Clinical trial NCT04735978: Study of RP3 Monotherapy and RP3 in Combination With Nivolumab in Patients With Solid Tumours
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Advanced Solid Tumor
Keywords: Advanced solid tumors
Immunotherapy
Immuno-oncology
Oncolytic virus
Oncolytic immuno-gene therapy
Lead sponsor: Replimune Inc.
Sponsor class: INDUSTRY
Collaborators: name: Bristol-Myers Squibb
First posted: 2021-02-03
Enrollment: 123
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
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)
Primary purpose: TREATMENT

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

Eligibility 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.

Primary outcomes:
measure: Incidence of dose limiting toxicities (DLTs) during the DLT period
timeFrame: From Day 1 up to 30 days after last dose
measure: Incidence and severity of treatment emergent adverse events (TEAEs)
timeFrame: From Day 1 up to 60 days after last dose
measure: Incidence and severity of serious adverse events (SAEs)
timeFrame: From Day 1 up to 60 days after last dose
measure: Incidence of TEAEs ≥ Grade 3
timeFrame: From Day 1 up to 60 days after last dose
measure: Percentage of events requiring withdrawal
timeFrame: From Day 1 up to last dose (up to 8 weeks in escalation phase and up to 2 years in combination phase)
measure: Recommended phase 2 dose (RP2D) of RP3
timeFrame: 7 months
Secondary outcomes:
measure: Percentage of biologic activity
timeFrame: 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
measure: Incidence of clearance of RP3 from blood and urine
timeFrame: 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
measure: Percentage of participants with detectable RP3.
timeFrame: 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
measure: Change in HSV-1 antibody levels
timeFrame: From Day 1 to Day 43
measure: Percentage of HSV-1 seronegative patients with TEAEs
timeFrame: From Day 1 to 60 days following last dose in dose escalation. From Day 1 to 100 days post last dose in dose combination
measure: Percentage of objective overall response rate (ORR)
timeFrame: Up to 3 years since first patient in
measure: Median duration of response
timeFrame: Up to 3 years since first patient in
measure: Percentage of complete response (CR)
timeFrame: 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)
measure: Percentage of partial response (PR)
timeFrame: 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)
measure: Percentage of stable disease (SD)
timeFrame: 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)
measure: Progression-free survival by Investigator review
timeFrame: From Day 1 to day of last follow-up
measure: One-year and 2-year OS rates
timeFrame: From Day 1 to Day 730
Other outcomes:
Locations:
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Pittsburgh
country: United States
facility: UPMC Hillman Cancer Center
state: Pennsylvania
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Villejuif
country: France
facility: Laboratoire de Recherche Translationnelle en Immunotherapie (LRTI), Gustave Roussy
city: Athens
country: Greece
facility: University of Athens
city: Athens
country: Greece
facility: University General Hospital Attikon
city: Barcelona
country: Spain
facility: Vall d'Hebron Hospital Hospital Universitario Vall d´Hebron (Vall d'Hebron University Hospital)
city: Barcelona
country: Spain
facility: Hospital Clinic Barcelona
city: Madrid
country: Spain
facility: START Madrid CIO Clara Campal, Hospital Universitario HM Sanchinarro Unidad de Ensayos Fase I Panta 3
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia
city: Bebington
country: United Kingdom
facility: The Clatterbridge Cancer Centre NHS Foundation Trust
state: Merseyside
city: London
country: United Kingdom
facility: The Royal Marsden NHS Foundation Trust
city: Oxford
country: United Kingdom
facility: Churchill Hospital
Study officials:
affiliation: Replimune Inc.
name: Shaheen Kumar, MD
role: STUDY_DIRECTOR
References: