IRB Study Number 25-230
Status Recruiting
Phase Phase 1
Location Cleveland Clinic Main Campus
Institute Taussig Cancer Institute
Description
Primary Objectives:
• To assess the efficacy of RP1 as determined by objective response rate (ORR) in transplant patients with locally advanced or metastatic (to skin, soft tissue, or lymph nodes) cutaneous squamous cell carcinoma (CSCC), by investigator review
• To assess the safety and tolerability of RP1 in transplant patients with cutaneous malignancies, as determined by the incidence of all treatment-emergent adverse events (TEAEs), ≥ Grade 3 TEAEs, serious adverse events (SAEs), fatal adverse events (AEs), TEAEs requiring withdrawal from RP1, and the percentage of patients with biopsy-proven clinical allograft rejection.
Secondary Objectives:
• To assess the efficacy of RP1 as determined by ORR in all transplant patients treated, by investigator review
• To estimate duration of response (DOR), complete response (CR) rate, disease control rate (DCR), and progression-free survival (PFS) for CSCC and all patients treated, by investigator review.
• To evaluate efficacy by one-year and two-year overall survival (OS) rates in CSCC and all patients treated.
• To assess evidence of biological activity as determined by individual tumor size, erythema, inflammation, and necrosis
• To assess the change in quality of life (QoL) score using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30)
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.
Male or female ≥ 18 years of age on the day of signed informed consent.
Solid organ or allogeneic hematopoietic cell transplant 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 (BCC), Merkel cell carcinoma (MCC), and melanoma. Note: Hematopoietic cell transplant type must be allogeneic and have occurred > 12 months prior to dosing. Patients who have received more than 1 prior transplant may be eligible based on discussion with the Medical Monitor.
Patients must have progressed following local resection and/or prior radiation and have received no more than 1 prior systemic therapy. Note: If a previously irradiated lesion is to be followed as a target lesion, the progression of that lesion must be confirmed by biopsy after radiation therapy. Previously irradiated lesions may be followed as nontarget lesions if there is at least 1 other measurable target lesion.
Documentation from the patient’s transplant physician confirming that the patient’s allograft is stable, as determined by appropriate assessment of allograft function such as spirometry, cardiac imaging diagnostics ( e.g., echocardiogram, cardiac MRI, nuclear stress test, coronary angiogram), blood and/or urine analysis, or surveillance biopsies, and by no medical history of antibody or cell-mediated allograft rejection within 12 months prior to study participation. Note: For dual transplant recipients, a failure of 1 of the transplanted organs is allowed.
Patients for whom surgical treatment of lesions is contraindicated (i.e., complete resection is not possible or not expected to be clinically beneficial) or the patient refuses surgical or radiation treatment.
At least 1 measurable tumor of ≥ 1.0 cm in longest diameter or ≥ 1.5 cm in shortest diameter for lymph nodes and injectable lesions which in aggregate comprise ≥ 1.0 cm in longest diameter.
ECOG performance status ≤ 1.
Adequate function in the end organ of transplantation as confirmed by the transplant clinician.
a. For renal transplant recipients, serum creatinine increase of no more than 0.3 mg/dL or <25% mean increase over the past 6 months and absence of significant proteinuria defined as an absolute cutoff of 1000 mg/day (or 1000 mg/g on spot check).
b. For lung transplant recipients, stable forced expiratory volume in 1 second (FEV1) of at least 50% predicted with no more than a 10% decline in the absolute FEV1 over the past 12 months.
c. For heart transplant recipients, at least 50% ejection fraction with not more than an absolute change of 5% and no evidence of hemodynamically or angiographically significant cardiac allograft vasculopathy (CAV), CAV2, or CAV3 (Appendix 7), or positive ischemia by appropriate diagnostic imaging over the past 12 months.
d. For patients with stable pancreas transplant, amylase and lipase should be ≤ 3 x ULN and asymptomatic for at least 6 months prior to enrollment.
- Adequate hepatic function, including both of the following:
a. Total bilirubin ≤ 1.5 × institutional upper limit of normal (ULN) (except patients with Gilbert’s Syndrome who must have a total bilirubin of < 3 × ULN) or direct bilirubin ≤ ULN for a patient with total bilirubin level > 1.5 × ULN.
b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × ULN and alkaline phosphatase (ALP) ≤ 2.5 × ULN.
Adequate renal function as indicated by a serum creatinine ≤ 1.5 × ULN or estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2 determined based on the Chronic Kidney Disease-Epidemiology Collaboration equation.
