Calcium and Magnesium in Preventing Peripheral Neuropathy Caused by Ixabepilone in Patients With Breast Cancer

Study Overview
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Brief Summary
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This randomized phase III trial studies calcium and magnesium to see how well they work in preventing peripheral neuropathy caused by ixabepilone in patients with breast cancer. Giving calcium together with magnesium may stop or delay the development of peripheral neuropathy in patients with cancer who are receiving treatment with ixabepilone. It is not yet known whether calcium and magnesium are effective in preventing peripheral neuropathy caused by ixabepilone.

Detailed Description
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PRIMARY OBJECTIVES: I. To compare ixabepilone-induced peripheral neuropathy (sensory) as measured by European Organization for Research and Treatment of Cancer (EORTC) Quality of life Questionnaire (QLQ)-Chemotherapy-Induced Peripheral Neuropathy (CIPN)20 sensory subscale between calcium (Ca) Magnesium (Mg) and placebo arms. SECONDARY OBJECTIVES: I. To compare the incidence of CTCAE measured grade 2+ and/or grade 3+ peripheral neuropathy between CaMg and placebo arms. II. To compare the times to onset of CTCAE measured grade 2+ and/or grade 3+ peripheral neuropathy between CaMg and placebo arms. III. To compare the proportion of patients requiring ixabepilone dose reductions and/or stopping ixabepilone secondary to peripheral neuropathy (sensory) between CaMg and placebo arms. IV. To assess the toxicity of CaMg in this situation. V. To document the incidence and severity of the acute pain syndrome (APS, commonly known as arthralgias/myalgias) induced by ixabepilone. VI. To evaluate whether CaMg will decrease the acute pain syndrome (APS). VII. To evaluate the incidence and characteristics of, and change in, ixabepilone-APS over several cycles. VIII. To evaluate the association between the ixabepilone-APS and eventual chemotherapy-induced neuropathy. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive calcium gluconate and magnesium sulfate IV over 30 minutes immediately before and after each ixabepilone administration. ARM II: Patients receive placebo IV over 30 minutes immediately before and after each ixabepilone administration. After completion of study treatment, patients are followed up monthly for 12 months.

Official Title
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The Use of Calcium and Magnesium for Prevention of Ixabepilone Induced Peripheral Neuropathy: A Phase III Double-Blind Placebo Controlled Study

Conditions
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Recurrent Breast Carcinoma, Neuropathy, Pain, Stage IV Breast Cancer

Intervention / Treatment
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* Drug: Calcium Gluconate
* Drug: Magnesium Sulfate
* Other: Placebo
* Other: Quality-of-Life Assessment
* Other: Questionnaire Administration
* Drug: Ixabepilone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Scheduled to undergo cancer treatment for metastatic breast cancer (weekly or once every three weeks) with ixabepilone with no prior exposure to ixabepilone and no more than 2 prior chemotherapy regimens for metastatic disease Serum calcium =< 1.2 x upper normal limit (UNL) Serum magnesium =< UNL Serum creatinine =< 1.5 x UNL Ability to sign informed consent and understand the nature of a placebo-controlled trial Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0, 1, or 2 Ability to complete questionnaire(s) by themselves or with assistance Life expectancy >= 4 months Presence of a central line Exclusion Criteria: Pre-existing history of peripheral neuropathy >= grade 2 (National Cancer Institute [NCI] CTCAE Active Version) due to any cause (chemotherapy, diabetes, alcohol, toxin, hereditary, etc.) Concurrent treatment with anticonvulsants, tricyclic antidepressants, or other neuropathic pain medications agents such as carbamazepine, phenytoin, valproic acid, gabapentin, lamotrigine, topical lidocaine patch, capsaicin cream, etc., or any other treatments specifically for prevention or treatment of neuropathy Other medical conditions, which in the opinion of the treating physician/allied health professional would make this protocol unreasonably hazardous for the patient Any of the following: Pregnant women Nursing women Women of childbearing potential (per physician judgment) Diagnosed diabetes requiring insulin or oral hypoglycemic medications Receiving digoxin or digitoxin History of heart block (any degree) Current treatment for arrhythmias Concurrent treatment with other neuropathic chemotherapy agents

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (calcium gluconate, magnesium sulfate)<br>Patients receive calcium gluconate and magnesium sulfate IV over 30 minutes immediately before and after each ixabepilone administration. | Drug: Calcium Gluconate<br>* Given IV<br>* Other names: Calglucon;Drug: Magnesium Sulfate<br>* Given IV<br>* Other names: Magnesium Sulfate whiskers;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>Drug: Ixabepilone<br>* Given IV<br>* Other names: IXEMPRA;|
| Placebo Comparator: Arm II (placebo)<br>Patients receive placebo IV over 30 minutes immediately before and after each ixabepilone administration. | Other: Placebo<br>* Given IV<br>* Other names: sham therapy;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>Drug: Ixabepilone<br>* Given IV<br>* Other names: IXEMPRA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of Chemotherapy-induced Peripheral Neuropathy Between Calcium With Magnesium (CaMg) and Placebo Arms, as Measured by the Sensory Subscale of EORTC QLQ-CIPN20 | European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Chemotherapy-Induced Peripheral Neuropathy Module (EORTC QLQ-CIPN20) sensor subscale score was calculated following the standard scoring algorithm and was transformed to a 0 to 100 scale with 0=Low QOL and 100=Best QOL for data analysis. | During the first 18 weeks of ixabepilone-based therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients With Grade 2+ and/or Grade 3+ Neurotoxicity as Measured by NCI CTCAE Active Version Neuropathy Scale |  | Up to 12 months from initiation of ixabepilone | 
| Time to Onset of Grade 2+ and/or Grade 3+ Neurotoxicity as Assessed by NCI CTCAE Active Version | Time to onset of grade 2+ neurotoxicity was defined as time from randomization to the first occurrence of grade 2+ neurotoxicity. Time to onset of grade 3+ neurotoxicity was defined as time from randomization to the first occurrence of grade 3+ neurotoxicity. | Up to 12 months from initiation of ixabepilone | 
| Proportion of Patients Undergoing Dose Reduction or Discontinuing Ixabepilone Secondary to Peripheral Neuropathy |  | Up to 12 months from initiation of ixabepilone | 
| Average Cumulative Ixabepilone Dose |  | Up to 12 months from initiation of ixabepilone | 
| Toxicity Profile of CaMg Per CTCAE Active Version |  | Up to 12 months from initiation of ixabepilone | 
| Incidence of the Acute Pain Syndrome (APS) | APS was measured using the pain item which evaluated the aches/pains at its WORST in the last 24 hours in the scale of 0 to 10, with 0=no aches/pain and 10=aches/pains as bad as can be. The outcome measures for each subsequent cycle will be analyzed in a similar fashion. | Treatment initiation to day 21 (Cycle 1) | 
| Severity of the Acute Pain Syndrome (APS) | APS was measured using the pain item which evaluated the aches/pains at its WORST in the last 24 hours in the scale of 0 to 10, with 0=no aches/pain and 10=aches/pains as bad as can be. The outcome measures for each subsequent cycle will be analyzed in a similar fashion. | Treatment initiation to day 21 (Cycle 1) | 
| Association Between the Ixabepilone-APS and Eventual Chemotherapy-induced Neuropathy | Correlation coefficients will be produced relating the worst pain scores in the first cycle of therapy and the subsequent neuropathy scores as judged from the daily and weekly questions. | First cycle of therapy (up to 21 days) |