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

Phase 3

Terminated

Conditions: Recurrent Breast Carcinoma
Neuropathy
Pain
Stage IV Breast Cancer

Interventions: Drug: Calcium Gluconate
Other: Placebo
Drug: Magnesium Sulfate
Other: Quality-of-Life Assessment
Other: Questionnaire Administration
Drug: Ixabepilone

Registration Number: NCT00998738

Lead Sponsor: Mayo Clinic

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 1

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm I (calcium gluconate, magnesium sulfate)	Questionnaire Administration	Patients receive calcium gluconate and magnesium sulfate IV over 30 minutes immediately before and after each ixabepilone administration.
Arm II (placebo)	Questionnaire Administration	Patients receive placebo IV over 30 minutes immediately before and after each ixabepilone administration.
Arm I (calcium gluconate, magnesium sulfate)	Quality-of-Life Assessment	Patients receive calcium gluconate and magnesium sulfate IV over 30 minutes immediately before and after each ixabepilone administration.
Arm I (calcium gluconate, magnesium sulfate)	Calcium Gluconate	Patients receive calcium gluconate and magnesium sulfate IV over 30 minutes immediately before and after each ixabepilone administration.
Arm II (placebo)	Placebo	Patients receive placebo IV over 30 minutes immediately before and after each ixabepilone administration.
Arm II (placebo)	Quality-of-Life Assessment	Patients receive placebo IV over 30 minutes immediately before and after each ixabepilone administration.
Arm I (calcium gluconate, magnesium sulfate)	Ixabepilone	Patients receive calcium gluconate and magnesium sulfate IV over 30 minutes immediately before and after each ixabepilone administration.
Arm I (calcium gluconate, magnesium sulfate)	Magnesium Sulfate	Patients receive calcium gluconate and magnesium sulfate IV over 30 minutes immediately before and after each ixabepilone administration.
Arm II (placebo)	Ixabepilone	Patients receive placebo IV over 30 minutes immediately before and after each ixabepilone administration.

Primary Outcome Measures

Name	Time	Method
Comparison of Chemotherapy-induced Peripheral Neuropathy Between Calcium With Magnesium (CaMg) and Placebo Arms, as Measured by the Sensory Subscale of EORTC QLQ-CIPN20	During the first 18 weeks of ixabepilone-based therapy	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.

Secondary Outcome Measures

Name	Time	Method
Severity of the Acute Pain Syndrome (APS)	Treatment initiation to day 21 (Cycle 1)	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.
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	Up to 12 months from initiation of ixabepilone	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.
Proportion of Patients Undergoing Dose Reduction or Discontinuing Ixabepilone Secondary to Peripheral Neuropathy	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)	Treatment initiation to day 21 (Cycle 1)	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.
Average Cumulative Ixabepilone Dose	Up to 12 months from initiation of ixabepilone
Association Between the Ixabepilone-APS and Eventual Chemotherapy-induced Neuropathy	First cycle of therapy (up to 21 days)	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.