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

NCT02834403 | Completed Phase 1 Results FDA Drug

• 1 other identifier: Pro00011685
• Study Type: interventional
• Target: 37
• Locations: 1 country
• Sites: 1

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.

Conditions

Metastatic Triple Negative Breast Cancer

Keywords

breast cancer; nitric oxide synthase; docetaxel; L-NMMA

Outcome Measures

Primary Outcomes (3)

• 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.

  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

  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.

  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

  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.

Other Outcomes (2)

• Area Under the Plasma Concentration Curve of the L-NMMA and Docetaxel Combination

  18 weeks

• Predictive Biomarkers

  18 weeks

Study Arms (7)

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.

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.

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.

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.

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.

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.

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.

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

Interventions

L-NMMA DRUG

Nitric oxide synthase inhibitor

Also known as: NG-monomethyl-l-arginine

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

Docetaxel DRUG

Mitotic inhibitor, cytotoxic

Also known as: TAXOTERE

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

Amlodipine DRUG

Long-acting calcium channel blocker

Also known as: besylate salt of amlodipine; NORVASC

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

Pegfilgrastim DRUG

Colony-stimulating factor

Also known as: NEULASTA

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 aspirin DRUG

non-steroidal anti-inflammatory drug

Also known as: acetylsalicylic acid

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

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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%)

You may not qualify if:

• 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

Sponsors & Collaborators

• The Methodist Hospital Research Institute: lead

Study Sites (1)

Houston Methodist Hospital

Houston, Texas, 77030, United States

Location

MeSH Terms

Conditions

Triple Negative Breast Neoplasms; Breast Neoplasms

Interventions

omega-N-Methylarginine; Docetaxel; Amlodipine; pegfilgrastim; Aspirin

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Arginine; Amino Acids, Basic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Diamino; Amino Acids, Essential; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes; Dihydropyridines; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Salicylates; Hydroxybenzoates; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic

Results Point of Contact

• Title: Polly Niravath, MD
• Organization: Houston Methodist Cancer Center

ccresearch@houstonmethodist.org

713-441-0629

Study Officials

• Polly Niravath, M.D.

  Houston Methodist Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator, Medical Oncologist

Study Record Dates

• First Submitted: June 29, 2016
• First Posted: July 15, 2016
• Study Start: November 1, 2016
• Primary Completion: January 1, 2021
• Study Completion: January 1, 2021
• Last Updated: December 15, 2023
• Results First Posted: December 15, 2023

Record last verified: 2023-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)