Study of RP2 Monotherapy and RP2 in Combination With Nivolumab in Patients With Solid Tumors

Study Overview
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Brief Summary
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RP2-001-18 is a Phase 1, multicenter, open label, single agent dose escalation and combination treatment study of RP2 in adult subjects with advanced 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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RP2 is a genetically modified herpes simplex type 1 virus (HSV-1) that expresses an anti-CTLA-4 antibody and is designed to directly destroy tumors and to generate an anti-tumor immune response. This is a Phase 1, multicenter, open label, dose escalation and expansion, first-in-human (FIH) clinical study to evaluate the safety and tolerability, biodistribution, shedding, and preliminary efficacy of RP2 alone and in combination with nivolumab in adult subjects with advanced solid tumors. The study will be conducted in two parts. The first part of the study is an open-label, dose escalation FIH Phase 1 study to assess the safety and tolerability of RP2 and to determine the recommended Phase 2 dose (RP2D) to be used in the second part of the study. The second part of the study is an open label design to further investigate safety of RP2 in combination with nivolumab. It will also assess the biological activity of multiple doses of RP2 in combination with nivolumab. An expansion to the second part of the study will include enrolment of a further 30 patients on RP2 in combination with nivolumab. Following completion of the expansion in part 2, part 3 will enroll a further 15 patients on RP3 monotherapy. The expansion to part 2 and part 3 will focus on patients with advanced or metastatic uveal melanoma, lung cancer, breast cancer or GI cancers and patients with liver metastasis.

Official Title
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An Open-Label, Multicenter, Phase 1 Study of RP2 as a Single Agent and in Combination With PD1 Blockade in Patients With Solid Tumors

Conditions
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Cancer

Intervention / Treatment
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* Biological: RP2
* Biological: nivolumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to participate and comply with all trial requirements and able to provide signed and dated informed consent prior to initiation of any trial procedures Male or Female ≥ 18 years of age Patients with advanced or metastatic non-neurological solid tumors, who have progressed on standard therapy or cannot tolerate standard therapy, or for which there is no standard therapy preferred to enrolment in a clinical trial Consent to provide archival tumour biopsy samples within 6 months, or a fresh tumour biopsy is needed. Patients must also consent to provide on-treatment biopsies as per protocol At least one measurable and injectable tumor of ≥ 1 cm in longest diameter (or shorter diameter for lymph nodes). Women of child-bearing potential (WOCBP) must have a negative urine pregnancy test at screening and a negative urine pregnancy test prior to administration of each dose of RP2 or nivolumab WOCBP must agree to use adequate birth control throughout their participation and for 3 months after RP2 alone and 5 months after nivolumab last study treatment Males with partners of child-bearing potential must agree to use adequate birth control throughout their participation and for 3 months for RP2 alone and 7 months after nivolumab last study treatment Have laboratory values (obtained ≤ 28 days prior to first infusion day) in accordance with the study protocol Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1 Cohort 2a only: Baseline ECG that does not show abnormalities according to the protocol Baseline troponin < 0.06 ng/mL Baseline oxygen saturation levels that do not show abnormalities according to the protocol Cohort 2b and Part 3 only: Patients in Cohort 2b should have histologically or cytologically confirmed diagnosis of advanced or metastatic uveal melanoma, lung cancer, breast cancer, or gastrointestinal cancers (including but not limited to colorectal cancer [CRC] [microsatellite stable], gastric cancer, gastroesophageal junction cancer, and oesophageal cancer) (n=30) Patients with HCC and a diagnosis of hepatitis B must be off antiviral therapy for at least 4 weeks prior to enrollment. Patients with acute or chronic hepatitis B or C must be expected to not require antiviral therapy during the RP2 treatment period. Patients with HCC who have evidence of acute or chronic hepatitis C infection must have completed treatment for hepatitis C at least 1 month prior to study enrollment Patients in Part 3 should have solid tumours (excluding skin cancers) that the investigator deems suitable for RP2 monotherapy, including at least 10 patients with liver metastases from prevalent tumour types (e.g. lung, breast [including recurrent chest wall], and gastrointestinal cancers [colorectal, gastric, and oesophageal cancers]) (n=15) Patient has progressed during or after one to three prior systemic anticancer therapies for advanced or metastatic disease or during or within six months of receiving adjuvant therapy. Patients who, in the opinion of the investigator, are deemed not appropriate candidates for standard-of-care systemic anticancer therapy for advanced or metastatic disease, or who, after documented consultation with their treating physician, refuse standard-of-care systemic anticancer therapy may be eligible after discussion with the medical monitor Exclusion Criteria: Prior treatment with an oncolytic virus therapy History of viral infections according to the protocol Systemic infection requiring IV antibiotics within 14 days prior to dosing Prior complications with herpes infections Chronic use of anti-virals Systemic therapies for cancer within five half-lives or 4 weeks of first dose; whichever is shorter Conditions that require certain doses of steroids (some doses and types will be permitted) Known active brain metastases - previously treated brain metastases may be permitted Major surgery ≤ 2 weeks prior to starting study drug Prior malignancy active with the previous 3 years; except for locally curable cancers that have apparently been cured Female who has a positive urine pregnancy test or is breast-feeding or planning to become pregnant during study treatment and 90 days for RP2 alone or 5 months for RP2 and nivolumab after the last dose of treatment Participation in another clinical study within 4 weeks prior to the first dose History of myocarditis or congestive heart failure (as defined by the New York Heart Association Functional Classification III or IV), or unstable angina, serious uncontrolled cardiac arrhythmia, uncontrolled infection, or myocardial infarction within 6 months of randomization History of allergy or sensitivity to study drug components Has known psychiatric or substance abuse disorders that would interfere with cooperating with the requirements of the study Part 2 patients only: Participants with history of life-threatening toxicity related to prior immune therapy except those that are likely to re-occur with standard countermeasures Treatment with botanical preparations within 2 weeks prior to treatment Certain autoimmune diseases, some types will be permitted History of interstitial lung disease Severe hypersensitivity to another monoclonal antibody Has received radiotherapy within 2 weeks of start of study treatment Has received a live vaccine within 28 days prior to first dose of study drug History of non-infectious pneumonitis History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study Other serious or uncontrolled medical disorders Cohort 2b and Part 3 (only for the subset of patients with liver metastases suitable and intended for injection) Presence of liver metastases that are estimated to invade more than one-third of the liver Macroscopic intravascular invasion into the main portal vein, hepatic vein or vena cava Significant bleeding event within the last 12 months that places the patient at risk for intrahepatic intratumoral injection procedure based on investigator assessment Prior chemoembolization, radioembolization, or other locoregional liver-directed procedures to the lesion selected for intratumoral injection

