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

Study Overview
=================
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.

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

Conditions
-----------------
Advanced Solid Tumors

Intervention / Treatment
-----------------
* Biological: MK-4621
* Biological: Pembrolizumab


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MK-4621 Monotherapy (Arm 1)<br>Participants receive MK-4621 once a week (Q1W) during each 21-day cycle for a maximum duration of 6 cycles. | Biological: MK-4621<br>* 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.<br>|
| Experimental: MK-4621 + Pembrolizumab (Arm 2)<br>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<br>* 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.<br>Biological: Pembrolizumab<br>* 200 mg administered intravenously (IV) on Day 1 of each 21-day cycle beginning with Cycle 1 (Arm 2) or Cycle 2 (Arm 3).<br>|
| Experimental: Intrahepatic MK-4621 + Pembrolizumab (Arm 3)<br>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<br>* 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.<br>Biological: Pembrolizumab<br>* 200 mg administered intravenously (IV) on Day 1 of each 21-day cycle beginning with Cycle 1 (Arm 2) or Cycle 2 (Arm 3).<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Concentration-time Curve (AUC) of MK-4621 | AUC is the area under the plot of plasma concentration of drug against time after drug administration and is of particular use in estimating bioavailability of drugs, and in estimating total clearance of drugs. Blood samples were collected at multiple time points (pre-dose and post-dose) during the study to assess the 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 | Cmin was defined as the minimum or trough concentration of MK-4621 observed after its administration and just prior to the administration of a subsequent dose. Blood samples were collected at multiple time points (pre-dose and post-dose) during the study to assess the 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 | Cmax was defined as the maximum or peak concentration of MK-4621 observed after its administration. Blood samples were collected at multiple time points (pre-dose and post-dose) to assess the 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) | ORR was defined as the percentage of participants who had a Complete Response (CR, disappearance of all evidence of disease) or Partial Response (PR, ≥30% decrease in the sum of diameters of target lesions) as assessed by Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) based upon investigator assessment. ORR was reported for each treatment arm. | Up to approximately 22 months (through data cut-off of 02-Mar-2021) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Programmed Death-1 (PD-1, PD1),, Programmed Death-Ligand 1 (PD-L1, PDL1), Programmed Cell Death 1 Ligand 2 (PDL2, PD-L2)