A Phase Ib Dose Escalation Study of MM-398 Plus Irinotecan in Patients With Unresectable Advanced Cancer - DOUBLIRI
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 10
- 试验地点
- 1
- 主要终点
- Adverse Event (AE)
研究概览
简要总结
MM-398 (also known as PEP02) is nanoliposomal encapsulated irinotecan: the liposomal formulation is designed to extend plasma circulation and to increase accumulation in the tumor through the enhanced permeability and retention (EPR) effect.
This study introduces a new concept of combining free and nanoliposomal drugs.
详细描述
This is a dose-finding and therapeutic exploratory phase Ib multi-center, open label study of MM-398 plus irinotecan in two different settings:
- Group A : patients with unresectable advanced non-colorectal cancer who should receive only MM-398 and irinotecan
- Group B : patients with unresectable metastatic colorectal cancer who should receive MM-398 and irinotecan combined with leucovorin, 5-fluorouracil and bevacizumab.
These groups will be enrolling in parallel. Pharmacokinetic and biomarker sampling will also be performed.
There are three periods to this study :
Screening period (up to -28d): patients undergo screening assessments to determine the eligibility for the study
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 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age 18 - 75 years
- •Histologically proven carcinoma,
- •Documented advanced or metastatic disease not suitable for complete surgical resection
- •Measurable or evaluable lesions according to RECIST v1.1 criteria
- •ECOG performance status 0 - 1
- •Adequate Bone marrow reserves as evidenced by:
- •Absolute Neutrophil Count (ANC) ≥1.5 x 109/L without the use of hematopoietic growth factors
- •platelets ≥ 100 x 109/L
- •hemoglobin > 9 g/dL (may be transfused to maintain or exceed this level)
- •International Normalized Ratio (INR) ≤1.5; aPTT<1.5 x upper normal limit (UNL); EXEMPTION: patients on full anticoagulation therapy due to Venous Thromboembolism (VTE) must have an in-range INR (usually between 2 and 3).
- •Adequate renal function as evidenced by:
- •serum creatinine: < 150µmol/l
- •calculated creatinine clearance > 50ml/min. (recommendation: to be calculated according to the MDRD formula)
- •Total bilirubin < 1.0 x upper normal limit (UNL)
- •Normal ECG or ECG without any clinically significant findings
- •Regular follow-up feasible. A registered patient must be treated and followed at the participating center.
- •Able to understand and sign an informed consent
- •No contraindication to any study drugs
- •Registration in a national health care system (CMU included for France). NB.: prior exposure to irinotecan is allowed, except for irinotecan-refractory patients (i.e. exclusion criteria)
排除标准
- •Active central nervous system metastases (indicated by clinical symptoms, cerebral edema, steroid requirement, or progressive disease)
- •Bone-only disease
- •Clinically significant gastrointestinal (GI) disorder including hepatic disorders, bleeding, inflammation, GI obstruction, or diarrhea > grade 1
- •Patients refractory to irinotecan (i.e. prior exposure to irinotecan-based therapy with progressive disease as best response)
- •Known Dose Limiting Toxicity (DLT) responses to irinotecan
- •Patients known to be homozygous for UGT1A1 *28
- •History of any second malignancy in the last 3 years; patients with prior history of in-situ cancer or basal or squamous cell skin cancer are eligible. Patients with a history of other malignancies are eligible if they have been continuously disease-free for at least 3 years
- •Prior exposure to MM-398
- •Known hypersensitivity to any of the components of MM-398, or other liposomal products
- •Concurrent illnesses that would be a relative contraindication to trial participation such as active cardiac or liver disease
- •Severe arterial thromboembolic events (myocardial infarction, unstable angina pectoris, stroke) less than 6 months before inclusion
- •NYHA Class III or IV congestive heart failure, ventricular arrhythmias
- •Chronic inflammatory bowel disease and/or bowel obstruction
- •Active infection or an unexplained fever >38.5°C during screening visits or on the first scheduled day of dosing (at the discretion of the investigator, patients with tumor fever may be enrolled), which in the investigator's opinion might compromise the patient's participation in the trial or affect the study outcome
- •Prior chemotherapy administered within 3 weeks, or within a time interval less than at least 5 half-lives of the agent, whichever is longer, prior to the first scheduled day of dosing in this study
- •Uncontrolled hypertension (defined as persistent systolic blood pressure >150 mmHg and/or diastolic blood pressure >100 mmHg), or history of hypertensive crisis, or hypertensive encephalopathy
- •Received radiation therapy in the last 14 days
- •Major surgery or traumatic injury within the last 28 days
- •Any other medical or social condition deemed by the Investigator to be likely to interfere with a patient's ability to sign informed consent, cooperate and participate in the study, or interfere with the interpretation of the results including tutelage and guardianship
- •Pregnant or breast feeding; females of child-bearing potential must test negative for pregnancy at the time of enrollment based on a urine or serum pregnancy test. Both male and female patients of reproductive potential must agree to use a reliable method of birth control, during the study and for 6 months following the last dose of study drug.