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 - Patients will be enrolled into three sequential dose level cohorts. Part 2 - Dose expansion - Patients will receive a fixed dose of RP2 in combination with Nivolumab. Part 3 - Patients will receive four doses of RP2 monotherapy
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose escalation of RP2 - superficial tumors<br>Dose escalation of RP2 alone in 3 cohorts with IT injections in superficial tumors. | Biological: RP2<br>* Genetically modified herpes simplex type 1 virus for tumor lysis and immune stimulation<br>|
| Experimental: Dose escalation of RP2 - deep/visceral tumors<br>Dose escalation of RP2 alone in 3 cohorts with imaging guided IT injections in deep/visceral tumors. | Biological: RP2<br>* Genetically modified herpes simplex type 1 virus for tumor lysis and immune stimulation<br>|
| Experimental: Dose expansion of RP2 and nivolumab - superficial tumors<br>Doses of RP2 (IT) in superficial tumors with nivolumab (IV). | Biological: RP2<br>* Genetically modified herpes simplex type 1 virus for tumor lysis and immune stimulation<br>Biological: nivolumab<br>* Programmed death receptor (PD-1) blocking antibody<br>* Other names: Opdivo;|
| Experimental: Dose expansion of RP2 and nivolumab - deep/visceral tumors<br>Imaging guided doses of RP2 (IT) in deep/visceral tumors. | Biological: RP2<br>* Genetically modified herpes simplex type 1 virus for tumor lysis and immune stimulation<br>Biological: nivolumab<br>* Programmed death receptor (PD-1) blocking antibody<br>* Other names: Opdivo;|
| Experimental: Seronegative cohort<br>Doses of RP2 (IT) in HSV seronegative participants. | Biological: RP2<br>* Genetically modified herpes simplex type 1 virus for tumor lysis and immune stimulation<br>|

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 AEs | From Day 1 up to 60 days after last dose | 
| Percentage of serious adverse events (SAEs) | Percentage of subjects with SAEs | From Day 1 up to 60 days after last dose | 
| Percentage of dose limiting toxicities (DLTs) | Percentage of subjects with DLTs | From Day 1 up to 30 days after last dose. | 
| Percentage of treatment emergent adverse events (TEAEs) | Percentage of subjects with TEAEs | From Day 1 up to 60 days after last dose. | 
| Percentage of TEAEs ≥ Grade 3 | Percentage of subjects with TEAEs ≥ Grade 3 | From Day 1 up to 60 days after last dose. | 
| Percentage of events requiring withdrawal | Percentage of subjects experiencing events requiring withdrawal from treatment. | From Day 1 up to last dose (up to 8 weeks for dose escalation phase and up to 2 years for expansion phase)). | 
| Maximum tolerated dose (MTD) of RP2 | MTD on the safety and response data collected during the dose escalation phase (Part 1). | 7 months | 
| Recommended Phase 2 dose (RP2D) of RP2 | RP2D of RP2 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 subjects with biological activity determined by tumor biopsies and biomarker data | 20 weeks | 
| Percentage of subjects with detectable RP2 | Data gathered from blood, urine, swabs of injection site, dressings, and oral mucosa to determine the shedding and biodistribution of RP2. | 20 weeks | 
| Change in HSV-1 antibody levels | Change in HSV-1 antibody levels during treatment compared to baseline | From Day 1 up to last dose (up to 4 months for dose escalation phase and up to 5.5 months for expansion phase)). | 
| Percentage of overall response rate (ORR) | Percentage of ORR. | 3 years | 
| Median duration of response | Median duration of response of subjects | 3 years | 
| Median progression-free survival | Median duration of progression-free survival of subjects | 3 years | 
| Median overall survival | Median overall survival rate of subjects | 3 years | 
| Percentage of complete response (CR) | Percentage of subjects with a CR | From Day 1 up to last dose (up to 8 weeks for escalation phase and up to 2 years for expansion phase). | 
| Percentage of partial response (PR) | Percentage of subjects with a PR | From Day 1 up to last dose (up to 8 weeks for escalation phase and up to 2 years for expansion phase). | 
| Percentage of stable disease (SD) | Percentage of subjects with SD | From Day 1 up to last dose (up to 8 weeks for escalation phase and up to 2 years for expansion phase). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gastrointestinal Cancers, Lung Cancer, Breast Cancer, Uveal Melanoma