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Study of Intralesional Administration of MK-4621 (RGT100) in Adult Participants With Advanced or Recurrent Tumors (MK-4621-001/RGT100-001)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03065023
Recruitment Status : Terminated (Group B not started for business reasons.)
First Posted : February 27, 2017
Results First Posted : July 16, 2019
Last Update Posted : July 30, 2019
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Brief Summary:
This is a Phase I/II multicenter, first-in-human open-label, dose escalation study to evaluate the safety, tolerability, and anti-tumor activity of intratumoral (IT)/intralesional (IL) injections of MK-4621 (RGT100) in adult participants with selected advanced or recurrent tumors.

Condition or disease Intervention/treatment Phase
Advanced Solid Tumors Drug: MK-4621 Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 15 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

The study was to be conducted in 2 groups:

  • Group A: participants with transdermally/transmucosally injectable tumors, and
  • Group B: participants with injectable liver tumors or liver metastases. However, Group B was not started.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II, Multicenter, Open-label, Clinical Trial of Intratumoral/Intralesional Administration of RGT100 in Subjects With Advanced or Recurrent Tumors
Actual Study Start Date : April 25, 2017
Actual Primary Completion Date : May 18, 2018
Actual Study Completion Date : May 18, 2018

Arm Intervention/treatment
Experimental: Group A: Cutaenous lesions
Participants with transdermally/transmucosally injectable tumors including cutaneous, subcutaneous or lymph node injectable tumors received escalating doses of MK-4621 via intratumoral (IT)/intralesional (IL) injection twice each week (Q2W) over a period of 4 weeks. Participants may have continued to receive study treatment beyond Cycle 1 for the remaining duration of the study as long as clinical benefit (no overt clinical progression or toxicity considered to be intolerable as per Investigator's assessment) was present (up to approximately 2 years).
Drug: MK-4621
IT/IL injection Fixed concentration of 0.2 mg/mL Starting dose: 0.2 mg
Other Name: RGT100

Experimental: Group B: Liver lesions
Participants with injectable liver tumors or liver metastases were to receive escalating doses of MK-4621 via intratumoral (IT)/intralesional (IL) injection once each week over a period of 4 weeks. Participants were to have been able to continue to receive study treatment beyond Cycle 1 for the remaining duration of the study as long as clinical benefit (no overt clinical progression or toxicity considered to be intolerable as per Investigator's assessment) was present (up to approximately 2 years). (Group B was not started. Development will continue with new protocol.)
Drug: MK-4621
IT/IL injection Fixed concentration of 0.2 mg/mL Starting dose: 0.2 mg
Other Name: RGT100




Primary Outcome Measures :
  1. Number of Participants Who Experienced a Treatment-related Adverse Event (AE) or Laboratory Abnormality by Severity Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.03 Criteria [ Time Frame: Up to 90 days post last injection (Up to approximately 192 days) ]
    An AE was defined as any untoward medical occurrence in a study participant administered study treatment which did not necessarily have a causal relationship with this treatment. Treatment-related was defined as having a "Possible" or "Related" relationship to study treatment, as assessed by the Investigator. Severity of AE referred to the extent to which an AE affected the participants daily activities as assessed by the Investigator and was based on NCI CTCAE grades: Grade 1 (Mild); Grade 2 (Moderate); Grade 3 (Severe or medically significant but not immediately life-threatening); Grade 4 (Life-threatening consequences); or Grade 5 (Death related to AE). The number of participants who experienced at least one treatment-related AE or laboratory abnormality are presented by severity.

  2. Number of Participants Who Experienced a Serious Adverse Event (SAE) [ Time Frame: Up to 90 days post last injection (Up to approximately 192 days) ]

    A SAE was defined as any AE, regardless of dose, causality or expectedness, that:

    • Resulted in death;
    • Was life-threatening;
    • Required inpatient hospitalization or prolonged existing inpatient hospitalization;
    • Resulted in persistent or significant incapacity or disability;
    • Was a congenital anomaly or birth defect; or
    • Was any other medically important event.

  3. Number of Participants Who Discontinued Study Treatment Due to a Treatment-related Adverse Event (AE) [ Time Frame: Up to last injection (Up to approximately 102 days) ]
    An AE was defined as any untoward medical occurrence in a study participant administered a study treatment which did not necessarily have a causal relationship with this treatment. Treatment-related was defined as having a "Possible" or "Related" relationship to study treatment, as assessed by the Investigator. The number of participants who discontinued study treatment due to a treatment-related AE is presented.

  4. Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) by Severity Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.03 Criteria [ Time Frame: Cycle 1 (Up to approximately 28 days); Each cycle was 28 days. ]

    DLTs were assessed during the first treatment cycle (28 days) & were defined as any drug-related toxicity that occurred during the 28-day DLT period and included:

    • Non-hematologic toxicity grade ≥3 (except diarrhea, nausea, and vomiting unless lasting >3 days despite optimal supportive care);
    • Confirmed (with a second measurement after 24 hours) non-hematologic appropriately graded laboratory findings of Grade ≥3 that were ≤ Grade 1 at baseline;
    • Hematologic toxicity:

      • Grade 4 neutropenia ≥5 days, or Grade 3 neutropenia with fever (fever is >38.4ºC)
      • Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia lasting >7 days or with bleeding; and
    • Any other toxicity assessed as related to MK-4621, and which, in the opinion of the Investigator and the Sponsor physician constituted a DLT.

