Study of RP3 Monotherapy and RP3 in Combination With Nivolumab in Patients With Solid Tumours

Advanced Solid Tumor Clinical Trial

Official title:

An Open-Label, Multicenter, Phase 1 Study of RP3 as a Single Agent and in Combination With PD-1 Blockade in Patients With Solid Tumors

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04735978
• Other study ID #: RP3-301
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: December 29, 2020
• Est. completion date: April 2024

Study information

• Verified date: December 2023
• Source: Replimune Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a Phase 1, multicenter, open label, single agent dose escalation and combination treatment study of RP3 in adult participants with advanced solid tumors, to evaluate the safety and tolerability of RP3 both as a single agent and in combination with anti-PD1 therapy and to determine the recommended Phase 2 dose (RP2D) of RP3.

Description:

RP3 is a genetically modified herpes simplex type 1 virus (HSV-1) that expresses exogenous genes (anti-CTLA-4 antibody, CD40 ligand and h4-1BBL) designed to directly destroy tumors and generate an anti-tumor immune response

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 123
• Est. completion date: April 2024
• Est. primary completion date: April 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients with advanced or metastatic non-neurological solid tumors, who have progressed on standard therapy or cannot tolerate standard therapy, or for whom there is no standard therapy preferred to enrollment in a clinical study

• All patients must consent to provide archival tumor biopsy samples within 12 months, or a fresh tumor biopsy is needed. Patients must also consent to provide on treatment biopsies as per protocol

• At least one measurable tumor = 1 cm in longest diameter (or shortest diameter for lymph nodes)

• At least one injectable tumor = 1 cm in longest diameter or injectable tumors which in aggregate are = 1 cm in longest diameter (or shortest diameter for lymph nodes

• Have an Eastern Cooperative Oncology Group (ECOG) performance status 0-1

Note: Predefined inclusion criteria may apply for each additional expansion cohort.

Exclusion Criteria:

• Prior treatment with an oncolytic virus therapy

• History of viral infections according to the protocol

• Systemic infection requiring intravenous (IV) antibiotics

• Active significant herpetic infections or prior complications of HSV-1 infection (e.g., herpetic keratitis or encephalitis)

• Requires intermittent or chronic use of systemic antivirals

a. Hepatocellular carcinoma patients with a diagnosis of hepatitis B must be off antiviral therapy for at least 4 weeks prior to enrollment . Hepatocellular carcinoma patients with a history of or ongoing hepatitis C infection must have completed treatment for hepatitis C at least 1 month prior to study enrollment and hepatitis

• History of interstitial lung disease

• Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis

Additional Exclusion Criteria for Patients Enrolled in Part 2 (Expansion Cohorts):

• History of life-threatening toxicity related to prior immune treatment or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways

• Treatment with botanical preparations within 2 weeks prior to treatment.

• Active, known, or suspected autoimmune disease requiring systemic treatment.

• History of interstitial lung disease.

• Severe hypersensitivity to another monoclonal antibody.

• Has received prior radiotherapy within 2 weeks of start of study treatment.

• Has received a live vaccine within 28 days prior to the first dose of study treatment.

• History of (non-infectious) pneumonitis that required steroids or has current pneumonitis.

• History of myocarditis or congestive heart failure within 6 months of screening.

• Has a serious or uncontrolled medical disorder.

• Has a QT interval corrected for heart rate using Fridericia's formula (QTcF) > 480 msec, except for right bundle branch block.

Related Conditions & MeSH terms

• Advanced Solid Tumor
• Neoplasms

Intervention

Biological:
• RP3
Genetically modified HSV-1
• Nivolumab
anti-PD1 monoclonal antibody

