Clinical trial NCT03065023: Study of Intralesional Administration of MK-4621 (RGT100) in Adult Participants With Advanced or Recurrent Tumors (MK-4621-001/RGT100-001)
Official title: A Phase I/II, Multicenter, Open-label, Clinical Trial of Intratumoral/Intralesional Administration of RGT100 in Subjects With Advanced or Recurrent Tumors
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Advanced Solid Tumors
Keywords: Advanced tumor
Intratumoral injection
Intralesional injection
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2017-02-27
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.


Eligibility 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

Primary outcomes:
measure: 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
timeFrame: Up to 90 days post last injection (Up to approximately 192 days)
measure: Number of Participants Who Experienced a Serious Adverse Event (SAE)
timeFrame: Up to 90 days post last injection (Up to approximately 192 days)
measure: Number of Participants Who Discontinued Study Treatment Due to a Treatment-related Adverse Event (AE)
timeFrame: Up to last injection (Up to approximately 102 days)
measure: 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
timeFrame: Cycle 1 (Up to approximately 28 days); Each cycle was 28 days.
Secondary outcomes:
measure: Objective Response Rate as Evaluated Radiologically Using Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST)
timeFrame: Up to 60 days post last injection (Up to approximately 162 days)
Other outcomes:
measure: Mean Fold Change From Baseline in Plasma Cytokine Release by Cytokine Type: Day 1 (6 Hours Post Injection)
timeFrame: Baseline and Cycle 1 Day 1 (6 hours post injection) (Up to 1 day); Each cycle was 28 days.
measure: Mean Fold Change From Baseline in Plasma Cytokine Release by Cytokine Type: Day 1 (24 Hours Post Injection)
timeFrame: Baseline and Cycle 1 Day 1 (24 hours post injection) (Up to 2 days); Each cycle was 28 days.
measure: Mean Fold Change From Baseline in Plasma Cytokine Release by Cytokine Type: Day 25 (6 Hours Post Injection)
timeFrame: Baseline and Cycle 1 Day 25 (6 hours post injection) (Up to 25 days); Each cycle was 28 days.
measure: Mean Fold Change From Baseline in Plasma Cytokine Release by Cytokine Type: Day 25 (24 Hours Post Injection)
timeFrame: Baseline and Cycle 1 Day 25 (24 hours post injection) (Up to 26 days); Each cycle was 28 days.
measure: 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
timeFrame: 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.
measure: 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
timeFrame: 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.
measure: Maximum Plasma Concentration (Cmax) of MK-4621: Day 1
timeFrame: 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.
measure: Maximum Plasma Concentration (Cmax) of MK-4621: Day 25
timeFrame: 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.
measure: Immune Infiltration of Injected Tumors by CD3 T Cell Receptor and Ki-67 Nuclear Protein: Day 1
timeFrame: Day 1 prior to injection (Up to 1 day)
measure: Immune Infiltration of Injected Tumors by CD3 T Cell Receptor and Ki-67 Nuclear Protein: Day 25
timeFrame: Day 25 post injection (Up to 25 days)
Locations:
city: Dresden
country: Germany
facility: Universitätsklinikum Carl Gustav Carus - Phase I Unit
city: Essen
country: Germany
facility: Universitätsklinikum Essen
city: Heidelberg
country: Germany
facility: National Center for Tumor Diseases
city: Madrid
country: Spain
facility: START - Fundación Jiménez Díaz - Phase I Unit
city: Madrid
country: Spain
facility: START - Hospital Universitario HM Sanchinarro - Phase I Unit
city: Oxford
country: United Kingdom
facility: University of Oxford Department of Oncology, Churchill Hospital
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.