- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02834403
L-NMMA Plus Taxane Chemotherapy in Refractory Locally Advanced or Metastatic Triple Negative Breast Cancer Patients
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
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Study Type
Enrollment (Actual)
Phase
- Phase 2
- Phase 1
Contacts and Locations
Study Locations
-
-
Texas
-
Houston, Texas, United States, 77030
- Houston Methodist Hospital
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
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 Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Non-Randomized
- Interventional Model: Sequential Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: 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.
|
Nitric oxide synthase inhibitor
Other Names:
Mitotic inhibitor, cytotoxic
Other Names:
Long-acting calcium channel blocker
Other Names:
Colony-stimulating factor
Other Names:
non-steroidal anti-inflammatory drug
Other Names:
|
Experimental: 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.
|
Nitric oxide synthase inhibitor
Other Names:
Mitotic inhibitor, cytotoxic
Other Names:
Long-acting calcium channel blocker
Other Names:
Colony-stimulating factor
Other Names:
non-steroidal anti-inflammatory drug
Other Names:
|
Experimental: 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.
|
Nitric oxide synthase inhibitor
Other Names:
Mitotic inhibitor, cytotoxic
Other Names:
Long-acting calcium channel blocker
Other Names:
Colony-stimulating factor
Other Names:
non-steroidal anti-inflammatory drug
Other Names:
|
Experimental: 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.
|
Nitric oxide synthase inhibitor
Other Names:
Mitotic inhibitor, cytotoxic
Other Names:
Long-acting calcium channel blocker
Other Names:
Colony-stimulating factor
Other Names:
non-steroidal anti-inflammatory drug
Other Names:
|
Experimental: 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.
|
Nitric oxide synthase inhibitor
Other Names:
Mitotic inhibitor, cytotoxic
Other Names:
Long-acting calcium channel blocker
Other Names:
Colony-stimulating factor
Other Names:
non-steroidal anti-inflammatory drug
Other Names:
|
Experimental: 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.
|
Nitric oxide synthase inhibitor
Other Names:
Mitotic inhibitor, cytotoxic
Other Names:
Long-acting calcium channel blocker
Other Names:
Colony-stimulating factor
Other Names:
non-steroidal anti-inflammatory drug
Other Names:
|
Experimental: 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.
|
Nitric oxide synthase inhibitor
Other Names:
Mitotic inhibitor, cytotoxic
Other Names:
Long-acting calcium channel blocker
Other Names:
Colony-stimulating factor
Other Names:
non-steroidal anti-inflammatory drug
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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.
|
DLTs assessment window is the duration required for completing one full cycle (through Day 21).
|
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.
|
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.
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.
|
DLTs assessment window is the duration required for completing one full cycle (through Day 21).
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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).
|
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.
|
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).
|
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. |
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).
|
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.
|
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.
|
Determine the time to maximum plasma concentration of the L-NMMA and docetaxel combination.
|
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.
|
Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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
|
18 weeks
|
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
|
18 weeks
|
Collaborators and Investigators
Investigators
- Principal Investigator: Polly Niravath, M.D., Houston Methodist Cancer Center
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimated)
Study Record Updates
Last Update Posted (Estimated)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Skin Diseases
- Neoplasms
- Neoplasms by Site
- Breast Diseases
- Breast Neoplasms
- Triple Negative Breast Neoplasms
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Antihypertensive Agents
- Vasodilator Agents
- Peripheral Nervous System Agents
- Enzyme Inhibitors
- Analgesics
- Sensory System Agents
- Anti-Inflammatory Agents, Non-Steroidal
- Analgesics, Non-Narcotic
- Anti-Inflammatory Agents
- Antirheumatic Agents
- Fibrinolytic Agents
- Fibrin Modulating Agents
- Platelet Aggregation Inhibitors
- Cyclooxygenase Inhibitors
- Antipyretics
- Antineoplastic Agents
- Tubulin Modulators
- Antimitotic Agents
- Mitosis Modulators
- Membrane Transport Modulators
- Calcium-Regulating Hormones and Agents
- Calcium Channel Blockers
- Aspirin
- Docetaxel
- Amlodipine
- omega-N-Methylarginine
Other Study ID Numbers
- Pro00011685
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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