A Phase 1b Dose Escalation Study of JX-594 (Thymidine Kinase-Inactivated Vaccinia Virus Plus GM-CSF) Administered by Biweekly (Every Two Weeks) Intravenous Infusion in Patients With Metastatic, Refractory Colorectal Carcinoma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 15
- 试验地点
- 1
- 主要终点
- Determine the maximally-tolerated dose (MTD) and/or maximum-feasible dose (MFD) of JX-594 administered by biweekly intravenous (IV) infusion
研究概览
简要总结
The purpose of this pilot safety study is to evaluate the safety and tolerability of JX-594 (Pexa-Vec) administered intravenously every 2 weeks in colorectal carcinoma patients who are refractory to or intolerant of oxaliplatin, irinotecan, and Erbitux treatments.
详细描述
This is a Phase Ib, open-label, dose-escalation study designed to evaluate the safety and tolerability of Pexa-Vec (JX-594), a vaccinia GM-CSF/thymidine kinase-deactivated virus, administered intravenously in patients with advanced/metastatic colorectal carcinoma (CRC) that is refractory to standard therapy. Vaccinia virus, from which Pexa-Vec is derived, shows a natural selectivity toward cancer relative to normal tissues after intravenous (IV) administration.
The study utilizes a sequential dose-escalating design to determine the maximum tolerated dose (MTD) and/or maximum feasible dose (MFD). Patients will receive 4 biweekly treatments of Pexa-Vec administered by IV infusion over 60 minutes on Days 1, 15, 29, and 43. Patients will be sequentially enrolled into one of three dose cohorts:
- Cohort 1: 1 × 10^6 pfu/kg
- Cohort 2: 1 × 10^7 pfu/kg
- Cohort 3: 3 × 10^7 pfu/kg Three patients will be treated at each dose level unless a dose-limiting toxicity (DLT) is observed, at which point the cohort may be expanded. All patients will receive hydration and will be observed in the clinic and/or hospital for a minimum of 24 hours after each infusion.
In addition to safety endpoints, secondary objectives include the evaluation of Pexa-Vec pharmacokinetics (PK), pharmacodynamics, immune response, and preliminary anti-tumoral activity. Tumor response assessments will be conducted using CT or MRI on Days 29 and 57 (±2 days) based on Response Evaluation Criteria in Solid Tumors (RECIST).
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
- •Histologically-confirmed, advanced/metastatic colorectal carcinoma
- •Failed both oxaliplatin and irinotecan based regimens for advanced/metastatic disease (if tumor advanced either immediately or within 3 months of the end of treatment)
- •Resistance to Erbitux: patients with Ras mutations, or for whom Erbitux has failed (if tumor advanced either immediately or within 3 months of the end of treatment, or there is no response to Erbitux therapy due to a lack of expression of EGFR (epidermal growth factor))
- •Karnofsky Performance Score (KPS) ≥ 70
- •Age ≥18 years
- •Laboratory Safety: WBC ≥ 3,500 cells/mm3 and ≤ 50,000 cells/mm3, ANC ≥ 1,500 cells/mm3, Hemoglobin ≥ 10 g/dL (transfusion allowed), Platelet count ≥ 100,000 plts/mm3,Total bilirubin ≤ 1.5 X ULN, INR ≤ 1.5, AST, ALT ≤ 2.5x ULN (in case of liver metastasis: AST,ALT ≤5.0 x ULN)
- •Serum chemistries within normal limits (WNL) or Grade 1 (excluding alkaline phosphatase) - If patients are diabetic, a fasting glucose must be done and patients must be > 160 mg/dL.
- •Patients who, if they are sexually active, are willing and able to refrain from sexual activity for 3 weeks following JX-594 administration. Patients who are willing and able to use a permitted contraceptive for 3 months after the final administration of JX-594.
排除标准
- •Significant immunodeficiency due to underlying illness (e.g. HIV/AIDS) and/or medication (e.g. systemic corticosteroids)
- •Known myeloproliferative disorders requiring systemic therapy
- •History of exfoliative skin condition (e.g. eczema or ectopic dermatitis) requiring systemic therapy
- •History of acquiring opportunistic infections.
