S0715: Acetyl-L-Carnitine in Preventing Neuropathy in Women With Stage I, II, or IIIA Breast Cancer Undergoing Chemo

OBJECTIVES:

Primary

* Compare whether treatment with acetyl-L-carnitine hydrochloride vs placebo prevents symptoms of neuropathy as measured by the 11-item neurotoxicity component of the FACT-Taxane Questionnaire at 12 weeks after study registration in women with stage I, II, or IIIA breast cancer undergoing adjuvant taxane-based chemotherapy.

Secondary

* Compare the functional status of these patients using the Trial Outcome Index from the Functional Assessment of Cancer Therapy (FACT)-Taxane Questionnaire.
* Compare fatigue in these patients using the Function Assessment of Chronic Illness Therapy (FACIT)-Fatigue Symptom Module.

Other

* Compare the proportion of patients experiencing grade 3 or 4 neuropathy.
* Compare serum nerve growth factor levels in these patients.
* Describe the total dose of taxane received and treatment delays, compliance with therapy, and use of concurrent medications, dietary supplements (e.g., glutamine), vitamin E, and complementary and alternative medicines in these patients.
* Explore the relationship between nerve growth factor levels and the degree of neuropathy and functional status in these patients.
* Explore the relationship between genetic markers responsible for taxane metabolism and clearance (e.g., CYP2C8, CYP3A4, CYP3A5, GSTM1, and GSTP1) and the degree of neuropathy in these patients.

OUTLINE: This is a multicenter study. Patients are stratified according to planned adjuvant chemotherapy regimen for breast cancer (paclitaxel weekly for 12 weeks vs paclitaxel biweekly for 4 courses \[8 weeks\] vs paclitaxel biweekly for 6 courses \[12 weeks\] vs docetaxel every 3 weeks for 4 courses \[12 weeks\] vs docetaxel every 3 weeks for 6 courses \[18 weeks\]) and age (< 60 years vs ≥ 60 years). Patients are randomized to 1 of 2 treatment arms.

* Arm I: Patients receive oral acetyl-L-carnitine hydrochloride 3 times daily for 24 weeks.
* Arm II: Patients receive oral placebo 3 times daily for 24 weeks. Patients complete the FACT-Taxane Trial Outcome Index and the FACIT-Fatigue Symptom Module questionnaires at baseline, at 12, 24, and 36 weeks, and at 1 and 2 years.

Blood samples are collected at baseline and at week 12 for biomarker analysis (nerve growth factor levels) by ELISA, DNA extraction, and genotyping analysis.

• acetyl-L-carnitine hydrochloride (Dietary supplement): Given orally
• placebo (Other): Given orally

Primary outcomes

• 12-week FACT-Taxane Neurotoxicity Model-adjusted Score in ALC and Placebo Groups [12 weeks post-registration]: Compare whether treatment with acetyl-L-carnitine hydrochloride vs placebo prevents symptoms of neuropathy as measured by the 11-item neurotoxicity (NTX) component of the Functional Assesment of Cancer Therapy (FACT)-Taxane Questionnaire at 12 weeks after study registration in women with breast cancer undergoing adjuvant taxane-based chemotherapy. Linear regression model adjusted for baseline score, taxane regiment, and age. Lower scores indicate worse CIPN. Total possible range is 0 to 64. For more information on this subscale, please see http://www.facit.org/FACITOrg/Questionnaires

Secondary outcomes

• 12-week FACT-Trial Outcome Index(TOI) Functional Status Model-adjusted Score in ALC and Placebo Groups [12 weeks post-registration]: Compare FACT-TOI outcome in treatment vs placebo groups at 12 weeks after study registration in women with breast cancer undergoing adjuvant taxane-based chemotherapy. Linear regression model adjusted for baseline score, taxane regiment, and age. Lower scores indicate worse functional status. Total possible range is 0 to 120. For more information on this subscale, please see http://www.facit.org/FACITOrg/Questionnaires
• 12-week FACIT-fatigue Model-adjusted Score in ALC and Placebo Groups [12 weeks post-registration]: Compare fatigue outcome between treatment and placebo groups as measured by the 13-item Functional Assessment of Chronic Illness Therapy FACIT-fatigue questionnaire at 12 weeks after study registration in women with breast cancer undergoing adjuvant taxane-based chemotherapy. Linear regression model adjusted for baseline score, taxane regiment, and age. Lower scores indicate more fatigue. Total possible range is 0 to 52. For more information on this subscale, please see http://www.facit.org/FACITOrg/Questionnaires

Other outcomes

• Proportion of Patients Experiencing Grade 3 or 4 Neuropathy [12 weeks post-registration]: Proportion of patients experiencing grade 3 or 4 neuropathy
• Serum Nerve Growth Factor Levels [12 weeks post-registration]
• Treatment and Concurrent Therapy [12 weeks post-registration]: total dose of taxane received and treatment delays, compliance with therapy, and use of concurrent medications, dietary supplements (e.g., glutamine), vitamin E, and complementary and alternative medicines
• Association Between Nerve Growth Factor Levels and the Degree of Neuropathy and Functional Status [12 weeks post-registration]: Explore the relationship between nerve growth factor levels and the degree of neuropathy and functional status in these patients.
• Association Between Genetic Markers Responsible for Taxane Metabolism and Clearance and the Degree of Neuropathy [12 weeks post-registration]: Explore the relationship between genetic markers responsible for taxane metabolism and clearance (e.g., CYP2C8, CYP3A4, CYP3A5, GSTM1, and GSTP1) and the degree of neuropathy in these patients.

