Clinical Phase Ib/II Trial of L-NMMA Plus Taxane Chemotherapy in the Treatment of Refractory Locally Advanced or Metastatic Triple Negative Breast Cancer Patients
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 37
- 试验地点
- 1
- 主要终点
- Asses the Maximum Tolerated Dose (MTD) of L-NMMA When Combined With Docetaxel/Amlodipine in the Treatment of Refractory Locally Advanced or Metastatic TNBC Patients, Based on the Number of Dose Limiting Toxicities (DLTs) Per Dose Level.
研究概览
简要总结
This is a Phase Ib/II study assessing the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), recommended Phase 2 dose (RP2D), and efficacy of L-NMMA when combined with docetaxel in refractory locally advanced or metastatic triple negative breast cancer patients. The Phase Ib portion of the study is designed to investigate the combination at two dose levels of docetaxel (75 and 100 mg/m2) and 7 dose levels of L-NMMA (5, 7.5, 10, 12.5, 15, 17.5, and 20 mg/kg). The starting dose of L-NMMA will be 7.5 mg/kg. In the Phase II portion of the study, the starting dose will be the RP2D determined in the Phase Ib portion of the study.
详细描述
This is a Phase Ib/II study assessing the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), recommended Phase 2 dose (RP2D), and efficacy of L-NMMA when combined with docetaxel in refractory locally advanced or metastatic triple negative breast cancer patients. The Phase Ib portion of the study is designed to investigate the combination at two dose levels of docetaxel (75 and 100 mg/m2) and 7 dose levels of L-NMMA (5, 7.5, 10, 12.5, 15, 17.5, and 20 mg/kg). The starting dose of L-NMMA will be 7.5 mg/kg. L-NMMA dose will escalate/de-escalate based on DLT occurrence. For the 5, 7.5, 10, 12.5, and 15 mg/kg L-NMMA doses, docetaxel will be administered at 75 mg/m2. For the 17.5 and 20 mg/kg L-NMMA doses, docetaxel will be administered at 100 mg/m2. In the Phase II portion of the study, the starting dose will be the RP2D determined in the Phase Ib portion of the study. In the phase II portion of the study, patients will be treated with L-NMMA and taxane (docetaxel, paclitaxel, or nab-paclitaxel) per physician's choice. Patients will be treated with L-NMMA and taxane chemotherapy (docetaxel, paclitaxel, or nab-paclitaxel) per physician's choice. L-NMMA will be administered on Days 1-5 and taxane chemotherapy on Day 1 Q3W or Day 1 Q1W. L-NMMA and docetaxel will be administered at the RP2D determined in the phase Ib portion of the study. Paclitaxel at 175 mg/m2 will be IV infused over 3 hours or 80 mg/m2 will be IV infused over 1 hour, and nab-paclitaxel at 260 mg/m2 will be IV infused over 30 minutes. For L-NMMA-induced hypertension, amlodipine (10 mg) and enteric-coated low-dose aspirin (81 mg) will be orally administered. Amlodipine will be administered for 6 days at each cycle, starting 24 hours before the first dose of L-NMMA. Enteric-coated low-dose aspirin will be administered once daily during the 6 21-day cycles. For docetaxel-induced leukopenia, pegfilgrastim (6 mg) will be administered via subcutaneous injection approximately 24 hours after every dose of docetaxel.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Patient must meet all of the following criteria:
- •Female patients with pathologically determined advanced (progressive disease or refractory to 3 cycles of standard chemotherapy) or metastatic (any line) triple negative breast cancer (TNBC). TNBC is defined as: Estrogen receptor negative and progesterone receptor negative (<10% staining by immunohistochemistry [IHC]).
- •Human epidermal growth factor receptor 2 (HER2) negative. HER2 negativity must be confirmed by one of the following:
- •Fluorescence in situ hybridization (FISH)-negative (FISH ratio <2), or
- •IHC 0-1+, or
- •IHC 2+ AND FISH-negative (FISH ratio <2). Eastern Cooperative Oncology Group performance status of ≤ 2
- •Age ≥ 18 years
- •Laboratory values within the following ranges:
- •Hemoglobin ≥9.0 g/dL (transfusions permitted)
- •Absolute neutrophil count ≥1500/mm3 (1.5 x 109/L)
- •Platelet count ≥100,000/mm3 (100 x 109/L)
- •Total bilirubin <2 X upper limit of normal (ULN)
- •Creatinine (Cr) <2 X ULN and Cr clearance (CrCl) ≥30 by Cockcroft and Gault
- •Alanine transaminase (ALT) and aspartate transaminase (AST) <2 X ULN (if liver metastases are present then ALT and AST must be <5 X ULN)
- •Have adequate organ function (cardiac ejection fraction of ≥ 45%)
- •Negative serum pregnancy test within 7 days of the administration of the first treatment dose for women of childbearing potential (WOCBP). For WOCBP, adequate contraception must be used throughout the study.
