Study of RP1 Monotherapy and RP1 in Combination With Nivolumab

Study Overview
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Brief Summary
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RPL-001-16 is a Phase 1/2, open label, dose escalation and expansion clinical study of RP1 alone and in combination with nivolumab in adult subjects with advanced and/or refractory solid tumors, to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D), as well as to evaluate preliminary efficacy.

Detailed Description
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RP1 is a genetically modified herpes simplex type 1 virus that is designed to directly destroy tumors and to generate an anti-tumor immune response. This is a Phase 1/2, open label, multicenter, dose escalation and expansion, first-in-human (FIH) clinical study to evaluate the safety and tolerability, biodistribution, shedding, and preliminary efficacy of RP1 alone and in combination with nivolumab in adult subjects with advanced and/or refractory solid tumors. The study will include a dose escalation phase for single agent RP1, an expansion phase with a combination of RP1 and nivolumab and a Phase 2 portion in specified tumor types for the combination therapy.

Official Title
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An Open-Label, Multicenter, Phase 1/2 Study of RP1 as a Single Agent and in Combination With PD1 Blockade in Patients With Solid Tumors

Conditions
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Cancer, Melanoma (Skin), Mismatch Repair Deficiency, Microsatellite Instability, Non-melanoma Skin Cancer, Cutaneous Melanoma, NSCLC

Intervention / Treatment
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* Biological: RP1
* Biological: nivolumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1. At least one measurable and injectable lesion Have provided a former tumor pathology specimen or be willing to supply a new tumor sample from a biopsy Have a predicted life expectancy of ≥ 3 months Measurable disease, according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria Subjects with MSI-H or dMMR tumors: has diagnosis of MSI-H or metatstatic dMMR tumor (according to protocol definition) who has progressed on prior anti-PD1/PD-L1 therapy. Subjects with NMSC: has diagnosis of locally advanced or metastatic NMSC that are not considered treatable by surgery including basal cell carcinoma, cutaneous squamous cell carcinoma, basosquamous carcinoma, Merkel cell carcinoma and other non-melanoma skin cancers (per protocol). Patients must have received 8 weeks of anti-PD1/PD-L1 as their last line of therapy and progressed while on treatment. Subjects with anti-PD1 failed cutaneous melanoma: has confirmed progressive disease while on anti-PD1 treatment for at least 8 weeks and documented BRAF mutation status Subjects with anti-PD1 failed NSCLC: must have failed prior treatment, including PD1/PD-L1 directed therapy administered either as monotherapy or in combination with platinum-based chemotherapy or anti-CTLA-4. The most recent treatment given must have included an anti-PD1/PD-L1 directed therapy with radiologic disease progression on or after treatment. Exclusion Criteria: Prior treatment with an oncolytic therapy History of viral infections according to the protocol Prior complications with herpes infections Chronic use of anti-virals Uncontrolled/untreated brain metastasis History of interstitial lung disease History of non-infectious pneumonitis History of clinically significant cardiovascular disease

