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 Description

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Brief 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.

Condition or disease	Intervention/treatment	Phase
Colorectal Cancer; Neurotoxicity	Drug: calcium gluconate; Drug: magnesium sulfate; Other: placebo	Phase 3

Detailed 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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	104 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Double (Participant, Investigator)
Primary Purpose:	Supportive Care
Official Title:	A Phase III Randomized, Placebo-Controlled, Double-Blind Study of Intravenous Calcium/Magnesium to Prevent Oxaliplatin-Induced Sensory Neurotoxicity
Study Start Date :	January 2006
Actual Primary Completion Date :	January 2008
Actual Study Completion Date :	November 2012

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Ca/Mg; 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; Given IV Drug: magnesium sulfate; Given IV
Placebo Comparator: Placebo; 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; Given IV

Outcome Measures

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Primary Outcome Measures :

1. Percentage of Patients With Oxaliplatin-induced Grade 2+ Chronic Neuropathic Adverse Event [ Time Frame: 127 days ]
   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)

Secondary Outcome Measures :

1. Time to Onset of Grade 2+ Chronic Neurotoxicity [ Time Frame: 127 days ]
   Neurotoxicity were assessed by Common Terminology Criteria for Adverse Events (CTCAE) v3.0.
2. Time to Onset of Grade 3+ Chronic Neurotoxicity [ Time Frame: 127 days ]
   Neurotoxicity was assessed by CTCAE v3.0.
3. Average Duration of Chronic Neuropathic Toxicity [ Time Frame: 127 days ]
   Neuropathic adverse events were assessed by CTCAE v3.0.
4. Percentage of Patients Discontinuing Therapy for Chronic Neurotoxicity [ Time Frame: 127 days ]
   Neurotoxicity were assessed by CTCAE v3.0.
5. Average Cumulative Oxaliplatin Dose [ Time Frame: 127 days ]
6. Average Duration of Oxaliplatin-containing Treatment [ Time Frame: 127 days ]
7. Percentage of Patients With Acute Neuropathic Adverse Event [ Time Frame: 127 days ]
   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.
8. Incidence of Calcium Magnesium (CaMg)-Induced Adverse Event [ Time Frame: 127 days ]
   Adverse Events were measured using CTCAE V3.0.
9. Percentage of Patients Experiencing Impact on Activities of Daily Living (ADL) [ Time Frame: 127 days ]
   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).
10. Change From Baseline in Fatigue Score at One Month [ Time Frame: Baseline and 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.
11. Change From Baseline in Quality of Life (QOL) at One Month [ Time Frame: Baseline and 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.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

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Locations

United States, Georgia
MBCCOP - Medical College of Georgia Cancer Center
Augusta, Georgia, United States, 30912
United States, Iowa
Mercy Capitol Hospital
Des Moines, Iowa, United States, 50307
CCOP - Iowa Oncology Research Association
Des Moines, Iowa, United States, 50309
John Stoddard Cancer Center at Iowa Methodist Medical Center
Des Moines, Iowa, United States, 50309
Medical Oncology and Hematology Associates at John Stoddard Cancer Center
Des Moines, Iowa, United States, 50309
Medical Oncology and Hematology Associates at Mercy Cancer Center
Des Moines, Iowa, United States, 50314
Mercy Cancer Center at Mercy Medical Center - Des Moines
Des Moines, Iowa, United States, 50314
John Stoddard Cancer Center at Iowa Lutheran Hospital
Des Moines, Iowa, United States, 50316
United States, North Dakota
Bismarck Cancer Center
Bismarck, North Dakota, United States, 58501
Medcenter One Hospital Cancer Care Center
Bismarck, North Dakota, United States, 58501
Mid Dakota Clinic, PC
Bismarck, North Dakota, United States, 58501
United States, South Dakota
Avera Cancer Institute
Sioux Falls, South Dakota, United States, 57105
Medical X-Ray Center, PC
Sioux Falls, South Dakota, United States, 57105
Sanford Cancer Center at Sanford USD Medical Center
Sioux Falls, South Dakota, United States, 57117-5039

Sponsors and Collaborators

Alliance for Clinical Trials in Oncology

National Cancer Institute (NCI)

North Central Cancer Treatment Group

Investigators

Study Chair:	Axel Grothey, MD	Mayo Clinic

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Publications of Results:

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 Clin Oncol. 2011 Feb 1;29(4):421-7. doi: 10.1200/JCO.2010.31.5911. Epub 2010 Dec 28.

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Pachman DR, Qin R, Seisler DK, Smith EM, Beutler AS, Ta LE, Lafky JM, Wagner-Johnston ND, Ruddy KJ, Dakhil S, Staff NP, Grothey A, Loprinzi CL. Clinical Course of Oxaliplatin-Induced Neuropathy: Results From the Randomized Phase III Trial N08CB (Alliance). J Clin Oncol. 2015 Oct 20;33(30):3416-22. doi: 10.1200/JCO.2014.58.8533. Epub 2015 Aug 17.

Responsible Party:	Alliance for Clinical Trials in Oncology
ClinicalTrials.gov Identifier:	NCT00316914 History of Changes
Other Study ID Numbers:	NCCTG-N04C7; CDR0000471238 ( Registry Identifier: NCI Physician Data Query )
First Posted:	April 21, 2006
Results First Posted:	March 25, 2013
Last Update Posted:	August 11, 2016
Last Verified:	July 2016

Keywords provided by Alliance for Clinical Trials in Oncology:

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

Additional relevant MeSH terms:

Neurotoxicity Syndromes; Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Nervous System Diseases; Poisoning; Chemically-Induced Disorders	Calcium, Dietary; Oxaliplatin; Magnesium Sulfate; Bone Density Conservation Agents; Physiological Effects of Drugs; Antineoplastic Agents; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Anesthetics; Central Nervous System Depressants; Anti-Arrhythmia Agents; Anticonvulsants; Calcium Channel Blockers; Membrane Transport Modulators