- •Ability to understand the requirements of the study, provide written informed consent and authorization of use and disclosure of protected health information, and agree to abide by the study restrictions and return for the required assessments.
- •Patient must be willing to undergo biopsies as required by the study protocol. Biopsies will be based on acceptable clinical risks as judged by investigator. Tissue from a previous biopsy will be accepted in the form of tissue slides.
排除标准
- •History of poorly controlled hypertension (defined as systolic blood pressure >150 mmHg at baseline)
- •Patients with metastatic disease who have received radiation therapy, chemotherapy, or non-cytotoxic investigational agents within 2 weeks of study treatment initiation.
- •Patients who received docetaxel at any line of treatment within the past 12 months
- •Evidence of New York Heart Association class III or greater cardiac disease
- •History of myocardial infarction, stroke, ventricular arrhythmia, or symptomatic conduction abnormality within the past 12 months
- •History of congenital QT prolongation
- •Absolute corrected QT interval of >480 msec in the presence of potassium >4.0 milliequivalent/L and magnesium >1.8 mg/dL
- •Any medical or psychiatric condition that would prevent informed consent or limit expected survival to less than 4 weeks
- •Symptomatic central nervous system metastases
- •Pregnant or nursing women
- •Hypersensitivity or intolerance to L-NMMA, docetaxel, amlodipine, pegfilgrastim, or their components
- •Use of amlodipine or another calcium channel blocker in the past 14 days
- •Alcoholism or hepatic disease with the exception of liver metastases
- •Severe renal insufficiency (CrCl <30 mL/min [Cockcroft and Gault])
- •History of gastrointestinal bleeding, ulceration, or perforation
- •Concurrent use of potent cytochrome P450 (CYP)3A4 inhibitors
- •Concurrent use of potent CYP3A4 inducers
- •Concurrent use of medications that interact with nitrate/nitrites
- •Use of an investigational drug within 14 days preceding the first dose of study medication.
- •Concurrent use of any complementary or alternative medicines
- •Patients with > Grade 2 neuropathy
- •Inability to take aspirin
研究组 & 干预措施
L-NMMA 7.5 mg/kg and Docetaxel 75 mg/m2
Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 7.5 mg/kg (starting dose) will be administered IV on Days 1-5. Docetaxel will be administered at 75 mg/m2 as an IV 15 min after L-NMMA infusion Day 1.
干预措施: L-NMMA (Drug)
L-NMMA 7.5 mg/kg and Docetaxel 75 mg/m2
Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 7.5 mg/kg (starting dose) will be administered IV on Days 1-5. Docetaxel will be administered at 75 mg/m2 as an IV 15 min after L-NMMA infusion Day 1.
干预措施: Docetaxel (Drug)
L-NMMA 7.5 mg/kg and Docetaxel 75 mg/m2
Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 7.5 mg/kg (starting dose) will be administered IV on Days 1-5. Docetaxel will be administered at 75 mg/m2 as an IV 15 min after L-NMMA infusion Day 1.
干预措施: Amlodipine (Drug)
L-NMMA 7.5 mg/kg and Docetaxel 75 mg/m2
Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 7.5 mg/kg (starting dose) will be administered IV on Days 1-5. Docetaxel will be administered at 75 mg/m2 as an IV 15 min after L-NMMA infusion Day 1.
干预措施: Pegfilgrastim (Drug)
L-NMMA 7.5 mg/kg and Docetaxel 75 mg/m2
Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 7.5 mg/kg (starting dose) will be administered IV on Days 1-5. Docetaxel will be administered at 75 mg/m2 as an IV 15 min after L-NMMA infusion Day 1.
干预措施: Enteric-coated aspirin (Drug)
L-NMMA 10 mg/kg and Docetaxel 75 mg/m2
Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 10 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 75 mg/m2 as an IV 15 min after L-NMMA infusion Day 1.
干预措施: L-NMMA (Drug)
L-NMMA 10 mg/kg and Docetaxel 75 mg/m2
Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 10 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 75 mg/m2 as an IV 15 min after L-NMMA infusion Day 1.
干预措施: Docetaxel (Drug)
L-NMMA 10 mg/kg and Docetaxel 75 mg/m2
Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 10 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 75 mg/m2 as an IV 15 min after L-NMMA infusion Day 1.
干预措施: Amlodipine (Drug)
L-NMMA 10 mg/kg and Docetaxel 75 mg/m2
Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 10 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 75 mg/m2 as an IV 15 min after L-NMMA infusion Day 1.
