Metastatic Triple Negative Breast CancerPhase 1/2NCT02834403
L-NMMA Plus Taxane Chemotherapy in Refractory Locally Advanced or Metastatic Triple Negative Breast Cancer Patients
A Phase 1/2 study testing L-NMMA, Docetaxel and Amlodipine in people with Metastatic Triple Negative Breast Cancer, run by The Methodist Hospital Research Institute at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older, women only
- Conditions the study is for
- Metastatic Triple Negative Breast Cancer
- What is being tested?
- L-NMMA, Docetaxel and Amlodipine
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 37 participants
- Where
- 1 siteUnited States
- Study dates
- Nov 2016to Jan 2021
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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.
Who cannot join
- 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
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- 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
Trial locations and contacts
1 site in 1 country.
About this study
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
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.
Read the 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.
- Conditions
- Metastatic Triple Negative Breast Cancer
- Being tested
- L-NMMA, Docetaxel, Amlodipine, Pegfilgrastim, Enteric-coated aspirin
- Keywords
- breast cancer, nitric oxide synthase, docetaxel, L-NMMA
- Medical subject headings
- Triple Negative Breast Neoplasms, Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
L-NMMADrug
Also called NG-monomethyl-l-arginine
Nitric oxide synthase inhibitor
DocetaxelDrug
Also called TAXOTERE
Mitotic inhibitor, cytotoxic
AmlodipineDrug
Also called besylate salt of amlodipine; NORVASC
Long-acting calcium channel blocker
PegfilgrastimDrug
Also called NEULASTA
Colony-stimulating factor
Enteric-coated aspirinDrug
Also called acetylsalicylic acid
non-steroidal anti-inflammatory drug
| Study group | Role | What they receive |
|---|---|---|
| L-NMMA 7.5 mg/kg and Docetaxel 75 mg/m2 | Experimental | 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. Receives: Drug: L-NMMA; Drug: Docetaxel; Drug: Amlodipine; Drug: Pegfilgrastim; Drug: Enteric-coated aspirin |
| L-NMMA 10 mg/kg and Docetaxel 75 mg/m2 | Experimental | 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. Receives: Drug: L-NMMA; Drug: Docetaxel; Drug: Amlodipine; Drug: Pegfilgrastim; Drug: Enteric-coated aspirin |
| L-NMMA 12.5 mg/kg and Docetaxel 75 mg/m2 | Experimental | 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. Receives: Drug: L-NMMA; Drug: Docetaxel; Drug: Amlodipine; Drug: Pegfilgrastim; Drug: Enteric-coated aspirin |
| L-NMMA 15 mg/kg and Docetaxel 75 mg/m2 | Experimental | 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. Receives: Drug: L-NMMA; Drug: Docetaxel; Drug: Amlodipine; Drug: Pegfilgrastim; Drug: Enteric-coated aspirin |
| L-NMMA 17.5 mg/kg and Docetaxel 100 mg/m2 | Experimental | 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. Receives: Drug: L-NMMA; Drug: Docetaxel; Drug: Amlodipine; Drug: Pegfilgrastim; Drug: Enteric-coated aspirin |
| L-NMMA 20 mg/kg and Docetaxel 100 mg/m2 | Experimental | 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. Receives: Drug: L-NMMA; Drug: Docetaxel; Drug: Amlodipine; Drug: Pegfilgrastim; Drug: Enteric-coated aspirin |
| Phase II: RP2D determined in the Phase Ib | Experimental | Phase II: L-NMMA starting dose will be the RP2D determined in the Phase Ib portion of the study. Receives: Drug: L-NMMA; Drug: Docetaxel; Drug: Amlodipine; Drug: Pegfilgrastim; Drug: Enteric-coated aspirin |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
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.
Measured: DLTs assessment window is the duration required for completing one full cycle (through Day 21).
Clinical Benefit Rate
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
Measured: 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).
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.
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.
Measured: DLTs assessment window is the duration required for completing one full cycle (through Day 21).
Secondary outcomes (4)
Dose Limiting Toxicities (DLTs) and Other Adverse Events
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.
Measured: 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
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.
Measured: The Dose Limiting Toxicities (DLT) assessment window is the duration required for completing one full cycle (through Day 21).
Antitumor Activity
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
Measured: 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
Determine the time to maximum plasma concentration of the L-NMMA and docetaxel combination.
Measured: 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.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Jul 2016 (estimated)
- Study startNov 2016
- Primary completionJan 2021
- Study completionJan 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Metastatic Triple Negative Breast CancerStudies of the same condition, open and under way.
