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

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

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

Primary outcomes

• 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
• 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
• 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.
• 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)

Secondary outcomes

• 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).
• 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 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
• 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
• Percentage of objective overall response rate (ORR) [Up to 3 years since first patient in]: Percentage of ORR
• Median duration of response [Up to 3 years since first patient in]: Median duration of response of participants
• 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
• 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
• 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

Sex: All, ages: 18 Years to any

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.

• Gary Vanasse, MD, Study director, Replimune, Inc.