Clinical trial NCT00316914: 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
Official title: A Phase III Randomized, Placebo-Controlled, Double-Blind Study of Intravenous Calcium/Magnesium to Prevent Oxaliplatin-Induced Sensory Neurotoxicity
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Colorectal Cancer
Neurotoxicity
Keywords: 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
Lead sponsor: Alliance for Clinical Trials in Oncology
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
name: North Central Cancer Treatment Group
First posted: 2006-04-21
Enrollment: 104
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SUPPORTIVE_CARE

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.

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.

Eligibility 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

Primary outcomes:
measure: Percentage of Patients With Oxaliplatin-induced Grade 2+ Chronic Neuropathic Adverse Event
timeFrame: 127 days
Secondary outcomes:
measure: Time to Onset of Grade 2+ Chronic Neurotoxicity
timeFrame: 127 days
measure: Time to Onset of Grade 3+ Chronic Neurotoxicity
timeFrame: 127 days
measure: Average Duration of Chronic Neuropathic Toxicity
timeFrame: 127 days
measure: Percentage of Patients Discontinuing Therapy for Chronic Neurotoxicity
timeFrame: 127 days
measure: Average Cumulative Oxaliplatin Dose
timeFrame: 127 days
measure: Average Duration of Oxaliplatin-containing Treatment
timeFrame: 127 days
measure: Percentage of Patients With Acute Neuropathic Adverse Event
timeFrame: 127 days
measure: Incidence of Calcium Magnesium (CaMg)-Induced Adverse Event
timeFrame: 127 days
measure: Percentage of Patients Experiencing Impact on Activities of Daily Living (ADL)
timeFrame: 127 days
measure: Change From Baseline in Fatigue Score at One Month
timeFrame: Baseline and One month
measure: Change From Baseline in Quality of Life (QOL) at One Month
timeFrame: Baseline and One month
Other outcomes:
Locations:
city: Augusta
country: United States
facility: MBCCOP - Medical College of Georgia Cancer Center
state: Georgia
city: Des Moines
country: United States
facility: Mercy Capitol Hospital
state: Iowa
city: Des Moines
country: United States
facility: CCOP - Iowa Oncology Research Association
state: Iowa
city: Des Moines
country: United States
facility: John Stoddard Cancer Center at Iowa Methodist Medical Center
state: Iowa
city: Des Moines
country: United States
facility: Medical Oncology and Hematology Associates at John Stoddard Cancer Center
state: Iowa
city: Des Moines
country: United States
facility: Medical Oncology and Hematology Associates at Mercy Cancer Center
state: Iowa
city: Des Moines
country: United States
facility: Mercy Cancer Center at Mercy Medical Center - Des Moines
state: Iowa
city: Des Moines
country: United States
facility: John Stoddard Cancer Center at Iowa Lutheran Hospital
state: Iowa
city: Bismarck
country: United States
facility: Bismarck Cancer Center
state: North Dakota
city: Bismarck
country: United States
facility: Medcenter One Hospital Cancer Care Center
state: North Dakota
city: Bismarck
country: United States
facility: Mid Dakota Clinic, PC
state: North Dakota
city: Sioux Falls
country: United States
facility: Avera Cancer Institute
state: South Dakota
city: Sioux Falls
country: United States
facility: Medical X-Ray Center, PC
state: South Dakota
city: Sioux Falls
country: United States
facility: Sanford Cancer Center at Sanford USD Medical Center
state: South Dakota
Study officials:
affiliation: Mayo Clinic
name: Axel Grothey, MD
role: STUDY_CHAIR
References:
citation: 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.
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. [Abstract] J Clin Oncol 26 (Suppl 15): A-4009, 2008.
citation: 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.