- More trials run by The Methodist Hospital Research InstituteThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 37 participants (actual)
Sponsor and investigators
- Lead sponsor
- The Methodist Hospital Research Institute
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Polly A. Niravath, MD, The Methodist Hospital Research Institute
- Investigators
- Polly Niravath, M.D., Principal investigator, Houston Methodist Cancer Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02834403
- Sponsor's protocol ID
- Pro00011685
- Status last verified
- Dec 2023
- First submitted
- 29 Jun 2016
- Last updated
- 15 Dec 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 15 Dec 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT02834403
- Acronym / sponsor ID
- Pro00011685
- Conditions
- Metastatic Triple Negative Breast Cancer
- Keywords
- breast cancer, nitric oxide synthase, docetaxel, L-NMMA
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 37 participants (actual)
- Lead sponsor
- The Methodist Hospital Research InstituteUniversity, hospital or other
- Study start
- Nov 2016 (actual)
- Primary completion
- Jan 2021 (actual)
- Study completion
- Jan 2021 (actual)
- First posted
- 15 Jul 2016 (estimated)
- Results
- Posted 15 Dec 2023
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 7
| Arm | Type | Receives |
|---|---|---|
| L-NMMA 7.5 mg/kg and Docetaxel 75 mg/m2 | Experimental | Drug: L-NMMA, Drug: Docetaxel, Drug: Amlodipine, Drug: Pegfilgrastim, Drug: Enteric-coated aspirinPhase 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 | Experimental | Drug: L-NMMA, Drug: Docetaxel, Drug: Amlodipine, Drug: Pegfilgrastim, Drug: Enteric-coated aspirinPhase 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 | Experimental | Drug: L-NMMA, Drug: Docetaxel, Drug: Amlodipine, Drug: Pegfilgrastim, Drug: Enteric-coated aspirinPhase 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 | Experimental | Drug: L-NMMA, Drug: Docetaxel, Drug: Amlodipine, Drug: Pegfilgrastim, Drug: Enteric-coated aspirinPhase 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 | Experimental | Drug: L-NMMA, Drug: Docetaxel, Drug: Amlodipine, Drug: Pegfilgrastim, Drug: Enteric-coated aspirinPhase 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 20 mg/kg and Docetaxel 100 mg/m2 | Experimental | Drug: L-NMMA, Drug: Docetaxel, Drug: Amlodipine, Drug: Pegfilgrastim, Drug: Enteric-coated aspirinPhase 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. |
| Phase II: RP2D determined in the Phase Ib | Experimental | Drug: L-NMMA, Drug: Docetaxel, Drug: Amlodipine, Drug: Pegfilgrastim, Drug: Enteric-coated aspirinPhase II: L-NMMA starting dose will be the RP2D determined in the Phase Ib portion of the study. |
Who may qualify
- Ages
- 18 years and older
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (18 listed)
- 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
Key exclusion criteria (22 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| L-NMMAAlso: NG-monomethyl-l-arginineNitric oxide synthase inhibitor | Drug | L-NMMA 10 mg/kg and Docetaxel 75 mg/m2, L-NMMA 12.5 mg/kg and Docetaxel 75 mg/m2, L-NMMA 15 mg/kg and Docetaxel 75 mg/m2, L-NMMA 17.5 mg/kg and Docetaxel 100 mg/m2, L-NMMA 20 mg/kg and Docetaxel 100 mg/m2, L-NMMA 7.5 mg/kg and Docetaxel 75 mg/m2, Phase II: RP2D determined in the Phase Ib |
| DocetaxelAlso: TAXOTEREMitotic inhibitor, cytotoxic | Drug | L-NMMA 10 mg/kg and Docetaxel 75 mg/m2, L-NMMA 12.5 mg/kg and Docetaxel 75 mg/m2, L-NMMA 15 mg/kg and Docetaxel 75 mg/m2, L-NMMA 17.5 mg/kg and Docetaxel 100 mg/m2, L-NMMA 20 mg/kg and Docetaxel 100 mg/m2, L-NMMA 7.5 mg/kg and Docetaxel 75 mg/m2, Phase II: RP2D determined in the Phase Ib |
| AmlodipineAlso: besylate salt of amlodipine; NORVASCLong-acting calcium channel blocker | Drug | L-NMMA 10 mg/kg and Docetaxel 75 mg/m2, L-NMMA 12.5 mg/kg and Docetaxel 75 mg/m2, L-NMMA 15 mg/kg and Docetaxel 75 mg/m2, L-NMMA 17.5 mg/kg and Docetaxel 100 mg/m2, L-NMMA 20 mg/kg and Docetaxel 100 mg/m2, L-NMMA 7.5 mg/kg and Docetaxel 75 mg/m2, Phase II: RP2D determined in the Phase Ib |
| PegfilgrastimAlso: NEULASTAColony-stimulating factor | Drug | L-NMMA 10 mg/kg and Docetaxel 75 mg/m2, L-NMMA 12.5 mg/kg and Docetaxel 75 mg/m2, L-NMMA 15 mg/kg and Docetaxel 75 mg/m2, L-NMMA 17.5 mg/kg and Docetaxel 100 mg/m2, L-NMMA 20 mg/kg and Docetaxel 100 mg/m2, L-NMMA 7.5 mg/kg and Docetaxel 75 mg/m2, Phase II: RP2D determined in the Phase Ib |
| Enteric-coated aspirinAlso: acetylsalicylic acidnon-steroidal anti-inflammatory drug | Drug | L-NMMA 10 mg/kg and Docetaxel 75 mg/m2, L-NMMA 12.5 mg/kg and Docetaxel 75 mg/m2, L-NMMA 15 mg/kg and Docetaxel 75 mg/m2, L-NMMA 17.5 mg/kg and Docetaxel 100 mg/m2, L-NMMA 20 mg/kg and Docetaxel 100 mg/m2, L-NMMA 7.5 mg/kg and Docetaxel 75 mg/m2, Phase II: RP2D determined in the Phase Ib |
Primary outcome
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.
Time frame: 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
Time frame: 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.
Time frame: 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.
4 secondary outcomes
Dose Limiting Toxicities (DLTs) and Other Adverse Events
Time frame: 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
Time frame: The Dose Limiting Toxicities (DLT) assessment window is the duration required for completing one full cycle (through Day 21).
Antitumor Activity
Time frame: 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
Time frame: 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.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Dec 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Polly Niravath, M.D. principal investigator
Houston Methodist Cancer Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing L-NMMA, Docetaxel and Amlodipine in people with Metastatic Triple Negative Breast Cancer, run by The Methodist Hospital Research Institute at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 18 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 15 Dec 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 15 Dec 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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. (time frame: DLTs assessment window is the duration required for completing one full cycle (through Day 21).). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Dec 2023.