- •Concomitant administrations use with St John Worth, or CYP3A4 inducing anticonvulsants (phenytoin, Phenobarbital, carbamazepine), ketoconazole, itraconazole, troleandomycin, erythromycin, diltiazem and verapamil
- •Concomitant administration of live attenuated virus vaccine such as yellow fever vaccine
- •Known dihydropyrimidine dehydrogenase (DPD) deficiency
- •Known active hepatitis B or C and/or active or chronic human immunodeficiency virus (HIV)
研究组 & 干预措施
GROUP A / GROUP B (two differents cohorts)
GROUP A (Patients with unresectable advanced non-colorectal cancer ) - irinotecan + MM-398 dose escalation (3-18 patients)
Level 1 : initial DOUBLIRI dose 60/90 (0-3 patients)
- MM-398 : 60mg/m²
- Irinotecan (CPT-11) : 90mg/m²
Level 2: DOUBLIRI dose 80/90 (9 - 18 patients)
- MM-398 : 80mg/m²
- CPT-11: 90mg/m²
Level 3A: DOUBLIRI dose 60/120 (12-18 patients)
- MM-398 : 60mg/m²
- CPT-11: 120mg/m²
Level 3B: DOUBLIRI dose : 80/120 (12-18 patients)
- MM-398 : 80mg/m²
- CPT-11 : 120 mg/m²
GROUP B (Patients with unresectable metastatic colorectal cancer)- LV/5FU-bevacizumab+irinotecan+MM-398 dose Escalation (3-18 patients)
same level as group A + LV/5FU - bevacizumab regimen :
- Bevacizumab : 5mg/kg(day (d) 1)
- Leucovorin (LV) : 400mg/m² (d1)
- 5-fluorouracile infusion (5 FU) :2400mg/m² (d1,2)
干预措施: MM-398 (Drug)
GROUP A / GROUP B (two differents cohorts)
GROUP A (Patients with unresectable advanced non-colorectal cancer ) - irinotecan + MM-398 dose escalation (3-18 patients)
Level 1 : initial DOUBLIRI dose 60/90 (0-3 patients)
- MM-398 : 60mg/m²
- Irinotecan (CPT-11) : 90mg/m²
Level 2: DOUBLIRI dose 80/90 (9 - 18 patients)
- MM-398 : 80mg/m²
- CPT-11: 90mg/m²
Level 3A: DOUBLIRI dose 60/120 (12-18 patients)
- MM-398 : 60mg/m²
- CPT-11: 120mg/m²
Level 3B: DOUBLIRI dose : 80/120 (12-18 patients)
- MM-398 : 80mg/m²
- CPT-11 : 120 mg/m²
GROUP B (Patients with unresectable metastatic colorectal cancer)- LV/5FU-bevacizumab+irinotecan+MM-398 dose Escalation (3-18 patients)
same level as group A + LV/5FU - bevacizumab regimen :
- Bevacizumab : 5mg/kg(day (d) 1)
- Leucovorin (LV) : 400mg/m² (d1)
- 5-fluorouracile infusion (5 FU) :2400mg/m² (d1,2)
干预措施: Irinotecan (Drug)
GROUP A / GROUP B (two differents cohorts)
GROUP A (Patients with unresectable advanced non-colorectal cancer ) - irinotecan + MM-398 dose escalation (3-18 patients)
Level 1 : initial DOUBLIRI dose 60/90 (0-3 patients)
- MM-398 : 60mg/m²
- Irinotecan (CPT-11) : 90mg/m²
Level 2: DOUBLIRI dose 80/90 (9 - 18 patients)
- MM-398 : 80mg/m²
- CPT-11: 90mg/m²
Level 3A: DOUBLIRI dose 60/120 (12-18 patients)
- MM-398 : 60mg/m²
- CPT-11: 120mg/m²
Level 3B: DOUBLIRI dose : 80/120 (12-18 patients)
- MM-398 : 80mg/m²
- CPT-11 : 120 mg/m²
GROUP B (Patients with unresectable metastatic colorectal cancer)- LV/5FU-bevacizumab+irinotecan+MM-398 dose Escalation (3-18 patients)
same level as group A + LV/5FU - bevacizumab regimen :
- Bevacizumab : 5mg/kg(day (d) 1)
