An Open-Label, Multicenter, Phase 1B/2 Study of RP1 in Solid Organ and Hematopoietic Cell Transplant Recipients With Advanced Cutaneous Malignancies (ARTACUS)
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 69
- 试验地点
- 52
- 主要终点
- Primary Safety Outcome Measure
研究概览
简要总结
The purpose of this study is to assess the safety and efficacy of RP1 (administered into the tumor) in 90 patients who have received an organ transplant in the past and currently have skin cancer. The skin cancer is either locally advanced (large tumors in the skin, muscles or nerves) or metastatic (spread to other parts of the body).
This study will consist of a 28-day Screening Period, a Treatment Period, and a Follow-up Period. During the Treatment Period, patients will be dosed with RP1 every two weeks for up to 2 years (104 weeks). Tumor measurements will be done approximately every 8 weeks (and additionally if needed) until progressive disease, start of subsequent anticancer therapy, or completion/discontinuation of the study. During the Follow-up Period, patients will visit the clinic at 30, 60, and 100-150 days after their last dose of RP1 for safety and quality of life assessments. Patients will continue follow-up for up to 3 years from the day of the last patient's first dose.
详细描述
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, study evaluating the objective response rate and the safety and tolerability of RP1 in adult hepatic, renal, heart, lung, other solid organs, and/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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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 at birth and at least 18 years of age prior to signing informed consent.
- •Solid organ or allogeneic hematopoietic cell transplant patients with histologically or cytologically confirmed recurrent, cutaneous malignancies including locally advanced CSCC, metastatic (to skin, soft tissue, or lymph nodes) or locally advanced BCC, metastatic or locally advanced MCC, and melanoma.
- •Patients must have progressed or experienced recurrence from previous local resection and/or prior radiation.
- •Documentation from the patient's transplant physician confirming that the patient's allograft is stable. For dual transplant recipients, a failure of 1 of the transplanted organs is allowed.
- •Patients for whom surgical or radiation treatment of lesions is contraindicated or are considered to be inoperable.
- •Patients must have at least 1 measurable tumor of at least 1 cm in longest diameter. All measurable lesions identified at screening must be injectable and planned to be injected during the course of the study.
- •ECOG performance status of at most
- •Adequate allograft function as determined by functional testing and as confirmed by the transplant clinician.
- •For renal transplant recipients, patients must have serum creatinine increase of < 30% mean increase over the past 6 months.
- •For lung transplant recipients, patients must have stable forced exploratory 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.
- •For cardiac transplant recipients, patients must have:
- •ci. At least 50% ejection fraction with not more than an absolute change of 5% over the past 12 months. If the absolute change in ejection fraction is greater than 5% and there is no clinical suspicion for rejection by the transplant center, left ventricular ejection fraction (LVEF) stability needs to be shown by a repeat echo within 28 days after the most recent ECHO.
- •cii. No evidence of hemodynamically or angiographically significant cardiac allograft vasculopathy (CAV) (i.e., patients must not have CAV2 or CAV3), or no ischemia by appropriate diagnostic imaging over the past 12 months.
- •For patients with stable pancreas transplant, amylase and lipase should be ≤ 3 x upper limit of normal (ULN) for at least 6 months prior to enrollment.
- •Adequate hepatic function
- •Adequate renal function as indicated by a serum creatinine or estimated glomerular filtration rate (eGFR) determined based on the Chronic Kidney Disease-Epidemiology Collaboration equation.
- •Adequate hematologic function
- •Adequate coagulation parameters
- •Anticipated life expectancy > 6 months.
- •Have provided either formalin-fixed, paraffin-embedded (FFPE) tissue block and/or unstained tumor tissue sections, obtained within 90 days prior to enrollment, with an associated pathology report, which must be submitted to the central laboratory for inclusion or a fresh excisional, incisional, or core needle biopsy taken prior to dosing on C1D1 if an archival biopsy (collected within 90 days prior to enrollment) is not available.