Adequate hematologic function, including all the following:
a. Hemoglobin ≥ 9.0 g/dL
b. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L (Note: If the ANC has been < 1.0 × 109/L at any point in the previous 3 months, the subject is excluded).
c. Platelet count ≥ 50 × 109/L
- Adequate coagulation parameters, including both of the following:
a. Prothrombin time (PT) or international normalization ratio (INR) ≤ 1.5 × ULN, unless the patient is receiving anticoagulant therapy, in which case PT and partial thromboplastin time (PTT)/activated PTT (aPTT) must be within therapeutic ranges of intended use of anticoagulants.
b. PTT or aPTT ≤ 1.5 × ULN unless the patient is receiving anticoagulant therapy and PT and PTT/aPTT are within the therapeutic ranges of intended use of anticoagulants.
Anticipated life expectancy > 6 months.
Have provided either formalin-fixed, paraffin-embedded (FFPE) tissue block or unstained tumor tissue sections, obtained within 60 days prior to enrollment, with an associated pathology report, which must be submitted to the central laboratory for inclusion. Biopsy should be excisional, incisional, or core needle. Fine needle aspiration is unacceptable for submission. A fresh biopsy is required at screening if an archival biopsy (within 60 days prior to enrollment) is not available.
Exclusion Criteria
Prior treatment with an oncolytic therapy.
Patients with visceral metastases.
Active significant herpetic infections or prior complications of HSV-1 infection (e.g., herpetic keratitis or encephalitis). Patients requiring use of systemic (oral/intravenous [IV]) antiviral agents with known antiherpetic activity. Note: Patients with sporadic cold sores may be enrolled as long as no active cold sores are present at the time of first dose of RP1.
Patients requiring cytotoxic T-lymphocyte antigen 4–Ig (CTLA-4-Ig) medications.
Had systemic infection requiring IV antibiotics or other serious infection within 14 days prior to dosing.
Patients with an active, known, or suspected autoimmune disease that requires systemic immunosuppressive treatment beyond immunosuppressive medications required for maintenance of allograft rejection prevention. Patients with vitiligo, childhood asthma that has resolved, type 1 diabetes mellitus, hypothyroidism only requiring hormone replacement, or psoriasis that does not require systemic treatment are permitted to enroll.
Patients with a history of any positive test result for hepatitis B virus (HBV) or hepatitis C virus (HCV) indicating the presence of the virus, e.g., hepatitis B surface antigen [HbsAg] positive or hepatitis C antibody (anti-HCV) positive (except if HCV RNA negative), or human immunodeficiency virus (HIV) positive. Patients with a history of HBV or HCV infection must have undetectable viral load within 3 months of study entry. Note: Testing for HBV, HCV, or HIV is not required unless mandated by local health authorities.
A history of transplant-related viral infections requiring treatment or modification to immunosuppression, such as BKV, EBV or CMV within 3 months of study entry.
Had clinically significant cardiovascular disease within 6 months from first dose of study drug, including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction or stroke/transient ischemic attack or significant cardiac arrhythmias associated with hemodynamic instability.
Radiation therapy within 14 days of first dose of RP1, or topical therapy within 30 days of RP1, is not allowed. The patient must have recovered from all AEs due to previous therapies to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE version 5.0) Grade 1 or baseline. Participants with unresolved radiation-induced xerostomia are eligible.
Documented history of allergic reactions or acute hypersensitivity reaction attributed to RP1 or to any of the excipients.
Females who have a positive serum beta-human chorionic gonadotropin (β-hCG) test for pregnancy (at screening within 72 hours before dosing), positive urine pregnancy test on C1D1, or is breast-feeding or planning to become pregnant during the study and for at least 90 days after the last dose.
Any active malignancy within 3 years of the date of first planned dose of RP1, except for the specific cancer under investigation in this study and tumors with negligible risk of metastasis or death, squamous cell carcinoma in situ (SCCIS), carcinoma in situ of the cervix, ductal carcinoma in situ of the breast, low-risk early stage prostate adenocarcinoma (T1-T2aN0M0), Gleason score ≤ 6, and prostate specific antigen (PSA) ≤ 10 ng/mL) for which the management plan is active surveillance, or prostate adenocarcinoma with biochemical-only recurrence with documented PSA doubling time of > 12 months for which the management plan is active surveillance. Patients with hematologic malignancies are excluded, except for patients with chronic lymphocytic leukemia (CLL) who are considered stable and not on active treatment.
Any acute or chronic psychiatric problems, alcohol abuse, or substance abuse disorders that, in the opinion of the investigator, would interfere with the patient’s ability to comply with the requirements of the study.
Any co-morbidity, physical examination finding, metabolic dysfunction, or clinical laboratory abnormality that, in the opinion of the investigator, renders the patient unsuitable for participation due to safety risks or potential to affect interpretation of results of the study.
Treatment with botanical preparations (e.g., herbal supplements or traditional Chinese medicines) intended for general health support or to treat the disease under study within 2 weeks prior to the first dose of RP1 and throughout the study as per Section 5.10.2.
Has received a live vaccine within 30 days prior to the first dose of study drug.
Active or history of leptomeningeal disease or brain metastasis.
Active graft versus host disease within the last 12 months requiring systemic treatment.
