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

Study Overview
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Brief Summary
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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
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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

Official Title
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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

Conditions
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Advanced Solid Tumor

Intervention / Treatment
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* Biological: RP3
* Biological: Nivolumab


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional 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)


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced solid tumors, Immunotherapy, Immuno-oncology, Oncolytic virus, Oncolytic immuno-gene therapy