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

Sponsor

Replimune Inc. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04735978

Collaborator

Bristol-Myers Squibb (Industry)

123

Enrollment

Locations

Arms

39.1

Anticipated Duration (Months)

30.8

Patients Per Site

0.8

Patients Per Site Per Month

Study Details

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

Anticipated 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)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 :

Dec 29, 2020

Anticipated Primary Completion Date :

Apr 1, 2024

Anticipated Study Completion Date :

Apr 1, 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

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

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 Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

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

Locations

	Site	City	State	Country	Postal Code
1	The Clatterbridge Cancer Centre NHS Foundation Trust	Bebington	Merseyside	United Kingdom	CH63 4JY
2	The Royal Marsden NHS Foundation Trust	London		United Kingdom	SW3 6JJ
3	Churchill Hospital	Oxford		United Kingdom	OX3 9DU
4	Royal Marsden Hospital	Sutton		United Kingdom	SM2 5PT