A Phase I/II, Open-label Study to Evaluate the Safety and Anti-tumor Effects of NV1020 Administered Repeatedly Via Hepatic Artery Infusion Prior to Second-line Chemotherapy, in Patients With Colorectal Adenocarcinoma Metastatic to the Liver
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- MediGene
- 入组人数
- 32
- 试验地点
- 5
- 主要终点
- Incidence of Adverse Events and Dose Limiting Adverse Events
研究概览
简要总结
This study is an open-label study. It has two stages. Stage 1 is a dose escalation phase of the study to determine and evaluate the safety and tolerability of repeated treatments with a genetically engineered herpes simplex virus NV1020 administered locoregionally to the liver.
Stage 2 is to evaluate the dose found in Stage 1 to be "optimally tolerated". Stage 2 is to assess the efficacy of the optimally tolerated dose of NV1020 by itself and in combination with second-line chemotherapy.
Assignment to Stage 1 or Stage 2 of the study is determined by when the patient enters the study.
详细描述
This study is designed to evaluate the effects of repeated treatments with NV1020, prior to second-line chemotherapy, and to determine an appropriate dose level of NV1020 in a multiple dose regimen for later Phase II studies.
Sequential, open-label cohort dose escalation of NV1020 (stage 1) followed by an expansion of one selected dose cohort (stage 2).
Study results will be reviewed periodically by an independent DSMB who will approve each cohort dose escalation.
During the dose escalation stage, 3 cohorts of patients (3 in each) will be treated with 4 fixed doses of NV1020, with the dose level increasing for successive cohorts. A patient will be observed for a minimum of 7 days after the first NV1020 infusion before the next patient in the same cohort is given NV1020. The first patient in the next higher dose cohort will receive NV1020 no earlier than 14 days after the last patient in the prior cohort has finished NV1020 infusions. One additional cohort (half log higher increment) may be approved by the DSMB, if considered necessary to define MTD. Dose-limiting toxicity will be determined using NCI CTC criteria and a suitable dose level for later evaluation will be selected.
In the second stage of the study, the dose cohort considered to show the best therapeutic index will be expanded by the addition of 18 further patients. For all patients in this study, investigational treatment with NV1020 will be followed by a minimum of two cycles of second-line therapy using anti-neoplastic drugs approved by the FDA for colorectal cancer and selected by the investigator.
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
- •Ability to understand and willingness to sign a written informed consent (includes willingness to avoid physical intimacy during and for 2 weeks post NV1020 treatment)
- •18 years or more of age
- •Colorectal adenocarcinoma histologically confirmed within one year prior to enrollment in the study
- •Liver dominant metastases (CT-measurable lesions with less than 50% total liver involvement), histologically confirmed
- •Failed conventional chemotherapy for metastatic disease (e.g. tumors no longer responding to 5-FU/leucovorin in combination with irinotecan or oxaliplatin with or without one monoclonal antibody)
- •Candidate for additional chemotherapy (and/or experimental anti-cancer therapy, if this is the only remaining treatment option)
- •Karnofsky Performance Status 70% or greater
- •Life expectancy greater than or equal to 4 months, based on the investigator's opinion
- •Seropositive for herpes simplex virus-1 (HSV-1)
- •Fecund females: negative for pregnancy test (urine or serum)
- •Effective double-barrier contraception for a minimum of 2 months following final infusion of NV1020
排除标准
- •Dominant extrahepatic disease, including cerebral metastases, significant malignant ascites or other extrahepatic metastases that are symptomatic, in critical locations or otherwise likely to confound NV1020 evaluations, in the opinion of the investigator
- •Seronegative for HSV-1
- •Significant active/unstable non-malignant disease or laboratory test (hematology and chemistry) results that meet any of the following:
- •White blood cell count (WBC) less than or equal to 3 x 10e3/mm3
- •Absolute neutrophil count (ANC) less than or equal to 1.5 x 10e3/mm3
- •Platelets less than or equal to 100,000/mm3
- •Hemoglobin (Hgb) less than or equal to 9.0 g/dL
- •Prothrombin time/partial thromboplastin time (PT/PTT) > upper limit of normal (ULN)
- •Serum creatinine > 2.0 mg/dL
- •Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 times ULN or total bilirubin > 1.5 times ULN
- •Alkaline phosphatase > 2.5 times ULN
- •Chemotherapy < 4 weeks prior to the first NV1020 infusion (mitomycin or nitrosurea < 6 weeks)
- •Immunotherapy < 6 weeks prior to the first NV1020 infusion
- •Radiotherapy (external or internal) to the liver
- •Major surgery (excluding pump placement and cholecystectomy) ≤ 2 weeks prior to the first NV1020 infusion but the subject must be clinically stable. Pump placement and cholecystectomy ≤ 1 week prior to the first NV1020 infusion but the subject must be clinically stable
- •Female who is pregnant or nursing
- •Patients wishing to conceive within 2 months after the last infusion of NV1020
- •Any investigational agent administered less than or equal to 4 weeks prior to NV1020 infusion
- •Acute HSV infection requiring systemic antiviral therapy or history of serious HSV infection (e.g., ocular, encephalitic, etc.)