Locations

Country	Name	City	State
France	Laboratoire de Recherche Translationnelle en Immunotherapie (LRTI), Gustave Roussy	Villejuif
Greece	University General Hospital Attikon	Athens
Greece	University of Athens	Athens
Spain	Hospital Clinic Barcelona	Barcelona
Spain	Vall d'Hebron Hospital Hospital Universitario Vall d´Hebron (Vall d'Hebron University Hospital)	Barcelona
Spain	START Madrid CIO Clara Campal, Hospital Universitario HM Sanchinarro Unidad de Ensayos Fase I Panta 3	Madrid
Spain	Hospital Clinico Universitario de Valencia	Valencia
United Kingdom	The Clatterbridge Cancer Centre NHS Foundation Trust	Bebington	Merseyside
United Kingdom	The Royal Marsden NHS Foundation Trust	London
United Kingdom	Churchill Hospital	Oxford
United Kingdom	Royal Marsden Hospital	Sutton
United States	University of Maryland	Baltimore	Maryland
United States	MD Anderson Cancer Center	Houston	Texas
United States	University of Iowa	Iowa City	Iowa
United States	UPMC Hillman Cancer Center	Pittsburgh	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
Replimune Inc.	Bristol-Myers Squibb

Countries where clinical trial is conducted

United States,  France,  Greece,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of dose limiting toxicities (DLTs) during the DLT period	Percentage of participants with DLTs	From Day 1 up to 30 days after last dose
Primary	Incidence and severity of treatment emergent adverse events (TEAEs)	Percentage of participants with TEAEs	From Day 1 up to 60 days after last dose
Primary	Incidence and severity of serious adverse events (SAEs)	Percentage of participants with SAEs	From Day 1 up to 60 days after last dose
Primary	Incidence of TEAEs = Grade 3	Percentage of participants with TEAEs = Grade 3	From Day 1 up to 60 days after last dose
Primary	Percentage of events requiring withdrawal	Percentage of participants experiencing events requiring withdrawal from treatment.	From Day 1 up to last dose (up to 8 weeks in escalation phase and up to 2 years in combination phase)
Primary	Recommended phase 2 dose (RP2D) of RP3	RP2D of RP3 based on the safety and response data collected during the dose escalation phase (Part 1)	7 months
Secondary	Percentage of biologic activity	Percentage of participants with biological activity as assessed by individual tumor responses (including erythema, necrosis, and/or inflammation and changes in tumor sizes, in injected and uninjected tumors).	From Day 1 to 24 months following the last dose in dose escalation. From Day 1 to 100 days following the last dose in dose combination
Secondary	Incidence of clearance of RP3 from blood and urine	Incidence of clearance of RP3 from blood and urine before and after each injection	From Day 1 to 60 days following the last dose in dose escalation. From Day 1 to 100 days following the last dose in dose combination
Secondary	Percentage of participants with detectable RP3.	Data gathered from blood, urine, swabs of injection site, dressing and oral mucosa to determine the shedding and biodistribution of RP3	From Day 1 to 60 days following the last dose in dose escalation. From Day 1 to 100 days following the last dose in dose combination
Secondary	Change in HSV-1 antibody levels	Change in HSV-1 antibody levels during treatment compared to baseline	From Day 1 to Day 43
Secondary	Percentage of HSV-1 seronegative patients with TEAEs	Percentage of HSV-1 seronegative patients with TEAEs	From Day 1 to 60 days following last dose in dose escalation. From Day 1 to 100 days post last dose in dose combination
Secondary	Percentage of objective overall response rate (ORR)	Percentage of ORR	Up to 3 years since first patient in
Secondary	Median duration of response	Median duration of response of participants	Up to 3 years since first patient in
Secondary	Percentage of complete response (CR)	Percentage of participants with a CR	From Day 1 up to last dose (Day 57 or 8th Re-initiation dose in escalation phase and up to 2 years for combination phase)
Secondary	Percentage of partial response (PR)	Percentage of participants with a PR	From Day 1 up to last dose (Day 57 or 8th Re-initiation dose in escalation phase and up to 2 years for combination phase)
Secondary	Percentage of stable disease (SD)	Percentage of participants with SD	From Day 1 up to last dose (Day 57 or 8th Re-initiation dose in escalation phase and up to 2 years for combination phase)
Secondary	Progression-free survival by Investigator review	Length of time during and after treatment, that a patient lives with disease but it does not get worse	From Day 1 to day of last follow-up
Secondary	One-year and 2-year OS rates	Percentage of participants from Day 1 of treatment who reach one year or two year survival	From Day 1 to Day 730