    The number of participants who experienced a DLT is presented by NCI CTCAE version 4.03 severity grade.



Secondary Outcome Measures :
  1. Objective Response Rate as Evaluated Radiologically Using Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) [ Time Frame: Up to 60 days post last injection (Up to approximately 162 days) ]
    ORR was defined as the percentage of participants who had a Complete Response (CR) or a Partial Response. Per irRECIST, CR (irCR) was defined as the complete disappearance of all measurable and non-measurable lesions. Lymph nodes must also have decreased to <0 mm in short axis. And, per irRECIST, Partial Response (irPR) was defined as a decrease of ≥30% in total measured tumor burden (TMTB) relative to baseline. For this study, irRECIST was modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The percentage of participants who experienced an irCR or irPR based on irRECIST is presented.


Other Outcome Measures:
  1. Mean Fold Change From Baseline in Plasma Cytokine Release by Cytokine Type: Day 1 (6 Hours Post Injection) [ Time Frame: Baseline and Cycle 1 Day 1 (6 hours post injection) (Up to 1 day); Each cycle was 28 days. ]
    Blood samples were collected at various time points for the analysis of mean fold change from baseline in cytokine release for selected cytokines (Interleukin-6 [IL-6] and tumor necrosis factor-alpha [TNF-a]) in plasma.

  2. Mean Fold Change From Baseline in Plasma Cytokine Release by Cytokine Type: Day 1 (24 Hours Post Injection) [ Time Frame: Baseline and Cycle 1 Day 1 (24 hours post injection) (Up to 2 days); Each cycle was 28 days. ]
    Blood samples were collected at various time points for the analysis of mean fold change from baseline in cytokine release for selected cytokines (Interleukin-6 [IL-6] and tumor necrosis factor-alpha [TNF-a]) in plasma.

  3. Mean Fold Change From Baseline in Plasma Cytokine Release by Cytokine Type: Day 25 (6 Hours Post Injection) [ Time Frame: Baseline and Cycle 1 Day 25 (6 hours post injection) (Up to 25 days); Each cycle was 28 days. ]
    Blood samples were collected at various time points for the analysis of mean fold change from baseline in cytokine release for selected cytokines (Interleukin-6 [IL-6] and tumor necrosis factor-alpha [TNF-a]) in plasma.

  4. Mean Fold Change From Baseline in Plasma Cytokine Release by Cytokine Type: Day 25 (24 Hours Post Injection) [ Time Frame: Baseline and Cycle 1 Day 25 (24 hours post injection) (Up to 26 days); Each cycle was 28 days. ]
    Blood samples were collected at various time points for the analysis of mean fold change from baseline in cytokine release for selected cytokines (Interleukin-6 [IL-6] and tumor necrosis factor-alpha [TNF-a]) in plasma.

  5. Area Under the Concentration-Time Curve From Start of Dosing to Last Observed Concentration Above Limit of Quantitation (AUC0-t) of MK-4621: Day 1 [ Time Frame: Cycle 1 Day 1: Predose, 5 and 30 minutes, 2, 4, 6 and 24 hours post dose (Up to 2 days); Each cycle was 28 days. ]
    Blood samples were collected at various time points during Cycle 1 for the determination of MK-4621 AUC0-t on Day 1, which was defined as the AUC from the start time of dosing to the time of the last observed concentration above the limit of quantitation (LOQ).

  6. Area Under the Concentration-Time Curve From Start of Dosing to Last Observed Concentration Above Limit of Quantitation (AUC0-t) of MK-4621: Day 25 [ Time Frame: Cycle 1 Day 25: Predose, 5 and 30 minutes, 2, 4, 6 and 24 hours post dose (Up to 26 days); Each cycle was 28 days. ]
    Blood samples were collected at various time points during Cycle 1 for the determination of MK-4621 AUC0-t on Day 25, which was defined as the AUC from the start time of dosing to the time of the last observed concentration above the limit of quantitation (LOQ).

  7. Maximum Plasma Concentration (Cmax) of MK-4621: Day 1 [ Time Frame: Cycle 1 Day 1: Predose, 5 and 30 minutes, 2, 4, 6 and 24 hours post dose (Up to 2 days); Each cycle was 28 days. ]
    Blood samples were collected at various time points during Cycle 1 for the determination of MK-4621 Cmax on Day 1.

  8. Maximum Plasma Concentration (Cmax) of MK-4621: Day 25 [ Time Frame: Cycle 1 Day 25: Predose, 5 and 30 minutes, 2, 4, 6 and 24 hours post dose (Up to 26 days); Each cycle was 28 days. ]
    Blood samples were collected at various time points during Cycle 1 for the determination of MK-4621 Cmax on Day 25.

