Study of MK-2118 Administered as Intratumoral Injection as Monotherapy and in Combination With Pembrolizumab (MK-3475) or by Subcutaneous Injection in Combination With Pembrolizumab in the Treatment of Adults With Advanced/Metastatic Solid Tumors or Lymphomas (MK-2118-001)

• ClinicalTrials.gov Identifier: NCT03249792
• Recruitment Status: Completed
• First Posted: August 15, 2017
• Last Update Posted: January 25, 2023
• Sponsor: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Merck Sharp & Dohme LLC

Tracking Information

• First Submitted Date: August 9, 2017
• First Posted Date: August 15, 2017
• Last Update Posted Date: January 25, 2023
• Actual Study Start Date: September 20, 2017
• Actual Primary Completion Date: December 28, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 31, 2020)

• Dose-limiting Toxicities (DLTs) [ Time Frame: Arms 1, 2 & 3: Cycle 1 (Up to 21 days); Arm 4: Cycles 1 & 2 (Up to 35 days) ]
  A DLT is defined as the following toxicities, if related to study treatment: Grade 4 nonhematologic toxicity; Grade 4 hematologic toxicity lasting ≥7 days, except thrombocytopenia (Grade 4 thrombocytopenia of any duration, Grade 3 thrombocytopenia with clinically significant bleeding); Non-hematologic adverse event (AE) ≥Grade 3 (with exceptions); Grade 3 or Grade 4 nonhematologic abnormality; Febrile neutropenia Grade 3 or 4; Any toxicity causing treatment discontinuation or causing participant to miss ≥1 dose during the DLT period; Any toxicity that causes a >2 week delay initiating Cycle 2 of pembrolizumab; Any elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) value that is ≥3× upper limit of normal (ULN) & an elevated total bilirubin value that is ≥2× ULN & an alkaline phosphatase value that is <2× ULN with no alternative explanation; Any ≥Grade 2 immune-mediated uveitis; Grade 5 toxicity. The number of participants who experience a DLT will be presented.
• Adverse Events (AEs) [ Time Frame: Up to approximately 31 months ]
  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. The number of participants who experience at least one AE will be reported.
• Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE) [ Time Frame: Up to approximately 27 months ]
  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. The number of participants who discontinue study treatment due to an AE will be presented.

Original Primary Outcome Measures (submitted: August 11, 2017)

• Dose-limiting Toxicities (DLTs) [ Time Frame: Cycle 1 (Up to 21 days) ]
  A DLT is defined as the any of the following toxicities, if assessed as being related to study treatment: Grade 4 nonhematologic toxicity; Grade 4 hematologic toxicity lasting ≥ 7 days, except thrombocytopenia (Grade 4 thrombocytopenia of any duration, Grade 3 thrombocytopenia if associated with bleeding); Non-hematologic adverse event (AE) ≥ Grade 3; Grade 3 or Grade 4 nonhematologic abnormality; Febrile neutropenia Grade 3 or Grade 4; Any toxicity that causes treatment discontinuation or causes the participant to miss ≥1 dose during Cycle 1; Any toxicity that causes a >2 week delay in initiation of Cycle 2; Any elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) value that is ≥ 3× upper limit of normal (ULN) and an elevated total bilirubin value that is ≥ 2× ULN and an alkaline phosphatase value that is < 2× ULN; Any ≥ Grade 2 immune-mediated uveitis; Grade 5 toxicity. The number of participants who experience a DLT will be presented.
• Adverse Events (AEs) [ Time Frame: Up to approximately 28 months ]
  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. The number of participants who experience at least one AE will be reported.

Current Secondary Outcome Measures (submitted: August 31, 2020)

