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

• ClinicalTrials.gov Identifier: NCT04735978
• Recruitment Status: Recruiting
• First Posted: February 3, 2021
• Last Update Posted: February 1, 2023
• Sponsor: Replimune Inc.
• Collaborator: Bristol-Myers Squibb
• Information provided by (Responsible Party): Replimune Inc.

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Advanced Solid Tumor	Biological: RP3; Biological: Nivolumab	Phase 1

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 123 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment

Intervention Model Description

Part 1 - Dose Escalation - Participants will be enrolled into two sequential dose level cohorts.

• Cohort 1: 1 × 105 plaque-forming units (PFU)/mL on Day 1 followed by 1 × 106 PFU/mL every 2 weeks (Q2W) for up to 5 doses.
• Cohort 2: 1 × 106 PFU/mL on Day 1 followed by 1 × 107 PFU/mL Q2W for up to 5 doses.

Part 2 - Dose Combination - Patients will be enrolled into 1 of 5 dose-expansion cohorts. Expansion Cohorts 1, 2, and 4 will enroll patients with head and neck cancer, lung cancer, breast cancer, or GI cancer. Expansion Cohort 3 will enroll patients with any solid organ malignancy who have at least 2 tumors that can be injected and biopsied. Expansion Cohort 5 will enroll patients with melanoma.

• Expansion Cohort 1 (RP3 + Nivolumab)
• Expansion Cohort 2 (RP3 Followed by Nivolumab)
• Expansion Cohort 3 (RP3 Monotherapy Translational Cohort)
• Expansion Cohort 4 (RP3 Monotherapy)
• Expansion Cohort 5 (RP3 + Nivolumab in Melanoma)

• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: December 29, 2020
• Estimated Primary Completion Date: April 2024
• Estimated Study Completion Date: April 2024

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Incidence of dose limiting toxicities (DLTs) during the DLT period [ Time Frame: From Day 1 up to 30 days after last dose ]
   Percentage of participants with DLTs
2. Incidence and severity of treatment emergent adverse events (TEAEs) [ Time Frame: From Day 1 up to 60 days after last dose ]
   Percentage of participants with TEAEs
3. Incidence and severity of serious adverse events (SAEs) [ Time Frame: From Day 1 up to 60 days after last dose ]
   Percentage of participants with SAEs
4. Incidence of TEAEs ≥ Grade 3 [ Time Frame: From Day 1 up to 60 days after last dose ]
   Percentage of participants with TEAEs ≥ Grade 3
5. Percentage of events requiring withdrawal [ Time Frame: 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.
6. Recommended phase 2 dose (RP2D) of RP3 [ Time Frame: 7 months ]
   RP2D of RP3 based on the safety and response data collected during the dose escalation phase (Part 1)

Secondary Outcome Measures :

1. Percentage of biologic activity [ Time Frame: 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).
2. Incidence of clearance of RP3 from blood and urine [ Time Frame: 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
3. Percentage of participants with detectable RP3. [ Time Frame: 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
4. Change in HSV-1 antibody levels [ Time Frame: From Day 1 to Day 43 ]
   Change in HSV-1 antibody levels during treatment compared to baseline
5. Percentage of HSV-1 seronegative patients with TEAEs [ Time Frame: 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
6. Percentage of objective overall response rate (ORR) [ Time Frame: Up to 3 years since first patient in ]
   Percentage of ORR
7. Median duration of response [ Time Frame: Up to 3 years since first patient in ]
   Median duration of response of participants
8. Percentage of complete response (CR) [ Time Frame: 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
9. Percentage of partial response (PR) [ Time Frame: 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
10. Percentage of stable disease (SD) [ Time Frame: 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
11. Progression-free survival by Investigator review [ Time Frame: 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
12. One-year and 2-year OS rates [ Time Frame: From Day 1 to Day 730 ]
    Percentage of participants from Day 1 of treatment who reach one year or two year survival

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Contacts

Contact: Clinical Trials at Replimune; +44 1235 242 488; Clinicaltrials@replimune.com

Locations

United States, Texas

MD Anderson Cancer Center; Recruiting

Houston, Texas, United States, 77030

Principal Investigator: Sarina Piha-Paul, MD

Greece

University General Hospital Attikon; Recruiting

Athens, Greece, 12462

Principal Investigator: Amanda Psyrri, MD

Spain

Hospital Clinico Universitario de Valencia; Recruiting

Valencia, Spain, 46010

Principal Investigator: Andres M Cervantes Ruiperez, MD

United Kingdom

The Clatterbridge Cancer Centre NHS Foundation Trust; Recruiting

Bebington, Merseyside, United Kingdom, CH63 4JY

Principal Investigator: Joseph Sacco, MD

The Royal Marsden NHS Foundation Trust; Recruiting

London, United Kingdom, SW3 6JJ

Principal Investigator: Kevin Harrington, MD

Churchill Hospital; Recruiting

Oxford, United Kingdom, OX3 9DU

Principal Investigator: Mark Middleton, MD

Royal Marsden Hospital; Recruiting

Sutton, United Kingdom, SM2 5PT

Principal Investigator: Kevin Harrington, MD

Sponsors and Collaborators

Replimune Inc.

Bristol-Myers Squibb

Investigators

• Study Director: Johannes Wolff, MD; Replimune Inc.

More Information

• Responsible Party: Replimune Inc.
• ClinicalTrials.gov Identifier: NCT04735978
• Other Study ID Numbers: RP3-301
• First Posted: February 3, 2021
• Last Update Posted: February 1, 2023
• Last Verified: January 2023

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Replimune Inc.:

Advanced solid tumors; Immunotherapy; Immuno-oncology; Oncolytic virus; Oncolytic immuno-gene therapy

Additional relevant MeSH terms:

Neoplasms; Nivolumab; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action