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

A Phase I/II, Multicenter, Open-label, Clinical Trial of Intratumoral/Intralesional Administration of RGT100 in Subjects With Advanced or Recurrent Tumors

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.

Study Overview

• Status: Terminated
• Conditions: Advanced Solid Tumors
• Intervention / Treatment: Drug: MK-4621

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Germany
  • Dresden, Germany
    • Universitätsklinikum Carl Gustav Carus - Phase I Unit
  • Essen, Germany
    • Universitätsklinikum Essen
  • Heidelberg, Germany
    • National Center for Tumor Diseases
• Spain
  • Madrid, Spain
    • START - Fundación Jiménez Díaz - Phase I Unit
  • Madrid, Spain
    • START - Hospital Universitario HM Sanchinarro - Phase I Unit
• United Kingdom
  • Oxford, United Kingdom
    • University of Oxford Department of Oncology, Churchill Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: 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 Names: RGT100

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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.	Up to 90 days post last injection (Up to approximately 192 days)
Number of Participants Who Experienced a Serious Adverse Event (SAE)	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.	Up to 90 days post last injection (Up to approximately 192 days)
Number of Participants Who Discontinued Study Treatment Due to a Treatment-related Adverse Event (AE)	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.	Up to last injection (Up to approximately 102 days)
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	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.	Cycle 1 (Up to approximately 28 days); Each cycle was 28 days.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate as Evaluated Radiologically Using Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST)	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.	Up to 60 days post last injection (Up to approximately 162 days)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Fold Change From Baseline in Plasma Cytokine Release by Cytokine Type: Day 1 (6 Hours Post Injection)	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.	Baseline and Cycle 1 Day 1 (6 hours post injection) (Up to 1 day); Each cycle was 28 days.
Mean Fold Change From Baseline in Plasma Cytokine Release by Cytokine Type: Day 1 (24 Hours Post Injection)	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.	Baseline and Cycle 1 Day 1 (24 hours post injection) (Up to 2 days); Each cycle was 28 days.
Mean Fold Change From Baseline in Plasma Cytokine Release by Cytokine Type: Day 25 (6 Hours Post Injection)	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.	Baseline and Cycle 1 Day 25 (6 hours post injection) (Up to 25 days); Each cycle was 28 days.
Mean Fold Change From Baseline in Plasma Cytokine Release by Cytokine Type: Day 25 (24 Hours Post Injection)	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.	Baseline and Cycle 1 Day 25 (24 hours post injection) (Up to 26 days); Each cycle was 28 days.
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	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).	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.
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	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).	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.
Maximum Plasma Concentration (Cmax) of MK-4621: Day 1	Blood samples were collected at various time points during Cycle 1 for the determination of MK-4621 Cmax on Day 1.	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.
Maximum Plasma Concentration (Cmax) of MK-4621: Day 25	Blood samples were collected at various time points during Cycle 1 for the determination of MK-4621 Cmax on Day 25.	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.
Immune Infiltration of Injected Tumors by CD3 T Cell Receptor and Ki-67 Nuclear Protein: Day 1	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.	Day 1 prior to injection (Up to 1 day)
Immune Infiltration of Injected Tumors by CD3 T Cell Receptor and Ki-67 Nuclear Protein: Day 25	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.	Day 25 post injection (Up to 25 days)

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 25, 2017
• Primary Completion (ACTUAL): May 18, 2018
• Study Completion (ACTUAL): May 18, 2018

Study Registration Dates

• First Submitted: February 10, 2017
• First Submitted That Met QC Criteria: February 21, 2017
• First Posted (ACTUAL): February 27, 2017

Study Record Updates

• Last Update Posted (ACTUAL): July 30, 2019
• Last Update Submitted That Met QC Criteria: July 22, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: Intratumoral injection; Intralesional injection; Advanced tumor
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Recurrence
• Other Study ID Numbers: 4621-001; 2016-003028-22 (EUDRACT_NUMBER); RGT100-001 (OTHER: Rigontec GMBH); MK-4621-001 (OTHER: Merck)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No