Is on chronic systemic steroid therapy in excess of replacement doses (prednisone ≤ 10 mg/day is acceptable), or on any other form of immunosuppressive medication.
  • Has a history of a second malignancy, unless potentially curative treatment has been completed, with no evidence of malignancy for 2 years.
  • Has clinically active central nervous system metastases and/or carcinomatous meningitis.
  • Has had a severe hypersensitivity reaction to treatment with a monoclonal antibody.
  • Has an active autoimmune disease that has required systemic treatment in the past 2 years.
  • Has a history of vasculitis.
  • Has an active infection requiring therapy.
  • Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
  • Has undergone prior allogeneic hematopoietic stem cell transplantation within the last 5 years.
  • Has Hepatitis B or C infection(s).
  • Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study.
  • Has not fully recovered from any effects of major surgery, and is free of significant detectable infection.
  • Has received a live vaccine within 30 days prior to first dose of study drug.
  • Has a history of re-irradiation for squamous cell carcinoma of the head & neck (SCCHN) at the projected injection site.
  • Has a tumor(s) in direct contact or encases a major blood vessel, and has ulceration and/or fungation onto the skin surface at the projected injection site.
  • HIV-infected participants with history of Kaposi's sarcoma and/or multicentric Castleman's disease
  • HIV-infected participants who have had an HIV-related opportunistic infection within 6 months
  • Has been treated with a Stimulator of Interferon Genes (STING) agonist (e.g. MK-1454, ADU-S100).
  • Part 2: Has experienced weight loss >10% over 2 months prior to first dose of study treatment.
  • Has clinically relevant ascites at baseline (defined as requiring paracentesis) or with moderate radiographic ascites. A minimal amount of radiographic ascites is allowed.
  • Part 2: Solid Tumors with Liver Metastases/Lesions Cohort
  • Participants with MSI-H CRC are excluded.
  • Part 2: Expansion Cohorts
  • Has a history of interstitial lung disease.

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): NCT03010176


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

Locations
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United States, Alabama
University of Alabama ( Site 0009) Recruiting
Birmingham, Alabama, United States, 35294
Contact: Study Coordinator    205-996-5530      
United States, California
University of California San Francisco ( Site 0007) Recruiting
San Francisco, California, United States, 94143
Contact: Study Coordinator    415-476-2351      
UCLA Medical Center ( Site 0005) Recruiting
Santa Monica, California, United States, 90404
Contact: Study Coordinator    310-582-4048      
United States, New York
Mount Sinai Hospital ( Site 0002) Recruiting
New York, New York, United States, 10029
Contact: Study Coordinator    646-543-2859      
Columbia University ( Site 0003) Recruiting
New York, New York, United States, 10032
Contact: Study Coordinator    646-317-3141      
United States, Texas
Mary Crowley Cancer Research Center ( Site 0001) Recruiting
Dallas, Texas, United States, 75230
Contact: Study Coordinator    214-658-1945      
United States, Utah
Huntsman Cancer Institute ( Site 0004) Recruiting
Salt Lake City, Utah, United States, 84112
Contact: Study Coordinator    801-585-3453      
France
Institut Gustave Roussy ( Site 0049) Recruiting
Villejuif, France, 94805
Contact: Study Coordinator    +33142114211      
Israel
Sheba Medical Center ( Site 0040) Recruiting
Ramat Gan, Israel, 5265601
Contact: Study Coordinator    +97235302542      
United Kingdom
The Royal Marsden Foundation Trust ( Site 0031) Recruiting
London, United Kingdom, SW3 6JJ
Contact: Study Coordinator    +442078118311      
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: NCT03010176     History of Changes
Other Study ID Numbers: 1454-001
2016-003160-40 ( EudraCT Number )
MK-1454-001 ( Other Identifier: Merck Protocol Number )
First Posted: January 4, 2017    Key Record Dates
Last Update Posted: March 15, 2019
Last Verified: March 2019
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

Additional relevant MeSH terms:
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Lymphoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Pembrolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents