Calcium Gluconate and Magnesium Sulfate in Preventing Neurotoxicity Caused By Oxaliplatin in Patients Receiving Combination Chemotherapy for Stage II, Stage III, or Stage IV Colorectal Cancer That Has Been Completely Removed By Surgery

Study Overview
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Brief Summary
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RATIONALE: Calcium gluconate and magnesium sulfate may prevent or lessen neurotoxicity caused by oxaliplatin. It is not yet known whether calcium gluconate and magnesium sulfate are more effective than a placebo in preventing neurotoxicity caused by oxaliplatin in patients receiving combination chemotherapy. PURPOSE: This randomized phase III trial is studying calcium gluconate and magnesium sulfate to see how well they work compared to a placebo in preventing neurotoxicity caused by oxaliplatin in patients receiving combination chemotherapy for stage II, stage III, or stage IV colorectal cancer that has been completely removed by surgery.

Detailed Description
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OBJECTIVES: Determine whether calcium gluconate and magnesium sulfate (CaMg) infusions can prevent or ameliorate chronic, cumulative oxaliplatin-induced neurotoxicity in patients receiving FOLFOX combination chemotherapy for stage II, III or IV colorectal cancer. Determine whether CaMg infusions can increase the cumulative oxaliplatin doses that can be delivered without chronic neurotoxicity. Determine whether CaMg infusions can ameliorate the acute neuropathy associated with oxaliplatin. Determine whether CaMg infusions cause any adverse events. Investigate whether CaMg infusions influence quality of life, fatigue, and activities of daily living of these patients. Determine if polymorphisms in the GSTP1 gene predict early onset of oxaliplatin-induced neurotoxicity. OUTLINE: This is a randomized, placebo-controlled, double-blind, multicenter study. Patients are stratified according to age (< 65 vs > 65), gender, and chemotherapy regimen (FOLFOX4 vs modified FOLFOX6). 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 oxaliplatin administration (once every 2 weeks) of their assigned chemotherapy regimen. Arm II: Patients receive a placebo IV over 30 minutes immediately before and after each oxaliplatin administration (once every 2 weeks) of their assigned chemotherapy regimen. In both arms, treatment continues until chemotherapy is discontinued (approximately 6 months). Patients complete quality of life questionnaires on day 1, a symptom experience diary on days 2-5 of their chemotherapy regimen, and questionnaires at 1 and 3 months after completion of study treatment. Blood samples are collected at baseline and tested for the GSTP1 gene. After completion of study treatment, patients are followed for at least 3 months. PROJECTED ACCRUAL: A total of 300 patients will be accrued for this study.

Official Title
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A Phase III Randomized, Placebo-Controlled, Double-Blind Study of Intravenous Calcium/Magnesium to Prevent Oxaliplatin-Induced Sensory Neurotoxicity

Conditions
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Colorectal Cancer, Neurotoxicity

Intervention / Treatment
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* Drug: calcium gluconate
* Drug: magnesium sulfate
* Other: placebo


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed adenocarcinoma of the colon or rectum Stage II disease Stage III disease Stage IV disease (completely resected with no evidence of residual tumor) Must have undergone curative resection for stage II or III disease Scheduled to receive 6 months of adjuvant treatment with either of the following FOLFOX chemotherapy regimens: FOLFOX4, comprising leucovorin calcium, fluorouracil, and oxaliplatin (2-week course) Modified FOLFOX6, comprising high-dose leucovorin calcium, high-dose fluorouracil, and oxaliplatin (2-week course) PATIENT CHARACTERISTICS: Absolute neutrophil count ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 Hemoglobin ≥ 10 g/dL WBC ≥ 3,000/mm^3 Bilirubin ≤ 1.5 times upper limit of normal (ULN) Creatinine ≤ 1.5 times ULN Calcium normal Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No pre-existing peripheral neuropathy of any grade No hypercalcemia No concurrent heart block or a history of heart block No other medical condition that, in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient No family history of a genetic/familial neuropathy PRIOR CONCURRENT THERAPY: See Disease Characteristics No prior treatment with neurotoxic chemotherapy such as oxaliplatin, cisplatin, taxanes, or vinca alkaloids Concurrent use of bevacizumab or cetuximab in combination with FOLFOX as part of a clinical trial or clinical practice are allowed No concurrent digitalis medication No concurrent digoxin No concurrent treatment with anticonvulsants such as carbamazepine, phenytoin, or valproic acid No other concurrent neurotropic agents such as gabapentin

