Intratumoral/Intralesional Administration of MK-4621/JetPEI™ With or Without Pembrolizumab in Participants With Advanced/Metastatic or Recurrent Solid Tumors (MK-4621-002)

NCT03739138 | Terminated Phase 1 Results FDA Drug

• 3 other identifiers: 4621-002MK-4621-0022018-000845-37
• Study Type: interventional
• Target: 30
• Locations: 4 countries
• Sites: 9

Brief Summary

The purpose of this study is to evaluate safety and tolerability, pharmacokinetics (PK), and preliminary antitumor activity of intratumoral (IT) / intralesional injections of MK-4621 delivered via the JetPEI™ in vivo linear polyethylenimine nucleic acid delivery system as monotherapy and in combination with pembrolizumab in participants with advanced/metastatic solid tumors.

Conditions

Advanced Solid Tumors

Keywords

Programmed Death-1 (PD-1, PD1),; Programmed Death-Ligand 1 (PD-L1, PDL1); Programmed Cell Death 1 Ligand 2 (PDL2, PD-L2)

Outcome Measures

Primary Outcomes (3)

• Percentage of Participants Experiencing Dose Limiting Toxicities (DLTs)

  The following toxicities during DLT evaluation period were considered DLT, if assessed by investigator to be possibly, probably, or definitely related to treatment: Grade (Gr) 4 nonhematologic toxicity; Gr 4 hematologic toxicity lasting ≥7 days or protocol-specified thrombocytopenia; any nonhematologic adverse event (AE) ≥Gr 3 in severity (with exceptions); any Gr 3/Gr 4 nonhematologic laboratory value if clinically significant medical intervention was required to treat the participant, or the abnormality led to hospitalization, or the abnormality persisted for \>1 week; or the abnormality resulted in a drug-induced liver injury; febrile neutropenia Gr 3/Gr 4; \>2 week delay in initiating Cycle 2 due to treatment-related toxicity; any treatment-related toxicity that caused the participant to discontinue treatment during Cycle 1; missing \>2 injections of MK-4621 during Cycle 1, or Gr 5 toxicity. The percentage of participants who experienced DLTs were reported for each arm.

  Up to 21 days (Cycle 1)

• Number of Participants Experiencing Adverse Events (AEs)

  An AE was defined as any untoward medical occurrence in a participant that was temporally associated with the use of study treatment, whether or not considered related to the study treatment. An AE could 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. The number of participants who experienced an AE was reported for each arm.

  Up to approximately 13 months

• Number of Participants Discontinuing Study Treatment Due to AEs

  An AE was defined as any untoward medical occurrence in a participant that was temporally associated with the use of study treatment, whether or not considered related to the study treatment. An AE could 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. The number of participants who discontinued study treatment due to an AE was reported for each arm.

  Up to approximately 13 months

Secondary Outcomes (4)

• Area Under the Concentration-time Curve (AUC) of MK-4621

  Day 1 of 21-day Cycles 1 and 2: pre-dose (1-8 hours), end of IT injection up to +5 minutes (0.0 hours), 0.5, 1.0, 2, 4, and 6 hours. Samples also collected at 24 hours after MK-4621 dose for Cycle 1 Day 1 only.

• Minimum Concentration (Cmin) of MK-4621

  Day 1 of 21-day Cycles 1 and 2: pre-dose (1-8 hours), end of IT injection up to +5 minutes (0.0 hours), 0.5, 1.0, 2, 4, and 6 hours. Samples also collected at 24 hours after MK-4621 dose for Cycle 1 Day 1 only.

• Maximum Concentration (Cmax) of MK-4621

  Day 1 of 21-day Cycles 1 and 2: pre-dose (1-8 hours), end of IT injection up to +5 minutes (0.0 hours), 0.5, 1.0, 2, 4, and 6 hours. Samples also collected at 24 hours after MK-4621 dose for Cycle 1 Day 1 only.

• Objective Response Rate (ORR)

  Up to approximately 22 months (through data cut-off of 02-Mar-2021)

Study Arms (3)

MK-4621 Monotherapy (Arm 1)

EXPERIMENTAL

Participants receive MK-4621 once a week (Q1W) during each 21-day cycle for a maximum duration of 6 cycles.

Biological: MK-4621

MK-4621 + Pembrolizumab (Arm 2)

EXPERIMENTAL

Participants receive escalating doses of MK-4621 Q1W during each 21-day cycle for a maximum duration of 6 cycles in combination with pembrolizumab at a fixed dose 200 mg every 3 weeks (Q3W) for a maximum duration of 6 cycles. Participants may continue on treatment with pembrolizumab after Cycle 6 for up to 35 cycles (Cycles 7-35, approximately 2 years) from the start of treatment. Dose escalation of MK-4621 will be based on safety and tolerability.

Biological: MK-4621; Biological: Pembrolizumab

Intrahepatic MK-4621 + Pembrolizumab (Arm 3)

EXPERIMENTAL

Participants receive MK-4621 as monotherapy on Day 1 only of the first 21-day cycle (run-in phase). After the run-in phase, participants receive escalating doses of MK-4621 Q3W in combination with pembrolizumab at a fixed dose 200 mg Q3W for a maximum duration of 5 cycles (Cycles 2-6). Participants may continue on treatment with pembrolizumab for up to 35 cycles (Cycles 7-35, approximately 2 years) from the start of treatment. Dose escalation of MK-4621 will be based on safety and tolerability.

