A Phase I Study in Patients Treated With MM-398 (Nanoliposomal Irinotecan, Nal-IRI) to Determine Tumor Drug Levels and to Evaluate the Feasibility of Ferumoxytol Magnetic Resonance Imaging to Measure Tumor Associated Macrophages and to Predict Patient Response to Treatment
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Ipsen
- 入组人数
- 45
- 试验地点
- 7
- 主要终点
- Pilot Phase: Tumour Levels of Irinotecan and SN-38 at Cycle 1 Day 4
研究概览
简要总结
This is a Phase I study to understand the biodistribution of MM-398 and to determine the feasibility of using Ferumoxytol as a tumor imaging agent.
详细描述
This study is conducted over two phases.
Pilot Phase: This study will enroll approximately 12 patients, up to 20 in total in the Pilot Phase and 30 patients in the Expansion Phase. The first three patients that are enrolled in the Pilot Phase can have any solid tumor type; however subsequent patients must have Non-small cell lung cancer (NSCLC), Colorectal cancer (CRC), Triple negative breast cancer (TNBC), Estrogen Receptor/Progesterone Receptor (ER/PR) positive breast cancer, pancreatic cancer, ovarian cancer, gastric cancer, gastro-oesophageal junction adenocarcinoma or head and neck cancer. No more than three patients with ER/PR positive breast cancer can be enrolled in the Pilot Phase and similar restrictions may be placed on other tumor types to ensure a heterogeneous population.
Expansion Phase: The expansion will enroll patients with advanced metastatic breast cancer into three cohorts of 10 patients each depending on sub-type of breast cancer:
Cohort 1: ER and/or PR-positive breast cancer Cohort 2: TNBC Cohort 3: BC with active brain metastasis
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Other
- 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
- •All subjects:
- •Pathologically confirmed diagnosis of solid tumors
- •Metastatic disease
- •Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 1
- •Adequate bone marrow, hepatic and renal function
- •Normal Electrocardiogram (ECG)
- •18 years of age or above
- •Able to understand and sign informed consent
- •Pilot study only:
- •CRC, TNBC, ER/PR Breast Cancer, NSCLC, Pancreatic Cancer, Ovarian Cancer, Gastric Cancer, Gastroesophageal Junction (GEJ) adenocarcinoma, Head and Neck Cancer
- •Expansion Phase Additional Criteria:
- •Locally advanced or metastatic breast cancer
- •Received at least one cytotoxic therapy in the locally advanced and metastatic setting
- •Received ≤ 5 prior lines of chemotherapy in the metastatic setting
- •Candidate for chemotherapy
- •Expansion Phase Cohort 3 additional inclusion criteria:
- •Breast cancer with active brain metastasis
- •Neurologically stable
排除标准
- •Active Central nervous system (CNS) metastasis (applies to pilot phase and expansion phase cohort 1 and 2 only)
- •Clinically significant GI disorders
- •Prior irinotecan or bevacizumab therapy within last 6 months and for Expansion Phase patients, have received any prior treatment with Topol inhibitor
- •Known hypersensitivity to MM-398 or ferumoxytol
- •Inability to undergo MRI
- •Active infection
- •Pregnant or breast feeding
- •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
- •Received radiation therapy in the last 14 days
- •Treated with parenteral iron in the previous 4 weeks
研究组 & 干预措施
Pilot Phase: Ferumoxytol followed by MM-398
Ferumoxytol 5 mg/kg IV at the rate of 1 mL/sec, given once on Day 1. MM-398 IV over 90 min on Days 1 and 15 of every 4 week cycle
干预措施: Ferumoxytol (Drug)
Pilot Phase: Ferumoxytol followed by MM-398
Ferumoxytol 5 mg/kg IV at the rate of 1 mL/sec, given once on Day 1. MM-398 IV over 90 min on Days 1 and 15 of every 4 week cycle
干预措施: MM-398 (Drug)
Expansion Phase: Ferumoxytol followed by MM-398
Ferumoxytol 5 mg/kg IV at the rate of 1 mL/sec, given once on Day 1. MM-398 IV over 90 min dose 1 on Days 1 and 15 of every 4 week cycle Cohort 1: ER and/or PR-positive BC Cohort 2: TNBC Cohort 3: BC with active brain metastasis
干预措施: Ferumoxytol (Drug)
Expansion Phase: Ferumoxytol followed by MM-398
Ferumoxytol 5 mg/kg IV at the rate of 1 mL/sec, given once on Day 1. MM-398 IV over 90 min dose 1 on Days 1 and 15 of every 4 week cycle Cohort 1: ER and/or PR-positive BC Cohort 2: TNBC Cohort 3: BC with active brain metastasis
干预措施: MM-398 (Drug)
结局指标
主要结局
Pilot Phase: Tumour Levels of Irinotecan and SN-38 at Cycle 1 Day 4
时间窗: At Cycle 1 Day 4 in the Pilot phase.