干预措施: Pegfilgrastim (Drug)
L-NMMA 10 mg/kg and Docetaxel 75 mg/m2
Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 10 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 75 mg/m2 as an IV 15 min after L-NMMA infusion Day 1.
干预措施: Enteric-coated aspirin (Drug)
L-NMMA 12.5 mg/kg and Docetaxel 75 mg/m2
Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 12.5 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 75 mg/m2 as an IV 15 min after L-NMMA infusion Day 1.
干预措施: L-NMMA (Drug)
L-NMMA 12.5 mg/kg and Docetaxel 75 mg/m2
Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 12.5 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 75 mg/m2 as an IV 15 min after L-NMMA infusion Day 1.
干预措施: Docetaxel (Drug)
L-NMMA 12.5 mg/kg and Docetaxel 75 mg/m2
Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 12.5 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 75 mg/m2 as an IV 15 min after L-NMMA infusion Day 1.
干预措施: Amlodipine (Drug)
L-NMMA 12.5 mg/kg and Docetaxel 75 mg/m2
Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 12.5 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 75 mg/m2 as an IV 15 min after L-NMMA infusion Day 1.
干预措施: Pegfilgrastim (Drug)
L-NMMA 12.5 mg/kg and Docetaxel 75 mg/m2
Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 12.5 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 75 mg/m2 as an IV 15 min after L-NMMA infusion Day 1.
干预措施: Enteric-coated aspirin (Drug)
L-NMMA 17.5 mg/kg and Docetaxel 100 mg/m2
Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 17.5 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 100 mg/m2 as an IV 15 min after L-NMMA infusion Day 1.
干预措施: L-NMMA (Drug)
L-NMMA 15 mg/kg and Docetaxel 75 mg/m2
Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 15 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 75 mg/m2 as an IV 15 min after L-NMMA infusion Day 1.
干预措施: L-NMMA (Drug)
L-NMMA 15 mg/kg and Docetaxel 75 mg/m2
Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 15 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 75 mg/m2 as an IV 15 min after L-NMMA infusion Day 1.
干预措施: Docetaxel (Drug)
L-NMMA 15 mg/kg and Docetaxel 75 mg/m2
Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 15 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 75 mg/m2 as an IV 15 min after L-NMMA infusion Day 1.
干预措施: Amlodipine (Drug)
L-NMMA 15 mg/kg and Docetaxel 75 mg/m2
Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 15 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 75 mg/m2 as an IV 15 min after L-NMMA infusion Day 1.
干预措施: Pegfilgrastim (Drug)
L-NMMA 15 mg/kg and Docetaxel 75 mg/m2
Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 15 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 75 mg/m2 as an IV 15 min after L-NMMA infusion Day 1.
干预措施: Enteric-coated aspirin (Drug)
L-NMMA 17.5 mg/kg and Docetaxel 100 mg/m2
Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 17.5 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 100 mg/m2 as an IV 15 min after L-NMMA infusion Day 1.
干预措施: Docetaxel (Drug)
L-NMMA 17.5 mg/kg and Docetaxel 100 mg/m2
Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 17.5 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 100 mg/m2 as an IV 15 min after L-NMMA infusion Day 1.
干预措施: Amlodipine (Drug)
L-NMMA 17.5 mg/kg and Docetaxel 100 mg/m2
Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 17.5 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 100 mg/m2 as an IV 15 min after L-NMMA infusion Day 1.
干预措施: Pegfilgrastim (Drug)
L-NMMA 17.5 mg/kg and Docetaxel 100 mg/m2
Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 17.5 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 100 mg/m2 as an IV 15 min after L-NMMA infusion Day 1.
干预措施: Enteric-coated aspirin (Drug)
L-NMMA 20 mg/kg and Docetaxel 100 mg/m2
Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 20 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 100 mg/m2 as an IV 15 min after L-NMMA infusion Day 1.
干预措施: L-NMMA (Drug)
L-NMMA 20 mg/kg and Docetaxel 100 mg/m2
Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 20 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 100 mg/m2 as an IV 15 min after L-NMMA infusion Day 1.
干预措施: Docetaxel (Drug)
L-NMMA 20 mg/kg and Docetaxel 100 mg/m2
Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 20 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 100 mg/m2 as an IV 15 min after L-NMMA infusion Day 1.
干预措施: Amlodipine (Drug)
L-NMMA 20 mg/kg and Docetaxel 100 mg/m2
Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 20 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 100 mg/m2 as an IV 15 min after L-NMMA infusion Day 1.
干预措施: Pegfilgrastim (Drug)
L-NMMA 20 mg/kg and Docetaxel 100 mg/m2
Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 20 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 100 mg/m2 as an IV 15 min after L-NMMA infusion Day 1.
干预措施: Enteric-coated aspirin (Drug)
Phase II: RP2D determined in the Phase Ib
Phase II: L-NMMA starting dose will be the RP2D determined in the Phase Ib portion of the study.