- Leucovorin (LV) : 400mg/m² (d1)
- 5-fluorouracile infusion (5 FU) :2400mg/m² (d1,2)
干预措施: Leucovorin (LV) (Drug)
GROUP A / GROUP B (two differents cohorts)
GROUP A (Patients with unresectable advanced non-colorectal cancer ) - irinotecan + MM-398 dose escalation (3-18 patients)
Level 1 : initial DOUBLIRI dose 60/90 (0-3 patients)
- MM-398 : 60mg/m²
- Irinotecan (CPT-11) : 90mg/m²
Level 2: DOUBLIRI dose 80/90 (9 - 18 patients)
- MM-398 : 80mg/m²
- CPT-11: 90mg/m²
Level 3A: DOUBLIRI dose 60/120 (12-18 patients)
- MM-398 : 60mg/m²
- CPT-11: 120mg/m²
Level 3B: DOUBLIRI dose : 80/120 (12-18 patients)
- MM-398 : 80mg/m²
- CPT-11 : 120 mg/m²
GROUP B (Patients with unresectable metastatic colorectal cancer)- LV/5FU-bevacizumab+irinotecan+MM-398 dose Escalation (3-18 patients)
same level as group A + LV/5FU - bevacizumab regimen :
- Bevacizumab : 5mg/kg(day (d) 1)
- Leucovorin (LV) : 400mg/m² (d1)
- 5-fluorouracile infusion (5 FU) :2400mg/m² (d1,2)
干预措施: 5-fluorouracile (5-FU) (Drug)
GROUP A / GROUP B (two differents cohorts)
GROUP A (Patients with unresectable advanced non-colorectal cancer ) - irinotecan + MM-398 dose escalation (3-18 patients)
Level 1 : initial DOUBLIRI dose 60/90 (0-3 patients)
- MM-398 : 60mg/m²
- Irinotecan (CPT-11) : 90mg/m²
Level 2: DOUBLIRI dose 80/90 (9 - 18 patients)
- MM-398 : 80mg/m²
- CPT-11: 90mg/m²
Level 3A: DOUBLIRI dose 60/120 (12-18 patients)
- MM-398 : 60mg/m²
- CPT-11: 120mg/m²
Level 3B: DOUBLIRI dose : 80/120 (12-18 patients)
- MM-398 : 80mg/m²
- CPT-11 : 120 mg/m²
GROUP B (Patients with unresectable metastatic colorectal cancer)- LV/5FU-bevacizumab+irinotecan+MM-398 dose Escalation (3-18 patients)
same level as group A + LV/5FU - bevacizumab regimen :
- Bevacizumab : 5mg/kg(day (d) 1)
- Leucovorin (LV) : 400mg/m² (d1)
- 5-fluorouracile infusion (5 FU) :2400mg/m² (d1,2)
干预措施: bevacizumab (Drug)
结局指标
主要结局
Adverse Event (AE)
时间窗: Assessed from study inclusion to 30 days after last dose
Maximal tolerated dose (MTD)
时间窗: after the last patient in each cohort up to 28 months
Dose Limiting Toxicities (DLT)
时间窗: DLTs will be evaluated during 28-day period following the first dose of study treatment
次要结局
- Best overall Response (BOR)(BOR is the best response recorded from the inclusion until treatment failure up to 28 months)
- Pharmacokinetic of MM-398 plus irinotecan combination therapy(cycle 1 Day 1 (1 cycle every 2 weeks) at Hour (H) 0, H+1, H+2.5, H+4.5, H+6.5, H+26.5, Day 3, Day 8, Day 15 and 30 days after the last dose of treatment)
- Overall survival (OS)(assessed from the date of inclusion to the date of patient death, due to any cause or to the last date the patient was known to be alive, up to 29 months)
- Response Rate (RR)(tumor responses will be evaluated every 8 weeks after start treatment up to 29 months)
- Progression free survival (PFS)(PFS is the time from the date of inclusion to the date of progressive disease or death up to 29 months)