Two tumour biopsies were collected 72 hours after the first MM-398 IV infusion during Cycle 1 of the MM-398 Treatment phase of the Pilot phase for determination of tumour levels of irinotecan and SN-38 (an active metabolite). The lesions selected for biopsy were based on the results of the FMX-MRI obtained on Days 1, 2 and 4 of the FMX phase, and were collected from a previously non-biopsied lesion. The first core biopsy was taken in the region of the tumour that showed the greatest signal change on either the T2 or T1 sequences, based on FMX-MRI. The second core biopsy was taken from the region that showed the least signal change based on FMX-MRI, avoiding areas of necrosis.
Expansion Phase: Impact of the Quality of MRI Scan on Tumour Evaluation
时间窗: Expansion phase Cycle 1: Pre FMX dose, 1-4 hours post FMX dose, 16-24 hours post FMX dose, 2 weeks Post FMX dose.
Feasibility of FMX quantitation in tumour lesion was assessed through the acquisition of baseline (pre-FMX dose) and follow-up (post FMX dose) scans of sufficient quality to enable quantitative analysis to be performed. Quality was assessed by summarising scans as adequate for tumour evaluation or suboptimal but for which evaluation was completed for evaluation. Two FMX-MRI scans were taken on Day 1 (pre-FMX dosing) and on Day 2 (16-24 hours post dose) of the FMX phase. One MRI scan was also taken at 1-4 hours post FMX dose (Day 1 of FMX phase) and at 2 weeks post FMX dose (Day 15 of the MM-398 phase). It was possible for a subject to have 2 FMX-MRI scans for the same visit and timepoint corresponding to a scan target location. The number of MRI scan results that were assessed to be adequate or suboptimal at each timepoint are presented.
Expansion Phase: Best Overall Tumour Response (BOR) by Tumour FMX Uptake Classification at 16 - 24 Hours Post-FMX Dose
时间窗: Expansion phase: C1D2 FMX phase, and every 8 weeks for RECIST assessments from C1D1 until disease progression, unacceptable toxicity or withdrawal of consent.
FMX tumour uptake was classified as 'low tumour uptake' or 'high tumour uptake', and was determined for 16 to 24-hours post-FMX dosing. The FMX uptake in a subject's lesions was classified using the median of the baseline-corrected FMX values at that timepoint across all subjects. The best radiological overall tumour response to MM-398 from the beginning to the end of the study was assessed using both the Investigator and imaging results per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 (Non-central nervous system \[CNS\] assessments; Cohorts 1, 2 and 3). Tumour response was classified as a Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progressive Disease (PD). BOR is presented by tumour uptake classification at 16-24 hours post-FMX dose by cohort for the non-CNS RECIST assessment.
次要结局
- Pilot Phase + Expansion Phase: Median Progression-free Survival (PFS) (Non-CNS Assessment)(Baseline and every 8 weeks from C1D1 until disease progression, unacceptable toxicity or withdrawal of consent.)
- Expansion Phase: BOR for Cohort 3 (CNS Assessment)(Baseline and every 8 weeks from C1D1 until disease progression, unacceptable toxicity or withdrawal of consent.)
- Expansion Phase: Median PFS for Cohort 3 (CNS Assessment)(Baseline and every 8 weeks from C1D1 until disease progression, unacceptable toxicity or withdrawal of consent.)
