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

Colorectal Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00316914
• Other study ID #: CDR0000471238
• Secondary ID: NCCTG-N04C7
• Status: Completed
• Phase: Phase 3
• First received: April 19, 2006
• Last updated: February 19, 2013
• Start date: January 2006
• Est. completion date: November 2012

Study information

• Verified date: February 2013
• Source: Alliance for Clinical Trials in Oncology
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 104
• Est. completion date: November 2012
• Est. primary completion date: January 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Supportive Care

Related Conditions & MeSH terms

• Colorectal Cancer
• Colorectal Neoplasms
• Neurotoxicity
• Neurotoxicity Syndromes

Intervention

Drug:
• calcium gluconate
Given IV
• magnesium sulfate
Given IV

Other:
• placebo
Given IV

Locations

Country	Name	City	State
United States	MBCCOP - Medical College of Georgia Cancer Center	Augusta	Georgia
United States	Bismarck Cancer Center	Bismarck	North Dakota
United States	Medcenter One Hospital Cancer Care Center	Bismarck	North Dakota
United States	Mid Dakota Clinic, PC	Bismarck	North Dakota
United States	CCOP - Iowa Oncology Research Association	Des Moines	Iowa
United States	John Stoddard Cancer Center at Iowa Lutheran Hospital	Des Moines	Iowa
United States	John Stoddard Cancer Center at Iowa Methodist Medical Center	Des Moines	Iowa
United States	Medical Oncology and Hematology Associates at John Stoddard Cancer Center	Des Moines	Iowa
United States	Medical Oncology and Hematology Associates at Mercy Cancer Center	Des Moines	Iowa
United States	Mercy Cancer Center at Mercy Medical Center - Des Moines	Des Moines	Iowa
United States	Mercy Capitol Hospital	Des Moines	Iowa
United States	Avera Cancer Institute	Sioux Falls	South Dakota
United States	Medical X-Ray Center, PC	Sioux Falls	South Dakota
United States	Sanford Cancer Center at Sanford USD Medical Center	Sioux Falls	South Dakota

Sponsors (3)

Lead Sponsor	Collaborator
Alliance for Clinical Trials in Oncology	National Cancer Institute (NCI), North Central Cancer Treatment Group

Country where clinical trial is conducted

United States, 

References & Publications (2)

Grothey A, Nikcevich DA, Sloan JA, Kugler JW, Silberstein PT, Dentchev T, Wender DB, Novotny PJ, Chitaley U, Alberts SR, Loprinzi CL. Intravenous calcium and magnesium for oxaliplatin-induced sensory neurotoxicity in adjuvant colon cancer: NCCTG N04C7. J — View Citation

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. [Abs

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Yes
Secondary	Time to Onset of Grade 2+ Chronic Neurotoxicity	Neurotoxicity were assessed by Common Terminology Criteria for Adverse Events (CTCAE) v3.0.	127 days	No
Secondary	Time to Onset of Grade 3+ Chronic Neurotoxicity	Neurotoxicity was assessed by CTCAE v3.0.	127 days	Yes
Secondary	Average Duration of Chronic Neuropathic Toxicity	Neuropathic adverse events were assessed by CTCAE v3.0.	127 days	No
Secondary	Percentage of Patients Discontinuing Therapy for Chronic Neurotoxicity	Neurotoxicity were assessed by CTCAE v3.0.	127 days	No
Secondary	Average Cumulative Oxaliplatin Dose		127 days	No
Secondary	Average Duration of Oxaliplatin-containing Treatment		127 days	No
Secondary	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	Yes
Secondary	Incidence of Calcium Magnesium (CaMg)-Induced Adverse Event	Adverse Events were measured using CTCAE V3.0.	127 days	Yes
Secondary	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	No
Secondary	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	No
Secondary	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	No