• MK-2118 Minimum Plasma Concentration (Cmin) [ Time Frame: At designated time points (Up to approximately 2 months) ]
  The observed Cmin of MK-2118 when administered as monotherapy and as combination therapy with pembrolizumab will be determined. Samples will be collected at the following designated time points: Cycle 1 Day 1: Predose and 0.5, 1, 2, 4, 6, 8, 12 and 24 hours postdose; Cycle 2 Day 1: Predose and 0.5, 1, 2, 4, 6 and 8 hours postdose. Arm 4 includes additional timepoints for Cycle 3 Day 1: Predose and 0.5, 1, 2, 4, 6 and 8 hours postdose. For Arms 1-3, each cycle is 3 weeks. For Arm 4, Cycle 1 is 2 weeks and Cycles 2 and beyond are 3 weeks.
• MK-2118 Maximum Plasma Concentration (Cmax) [ Time Frame: At designated time points (Up to approximately 2 months) ]
  The observed Cmax of MK-2118 when administered as monotherapy and as combination therapy with pembrolizumab will be determined. Samples will be collected at the following designated time points: Cycle 1 Day 1: Predose and 0.5, 1, 2, 4, 6, 8, 12 and 24 hours postdose; Cycle 2 Day 1: Predose and 0.5, 1, 2, 4, 6 and 8 hours postdose. Arm 4 includes additional timepoints for Cycle 3 Day 1: Predose and 0.5, 1, 2, 4, 6 and 8 hours postdose. For Arms 1-3, each cycle is 3 weeks. For Arm 4, Cycle 1 is 2 weeks and Cycles 2 and beyond are 3 weeks.
• MK-2118 Area Under the Concentration-time Curve from 0 to 24 hours (AUC 0-24hr) [ Time Frame: At designated time points (Up to approximately 24 hours) ]
  The AUC 0-24hr of MK-2118 when administered as monotherapy and as combination therapy with pembrolizumab will be determined. Samples will be collected at the following designated time points: Cycle 1 Day 1: Predose and 0.5, 1, 2, 4, 6, 8, 12 and 24 hours postdose. For Arms 1-3, each cycle is 3 weeks. For Arm 4, Cycle 1 is 2 weeks and Cycles 2 and beyond are 3 weeks.
• Pembrolizumab Cmin [ Time Frame: At designated time points (Up to approximately 27 months) ]
  The observed Cmin of pembrolizumab when administered as combination therapy with MK-2118 will be determined. This assessment will be performed only on participants in the MK-2118+Pembro combination therapy arms. Samples will be collected at the following designated time points: For Arms 1-3: Predose on Day 1 of Cycles 1, 2, 4, and every 4 cycles up to Cycle 35. For Arm 4: Predose on Day 1 of Cycles 2, 3, 5, and every 4 cycles up to Cycle 36. For Arms 1-3, each cycle is 3 weeks. For Arm 4, Cycle 1 is 2 weeks and Cycles 2 and beyond are 3 weeks.

Original Secondary Outcome Measures (submitted: August 11, 2017)

• MK-2118 Minimum Plasma Concentration (Cmin) [ Time Frame: Cycle 1 Day 1: Predose and 0.5, 1, 2, 4, 6, 8, 12 and 24 hours postdose; Cycle 2 Day 1: Predose and 0.5, 1, 2, 4, 6 and 8 hours postdose ]
  The observed Cmin of MK-2118 when administered as monotherapy and in combination therapy with pembrolizumab will be determined.
• MK-2118 Maximum Plasma Concentration (Cmax) [ Time Frame: Cycle 1 Day 1: Predose and 0.5, 1, 2, 4, 6, 8, 12 and 24 hours postdose; Cycle 2 Day 1: Predose and 0.5, 1, 2, 4, 6 and 8 hours postdose ]
  The observed Cmax of MK-2118 when administered as monotherapy and in combination therapy with pembrolizumab will be determined.
• MK-2118 Area Under the Concentration-time Curve from 0 to 24 hours (AUC0-24h) [ Time Frame: Cycle 1 Day 1: Predose and 0.5, 1, 2, 4, 6, 8, 12 and 24 hours postdose ]
  The AUC0-24h of MK-2118 when administered as monotherapy and in combination therapy with pembrolizumab will be determined.
• Pembrolizumab Cmin [ Time Frame: Cycle 1 Day 1: Predose and 0.5, 1, 2, 4, 6, 8, 12 and 24 hours postdose; Cycle 2 Day 1: Predose and 0.5, 1, 2, 4, 6 and 8 hours postdose; Cycle 4 Day 1 and every 4 cycles thereafter (up to 35 cycles): Predose and 0.5, 1, 2, 4, 6 and 8 hours postdose ]
  The observed Cmin of pembrolizumab when administered as combination therapy with MK-2118 will be determined. This assessment will be performed only on participants in the MK-2118+Pembro Combination Therapy arm.
• Pembrolizumab Cmax [ Time Frame: Cycle 1 Day 1: Predose and 0.5, 1, 2, 4, 6, 8, 12 and 24 hours postdose; Cycle 2 Day 1: Predose and 0.5, 1, 2, 4, 6 and 8 hours postdose; Cycle 4 Day 1 and every 4 cycles thereafter (up to 35 cycles): Predose and 0.5, 1, 2, 4, 6 and 8 hours postdose ]
  The observed Cmax of pembrolizumab when administered as combination therapy with MK-2118 will be determined. This assessment will be performed only on participants in the MK-2118+Pembro Combination Therapy arm.
• Pembrolizumab AUC0-24h [ Time Frame: Cycle 1 Day 1: Predose and 0.5, 1, 2, 4, 6, 8, 12 and 24 hours postdose ]
  The AUC0-24h of pembrolizumab when administered as combination therapy with MK-2118 will be determined. This assessment will be performed only on participants in the MK-2118+Pembro Combination Therapy arm.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of MK-2118 Administered as Intratumoral Injection as Monotherapy and in Combination With Pembrolizumab (MK-3475) or by Subcutaneous Injection in Combination With Pembrolizumab in the Treatment of Adults With Advanced/Metastatic Solid Tumors or Lymphomas (MK-2118-001)
• Official Title: A Phase 1 Open-label, Multicenter Study of MK-2118 Administered by Intratumoral Injection as Monotherapy and in Combination With Pembrolizumab or by Subcutaneous Injection in Combination With Pembrolizumab for Patients With Advanced/Metastatic Solid Tumors or Lymphomas
• Brief Summary: The purposes of this study are to: 1) assess the safety and tolerability and 2) establish a preliminary recommended Phase 2 dose (RP2D) and/or a maximum tolerated dose (MTD) or a maximum administered dose (MAD) of MK-2118 when administered via intratumoral (IT) injection as monotherapy and in combination with pembrolizumab (MK-3475) intravenous (IV) infusion, or via subcutaneous (SC) injection in combination with pembrolizumab IV infusion in the treatment of adult participants with advanced/metastatic solid tumors or lymphomas.

