Clinical trial NCT03739138: Intratumoral/Intralesional Administration of MK-4621/JetPEI™ With or Without Pembrolizumab in Participants With Advanced/Metastatic or Recurrent Solid Tumors (MK-4621-002)
Official title: A Phase 1/1b, Open-label Clinical Study of Intratumoral/Intralesional Administration of MK-4621/JetPEI as Monotherapy or in Combination With Pembrolizumab (MK-3475) in Participants With Advanced/Metastatic or Recurrent Solid Tumors
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
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)
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2018-11-13
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria:

* 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)

Exclusion Criteria:

* 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
* Has received a live-virus vaccine within 30 days of planned treatment start
* Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment. Prior exposure to immunotherapeutics is allowed, including PD-1 and PD-L1 inhibitors, provided participant did not experience a ≥Grade 3 drug-related toxicity on monotherapy with a PD-1 or PD-L1 inhibitor
* Has a history of re-irradiation for squamous cell carcinoma of head and 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

Primary outcomes:
measure: Percentage of Participants Experiencing Dose Limiting Toxicities (DLTs)
timeFrame: Up to 21 days (Cycle 1)
measure: Number of Participants Experiencing Adverse Events (AEs)
timeFrame: Up to approximately 13 months
measure: Number of Participants Discontinuing Study Treatment Due to AEs
timeFrame: Up to approximately 13 months
Secondary outcomes:
measure: Area Under the Concentration-time Curve (AUC) of MK-4621
timeFrame: 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.
measure: Minimum Concentration (Cmin) of MK-4621
timeFrame: 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.
measure: Maximum Concentration (Cmax) of MK-4621
timeFrame: 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.
measure: Objective Response Rate (ORR)
timeFrame: Up to approximately 22 months (through data cut-off of 02-Mar-2021)
Other outcomes:
Locations:
city: Bordeaux
country: France
facility: Institut Bergonie ( Site 3303)
city: Marseille
country: France
facility: CHU La Timone ( Site 3304)
city: Paris
country: France
facility: Institut Curie ( Site 3302)
city: Villejuif
country: France
facility: Institut Gustave Roussy ( Site 3301)
city: Berlin
country: Germany
facility: Charite Campus Benjamin Franklin ( Site 4903)
city: Dresden
country: Germany
facility: Universitaetsklinikum Carl Gustav Carus der TU Dresden ( Site 4901)
city: Madrid
country: Spain
facility: Hospital Universitario Fundacion Jimenez Diaz ( Site 3401)
city: Madrid
country: Spain
facility: Centro Integral Oncologico Clara Campal START Madrid ( Site 3402)
city: Oxford
country: United Kingdom
facility: Oxford University Hospital NHS Foundation Trust ( Site 4401)
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: 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.