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L-NMMA Plus Docetaxel 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 : October 24, 2018
Sponsor:
Collaborator:
The Methodist Hospital System
Information provided by (Responsible Party):
Polly A. Niravath, MD, The Methodist Hospital System

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.

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

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. Patients will receive up to 6 (21-day) cycles of the L-NMMA and docetaxel combination. L-NMMA will be administered via 2-hour intravenous (IV) infusion on Days 1-5 of each cycle. Docetaxel will be administered via 1-hour IV infusion approximately 15 minutes after the Day 1 L-NMMA infusion. 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 Type : Interventional  (Clinical Trial)
Estimated Enrollment : 48 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Clinical Phase Ib/II Trial of L-NMMA Plus Docetaxel in the Treatment of Refractory Locally Advanced or Metastatic Triple Negative Breast Cancer Patients
Study Start Date : July 2016
Estimated Primary Completion Date : August 2019
Estimated Study Completion Date : August 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer
Drug Information available for: Docetaxel

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




Primary Outcome Measures :
  1. MTD [ Time Frame: 18 weeks ]
    Primary outcome measure for Phase Ib: Assess the MTD of L-NMMA when combined with docetaxel/amlodipine

  2. 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 and docetaxel, as assessed by the RECIST 1.1


Secondary Outcome Measures :
  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

  2. 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

  3. Antitumor activity [ Time Frame: 18 weeks ]
    Assess the antitumor activity of L-NMMA when combined with docetaxel/amlodipine, as assessed by the RECIST 1.1.

  4. 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


Other Outcome Measures:
  1. 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

  2. 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
Criteria

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

Information from the National Library of Medicine

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


Contacts
Contact: Houston Methodist Cancer Center 713-441-0629 ccresearch@houstonmethodist.org

Locations
United States, Texas
Houston Methodist Hospital Recruiting
Houston, Texas, United States, 77030
Contact: Houston Methodist Cancer Center    713-441-0629    ccresearch@houstonmethodist.org   
Sponsors and Collaborators
Polly A. Niravath, MD
The Methodist Hospital System
Investigators
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     History of Changes
Other Study ID Numbers: Pro00011685
First Posted: July 15, 2016    Key Record Dates
Last Update Posted: October 24, 2018
Last Verified: October 2018
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

Keywords provided by Polly A. Niravath, MD, The Methodist Hospital System:
breast cancer
nitric oxide synthase
docetaxel
L-NMMA

Additional relevant MeSH terms:
omega-N-Methylarginine
Breast Neoplasms
Triple Negative Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Docetaxel
Aspirin
Nitric Oxide
Amlodipine
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