Detailed Description

Participants will receive either MK-2118 monotherapy or MK-2118 in combination with pembrolizumab for up to 35 cycles for Arms 1-3 or up to 36 cycles for Arm 4 (approximately 2 years).

All participants will undergo at least a 24-hour observation period following the first three administrations of MK-2118 (Arms 1-3: Cycle 1 Days 1, 8, and 15. Arm 4: Cycle 1 Days 1 and 8; and Cycle 2 Day 1).

• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Solid Tumor
• Lymphoma

Intervention

• Drug: MK-2118 (IT)
  IT injection
• Drug: MK-2118 (SC)
  SC injection
• Biological: Pembrolizumab
  IV infusion
  Other Name: MK-3475

Study Arms

• Experimental: Arm 1: MK-2118 IT Monotherapy
  Participants receive MK-2118 via IT injection once weekly (Q1W) on Days 1, 8 and 15 of Cycles 1-3 followed by MK-2118 via IT injection once every 3 weeks (Q3W) on Day 1 of Cycle 4 and beyond, for a total of up to 35 cycles (approximately 2 years). Each cycle is 3 weeks long.
  Intervention: Drug: MK-2118 (IT)
• Experimental: Arm 2: MK-2118 IT+Pembro Combo Therapy
  Participants receive pembrolizumab (pembro) 200 mg via IV infusion on Day 1 of each cycle for up to 35 cycles (approximately 2 years) and receive MK-2118 via IT injection Q1W on Days 1, 8 and 15 of Cycles 1-3 followed by MK-2118 IT injection Q3W on Day 1 of Cycle 4 and beyond, for a total of up to 35 cycles (approximately 2 years). Each cycle is 3 weeks long.
  Interventions:

  • Drug: MK-2118 (IT)
  • Biological: Pembrolizumab
• Experimental: Arm 3: MK-2118 Visceral IT+Pembro Combo Therapy
  Participants receive pembrolizumab 200 mg via IV infusion on Day 1 of each cycle for up to 35 cycles (approximately 2 years) and receive MK-2118 via IT injection Q1W on Days 1, 8 and 15 of Cycles 1-2 followed by MK-2118 IT injection Q3W on Day 1 of Cycle 3 and beyond, for a total of up to 35 cycles (approximately 2 years). Each cycle is 3 weeks long.
  Interventions:

  • Drug: MK-2118 (IT)
  • Biological: Pembrolizumab
• Experimental: Arm 4: MK-2118 SC+Pembro Combo Therapy
  Participants receive MK-2118 monotherapy via subcutaneous (SC) injection Q1W on Cycle 1 Days 1 and 8 followed by MK-2118 SC injection Q1W on Cycles 2-4 Days 1, 8 and 15, for a total of up to 36 cycles (approximately 2 years) plus pembrolizumab 200 mg via IV infusion on Day 1 of Cycle 2 and beyond for up to 36 cycles (approximately 2 years). Cycle 1 is 2 weeks long and Cycles 2 and beyond are 3 weeks long.
  Interventions:

  • Drug: MK-2118 (SC)
  • Biological: Pembrolizumab

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 23, 2023): 140
• Original Estimated Enrollment (submitted: August 11, 2017): 66
• Actual Study Completion Date: December 28, 2022
• Actual Primary Completion Date: December 28, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

Arms 1 and 2 Participants:

• Has any histologically or cytologically confirmed advanced/metastatic solid tumor by pathology report and has received, or have been intolerant to all treatment known to confer clinical benefit. Solid tumors and lymphomas of any type are eligible for enrollment. For cutaneous T-cell lymphoma (CTCL), histopathological diagnosis should be confirmed in a skin biopsy representative of disease.
• Has Stage III or Stage IV disease that is not surgically resectable. Stage IIB (T3N0M0B0-1) CTCL participants are eligible.

