L-NMMA Plus Taxane Chemotherapy in Refractory Locally Advanced or Metastatic Triple Negative Breast Cancer Patients
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ClinicalTrials.gov Identifier: NCT02834403 |
Recruitment Status :
Recruiting
First Posted : July 15, 2016
Last Update Posted : June 4, 2020
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Condition or disease | Intervention/treatment | Phase |
---|---|---|
Metastatic Triple Negative Breast Cancer | Drug: L-NMMA Drug: Docetaxel Drug: Amlodipine Drug: Pegfilgrastim Drug: Enteric-coated aspirin | Phase 1 Phase 2 |
Study Type : | Interventional (Clinical Trial) |
Estimated Enrollment : | 48 participants |
Allocation: | N/A |
Intervention Model: | Single Group Assignment |
Masking: | None (Open Label) |
Primary Purpose: | Treatment |
Official Title: | 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 |
Actual Study Start Date : | November 2016 |
Estimated Primary Completion Date : | December 2020 |
Estimated Study Completion Date : | March 2021 |

Arm | Intervention/treatment |
---|---|
Experimental: Experimental
Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 5, 7.5 (starting dose), 10, 12.5, 15, 17.5, and 20 mg/kg will be administered IV on Days 1-5. For 5-15 mg/kg L-NMMA doses, docetaxel will be administered at 75 mg/m2. For 17.5 and 20 mg/kg L-NMMA doses, docetaxel will be administered at 100 mg/m2. Docetaxel will be administered IV 15 min after the Day 1 L-NMMA infusion. Amlodipine (10 mg) will be orally administered daily for 6 days, starting 24 hours before the Day 1 L-NMMA infusion. Enteric-coated aspirin (81 mg) will be orally administered once daily during the 6 21-day cycles. Pegfilgrastim (6 mg) will be administered subcutaneously 24 h after docetaxel. Phase II: L-NMMA starting dose will be the RP2D determined in the Phase Ib portion of the study. |
Drug: L-NMMA
Nitric oxide synthase inhibitor
Other Name: NG-monomethyl-l-arginine Drug: Docetaxel Mitotic inhibitor, cytotoxic
Other Name: TAXOTERE Drug: Amlodipine Long-acting calcium channel blocker
Other Name: besylate salt of amlodipine; NORVASC Drug: Pegfilgrastim Colony-stimulating factor
Other Name: NEULASTA Drug: Enteric-coated aspirin non-steroidal anti-inflammatory drug
Other Name: acetylsalicylic acid |
- MTD [ Time Frame: 18 weeks ]Primary outcome measure for Phase Ib: Assess the MTD of L-NMMA when combined with docetaxel/amlodipine
- Clinical Benefit Rate [ Time Frame: 18 weeks ]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
- DLTs and other adverse events [ Time Frame: 18 weeks ]Describe the DLTs and other adverse events associated with L-NMMA when combined with docetaxel/amlodipine, as assessed by the CTCAE v4.03
- RP2D of the L-NMMA and docetaxel combination [ Time Frame: 18 weeks ]Determine the RP2D of the L-NMMA and docetaxel combination based on the occurrence of DLTs and MTD determination
- Antitumor activity [ Time Frame: 18 weeks ]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.
- Maximum plasma concentration of the L-NMMA and docetaxel combination [ Time Frame: 18 weeks ]Determine the maximum plasma concentration of the L-NMMA and docetaxel combination
- Area under the plasma concentration curve of the L-NMMA and docetaxel combination [ Time Frame: 18 weeks ]Determine the area under the plasma concentration curve of the L-NMMA and docetaxel combination
- Predictive biomarkers [ Time Frame: 18 weeks ]Determine potential predictive biomarkers including serum levels of nitrate/nitrite; serum levels of inflammatory biomarkers; angiogenesis-related biomarkers; and RPL39, MLF2, and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutations in cell-free DNA

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Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
Sexes Eligible for Study: | Female |
Accepts Healthy Volunteers: | No |
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

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02834403
Contact: Houston Methodist Cancer Center | 713-441-0629 | ccresearch@houstonmethodist.org |
United States, Texas | |
Houston Methodist Hospital | Recruiting |
Houston, Texas, United States, 77030 | |
Contact: Houston Methodist Cancer Center 713-441-0629 ccresearch@houstonmethodist.org |
Principal Investigator: | Polly Niravath, M.D. | Houston Methodist Cancer Center |
Responsible Party: | Polly A. Niravath, MD, Principal Investigator, Medical Oncologist, The Methodist Hospital System |
ClinicalTrials.gov Identifier: | NCT02834403 |
Other Study ID Numbers: |
Pro00011685 |
First Posted: | July 15, 2016 Key Record Dates |
Last Update Posted: | June 4, 2020 |
Last Verified: | June 2020 |
Individual Participant Data (IPD) Sharing Statement: | |
Plan to Share IPD: | No |
Studies a U.S. FDA-regulated Drug Product: | Yes |
Studies a U.S. FDA-regulated Device Product: | No |
breast cancer nitric oxide synthase docetaxel L-NMMA |
Breast Neoplasms Triple Negative Breast Neoplasms Neoplasms by Site Neoplasms Breast Diseases Skin Diseases Aspirin Docetaxel Amlodipine omega-N-Methylarginine Antineoplastic Agents Tubulin Modulators Antimitotic Agents Mitosis Modulators Molecular Mechanisms of Pharmacological Action |
Anti-Inflammatory Agents, Non-Steroidal Analgesics, Non-Narcotic Analgesics Sensory System Agents Peripheral Nervous System Agents Physiological Effects of Drugs Anti-Inflammatory Agents Antirheumatic Agents Fibrinolytic Agents Fibrin Modulating Agents Platelet Aggregation Inhibitors Cyclooxygenase Inhibitors Enzyme Inhibitors Antipyretics Antihypertensive Agents |