Advanced Solid Tumor
Conditions
Keywords
Advanced solid tumors, Immunotherapy, Immuno-oncology, Oncolytic virus, Oncolytic immuno-gene therapy
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
Interventions
BIOLOGICALRP3
Genetically modified HSV-1
BIOLOGICALNivolumab
anti-PD1 monoclonal antibody
Sponsors
Replimune Inc.
Bristol-Myers Squibb
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
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)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
Countries
France, Greece, Spain, United Kingdom, United States
Contacts
STUDY_DIRECTORGary Vanasse, MD
Replimune Inc.
Outcome results
None listed