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

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ClinicalTrials.gov Identifier: NCT03739138
Recruitment Status : Recruiting
First Posted : November 12, 2018
Last Update Posted : August 30, 2019
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

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 (MK-4621/JetPEI™) as monotherapy and in combination with pembrolizumab in participants with advanced/metastatic solid tumors.

Condition or disease Intervention/treatment Phase
Advanced Solid Tumors Biological: MK-4621/JetPEI™ Biological: Pembrolizumab Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 72 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : December 18, 2018
Estimated Primary Completion Date : April 15, 2021
Estimated Study Completion Date : April 15, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: MK-4621/JetPEI™ Monotherapy (Arm 1)
Participants receive MK-4621/JetPEI™ once a week (Q1W) during each 21-day cycle for a maximum duration of 6 cycles.
Biological: MK-4621/JetPEI™

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. Range administered will depend upon allocation and be based on emerging safety data.

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.


Experimental: MK-4621/JetPEI™ + Pembrolizumab (Arm 2)
Participants receive escalating doses of MK-4621/JetPEI™ 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/JetPEI™ will be based on safety and tolerability.
Biological: MK-4621/JetPEI™

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. Range administered will depend upon allocation and be based on emerging safety data.

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.


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

Experimental: Intrahepatic MK-4621/JetPEI™ + Pembrolizumab (Arm 3)
Participants receive MK-4621/JetPEI™ 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/JetPEI™ 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/JetPEI™ will be based on safety and tolerability.
Biological: MK-4621/JetPEI™

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. Range administered will depend upon allocation and be based on emerging safety data.

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.


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




Primary Outcome Measures :
  1. Number of Participants Experiencing Dose Limiting Toxicities (DLTs) [ Time Frame: Up to first two 21-day treatment cycles (up to 42 days) ]
    DLTs are toxicities that are possibly, probably, or definitely related to study therapy; that meet pre-defined severity criteria; and result in a change in the given dose. The number of participants who experience DLTs will be reported for each arm.

  2. Number of Participants Experiencing Adverse Events (AEs) [ Time Frame: Up to 2 years ]
    An AE is any untoward medical occurrence in a participant that is temporally associated with the use of study treatment, whether or not considered related to the study treatment. An AE can 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 experience an AE will be reported for each arm.

  3. Number of Participants Discontinuing Study Treatment Due to AEs [ Time Frame: Up to 2 years ]
    An AE is any untoward medical occurrence in a participant that is temporally associated with the use of study treatment, whether or not considered related to the study treatment. An AE can 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 discontinue study treatment due to an AE will be reported for each arm.


Secondary Outcome Measures :
  1. Area under the concentration-time curve (AUC) of MK-4621/JetPEI™ [ Time Frame: Day 1 of 21-day Cycles 1, 2, and 3 (Arm 3 only): pre-dose, end of IT injection up to +5 minutes (0.0 hours), 0.5, 1.0, 2, 4, 6, and 24 hours (Cycle 1 Day 1 only) after MK4621/JetPEI™ dose ]
    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 will be collected at multiple time points (pre-dose and post-dose) during the study to assess the AUC of MK-4621/JetPEI™.

  2. Minimum concentration (Cmin) of MK-4621/JetPEI™ [ Time Frame: Day 1 of 21-day Cycles 1, 2, and 3 (Arm 3 only): pre-dose, end of IT injection up to +5 minutes (0.0 hours), 0.5, 1.0, 2, 4, 6, and 24 hours (Cycle 1 Day 1 only) after MK4621/JetPEI™ dose ]
    Cmin is the minimum or "trough" concentration of a drug observed after its administration and just prior to the administration of a subsequent dose. Blood samples will be collected at multiple time points (pre-dose and post-dose) during the study to assess the Cmin of MK-4621/JetPEI™

  3. Maximum concentration (Cmax) of MK-4621/JetPEI™ [ Time Frame: Day 1 of 21-day Cycles 1, 2, and 3 (Arm 3 only): pre-dose, end of IT injection up to +5 minutes (0.0 hours), 0.5, 1.0, 2, 4, 6, and 24 hours (Cycle 1 Day 1 only) after MK4621/JetPEI™ dose ]
    Cmax is the maximum or "peak" concentration of a drug observed after its administration. Blood samples will be collected at multiple time points (pre-dose and post-dose) during the Dose Escalation phase to assess the Cmax of MK-4621/JetPEI™.

  4. Objective Response Rate (ORR) [ Time Frame: Up to 2 years ]
    ORR is defined as the percentage of participants who have a Complete Response ([CR], disappearance of all evidence of disease) or Partial Response ([PR], regression of measurable disease and no new sites) as assessed by Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1). Modified RECIST 1.1 for immune-based therapeutics (iRECIST) will be used by the site to confirm radiographic progression and tumor response. ORR will be determined for each treatment arm.



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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:

  • 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

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): NCT03739138


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

Locations
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France
Institut Bergonie ( Site 3303) Recruiting
Bordeaux, France, 33076
Contact: Study Coordinator    +33556333333      
CHU La Timone ( Site 3304) Recruiting
Marseille, France, 13005
Contact: Study Coordinator    +33491385590      
Institut Curie ( Site 3302) Recruiting
Paris, France, 75005
Contact: Study Coordinator    +33156246527      
Institut Gustave Roussy ( Site 3301) Recruiting
Villejuif, France, 94800
Contact: Study Coordinator    +33478782714      
Germany
Charite Campus Benjamin Franklin ( Site 4903) Recruiting
Berlin, Germany, 10117
Contact: Study Coordinator    +4930420513470      
Universitaetsklinikum Carl Gustav Carus der TU Dresden ( Site 4901) Recruiting
Dresden, Germany, 01307
Contact: Study Coordinator    +493514587566      
Spain
Hospital Universitario Fundacion Jimenez Diaz ( Site 3401) Recruiting
Madrid, Spain, 28040
Contact: Study Coordinator    +9155048002486      
Centro Integral Oncologico Clara Campal START Madrid ( Site 3402) Recruiting
Madrid, Spain, 28050
Contact: Study Coordinator    +34917567828      
United Kingdom
Oxford University Hospital NHS Foundation Trust ( Site 4401) Recruiting
Oxford, United Kingdom, OX3 7LE
Contact: Study Coordinator    +441865617331      
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: NCT03739138     History of Changes
Other Study ID Numbers: 4621-002
2018-000845-37 ( EudraCT Number )
MK-4621-002 ( Other Identifier: Merck Protocol Number )
First Posted: November 12, 2018    Key Record Dates
Last Update Posted: August 30, 2019
Last Verified: August 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
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Merck Sharp & Dohme Corp.:
Programmed Death-1 (PD-1, PD1),
Programmed Death-Ligand 1 (PD-L1, PDL1)
Additional relevant MeSH terms:
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Neoplasms
Pembrolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents