Interim analysis

This phase II trial tests the safety, side effects, and best dose of monosialotetrahexosylganglioside (GM1) and whether it works in reducing or preventing chemotherapy-induced peripheral neuropathy (CIPN) in patients with breast cancer that has spread from where it first started (primary site) to other places in the body (metastatic) who are receiving treatment with paclitaxel. Chemotherapy drugs, such as paclitaxel, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Exposure to chemotherapy drugs like paclitaxel may cause a side effect called CIPN, which is a condition of weakness, numbness, and pain from nerve damage (usually in the hands and feet). GM1 is a part of the body's natural system that insulates nerves and helps to protect nerves from damage. Giving GM1 may help reduce or prevent CIPN in breast cancer patients receiving treatment with paclitaxel.

PRIMARY OBJECTIVES:

I. To obtain data to further support the safety of increasing monosialotetrahexosylganglioside (GM1) doses when given on day 1, concomitantly with paclitaxel. (Early phase) II. To evaluate the preliminary efficacy of GM1 compared with placebo at preventing paclitaxel-induced peripheral neuropathy sensory symptoms as measured by the six individual Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy 20 (QLQ-CIPN20) questions that quantify numbness (N), tingling (T), and pain in the fingers/hands and toes/feet. (Phase II)

SECONDARY OBJECTIVES:

I. To obtain additional data to support the safety of GM1 in the treated population. (Phase II) II. To obtain data to support that GM1 looks promising for preventing/decreasing acute paclitaxel pain syndrome as measured by the Acute Pain Syndrome Questionnaire. (Phase II)

EXPLORATORY OBJECTIVES:

I. Conduct of this clinical trial provides the opportunity to facilitate the better understanding of the natural history of paclitaxel-induced neuropathy, akin to what is being examined in a currently active trial, S1714. (Phase II) II. This clinical trial also provides an opportunity to conduct correlative studies to understand the mechanism of CIPN and/or identify biomarkers of CIPN or GM1 efficacy. (Phase II) III. To obtain efficacy data to assess the impact of GM1 on the anti-tumor activity of paclitaxel as evaluated by progression-free survival and overall survival. (Phase II)

OUTLINE: This is an early phase dose-escalation study of GM1 followed by a phase II study.

EARLY PHASE: Patients receive GM1 intravenously (IV) over 1 hour either once every 7 days, or once every 7 days for 3 doses followed by one week off, prior to paclitaxel administration.

PHASE II: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive GM1 IV 1 hour prior to paclitaxel administration and paclitaxel IV weekly for 12 weeks or 3 weeks on/1 week off for 12 doses.

ARM II: Patients receive placebo IV 1 hour prior to paclitaxel administration and paclitaxel IV weekly for 12 weeks or 3 weeks on/1 week off for 12 doses.

Inclusion Criteria:

• Documentation of disease: Histologic diagnosis of metastatic breast cancer in women or men
• Prior treatment- No previous exposure to GM1
• Planned administration of paclitaxel, either given weekly, or weekly 3 weeks on/1 week off, to patients with metastatic cancer at a dose of 80 mg/m^2
• No planned treatment with concurrent immunotherapy
• Score of 1 (none) and/or 2 (a little) on the six individual European Organization for Research and Treatment of Cancer (EORTC) Quality of Life questionnaire (QLQ)- chemotherapy-induced peripheral neuropathy (CIPN)20 questions that quantify numbness (N), tingling (T), and pain in the fingers/hands and toes/feet (Items #31-36)
• No diagnosis of fibromyalgia
• No history of significant respiratory tract infection and/or infectious diarrhea within 14 days before registration
• No history of stroke or cerebrovascular accident in the past 6 months prior to registration
• No history of diagnosed neurologic or psychiatric disorders, including epilepsy or dementia
• For women of childbearing potential, not pregnant and not nursing, because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown.

Therefore, for women of childbearing potential, a negative pregnancy test done =< 7 days prior to registration is required. Of note, a female of childbearing potential is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months)

• Ability to complete questionnaires by themselves or with assistance
• In order to complete the mandatory patient-completed measures, participants must be able to speak and/or read English and/or Spanish
• Persons with impaired decision making such that they cannot understand the benefits or risks of trial participation, per the judgement of the consenting clinician, will not be eligible
• Age >= 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Absolute neutrophil count (ANC) >= 1,000/mm^3
• Platelet count >= 100,000/mm^3
• Creatinine =< 1.5 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN)
• Total bilirubin =< 1.5 x ULN
• No planned use of duloxetine
• No planned use of cryotherapy, compression therapy, or cryocompression therapy at study entry

Exclusion Criteria:

• N/A