Arm 3 Participants:

- Has metastatic liver and/or liver lesion 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.

All Participants:

• Has Stage III or Stage IV disease that is not surgically resectable.
• Has ≥1 injectable lesion that is amenable to injection and biopsy via visual inspection for a cutaneous lesion, or via ultrasound guidance for a subcutaneous lesion.
• Has ≥1 discrete, distant noninjected lesion that is amenable to biopsy via visual inspection or amenable to biopsy via image guidance.
• Has Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
• Demonstrates adequate organ function.

• A male participant is eligible to participate if he agrees to the following during the intervention period and for at least 120 days after the last dose of study intervetnion:

  1. Refrain from donating sperm.
  2. Be abstinent from heterosexual intercourse as their preferred and usual lifestyle and agree to remain abstinent OR must agree to use contraception unless confirmed to be azoospermic.

• A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:

  1. Is not a woman of childbearing potential (WOCBP).
  2. Is a WOCBP and using a contraceptive method that is highly effective with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis), during the intervention period and for at least 120 days after the last dose of study intervention, AND agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction during this period.

• Human Immunodeficiency Virus (HIV)-infected participants must meet these additional criteria:

  1. Has HIV-1 infection documented by laboratory test.
  2. Has well-controlled HIV on antiretroviral therapy (ART), defined as: 1) must have a 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 <50 or below 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).

Exclusion Criteria:

• Has history of a second malignancy, unless potentially curative treatment has been completed, with no evidence of malignancy for 2 years (except for successful definitive resection of basal cell carcinoma of the skin, superficial bladder cancer, or in situ cervical cancer).
• Has clinically active central nervous system metastases and/or carcinomatous meningitis.
• Has severe hypersensitivity reaction to treatment with a monoclonal antibody (mAb).
• Has active autoimmune disease that has required systemic treatment in the past 2 years.
• Has history of vasculitis.
• Has active infection requiring therapy.
• Has history of (noninfectious) pneumonitis that required steroids or current pneumonitis.
• Has undergone prior allogeneic hematopoietic stem cell transplantation within the last 5 years.
• Has known Hepatitis B or C infection.
• Has known psychiatric or substance abuse disorders that would interfere in cooperation with the requirements of the trial.
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study.
• Is not fully recovered from any effects of major surgery, and is free of significant detectable infection.
• 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 had chemotherapy, definitive radiation, or biological cancer therapy within 4 weeks (2 weeks for palliative radiation) prior to the first dose of study treatment, or has not recovered to baseline or Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 from the AEs due to cancer therapeutics administered >4 weeks earlier.
• Has been treated within 2 weeks of Cycle 1 Day1 with any of the following: strong/moderate Cytochrome P450 2C9 (CYP2C9) inhibitors, such as: amiodarone, felbamate, fluconazole, miconazole, piperine, oxandrolone, fluorouracil and its derivatives (combination drug tegafur/gimeracil/oteracil [TS-1], Uftoral [UFT], tegafur, carmofur, doxifluridine, capecitabine), sulfaphenazole, cyclosporine, bucurol, tienilic acid; UGT1A3 inhibitors (including ritonavir, quinidine, probenecid, and valproic acid); or strong carbonyl reductase (CBR) inhibitors (including quercetin, menadione, glycyrrhetinic acid, and flufenamic acid).
• 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-2118.
• 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. For CTCL, continued use of either prednisone ≤10 mg/day or continued use of topical steroids is acceptable.
• Has received a live vaccine within 28 days prior to first dose.
• Has been treated with a stimulator of interferon genes (STING) agonist (eg, MK-1454, ADU-S100 [synthetic cyclic dinucleotide (CDN)]).
• Has a history of re-irradiation for head and neck squamous cell carcinoma (HNSCC) 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Israel, United States

Administrative Information

• NCT Number: NCT03249792
• Other Study ID Numbers: 2118-001; MK-2118-001 ( Other Identifier: Merck )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

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

• Current Responsible Party: Merck Sharp & Dohme LLC
• Original Responsible Party: Same as current
• Current Study Sponsor: Merck Sharp & Dohme LLC
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme LLC

• PRS Account: Merck Sharp & Dohme LLC
• Verification Date: January 2023