- Pilot Phase: SN-38 Cmax(Pilot phase: C1D1 pre-MM-398 infusion, end of infusion, post-infusion (2, 72, 168 hours); C1D15 pre-infusion; 30 days follow-up visit.)
- Expansion Phase: SN-38 Cmax(Expansion phase: Cycles 1-3 pre-MM-398 infusion, end of infusion, post-infusion (2, 48,168 hours); D15 pre-infusion; 30 days follow-up visit.)
- Expansion Phase: Irinotecan AUC(0-tlast)(Expansion phase: Cycles 1-3 pre-MM-398 infusion, end of infusion, post-infusion (2, 48,168 hours); D15 pre-infusion; 30 days follow-up visit.)
- Pilot Phase + Expansion Phase: BOR (Non-CNS Assessment)(Baseline and every 8 weeks from C1D1 until disease progression, unacceptable toxicity or withdrawal of consent.)
- Pilot Phase + Expansion Phase: Median Duration of Objective Response (DOR) (Non-CNS Assessment)(Baseline and every 8 weeks from C1D1 until disease progression, unacceptable toxicity or withdrawal of consent.)
- Pilot Phase + Expansion Phase: Clinical Benefit Response (CBR) (Non-CNS Assessment)(Baseline and every 8 weeks from C1D1 until disease progression, unacceptable toxicity or withdrawal of consent.)
- Expansion Phase: CBR for Cohort 3 (CNS Assessment)(Baseline and every 8 weeks from C1D1 until disease progression, unacceptable toxicity or withdrawal of consent.)
- Pilot Phase: Time to Reach Maximum Plasma Concentration of Irinotecan and SN-38 (Tmax)(Pilot phase: C1D1 pre-MM-398 infusion, end of infusion, post-infusion (2, 72, 168 hours); C1D15 pre-infusion; 30 days follow-up visit.)
- Pilot Phase + Expansion Phase: Objective Response Rate (ORR) (Non-CNS Assessment)(Baseline and every 8 weeks from C1D1 until disease progression, unacceptable toxicity or withdrawal of consent.)
- Expansion Phase: ORR for Cohort 3 (CNS Assessment)(Baseline and every 8 weeks from C1D1 until disease progression, unacceptable toxicity or withdrawal of consent.)
- Expansion Phase: Median DOR for Cohort 3 (CNS Assessment)(Baseline and every 8 weeks from C1D1 until disease progression, unacceptable toxicity or withdrawal of consent.)
- Pilot Phase + Expansion Phase: Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAEs) Related to MM-398(From MM-398 treatment start up to 30 days after last dose.)
- Pilot Phase: Maximum Observed Plasma Concentration of Irinotecan (Cmax)(Pilot phase: C1D1 pre-MM-398 infusion, end of infusion, post-infusion (2, 72, 168 hours); C1D15 pre-infusion; 30 days follow-up visit.)
- Pilot Phase: SN-38 AUC(0-tlast)(Pilot phase: C1D1 pre-MM-398 infusion, end of infusion, post-infusion (2, 72, 168 hours); C1D15 pre-infusion; 30 days follow-up visit.)
- Expansion Phase: SN-38 AUC(0-tlast)(Expansion phase: Cycles 1-3 pre-MM-398 infusion, end of infusion, post-infusion (2, 48,168 hours); D15 pre-infusion; 30 days follow-up visit.)
- Expansion Phase: Irinotecan and SN-38 Tmax(Expansion phase: Cycles 1-3 pre-MM-398 infusion, end of infusion, post-infusion (2, 48,168 hours); D15 pre-infusion; 30 days follow-up visit.)
- Expansion Phase: Irinotecan Cmax(Expansion phase: Cycles 1-3 pre-MM-398 infusion, end of infusion, post-infusion (2, 48,168 hours); D15 pre-infusion; 30 days follow-up visit.)
- Pilot Phase: Area Under the Plasma Concentration Time Curve From Time Zero to Last Quantifiable Concentration (AUC[0-tlast]) for Irinotecan(Pilot phase: C1D1 pre-MM-398 infusion, end of infusion, post-infusion (2, 72, 168 hours); C1D15 pre-infusion; 30 days follow-up visit.)