- •Tumor(s) invading a major vascular structure (e.g. carotid artery)
- •Tumor(s) in location that would potentially result in significant clinical adverse effects if post-treatment tumor swelling were to occur
- •Clinically uncontrolled and/or rapidly accumulating ascites, pericardial and/or pleural effusions
- •History of severe or unstable cardiac disease
- •Current, known CNS malignancy (history of completely resected or irradiated brain metastases by WBRT or stereotactic radiosurgery allowed)
- •Administered anti-cancer therapy within 4 weeks prior to first treatment (6 weeks in case of mitomycin C or nitrosoureas)
- •Use of anti-viral, anti-platelet, or anti-coagulation medication [Patients who discontinue such medications within 7 days prior to first treatment may be eligible for this study.] Low dose aspirin (approximately 81 mg) allowed.
- •Pulse oximetry O2 saturation <90% Pulse oximetry O2 saturation <90% at rest
- •Experienced a severe systemic reaction or side-effect as a result of a previous smallpox vaccination
- •Pregnant or nursing
- •Household contact exclusions:
- •Women who are pregnant or nursing an infant
- •Children < 5 years old
- •People with skin disease (e.g. eczema, atopic dermatitis, and related diseases
- •Immunocompromised hosts (severe deficiencies in cell-mediated immunity, including AIDS, organ transplant recipients, hematologic malignancies)
研究组 & 干预措施
single arm; Dose escalation
Dose escalation 1e6 pfu/kg bw, 1e7 pfu/kg bw, 3e7 pfu/kg bw of Recombinant Vaccinia GM-CSF JX-594
干预措施: Recombinant Vaccinia GM-CSF; RAC VAC GM-CSF (JX-594) (Drug)
结局指标
主要结局
Determine the maximally-tolerated dose (MTD) and/or maximum-feasible dose (MFD) of JX-594 administered by biweekly intravenous (IV) infusion
时间窗: DLT evaluations through 14 days following last JX-594 treatment
Any of the following treatment related adverse events: Grade 4 toxicity, Grade 3 hematologic toxicity for \> 5 days, Grade 3 non-hematologic toxicities persisting for \> 7 days except for flu-like symptoms that respond to standard therapies.
Determine the safety of JX-594 administered by biweekly IV infusion
时间窗: Safety evaluations through 28 days after last dose of JX-594
Adverse events will be collected and assessed to assess safety and tolerability through 28 days after last dose of JX-594 (or until all events considered probably or possibly related to JX-594 have resolved, stabilized, or returned to baseline status).
Number of Participants Experiencing Dose-Limiting Toxicities (DLTs)
时间窗: Up to Day 57 (assessed through 14 days following the 4th and final biweekly JX-594 infusion, an average of 8 weeks).
A DLT is defined as any of the following treatment-related adverse events: Grade 4 toxicity, Grade 3 hematologic toxicity for \> 5 days, or Grade 3 non-hematologic toxicities persisting for \> 7 days except for flu-like symptoms that respond to standard therapies. The number of participants with DLTs was used to determine the Maximally-Tolerated Dose (MTD) and/or Maximum-Feasible Dose (MFD) of JX-594.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
时间窗: Up to Day 71 (assessed through 28 days following the 4th and final biweekly JX-594 infusion, an average of 10 weeks).
Adverse events were collected and assessed to evaluate safety and tolerability. A Treatment-Emergent Adverse Event (TEAE) is defined as an event with a start date on or after the date of the first dose of study treatment, or an event present at baseline that worsened in severity after the first dose.
次要结局
- Determine the anti-tumoral response of JX-594(Disease control and response assessment at Week 8)
- Determine the pharmacokinetics, pharmacodynamics and immune response activity of JX-594(Blood samples collected at assigned time points from baseline through Week 8)
- Number of Participants in Each Best Overall Tumor Response Category Based on RECIST(Up to Day 57 (Week 8))
- Overall Survival (OS)(From the first dose of Pexa-Vec until death from any cause, assessed up to 24 months)