Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Published Results
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase III Biomarker/Laboratory analysis, Supportive care, Treatment Closed 18 and over NCI NCCTG-N04C7 N04C7, NCT00316914

Objectives

1. 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.
2. Determine whether CaMg infusions can increase the cumulative oxaliplatin doses that can be delivered without chronic neurotoxicity.
3. Determine whether CaMg infusions can ameliorate the acute neuropathy associated with oxaliplatin.
4. Determine whether CaMg infusions cause any adverse events.
5. Investigate whether CaMg infusions influence quality of life, fatigue, and activities of daily living of these patients.
6. Determine if polymorphisms in the GSTP1 gene predict early onset of oxaliplatin-induced neurotoxicity.

Entry Criteria

Disease Characteristics:

• Histologically confirmed adenocarcinoma of the colon or rectum
  • Stage II disease
  • Stage III disease
  • Stage IV disease (completed 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)

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

Patient Characteristics:

• Absolute neutrophil count ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Hemoglobin ≥ 10 g/dL
• WBC ≥ 3,000/mm³
• 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

Expected Enrollment

A total of 300 patients will be accrued for this study.

Outcomes

Percentage of patients with oxaliplatin-induced neurotoxicity as assessed by CTCAE v3.0

Time to onset of grade 2+ chronic neurotoxicity as assessed by the Kaplan-Meier method
Time to onset of grade 3+ chronic neurotoxicity as assessed by the Kaplan-Meier method
Average duration of chronic neuropathic toxicity as assessed by the Kaplan-Meier method
Percentage of patients discontinuing therapy as assessed by the Chi-square method
Average cumulative oxaliplatin dose as assessed by the Chi-square method
Average duration of treatment as assessed by the Kaplan-Meier method
Percentage of patients with acute neuropathic toxicity as assessed by the Chi-square method
Incidence of calcium magnesium (CaMg)-induced toxicity as assessed by the Chi-square method and descriptive statistics
Percentage of patients experiencing impact on activities of daily living (ADL) as assessed by the Chi-square method
Average fatigue as measured by the 2-sample t-test from baseline to 1 month
Average quality of life as assessed by the 2-sample t-test from baseline to 1 month
Percentage of patients with grade 2+ chronic neuropathic toxicity who express the GSTP1 1105V polymorphism as assessed by the Chi-square method
Time to onset of grade 2+ chronic neuropathic toxicity comparison between patients who either express or don't express the GSTP1 1105V polymorphism as assessed by the Kaplan-Meier method

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.

Nikcevich DA, Grothey A, Sloan JA, et al.: Effect of intravenous calcium and magnesium (IV CaMg) on oxaliplatin-induced sensory neurotoxicity (sNT) in adjuvant colon cancer: results of the phase III placebo-controlled, double-blind NCCTG trial N04C7. [Abstract] J Clin Oncol 26 (Suppl 15): A-4009, 2008.

Trial Contact Information

Trial Lead Organizations

North Central Cancer Treatment Group

Charles Loprinzi, MD, Protocol co-chair		Ph: 507-284-2511 Email: cloprinzi@mayo.edu
Daniel Nikcevich, MD, PhD, Protocol co-chair		Ph: 218-786-3625; 888-203-7267 Email: dnikcevich@smdc.org
Axel Grothey, MD, Protocol chair		Ph: 507-284-2511 Email: grothey.axel@mayo.edu
Steven Alberts, MD, Protocol co-chair		Ph: 507-284-2511

Registry Information
Official Title		A Phase III Randomized, Placebo-Controlled, Double-Blind Study of Intravenous Calcium/Magnesium to Prevent Oxaliplatin-Induced Sensory Neurotoxicity
Trial Start Date		2006-01-13
Registered in ClinicalTrials.gov		NCT00316914
Date Submitted to PDQ		2006-02-27
Information Last Verified		2008-01-16
NCI Grant/Contract Number		CA25224