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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Advanced Solid Tumor
• Intervention / Treatment: Biological: RP3; Biological: Nivolumab

Detailed 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

• Study Type: Interventional
• Enrollment (Estimated): 123
• Phase: Phase 1

Contacts and Locations

Study Locations

• France
  • Villejuif, France, 94805
    • Laboratoire de Recherche Translationnelle en Immunotherapie (LRTI), Gustave Roussy
• Greece
  • Athens, Greece, 12462
    • University General Hospital Attikon
  • Athens, Greece, 11527
    • University of Athens
• Spain
  • Barcelona, Spain, 08036
    • Hospital Clinic Barcelona
  • Barcelona, Spain, 08035
    • Vall d'Hebron Hospital Hospital Universitario Vall d´Hebron (Vall d'Hebron University Hospital)
  • Madrid, Spain, 28050
    • START Madrid CIO Clara Campal, Hospital Universitario HM Sanchinarro Unidad de Ensayos Fase I Panta 3
  • Valencia, Spain, 46010
    • Hospital Clinico Universitario de Valencia
• United Kingdom
  • London, United Kingdom, SW3 6JJ
    • The Royal Marsden NHS Foundation Trust
  • Oxford, United Kingdom, OX3 9DU
    • Churchill Hospital
  • Merseyside
    • Bebington, Merseyside, United Kingdom, CH63 4JY
      • The Clatterbridge Cancer Centre NHS Foundation Trust
• United States
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • UPMC Hillman Cancer Center
  • Texas
    • Houston, Texas, United States, 77030
      • Md Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose escalation of RP3 - superficial and/or deep/visceral tumors; Dose escalation of RP3 alone in 2 cohorts with intratumoral (IT) injections including use of imaging guided injection for deep tumors.	Biological: RP3; Genetically modified HSV-1
Experimental: Dose combination of RP3 and anti-PD1 therapy - superficial and/or deep/visceral tumors; Dose combination of RP3 and anti-PD1 therapy. IT injections of RP3 including use of imaging guided injection for deep tumors.	Biological: RP3; Genetically modified HSV-1; Biological: Nivolumab; anti-PD1 monoclonal antibody
Experimental: Seronegative cohort; Doses of RP3 (IT) in HSV seronegative participants.	Biological: RP3; Genetically modified HSV-1

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
Incidence and severity of treatment emergent adverse events (TEAEs)	Percentage of participants with TEAEs	From Day 1 up to 60 days after last dose
Incidence and severity of serious adverse events (SAEs)	Percentage of participants with SAEs	From Day 1 up to 60 days after last dose
Incidence of TEAEs ≥ Grade 3	Percentage of participants with TEAEs ≥ Grade 3	From Day 1 up to 60 days after last dose
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)
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
Change in HSV-1 antibody levels	Change in HSV-1 antibody levels during treatment compared to baseline	From Day 1 to Day 43
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
Percentage of objective overall response rate (ORR)	Percentage of ORR	Up to 3 years since first patient in
Median duration of response	Median duration of response of participants	Up to 3 years since first patient in
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)
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)
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)
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
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

Collaborators and Investigators

• Sponsor: Replimune Inc.
• Collaborators: Bristol-Myers Squibb
• Investigators: Study Director: Gary Vanasse, MD, Replimune Inc.

Study record dates

Study Major Dates

• Study Start (Actual): December 29, 2020
• Primary Completion (Estimated): November 30, 2026
• Study Completion (Estimated): November 30, 2026

Study Registration Dates

• First Submitted: January 25, 2021
• First Submitted That Met QC Criteria: January 29, 2021
• First Posted (Actual): February 3, 2021

Study Record Updates

• Last Update Posted (Actual): February 27, 2026
• Last Update Submitted That Met QC Criteria: February 25, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Immunotherapy; Immuno-oncology; Oncolytic virus; Advanced solid tumors; Oncolytic immuno-gene therapy
• Additional Relevant MeSH Terms: Neoplasms; Amino Acids, Peptides, and Proteins; Proteins; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Nivolumab
• Other Study ID Numbers: RP3-301

Drug and device information, study documents

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