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: Ca/Mg<br>Patients receive calcium gluconate (Ca) and magnesium sulfate (Mg) IV over 30 minutes immediately before and after each oxaliplatin administration (once every 2 weeks) of their assigned chemotherapy regimen. | Drug: calcium gluconate<br>* Given IV<br>Drug: magnesium sulfate<br>* Given IV<br>|
| Placebo Comparator: Placebo<br>Patients receive a placebo IV over 30 minutes immediately before and after each oxaliplatin administration (once every 2 weeks) of their assigned chemotherapy regimen. | Other: placebo<br>* Given IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients With Oxaliplatin-induced Grade 2+ Chronic Neuropathic Adverse Event | Neuropathic adverse events were assessed by Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Neurotoxicity evaluation grade: loss of deep tendon reflexes or paresthesia, including tingling, but not interfering with function (Grade 1); objective sensory alteration or paresthesia, including tingling, interfering with function, but not with activities of daily living (Grade 2); sensory alteration or paresthesia interfering with activities of daily living (Grade 3); permanent sensory losses that are disabling (Grade 4) | 127 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Onset of Grade 2+ Chronic Neurotoxicity | Neurotoxicity were assessed by Common Terminology Criteria for Adverse Events (CTCAE) v3.0. | 127 days | 
| Time to Onset of Grade 3+ Chronic Neurotoxicity | Neurotoxicity was assessed by CTCAE v3.0. | 127 days | 
| Average Duration of Chronic Neuropathic Toxicity | Neuropathic adverse events were assessed by CTCAE v3.0. | 127 days | 
| Percentage of Patients Discontinuing Therapy for Chronic Neurotoxicity | Neurotoxicity were assessed by CTCAE v3.0. | 127 days | 
| Average Cumulative Oxaliplatin Dose |  | 127 days | 
| Average Duration of Oxaliplatin-containing Treatment |  | 127 days | 
| Percentage of Patients With Acute Neuropathic Adverse Event | Acute neuropathic toxicities were measured using the Symptom Experience Diary and supplemental quality of life questions in the scale of 0 (no symptom) to 10 (worst symptom). The item score was reversed and transformed into 0 (low QOL) to 100 (best QOL) scale for analysis. Any score greater than 0 was considered having acute neuropathy. | 127 days | 
| Incidence of Calcium Magnesium (CaMg)-Induced Adverse Event | Adverse Events were measured using CTCAE V3.0. | 127 days | 
| Percentage of Patients Experiencing Impact on Activities of Daily Living (ADL) | Activities of daily living were measured using the Symptom Experience Diary and supplemental quality of life questions. The questionnaires' items were in the scale of 0 (no symptom) to 10 (worst symptom). | 127 days | 
| Change From Baseline in Fatigue Score at One Month | Fatigue was measured by Brief Fatigue Inventory in the scale of 0 (no fatigue) to 10 (fatigue as bad as you can imagine). The item score was reversed and transformed into 0 (low quality of life (QOL)) to 100 (best QOL) scale for analysis. Change: score at one month minus score at baseline. | Baseline and One month | 
| Change From Baseline in Quality of Life (QOL) at One Month | Quality of Life (QOL) were measured using the Symptom Experience Diary and supplemental quality of life questions. Item score range: 0 (no symptom) to 10 (worst symptom). The score was reversed and transformed into 0 (low QOL) to 100 (best QOL) scale for analysis. Change: score at one month minus score at baseline. | Baseline and One month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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neurotoxicity, stage II colon cancer, stage III colon cancer, adenocarcinoma of the colon, stage II rectal cancer, stage III rectal cancer, stage IV rectal cancer, stage IV colon cancer, adenocarcinoma of the rectum