L-NMMA Plus Taxane Chemotherapy in Refractory Locally Advanced or Metastatic Triple Negative Breast Cancer Patients

Phase 1

Completed

Conditions: Metastatic Triple Negative Breast Cancer

Interventions: Drug: L-NMMA
Drug: Docetaxel
Drug: Amlodipine
Drug: Pegfilgrastim
Drug: Enteric-coated aspirin

Registration Number: NCT02834403

Lead Sponsor: The Methodist Hospital Research Institute

Brief Summary: 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.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 37

Inclusion Criteria

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.

Exclusion Criteria

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
L-NMMA 15 mg/kg and Docetaxel 75 mg/m2	Pegfilgrastim	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.
L-NMMA 20 mg/kg and Docetaxel 100 mg/m2	Pegfilgrastim	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.
L-NMMA 7.5 mg/kg and Docetaxel 75 mg/m2	Amlodipine	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.
L-NMMA 7.5 mg/kg and Docetaxel 75 mg/m2	Pegfilgrastim	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.
L-NMMA 7.5 mg/kg and Docetaxel 75 mg/m2	L-NMMA	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.
L-NMMA 7.5 mg/kg and Docetaxel 75 mg/m2	Docetaxel	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.
L-NMMA 10 mg/kg and Docetaxel 75 mg/m2	L-NMMA	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.
L-NMMA 10 mg/kg and Docetaxel 75 mg/m2	Docetaxel	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.
L-NMMA 10 mg/kg and Docetaxel 75 mg/m2	Amlodipine	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.
L-NMMA 10 mg/kg and Docetaxel 75 mg/m2	Pegfilgrastim	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.
L-NMMA 12.5 mg/kg and Docetaxel 75 mg/m2	Amlodipine	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.
L-NMMA 12.5 mg/kg and Docetaxel 75 mg/m2	Pegfilgrastim	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.
L-NMMA 12.5 mg/kg and Docetaxel 75 mg/m2	Enteric-coated aspirin	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.
L-NMMA 15 mg/kg and Docetaxel 75 mg/m2	L-NMMA	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.
L-NMMA 15 mg/kg and Docetaxel 75 mg/m2	Docetaxel	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.
L-NMMA 15 mg/kg and Docetaxel 75 mg/m2	Amlodipine	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.
L-NMMA 17.5 mg/kg and Docetaxel 100 mg/m2	L-NMMA	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.
L-NMMA 17.5 mg/kg and Docetaxel 100 mg/m2	Docetaxel	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.
L-NMMA 17.5 mg/kg and Docetaxel 100 mg/m2	Amlodipine	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.
L-NMMA 17.5 mg/kg and Docetaxel 100 mg/m2	Pegfilgrastim	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.
Phase II: RP2D determined in the Phase Ib	L-NMMA	Phase II: L-NMMA starting dose will be the RP2D determined in the Phase Ib portion of the study.
Phase II: RP2D determined in the Phase Ib	Docetaxel	Phase II: L-NMMA starting dose will be the RP2D determined in the Phase Ib portion of the study.
Phase II: RP2D determined in the Phase Ib	Enteric-coated aspirin	Phase II: L-NMMA starting dose will be the RP2D determined in the Phase Ib portion of the study.
Phase II: RP2D determined in the Phase Ib	Amlodipine	Phase II: L-NMMA starting dose will be the RP2D determined in the Phase Ib portion of the study.
Phase II: RP2D determined in the Phase Ib	Pegfilgrastim	Phase II: L-NMMA starting dose will be the RP2D determined in the Phase Ib portion of the study.
L-NMMA 15 mg/kg and Docetaxel 75 mg/m2	Enteric-coated aspirin	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.
L-NMMA 20 mg/kg and Docetaxel 100 mg/m2	Enteric-coated aspirin	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.
L-NMMA 7.5 mg/kg and Docetaxel 75 mg/m2	Enteric-coated aspirin	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.
L-NMMA 10 mg/kg and Docetaxel 75 mg/m2	Enteric-coated aspirin	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.
L-NMMA 17.5 mg/kg and Docetaxel 100 mg/m2	Enteric-coated aspirin	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.
L-NMMA 12.5 mg/kg and Docetaxel 75 mg/m2	L-NMMA	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.
L-NMMA 12.5 mg/kg and Docetaxel 75 mg/m2	Docetaxel	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.
L-NMMA 20 mg/kg and Docetaxel 100 mg/m2	L-NMMA	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.
L-NMMA 20 mg/kg and Docetaxel 100 mg/m2	Docetaxel	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.
L-NMMA 20 mg/kg and Docetaxel 100 mg/m2	Amlodipine	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.

Primary Outcome Measures

Name	Time	Method
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.	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	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.	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.

Secondary Outcome Measures

Name	Time	Method
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).	Describe the DLTs and other adverse events associated with L-NMMA when combined with docetaxel/amlodipine, as assessed by the CTCAE v4.03 Any Grade ≥ 3 Adverse Events (AE) unless there is clear alternative evidence that the AE was not caused by the study treatment.
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).	Determine the RP2D of the L-NMMA and docetaxel combination based on the occurrence of DLTs during Phase Ib portion of the study. As patients are accrued, they will start with 7.5 mg/kg of L-NMMA and 75 mg/m2 of docetaxel and their DLTs will be assessed after completion of the first cycle. This will determine the next cohort dose, until at least 4 patients receive the dose with minimal DLTs that won't require dose reduction.
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).	Assess the antitumor activity of L-NMMA when 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
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.	Determine the time to maximum plasma concentration of the L-NMMA and docetaxel combination.