- •Active viral hepatitis (evidence for infection with hepatitis A, B or C viruses)
- •Known infection with HIV
- •Known hypersensitivity to any component of the NV1020 formulation
- •History of, or current, bleeding or coagulation disorder
- •History of significant hepatic fibrosis, cirrhosis, or hemachromatosis
- •History of malignancy other than colorectal cancer, within 5 years prior to start of study participation, with the exception of in situ cervical or skin carcinoma
- •Active severe infection and any other concurrent disease or medical conditions that are likely to interfere with the study, as judged by the investigator
- •Systemic corticosteroid administration < 4 weeks prior to starting NV1020 treatment
- •Prior treatment with NV1020 or other putative oncolytic viruses
研究组 & 干预措施
Safety and antitumor effects of NV1020
Stage 1: Four escalating dose cohorts of NV1020 3x10^6 pfu, 1x10^7 pfu, 3x10^7 pfu, and 1x10^8 pfu administered via hepatic artery infusion, over 10 minutes and repeated every 1-2 weeks for 4-8 weeks followed by 2 cycles of chemotherapy.
Stage 2: Expansion of one dose cohort from Stage 1 of optimal NV1020 dose administered via hepatic artery infusion, over 10 minutes and repeated every 1-2 weeks for 4-8 weeks followed by 2 cycles of chemotherapy.
干预措施: NV1020 (Drug)
结局指标
主要结局
Incidence of Adverse Events and Dose Limiting Adverse Events
时间窗: From start of treatment through 12 months after completion of treatment
Incidence of adverse events for all patients (N=32); Overall incidence ≥20%; Adverse events listed by Medical Dictionary for Regulatory Activities (MedDRA) Preferred Term
NV1020 Pharmacokinetics - Presence of NV1020 in Body Fluids/Skin
时间窗: Daily for 2 weeks after the first and last NV1020 infusions
Number of patients with NV1020 detected in saliva, skin, and/or mucosal surfaces; Analysis by polymerase chain reaction (PCR)
Clinical Laboratory Safety - Hematology
时间窗: Screening; after each NV1020 infusion; +7h, +24h, and +72h after NV1020 infusion; each chemotherapy visit; +3d, +7d, +14d after each chemo visit; 1 week after end of treatment
Number of patients with clinically significant hematology laboratory abnormalities by NV1020 dose cohort (Post baseline)
Clinical Laboratory Safety - Chemistry
时间窗: Screening; after each NV1020 infusion; +7h, +24h, and +72h after NV1020 infusion; each chemotherapy visit; +3d, +7d, +14d after each chemo visit; 1 week after end of treatment
Number of patients with post-baseline clinically significant laboratory chemistry abnormalities by NV1020 dose cohort
Clinical Laboratory Safety - Coagulation
时间窗: Screening; after each NV1020 infusion; +7h, +24h, and +72h after NV1020 infusion; each chemotherapy visit; +3d, +7d, +14d after each chemo visit; 1 week after end of treatment
Number of patients with post-baseline clinically significant laboratory coagulation abnormalities by NV1020 dose cohort
次要结局
- Mean Change From Baseline in Serum Carcinoembryonic Antigen (CEA) After Administration of NV1020 and 2 Cycles of Chemotherapy(Screening (baseline), Chemo visit 1, Chemo visit 2, Follow-up Visit 1 (1 week after end of treatment), Follow-up Visit 2 (+6M), Follow-up Visit 3 (+9M), Follow-up Visit 4 (+12M))
- Liver Tumor Response After Administration of NV1020 Followed by Chemotherapy, Determined by Radiological (Computed Tomography [CT] Scan) Assessment(Screening (baseline), Chemo visit 1, Follow-up visits 1 (1 week post end of treatment), 2 (+6M), 3 (+9M), 4 (+12M))
- Pharmacodynamic Effects of NV1020: NV1020 Neutralizing Antibody Titer Assay(Screening, Chemo Visit 1, Follow-up Visits 1 (1 week post end of treatment), 2 (+6M), 3 (+9M), 4 (+12M))
- Time to Disease Progression; Survival Time(Progression: Chemo visit 1, FU1 (1 week post treatment), FU2 (+6M), FU3 (+9M), FU4 (+12M); Survival: death of patient)
- Pharmacodynamic Effects of NV1020: Serum Cytokines (TNF-alpha)(Baseline, after each NV1020 infusion (Visit 1, Visit 3, Visit 5, Visit 7))
- Pharmacodynamic Effects of NV1020: Serum Cytokines (INF Gamma)(Baseline, after each NV1020 infusion (Visit 1, Visit 3, Visit 5, Visit 7))
- Pharmacodynamic Effects of NV1020: Serum Cytokines (IL-6)(Baseline, after each NV1020 infusion (Visit 1, Visit 3, Visit 5, Visit 7))