- •Female and male patients (at birth) who meet the following criteria:
- •Female patients are eligible if not pregnant or breastfeeding and if one of the following applies 1) is a woman of non-childbearing potential (WNCBP) OR 2) is a woman of childbearing potential (WOCBP) and must agree to use a highly effective contraception method during the treatment period and for at least 90 days after last dose of RP
- •Male patients are eligible if they agree to the following during the study intervention period and for at least 90 days after the last dose of RP1: refrain from donating fresh unwashed semen plus either be abstinent from intercourse where pregnancy can occur OR must agree to use external condom and advise their partner to use a highly effective method of contraception.
排除标准
- •Prior treatment with an oncolytic therapy or checkpoint inhibitor.
- •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.
- •Patients requiring concurrent treatment with 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 a history of any positive test result for hepatitis B virus (HBV) or hepatitis C virus (HCV) indicating the presence of the virus, or human immunodeficiency virus (HIV) positive. Patients with a history of HBV or HCV must have undetectable viral load within 3 months of study entry.
- •A history of transplant-related viral infections such as BK virus (BKV), Epstein-Barr virus (EBV), or cytomegalovirus (CMV) requiring treatment or modification to immunosuppression within 3 months of study entry.
- •Had clinically significant cardiovascular disease within 6 months from first dose of RP1, 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 or any systemic therapy within 30 days of the first dose of RP
- •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), or a positive urine pregnancy test on C1D
- •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.
- •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 and throughout the study.
- •Has received a live vaccine within 30 days prior to the first dose of study drug. Note: Available COVID-19 vaccines do not contain live virus.
- •Active or history of leptomeningeal disease or brain metastasis.
- •Active graft versus host disease greater than Grade 1 within the last 12 months requiring systemic treatment.
研究组 & 干预措施
RP1, intra-tumoral injection, oncolytic virus
RP1 administered as an intra-tumoral injection every 2 weeks.
干预措施: RP1, intra-tumoral injection, oncolytic virus (Biological)
结局指标
主要结局
Primary Safety Outcome Measure
时间窗: 36 months
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
Incidence of subjects with fatal adverse events
时间窗: 36 months
Incidence of subjects with Serious adverse events (SAEs)
时间窗: 36 months
Primary Efficacy Outcome Measure
时间窗: 36 months
The objective response rate (ORR) according to investigator assessment using modified RECIST version 1.1.
Incidence of subjects with treatment-emergent adverse events greater than or equal to Grade 3
时间窗: 36 months
Treatment-emergent adverse events requiring withdrawal from IP and incidence of organ allograft rejection
时间窗: 36 months
Primary Objective for Patients with Locally Advances CSCC (laCSCC)
时间窗: 36 months
The effect of RP1 on objective response rate (ORR) as assessed by Independnet Central Review (ICR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1)
Primary Efficacy Objective for Patients with Other Skin Cancers
时间窗: 36 months
The effect of RP1 on ORR as assessed by investigator review per modified RECIST 1.1 (mRECIST 1.1)
Primary Safety Objective for Patients with Other Skin Cancers
时间窗: 36 months
The safety and tolerability of single-agent RP1 in solid organ transplant patients with other skin cancers as assessed by incidence of patients with treatment-emergent adverse events (TEAEs) and by incidence of patients with biopsy-proven allograft rejection.
次要结局
- Disease control rate (DCR) by investigator review(36 months)
- Disease-free Survival(36 months)
- 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)
- 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)
- To asses the efficacy of RP1 as determined by ORR in all transplant recipients treated, by investigator review(36 months)
- Biologic activity as assessed by changes in individual tumor sizes, erythema, inflammation and necrosis(36 months)
- Clinical benefit rate defined as the rate of Complete Response (CR), Partial Response (PR), or Stable Disease (SD)(36 months)
- Quality of life (QoL), as determined by patient-reported outcomes(36 months)
- Duration of Response (DOR) for Patients with laCSCC(36 months)
- Progression-Free Survival (PFS) for Patients with laCSCC(36 months)
- Disease Control Rate (DCR) for Patients with laCSCC(36 months)
- ORR for Patients with laCSCC by investigator review(36 months)
- Efficacy parameters for Patients with laCSCC by investigator review(36 months)
- Overall Survival for Patients with laCSCC(36 months)
- Secondary Safety Objective for Patients with laCSCC(36 months)
- Secondary Objective for Patients with Other Skin Cancers(36 months)