干预措施: L-NMMA (Drug)
Phase II: RP2D determined in the Phase Ib
Phase II: L-NMMA starting dose will be the RP2D determined in the Phase Ib portion of the study.
干预措施: Docetaxel (Drug)
Phase II: RP2D determined in the Phase Ib
Phase II: L-NMMA starting dose will be the RP2D determined in the Phase Ib portion of the study.
干预措施: Amlodipine (Drug)
Phase II: RP2D determined in the Phase Ib
Phase II: L-NMMA starting dose will be the RP2D determined in the Phase Ib portion of the study.
干预措施: Pegfilgrastim (Drug)
Phase II: RP2D determined in the Phase Ib
Phase II: L-NMMA starting dose will be the RP2D determined in the Phase Ib portion of the study.
干预措施: Enteric-coated aspirin (Drug)
结局指标
主要结局
Asses the Maximum Tolerated Dose (MTD) of L-NMMA When Combined With Docetaxel/Amlodipine in the Treatment of Refractory Locally Advanced or Metastatic TNBC Patients, Based on the Number of Dose Limiting Toxicities (DLTs) Per Dose Level.
时间窗: DLTs assessment window is the duration required for completing one full cycle (through Day 21).
The Phase Ib portion of the study is designed to investigate the combination at two dose levels of docetaxel (75 and 100 mg/m2) and 7 dose levels of L-NMMA (5, 7.5, 10, 12.5, 15, 17.5, and 20 mg/kg). The starting dose will be L-NMMA at 7.5 mg/kg and docetaxel at 75 mg/m2. As patients are accrued, a standard Bayesian model averaging continual reassessment method (CRM) approach will be used to determine the appropriate dosage. For a dose level to be chosen as the MTD, at least 4 patients must have received said dose without experiencing a significant number of DLTs based on the Bayesian Model Averaging Continual Reassessment Method.
Clinical Benefit Rate
时间窗: The approximate length of the study from Cycle 1, Day 1 will be approximately seven months (approximately four months of treatment plus three months of follow-up).
Primary Outcome Measure for Phase II: Determine the number of participants with complete response, partial response, or stable disease after 6 cycles of L-NMMA combined with taxane chemotherapy (docetaxel, paclitaxel, or nab-paclitaxel)/amlodipine, as assessed by the RECIST 1.1. * CR (complete response) = disappearance of all target lesions * PR (partial response) = 30% decrease in the sum of the longest diameter of target lesions * PD (progressive disease) = 20% increase in the sum of the longest diameter of target lesions * SD (stable disease) = small changes that do not meet above criteria * Treatment Failure: taken off the study because of adverse events before the first restaging scan after cycle 2
Asses the Maximum Tolerated Dose (MTD) of Docetaxel When Combined With L-NMMA/Amlodipine in the Treatment of Refractory Locally Advanced or Metastatic TNBC Patients, Based on the Number of Dose Limiting Toxicities (DLTs) Per Dose Level.
时间窗: DLTs assessment window is the duration required for completing one full cycle (through Day 21).
The Phase Ib portion of the study is designed to investigate the combination at two dose levels of docetaxel (75 and 100 mg/m2) and 7 dose levels of L-NMMA (5, 7.5, 10, 12.5, 15, 17.5, and 20 mg/kg). The starting dose will be L-NMMA at 7.5 mg/kg and docetaxel at 75 mg/m2. As patients are accrued, a standard Bayesian model averaging continual reassessment method (CRM) approach will be used to determine the appropriate dosage. For a dose level to be chosen as the MTD, at least 4 patients must have received said dose without experiencing a significant number of DLTs based on the Bayesian Model Averaging Continual Reassessment Method.
次要结局
- Dose Limiting Toxicities (DLTs) and Other Adverse Events(The approximate length of the study from Cycle 1, Day 1 will be approximately seven months (approximately four months of treatment plus three months of follow-up).)
- Recommended Phase 2 Dose (RP2D) of the L-NMMA and Docetaxel Combination(The Dose Limiting Toxicities (DLT) assessment window is the duration required for completing one full cycle (through Day 21).)
- Antitumor Activity(The approximate length of the study from Cycle 1, Day 1 will be approximately seven months (approximately four months of treatment plus three months of follow-up).)
- Time to Maximum Plasma Concentration of L-NMMA and Docetaxel(Blood samples will be collected predose (10-30 minutes before L-NMMA infusion) on Days 1, 2, and 5 of Cycle 1 and Days 1 and 5 of Cycle 2 for determination of L-NMMA plus docetaxel plasma PK.)
研究者
Polly A. Niravath, MD
Principal Investigator, Medical Oncologist
The Methodist Hospital Research Institute