Biological: MK-4621; Biological: Pembrolizumab

Interventions

MK-4621 BIOLOGICAL

MK-4621 is delivered via the JetPEI™ in vivo linear polyethylenimine nucleic acid delivery system as follows: For Arm 1: administered intratumorally Q1W, on Days 1, 8, and 15 of each 21-day cycle. For Arm 2: administered intratumorally Q1W, on Days 1, 8, and 15 of each 21-day cycle according to randomization. For Arm 3: administered intratumorally Q3W, on Day 1 of each 21-day cycle. Range administered will depend upon allocation and be based on emerging safety data.

Intrahepatic MK-4621 + Pembrolizumab (Arm 3); MK-4621 + Pembrolizumab (Arm 2); MK-4621 Monotherapy (Arm 1)

Pembrolizumab BIOLOGICAL

200 mg administered intravenously (IV) on Day 1 of each 21-day cycle beginning with Cycle 1 (Arm 2) or Cycle 2 (Arm 3).

Intrahepatic MK-4621 + Pembrolizumab (Arm 3); MK-4621 + Pembrolizumab (Arm 2)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Has a histologically- or cytologically-confirmed advanced/metastatic solid tumor by pathology report and has received, or been intolerant to, all treatment known to confer clinical benefit
• Has submitted an evaluable baseline tumor sample for analysis before start of treatment
• Performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale
• Demonstrates adequate organ function
• Male participants must agree to use approved 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 who are not pregnant or breastfeeding, and who are either not a woman of childbearing potential (WOCBP), or are a WOCBP who agrees to use approved contraception during the treatment period and for at least 120 days after the last dose of study treatment
• Arms 1 and 2: have 3 lesions defined as follows: 1) at least 1 cutaneous or subcutaneous lesion that is amenable to injection and biopsy (lesion 1) that is measurable as defined by RECIST 1.1, 2) at least 1 discrete non-injected, non-biopsied lesion that is measurable as defined by RECIST 1.1 (lesion 2), and 3) at least 1 discrete and/or distant non-injected lesion amenable for biopsy (lesion 3)
• Arm 3 only: 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 intratumoral liver injection. For Arm 3, at least 2 lesions have to be identified as follows: 1) at least 1 liver lesion amenable to image-guided intratumoral injection and biopsy via ultrasound guidance or cross-sectional imaging (CT/MRI) guidance and must be measurable as defined by RECIST 1.1 (lesion 1) and 2) at least 1 other discrete non-injected, non-biopsied lesion that is measurable as defined by RECIST 1.1 (lesion 2)

You may not qualify if:

• Has had chemotherapy, definitive radiation, or biological cancer therapy within 4 weeks prior to the first dose of study therapy, or has not recovered to Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or better from any AEs that were due to cancer therapeutics administered more than 4 weeks earlier
• History of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years
• Has hepatocellular carcinoma (for Arm 3 only)
• Has clinically active central nervous system (CNS) metastases and/or carcinomatous meningitis
• Has had a severe hypersensitivity reaction to treatment with a monoclonal antibody/components of the study treatment
• Has an active infection requiring therapy
• Has 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 past 2 years
• Has a known history of human immunodeficiency virus (HIV) infection and/or Hepatitis B or C infections, or known to be positive for Hepatitis B surface antigen (HBsAg)/Hepatitis B virus (HBV) DNA or Hepatitis C Antibody or RNA
• Has a history or current evidence of 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, or is not in the best interest of the participant to participate, in the opinion of the treating investigator
• Has known psychiatric or substance abuse disorder that would interfere with cooperating with the requirements of the study
• Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment
• Has not fully recovered from any effects of major surgery without significant detectable infection
• WOCBP who has a positive urine pregnancy test within 72 hours before the first dose of study treatment

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Study Sites (9)

Institut Bergonie ( Site 3303)

Bordeaux, 33076, France

Location

CHU La Timone ( Site 3304)

Marseille, 13005, France

Location

Institut Curie ( Site 3302)

Paris, 75005, France

Location

Institut Gustave Roussy ( Site 3301)

Villejuif, 94800, France

Location

Charite Campus Benjamin Franklin ( Site 4903)

Berlin, 10117, Germany

Location

Universitaetsklinikum Carl Gustav Carus der TU Dresden ( Site 4901)

Dresden, 01307, Germany

Location

Hospital Universitario Fundacion Jimenez Diaz ( Site 3401)

Madrid, 28040, Spain

Location

Centro Integral Oncologico Clara Campal START Madrid ( Site 3402)

Madrid, 28050, Spain

Location

Oxford University Hospital NHS Foundation Trust ( Site 4401)

Oxford, OX3 7LE, United Kingdom

Location

Related Publications (1)

• Moreno V, Calvo E, Middleton MR, Barlesi F, Gaudy-Marqueste C, Italiano A, Romano E, Marabelle A, Chartash E, Dobrenkov K, Zhou H, Connors EC, Zhang Y, Wermke M. Treatment with a retinoic acid-inducible gene I (RIG-I) agonist as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors: results from two phase 1 studies. Cancer Immunol Immunother. 2022 Dec;71(12):2985-2998. doi: 10.1007/s00262-022-03191-8. Epub 2022 May 21.

  PMID: 35596791 DERIVED

MeSH Terms

Conditions

Parkinson Disease 4, Autosomal Dominant Lewy Body

Interventions

pembrolizumab

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme Corp.

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 31, 2018
• First Posted: November 13, 2018
• Study Start: December 18, 2018
• Primary Completion: March 2, 2021
• Study Completion: March 2, 2021
• Last Updated: February 28, 2022
• Results First Posted: February 28, 2022

Record last verified: 2022-01

Data Sharing

• IPD Sharing: Will share

Locations

ES (2); GB (1); DE (2); FR (4)