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

Advanced Solid Tumors Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03065023
• Other study ID #: 4621-001
• Secondary ID: 2016-003028-22RG
• Status: Terminated
• Phase: Phase 1/Phase 2
• Start date: April 25, 2017
• Est. completion date: May 18, 2018

Study information

• Verified date: July 2019
• Source: Merck Sharp & Dohme Corp.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 15
• Est. completion date: May 18, 2018
• Est. primary completion date: May 18, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Advanced Solid Tumors

Intervention

Drug:
• MK-4621
IT/IL injection Fixed concentration of 0.2 mg/mL Starting dose: 0.2 mg

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Merck Sharp & Dohme Corp.

Countries where clinical trial is conducted

Germany,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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.
Other	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.
Other	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.
Other	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.
Other	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.
Other	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.
Other	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.
Other	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.
Other	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)
Other	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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	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)