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

Phase 1

Active, not recruiting

• Conditions: Advanced Solid Tumor
• Interventions: Biological: RP3; Biological: Nivolumab

• Registration Number: NCT04735978
• Lead Sponsor: Replimune Inc.

Brief 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.

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

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study Start: 2020-12-29
• Study First Submitted: 2021-01-25
• Study First Submitted QC: 2021-01-29
• Study First Posted: 2021-02-03
• Status Verified: 2024-08
• Last Update Submitted: 2024-08-06
• Last Update Posted: 2024-08-09
• Primary Completion: 2026-11-30
• Study Completion: 2026-11-30

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 123

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.

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Dose escalation of RP3 - superficial and/or deep/visceral tumors	RP3	Dose escalation of RP3 alone in 2 cohorts with intratumoral (IT) injections including use of imaging guided injection for deep tumors.
Dose combination of RP3 and anti-PD1 therapy - superficial and/or deep/visceral tumors	Nivolumab	Dose combination of RP3 and anti-PD1 therapy. IT injections of RP3 including use of imaging guided injection for deep tumors.
Dose combination of RP3 and anti-PD1 therapy - superficial and/or deep/visceral tumors	RP3	Dose combination of RP3 and anti-PD1 therapy. IT injections of RP3 including use of imaging guided injection for deep tumors.
Seronegative cohort	RP3	Doses of RP3 (IT) in HSV seronegative participants.

Primary Outcome Measures

Name	Time	Method
Incidence and severity of treatment emergent adverse events (TEAEs)	From Day 1 up to 60 days after last dose	Percentage of participants with TEAEs
Incidence and severity of serious adverse events (SAEs)	From Day 1 up to 60 days after last dose	Percentage of participants with SAEs
Incidence of TEAEs ≥ Grade 3	From Day 1 up to 60 days after last dose	Percentage of participants with TEAEs ≥ Grade 3
Recommended phase 2 dose (RP2D) of RP3	7 months	RP2D of RP3 based on the safety and response data collected during the dose escalation phase (Part 1)
Percentage of events requiring withdrawal	From Day 1 up to last dose (up to 8 weeks in escalation phase and up to 2 years in combination phase)	Percentage of participants experiencing events requiring withdrawal from treatment.
Incidence of dose limiting toxicities (DLTs) during the DLT period	From Day 1 up to 30 days after last dose	Percentage of participants with DLTs

Secondary Outcome Measures

Name	Time	Method
Percentage of biologic activity	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	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).
Percentage of partial response (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 participants with a PR
Percentage of stable disease (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)	Percentage of participants with SD
Percentage of complete response (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 participants with a CR
Incidence of clearance of RP3 from blood and urine	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	Incidence of clearance of RP3 from blood and urine before and after each injection
Percentage of objective overall response rate (ORR)	Up to 3 years since first patient in	Percentage of ORR
Percentage of participants with detectable 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	Data gathered from blood, urine, swabs of injection site, dressing and oral mucosa to determine the shedding and biodistribution of RP3
Progression-free survival by Investigator review	From Day 1 to day of last follow-up	Length of time during and after treatment, that a patient lives with disease but it does not get worse
One-year and 2-year OS rates	From Day 1 to Day 730	Percentage of participants from Day 1 of treatment who reach one year or two year survival
Change in HSV-1 antibody levels	From Day 1 to Day 43	Change in HSV-1 antibody levels during treatment compared to baseline
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 HSV-1 seronegative patients with TEAEs
Median duration of response	Up to 3 years since first patient in	Median duration of response of participants

Trial Locations

Locations (13)

University of Iowa; 🇺🇸 Iowa City, Iowa, United States

UPMC Hillman Cancer Center; 🇺🇸 Pittsburgh, Pennsylvania, United States

Laboratoire de Recherche Translationnelle en Immunotherapie (LRTI), Gustave Roussy; 🇫🇷 Villejuif, France

University of Athens; 🇬🇷 Athens, Greece

MD Anderson Cancer Center; 🇺🇸 Houston, Texas, United States

START Madrid CIO Clara Campal, Hospital Universitario HM Sanchinarro Unidad de Ensayos Fase I Panta 3; 🇪🇸 Madrid, Spain

Hospital Clinic Barcelona; 🇪🇸 Barcelona, Spain

Vall d'Hebron Hospital Hospital Universitario Vall d´Hebron (Vall d'Hebron University Hospital); 🇪🇸 Barcelona, Spain

Hospital Clinico Universitario de Valencia; 🇪🇸 Valencia, Spain

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

University General Hospital Attikon; 🇬🇷 Athens, Greece