Sex: Female, ages: 18 Years to 120 Years

DISEASE CHARACTERISTICS:

* Histologically confirmed primary invasive adenocarcinoma of the breast

  * Stage I-III disease
  * No metastatic disease
* Must have undergone modified radical mastectomy or breast-sparing surgery
* Planning to receive one of the following standard taxane-based systemic chemotherapy regimens as adjuvant therapy for breast cancer:

  * Paclitaxel 80 mg/m² weekly for 12 weeks
  * Paclitaxel 175 mg/m² every other week for 4 courses (8 weeks)
  * Paclitaxel 175 mg/m² every other week for 6 courses (12 weeks)
  * Docetaxel 75 mg/m² every 3 weeks for 4 courses (12 weeks)
  * Docetaxel 75 mg/m² every 3 weeks for 6 courses (18 weeks)
* No history of neuropathy
* Hormone receptor status not specified

PATIENT CHARACTERISTICS:

* Menopausal status not specified
* Zubrod performance status 0-2
* Serum creatinine ≤ 2.5 times upper limit of normal
* Not pregnant or nursing
* Fertile patients must use effective contraception
* Able to complete questionnaires in English or Spanish
* Willing to submit blood samples for DNA extraction, genotyping analysis, and nerve growth factor studies
* No history of diabetes
* No history of seizure disorder
* No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, ductal carcinoma in situ, or adequately treated stage I or stage II malignancy from which the patient is currently in complete remission

PRIOR CONCURRENT THERAPY:

* See Disease Characteristics
* Recovered from prior breast surgery
* Prior neoadjuvant or adjuvant chemotherapy allowed
* No prior taxane therapy
* No prior biologic therapy for treatment of breast cancer
* No concurrent vitamin E, glutamine, gabapentin, nortriptyline, amitriptyline, or duloxetine hydrochloride

  * Multivitamins containing vitamin E allowed provided vitamin E dose is < 1,000 IU
* No concurrent anti-seizure medications
* Concurrent hormonal therapy allowed
* Concurrent biologic therapy allowed (e.g., Herceptin)
* Concurrent participation in another therapeutic clinical trial allowed

Participant flow

Outcome results

• 12-week FACT-Taxane Neurotoxicity Model-adjusted Score in ALC and Placebo Groups (Primary), Mean, units on a scale: Arm I (Acetyl-L-carnitine Hydrochloride)) 35.4 (34.1 to 36.7); Arm II (Placebo) 36.3 (35 to 37.6) (p 0.17)
• 12-week FACT-Trial Outcome Index(TOI) Functional Status Model-adjusted Score in ALC and Placebo Groups (Secondary), Mean, units on a scale: Arm I (Acetyl-L-carnitine Hydrochloride)) 92.1 (89.3 to 94.9); Arm II (Placebo) 92.3 (89.4 to 95.1) (p 0.92)
• 12-week FACIT-fatigue Model-adjusted Score in ALC and Placebo Groups (Secondary), Mean, FACIT-fatigue score: Arm I (Acetyl-L-carnitine Hydrochloride)) 36.6 (34.7 to 38.6); Arm II (Placebo) 35.3 (33.4 to 37.3) (p 0.20)
• Proportion of Patients Experiencing Grade 3 or 4 Neuropathy (Other pre specified), Count of participants, Participants: Arm I (Acetyl-L-carnitine Hydrochloride)) 8; Arm II (Placebo) 1 (p 0.46)
• Serum Nerve Growth Factor Levels (Other pre specified)
• Treatment and Concurrent Therapy (Other pre specified)
• Association Between Nerve Growth Factor Levels and the Degree of Neuropathy and Functional Status (Other pre specified)
• Association Between Genetic Markers Responsible for Taxane Metabolism and Clearance and the Degree of Neuropathy (Other pre specified)

Adverse events

Time frame: Up to 25 weeks

Serious adverse events by term

Other adverse events by term

195 more sites not listed.

• Results publication: Hershman DL, Unger JM, Crew KD, Minasian LM, Awad D, Moinpour CM, Hansen L, Lew DL, Greenlee H, Fehrenbacher L, Wade JL 3rd, Wong SF, Hortobagyi GN, Meyskens FL, Albain KS. Randomized double-blind placebo-controlled trial of acetyl-L-carnitine for the prevention of taxane-induced neuropathy in women undergoing adjuvant breast cancer therapy. J Clin Oncol. 2013 Jul 10;31(20):2627-33. doi: 10.1200/JCO.2012.44.8738. Epub 2013 Jun 3. PMID 23733756

• Laurence H. Baker, DO, FACOI, Principal investigator, University of Michigan Rogel Cancer Center

NIH grants: U10CA037429