Clinical Trials /

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

NCT02834403

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. In the Phase II portion of the study, the starting dose will be the RP2D determined in the Phase Ib portion of the study.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title:L-NMMA Plus Docetaxel in Refractory Locally Advanced or Metastatic Triple Negative Breast Cancer Patients
  • Official Title:Clinical Phase Ib Trial of L-NMMA Plus Docetaxel in the Treatment of Refractory Locally Advanced or Metastatic Triple Negative Breast Cancer Patients

Clinical Trial IDs

  • ORG STUDY ID: Pro00011685
  • NCT ID: NCT02834403

Trial Conditions

  • Metastatic Triple Negative Breast Cancer

Trial Interventions

DrugSynonymsArms
L-NMMANG-monomethyl-l-arginineExperimental
DocetaxelTAXOTEREExperimental
Amlodipinebesylate salt of amlodipine; NORVASCExperimental
PegfilgrastimNEULASTAExperimental

Trial Purpose

This is a Phase Ib study assessing the maximum tolerated dose (MTD) and dose-limiting toxicities of L-NMMA when combined with docetaxel in refractory locally advanced or metastatic triple negative breast cancer patients. The study will be conducted in two stages. Stage 1 of the study will determine the MTD of L-NMMA when combined with 75 mg/m2 docetaxel. Stage 2 of the study will determine the MTD of L-NMMA when combined with 60 mg/m2 docetaxel. Five dose levels of L-NMMA (5, 7.5, 10, 12.5, and 15 mg/kg) will be investigated in stage 1. The starting dose of L-NMMA will be 7.5 mg/kg. As patients are accrued, a standard Bayesian model averaging continual reassessment method (CRM) approach will be used to determine the appropriate L-NMMA dosage. In stage 2, the starting dose will be one dose level above the MTD determined in stage 1. Again the CRM will be used to determine the appropriate L-NMMA dosage.

Detailed Description

This is a Phase Ib study assessing the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of L-NMMA when combined with docetaxel in refractory locally advanced or metastatic triple negative breast cancer patients. The study will be conducted in two stages. Stage 1 of the study will determine the MTD of L-NMMA when combined with 75 mg/m2 docetaxel. Stage 2 of the study will determine the MTD of L-NMMA when combined with 60 mg/m2 docetaxel. Five dose levels of L-NMMA (5, 7.5, 10, 12.5, and 15 mg/kg) will be investigated in stage 1. The starting dose of L-NMMA will be 7.5 mg/kg. As patients are accrued, a standard Bayesian model averaging continual reassessment method (CRM) approach will be used to determine the appropriate L-NMMA dosage. In stage 2, the starting dose will be one dose level above the MTD determined in stage 1. Again the CRM will be used to determine the appropriate L-NMMA dosage. 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 infusion on Days 1-5 of each cycle. Docetaxel will be administered via 1-hour intravenous infusion approximately 15 minutes after the Day 1 L-NMMA infusion. For L-NMMA-induced hypertension, amlodipine (10 mg) will be orally administered for 6 days at each cycle. Amlodipine administration will start 24 hours before the first dose of L-NMMA. For docetaxel-induced leukopenia, pegfilgrastim (6 mg) will be administered via subcutaneous injection approximately 24 hours after every dose of docetaxel. In addition to MTD and DLT assessment, this study will also determine the recommended phase 2 dose, antitumor activity, and pharmacokinetics of the L-NMMA as well as explore tissue and blood-based markers of treatment response and toxicity.

Trial Arms

NameTypeDescriptionInterventions
ExperimentalExperimentalStage 1: L-NMMA at a starting dose of 7.5 mg/kg will be administered intravenously on Days 1-5. Depending on DLT occurrence, L-NMMA dose will de-escalate (5 mg/kg) or escalate (10, 12.5, or 15 mg/kg) in 2.5-mg/kg increments. Docetaxel at a dose of 75 mg/m2 will be administered intravenously 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 first L-NMMA dose. Pegfilgrastim (6 mg) will be administered subcutaneously 24 h after docetaxel. The maximum number of cycles will be 6 (21 days). Stage 2: The starting dose of L-NMMA will be one dose level above the stage 1 MTD. Depending on the occurrence of DLTs, L-NMMA dose will de-escalate or escalate as described for stage 1. Docetaxel dose will be fixed at 60 mg/m2.
  • L-NMMA
  • Docetaxel
  • Amlodipine
  • Pegfilgrastim

Eligibility 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. For this study, acceptable contraception methods are defined in Section 12.4.

- 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 may not receive any other antineoplastic treatment during the study or follow-up period.

- 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 >460 msec in the presence of potassium >4.0 mEq/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, such as ketoconazole, itraconazole, clarithromycin, atanazir, indinavir, nefazodone, neflinavir, ritonavir, saquinavir, telithromycin, and voriconazole

- Concurrent use of potent CYP3A4 inducers, such as dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbitol, and St. John's wort.

- 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

Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose (MTD)
Time Frame:18 weeks
Safety Issue:Yes
Description:Assess the MTD of L-NMMA when combined with docetaxel/amlodipine

Secondary Outcome Measures

Measure:Dose Limiting Toxicities (DLTs) and other adverse events
Time Frame:18 weeks
Safety Issue:Yes
Description:Describe the DLTs and other adverse events associated with L-NMMA when combined with docetaxel/amlodipine, as assessed by the CTCAE v4.03
Measure:Recommended phase 2 dose of the L-NMMA and docetaxel combination
Time Frame:18 weeks
Safety Issue:Yes
Description:Determine the recommended phase 2 dose of the L-NMMA and docetaxel combination based on the occurrence of DLTs and MTD determination
Measure:Antitumor activity
Time Frame:18 weeks
Safety Issue:No
Description:Assess the antitumor activity of L-NMMA when combined with docetaxel/amlodipine, as assessed by the RECIST 1.1.
Measure:Maximum plasma concentration of the L-NMMA and docetaxel combination
Time Frame:18 weeks
Safety Issue:Yes
Description:Determine the maximum plasma concentration of the L-NMMA and docetaxel combination

Trial Keywords

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