A Phase 1B/2 Study of RP1 in Solid Organ Transplant Patients With Advanced Cutaneous Malignancies

Study Overview
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Brief Summary
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This Phase 1B/2 study is a multicenter, open-label, study of RP1 to investigate the (a) objective response rate, in addition to (b) safety and tolerability of RP1 for the treatment of advanced cutaneous malignancies in up to 65 evaluable organ transplant recipients. This will include patients with either previous renal, hepatic, heart, lung, or other solid organ transplantation or hematopoietic cell transplant and experiencing subsequent documented locally advanced or metastatic cutaneous malignancies. The study will enroll a total of 65 evaluable patients. Patients will participate up to approximately 3 years including a 28-day screening period, up to approximately 1 year treatment period, and a 2-year follow-up period.

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 1B/2, open label, multicenter, trial evaluating the objective response rate and the safety and tolerability, biodistribution, shedding, and preliminary efficacy of RP1 in adult hepatic, renal, heart, lung, other solid organs, or hematopoietic cell transplant recipients who subsequently experienced advanced or metastatic cutaneous malignancies. Patients will be dosed with RP1 by direct or ultrasound guided intra-tumoral injection into superficial, subcutaneous or nodal tumors. No transplanted organs will be injected.

Official Title
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An Open-Label, Multicenter, Phase 1B/2 Study of RP1 in Solid Organ and Hematopoietic Cell Transplant Recipients With Advanced Cutaneous Malignancies

Conditions
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Cutaneous Squamous Cell Carcinoma, Merkel Cell Carcinoma, Basal Cell Carcinoma, Melanoma

Intervention / Treatment
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* Biological: RP1, intra-tumoral injection, oncolytic virus


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Voluntary agreement to provide written informed consent prior to any study procedures and the willingness and ability to comply with all aspects of the protocol and understand the risk to their organ allograft. Patients with histologically or cytologically confirmed recurrent, locally advanced or metastatic (to skin, soft tissue or lymph nodes) cutaneous malignancies, including CSCC, basal cell carcinoma, Merkel cell carcinoma, and melanoma Patients must have progressed following local resection, prior radiation, topical or systemic therapies. Documentation from the patient's transplant physician confirming that the patient's allograft is stable. Patients for whom surgical or radiation treatment of lesions is contraindicated. At least 1 lesion that is measurable and injectable by study criteria (tumor of ≥1cm in longest diameter or ≥1.5 cm in shortest diameter for lymph nodes). Eastern Cooperative Oncology Group (ECOG) performance status ≤1. Anticipated life expectancy > 6 months Baseline ECG without evidence of acute ischemia. All patients must consent to provide archived or newly obtained tumor material (either formalin-fixed, paraffin-embedded [FFPE] block or 20 unstained slides). Key Exclusion Criteria: Prior treatment with an oncolytic therapy. Patients with visceral metastases. Patients with active herpetic infections or prior complications of HSV-1 infection (e.g., herpetic keratitis or encephalitis). Patients with a history of organ graft rejection within 12 months. Had systemic infection requiring intravenous (IV) antibiotics or anti-virals, or other serious infection within 60 days prior to dosing. Patients who require intermittent or chronic use of systemic (oral or intravenous) anti-virals with known anti-herpetic activity (e.g., acyclovir) unless for organ allograft preservation. Patients requiring CTLA-4-Ig medications. Ongoing or recent (within 5 years) evidence of significant autoimmune disease that required treatment with systemic immunosuppressive treatments beyond that required for maintenance allograft rejection prevention. The following are not exclusionary: vitiligo, childhood asthma that has resolved, type 1 diabetes, residual hypothyroidism that requires only hormone replacement, or psoriasis that does not require systemic treatment. Active infection with hepatitis B virus (HBV), hepatitis C virus (HCV) or human immunodeficiency virus (HIV). Any history of transplant-related viral infections, such as BKV, EBV or CMV, within 3 months of study entry. Patients with a history of hepatitis B or C virus must have undetectable viral load within 3 months of study entry. Patients with a condition requiring an increase in the patient's usual immunosuppressive medications within 60 days of study treatment. Known active CNS metastases and/or carcinomatous meningitis.

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
Intervention Model: Single Group Assignment
Interventional Model Description: RP1 injection
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RP1, intra-tumoral injection, oncolytic virus<br>RP1 administered as an intra-tumoral injection every 2 weeks. | Biological: RP1, intra-tumoral injection, oncolytic virus<br>* Genetically modified herpes simplex type 1 virus<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary Safety Outcome Measure | Assess the safety and tolerability of single-agent RP1 in solid organ transplant patients with cutaneous malignancies by incidence of subjects with treatment-emergent adverse events | 36 months | 
| Primary Efficacy Outcome Measure | The objective response rate (ORR) according to investigator assessment using modified RECIST version 1.1. | 36 months | 
| Incidence of subjects with treatment-emergent adverse events greater than or equal to Grade 3 |  | 36 months | 
| Incidence of subjects with Serious adverse events (SAEs) |  | 36 months | 
| Incidence of subjects with fatal adverse events |  | 36 months | 
| Treatment-emergent adverse events requiring withdrawal from IP and incidence of organ allograft rejection |  | 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of response (DOR) by investigator among subjects who experience Complete Response (CR) or Progressive Disease (PD) |  | 36 months | 
| CR rate by investigator assessment |  | 36 months | 
| Disease control rate (DCR) by investigator review |  | 36 months | 
| Clinical benefit rate defined as the rate of Complete Response (CR), Partial Response (PR), or Stable Disease (SD) |  | 36 months | 
| Progression Free Survival (PFS) by investigator review Duration of clinical benefit (DOCB) during active treatment and for up to one year after last treatment by investigator review |  | 36 months | 
| Overall survival (OS) at one year and two years |  | 36 months | 
| 3-year survival rate of subjects |  | 36 months | 
| Quality of life (QoL), as determined by patient-reported outcomes |  | 36 months | 
| Biologic activity as assessed by changes in individual tumor sizes, erythema, inflammation and necrosis | Percentage of patients with biopsy-proven clinical rejection and percentage of patients who require an increase in immune suppressive therapy, during active treatment and for up to 1 year after last treatment | 36 months | 
| Disease-free Survival |  | 36 months | 
| To asses the efficacy of RP1 as determined by ORR in all transplant recipients treated, by investigator review |  | 36 months |