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose escalation of RP1 by intratumoral (IT) injection in superficial tumors<br>Dose escalation of RP1 alone in 3 cohorts with IT injections in superficial tumors | Biological: RP1<br>* Genetically modified herpes simplex type 1 virus<br>|
| Experimental: Dose escalation of RP1 by intratumoral (IT) injection in deep/visceral tumors<br>Dose escalation of RP1 alone in 3 cohorts with IT injections in deep/visceral tumors | Biological: RP1<br>* Genetically modified herpes simplex type 1 virus<br>|
| Experimental: Dose expansion of RP1 and nivolumab (IV) in superficial tumors<br>Doses of RP1 (IT) in superficial tumors with nivolumab (IV) | Biological: RP1<br>* Genetically modified herpes simplex type 1 virus<br>Biological: nivolumab<br>* anti-PD-1 monoclonal antibody<br>* Other names: Opdivo;|
| Experimental: Dose expansion of RP1 and nivolumab (IV) in deep/visceral tumors<br>Doses of RP1 (IT) in deep/visceral tumors with nivolumab (IV) | Biological: RP1<br>* Genetically modified herpes simplex type 1 virus<br>Biological: nivolumab<br>* anti-PD-1 monoclonal antibody<br>* Other names: Opdivo;|
| Experimental: RP1 (IT) and nivolumab (IV) in melanoma<br>Doses of RP1 (IT) in superficial or deep tumors with nivolumab (IV) in subjects with melanoma | Biological: RP1<br>* Genetically modified herpes simplex type 1 virus<br>Biological: nivolumab<br>* anti-PD-1 monoclonal antibody<br>* Other names: Opdivo;|
| Experimental: RP1 (IT) and nivolumab (IV) in MSI-H/dMMR solid tumors<br>Doses of RP1 (IT) in superficial or deep tumors with nivolumab (IV) in subjects with MSI-H or dMMR solid tumors | Biological: RP1<br>* Genetically modified herpes simplex type 1 virus<br>Biological: nivolumab<br>* anti-PD-1 monoclonal antibody<br>* Other names: Opdivo;|
| Experimental: RP1 (IT) and nivolumab (IV) in NMSC<br>Doses of RP1 (IT) in superficial or deep tumors with nivolumab (IV) in subjects with non-melanoma skin cancer | Biological: RP1<br>* Genetically modified herpes simplex type 1 virus<br>Biological: nivolumab<br>* anti-PD-1 monoclonal antibody<br>* Other names: Opdivo;|
| Experimental: RP1(IT) and nivolumab (IV) in anti-PD1 Failed Cutaneous Melanoma<br>Doses of RP1 (IT) in superficial or deep tumors with nivolumab (IV) in subjects with cutaneous melanoma who have been previously treated with anti-PD1 therapy | Biological: RP1<br>* Genetically modified herpes simplex type 1 virus<br>Biological: nivolumab<br>* anti-PD-1 monoclonal antibody<br>* Other names: Opdivo;|
| Experimental: RP1(IT) and nivolumab (IV) in anti-PD1/PD-L1 Failed NMSC<br>Doses of RP1 (IT) in superficial or deep tumors with nivolumab (IV) in subjects with non-melanoma skin cancer who have been previously treated with anti-PD1/PD-L1 therapy | Biological: RP1<br>* Genetically modified herpes simplex type 1 virus<br>Biological: nivolumab<br>* anti-PD-1 monoclonal antibody<br>* Other names: Opdivo;|
| Experimental: RP1(IT) and nivolumab (IV) in anti-PD1/PD-L1 Failed NSCLC<br>Doses of RP1 (IT) in superficial or deep tumors with nivolumab (IV) in subjects with non small cell lung cancer who have been previously treated with anti-PD1/PD-L1 therapy | Biological: RP1<br>* Genetically modified herpes simplex type 1 virus<br>Biological: nivolumab<br>* anti-PD-1 monoclonal antibody<br>* Other names: Opdivo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of adverse events (AEs) | Percentage of subjects with adverse events (AEs) | 26 months | 
| Percentage of serious adverse events (SAEs) | Percentage of subjects with serious adverse events (SAEs) | 26 months | 
| Percentage of dose limiting toxicities (DLTs) | Percentage of subjects with dose limiting toxicities (DLTs) | 26 months | 
| Percentage of overall response rate (ORR) | Percentage of overall response rate (ORR) for all participants | 26 months | 
| Maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of RP1 | Assess the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of RP1 based on the safety and response data collected during Phase 1 Escalation | 20 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of biologic activity | Percentage of subjects with biological activity determined by tumor biopsies and biomarker data | 20 weeks | 
| Percentage subjects with detectable RP1 | Data gathered from blood, urine, swabs of injection site, dressings, and oral mucosa to determine the shedding and biodistribution of RP1 | 20 weeks | 
| Percentage of complete response (CR) | Percentage of subjects with a complete response (CR) | 26 months | 
| Median duration of response | Median duration of response of subjects | 26 months | 
| Median progression-free survival | Median duration of progression-free survival of subjects | 26 months | 
| Median overall survival | Median overall survival rate of subjects | 26 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Oncolytic virus, Oncolytic Immuno-gene therapy, Non-melanoma Skin Cancer, Cutaneous Melanoma, Anti-PD1 failed, Melanoma (skin)