  9. Immune Infiltration of Injected Tumors by CD3 T Cell Receptor and Ki-67 Nuclear Protein: Day 1 [ Time Frame: Day 1 prior to injection (Up to 1 day) ]
    Sequential participant tumor biopsies were assessed via immunohistochemistry for the presence of tumor infiltrating CD3 T cell co-receptor-marked cells and Ki-67 nuclear protein-marked cells in tumor biopsies. CD3 is a marker of T cells and KI-67 is a cell marker of proliferation and activation. The percentage of positive CD3-marked cells and double-positive CD3 and Ki-67 nuclear protein-marked cells in tumor biopsies predose on Day 1 are presented.

  10. Immune Infiltration of Injected Tumors by CD3 T Cell Receptor and Ki-67 Nuclear Protein: Day 25 [ Time Frame: Day 25 post injection (Up to 25 days) ]
    Sequential participant tumor biopsies were assessed via immunohistochemistry for the presence of tumor infiltrating CD3 T cell co-receptor-marked cells and Ki-67 nuclear protein-marked cells in tumor biopsies. CD3 is a marker of T cells and KI-67 is a cell marker of proliferation and activation. The percentage of positive CD3-marked cells and double-positive CD3 and Ki-67 nuclear protein-marked cells in tumor biopsies postdose on Day 25 are presented.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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:

  1. Male or female aged ≥18 years
  2. Participants with histologically or cytologically confirmed diagnosis of advanced or recurrent tumors (including lymphomas) for whom all standard treatments have been used or are not feasible and MK-4621 (RGT100) is a suitable treatment option and:

    1. For Group A: has cutaneous, sub-cutaneous (SC), or lymph node injectable tumors
    2. For Group B: has injectable liver tumors or liver metastases
  3. Eastern Cooperative Oncology Group (ECOG) performance status 0-2
  4. Life expectancy >3 months as assessed by the Investigator
  5. Adequate organ function
  6. Negative serum pregnancy test within 2 weeks before first dose of study drug if the participant is a woman of childbearing potential. Participants and participant's partners of childbearing potential must agree to use birth control consistently and correctly during the study and for at least 6 months after the last study drug application.
  7. At least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) and 1 separate injectable lesion with diameter ≥1 cm but <7 cm
  8. Ability to provide written informed consent before any study drug-related screening procedures being performed

Exclusion Criteria:

  1. Any tumor-directed therapy within 4 weeks before study treatment
  2. Treatment with investigational drugs within 4 weeks before study enrolment
  3. Systemic steroids at a dose of >10 mg of prednisolone, >2 mg of dexamethasone a day or equivalent, except topical (inhaled, topical, nasal) for the last 28 days and ongoing
  4. Participants with rapidly progressing disease (as determined by the Investigator)
  5. Ongoing immune-related adverse events (irAEs) and/or adverse events (AEs) ≥ grade 2 not resolved from previous therapies except vitiligo, stable neuropathy grade 2, hair loss, and stable endocrinopathies with substitutive hormone therapy
  6. Within 4 weeks of major surgery
  7. Prior splenectomy
  8. Documented history of active autoimmune disorders requiring systemic immunosuppressive therapy
  9. Primary or secondary immune deficiency
  10. Active allergy requiring systemic medication or active infections requiring anti-infectious therapy
  11. Seropositive (except after vaccination) for human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV)
  12. Clinically significant cardiac disease including heart failure (New York Heart Association, Class III or IV), pre-existing arrhythmia, uncontrolled angina pectoris, or myocardial infarction within 1 year before study entry
  13. Dementia or altered mental status that would prohibit informed consent
  14. Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study assessed by the Investigator
  15. History of stroke, seizures, encephalitis, or multiple sclerosis
  16. Gastric ulcer or inflammatory bowel disease or Crohn's disease or ulcerative colitis in the last 6 months
  17. Active drug or alcohol abuse
  18. Pregnant or breast feeding

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): NCT03065023


Locations
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Germany
Universitätsklinikum Carl Gustav Carus - Phase I Unit
Dresden, Germany
Universitätsklinikum Essen
Essen, Germany
National Center for Tumor Diseases
Heidelberg, Germany
Spain
START - Fundación Jiménez Díaz - Phase I Unit
Madrid, Spain
START - Hospital Universitario HM Sanchinarro - Phase I Unit
Madrid, Spain
United Kingdom
University of Oxford Department of Oncology, Churchill Hospital
Oxford, United Kingdom
Sponsors and Collaborators
Merck Sharp & Dohme Corp.
Investigators
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Study Director: Medical Director Merck Sharp & Dohme Corp.
  Study Documents (Full-Text)

Documents provided by Merck Sharp & Dohme Corp.:

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Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT03065023    
Other Study ID Numbers: 4621-001
2016-003028-22 ( EudraCT Number )
RGT100-001 ( Other Identifier: Rigontec GMBH )
MK-4621-001 ( Other Identifier: Merck )
First Posted: February 27, 2017    Key Record Dates
Results First Posted: July 16, 2019
Last Update Posted: July 30, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf
URL: http://engagezone.msd.com/ds_documentation.php

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Merck Sharp & Dohme Corp.:
Advanced tumor
Intratumoral injection
Intralesional injection
Additional relevant MeSH terms:
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Neoplasms