Calcium Gluconate and Magnesium Sulfate in Preventing Neurotoxicity in Patients With Colon Cancer or Rectal Cancer Receiving Oxaliplatin-Based Combination Chemotherapy

Alliance for Clinical Trials in Oncology

Status and phase

Completed

Phase 3

Conditions

Chemotherapeutic Agent Toxicity

Neuropathy

Neurotoxicity

Colorectal Cancer

Treatments

Drug: oxaliplatin

Drug: magnesium sulfate

Drug: calcium gluconate

Other: placebo

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT01099449

N08CB

NCI-2011-02036 (Registry Identifier)

CDR0000669660 (Registry Identifier)

NCCTG-N08CB

Details and patient eligibility

About

RATIONALE: Chemoprotective drugs, such as calcium gluconate and magnesium sulfate, may prevent neurotoxicity caused by oxaliplatin. It is not yet known which administration schedule of calcium gluconate and magnesium sulfate is more effective in preventing neurotoxicity.

PURPOSE: This randomized phase III trial is studying different administration schedules of calcium gluconate and magnesium sulfate and comparing how well they work in neurotoxicity in patients with colon cancer or rectal cancer receiving oxaliplatin-based combination chemotherapy.

Full description

OBJECTIVES:

Primary

To determine whether 2 schedules of calcium gluconate and magnesium sulfate infusions (given before and after chemotherapy or just before chemotherapy) can prevent or ameliorate chronic, cumulative oxaliplatin-induced sensory neurotoxicity in patients with colon or rectal cancer receiving adjuvant FOLFOX chemotherapy comprising leucovorin calcium, fluorouracil, and oxaliplatin.

Secondary

To determine whether these 2 infusion schedules can increase the cumulative oxaliplatin doses that can be delivered without dose-limiting chronic neurotoxicity.
To determine whether these 2 infusion schedules can ameliorate acute neuropathy associated with oxaliplatin.
To determine whether these 2 infusion schedules cause adverse events.
To investigate whether these 2 infusions schedules influence patient quality of life.
To describe baseline and post-treatment neurological quantitative sensory testing abnormalities in the study participants.

Tertiary

To explore if polymorphisms in the GSTP1, GSTM1, ERCC2, and XRCC1 genes are associated with early onset of oxaliplatin-induced neurotoxicity.

OUTLINE: This is a multicenter study. Patients are stratified according to age (< 65 years vs ≥ 65 years), gender, regimen (FOLFOX4 vs modified FOLFOX6 vs other), and stage of disease (II vs III vs IV). Patients are randomized to 1 of 3 treatment arms.

Arm I: Patients receive calcium gluconate IV and magnesium sulfate IV over 30 minutes immediately before and after oxaliplatin administration (part of FOLFOX chemotherapy comprising leucovorin calcium, fluorouracil, and oxaliplatin).
Arm II: Patients receive placebo IV over 30 minutes immediately before and after oxaliplatin administration (part of FOLFOX chemotherapy).
Arm III: Patients receive calcium gluconate and magnesium sulfate IV over 30 minutes immediately before and placebo IV over 30 minutes immediately after oxaliplatin administration (part of FOLFOX chemotherapy).

In all arms, courses repeat every 14 days for 6 months in the absence of disease progression or unacceptable toxicity.

Blood samples are collected before the second course of treatment for translational research.

Patients complete questionnaires on side effects, quality of life, and chemotherapy-induced peripheral neuropathy periodically.

After completion of study treatment, patients are followed up at 3, 6, 12, and 18 months.

Enrollment

362 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

DISEASE CHARACTERISTICS:

Histologically confirmed adenocarcinoma of the colon or rectum
Has undergone curative resection and is considered to have stage II or III disease or completely resected stage IV disease with no evidence of residual tumor
Scheduled to receive 6 months of oxaliplatin-based adjuvant chemotherapy with 85 mg/m^2 oxaliplatin every 2 weeks (this includes, for instance, FOLFOX4 or modified FOLFOX6)
- Patients receiving bevacizumab or cetuximab in combination with FOLFOX as part of a clinical trial or clinical practice are eligible

PATIENT CHARACTERISTICS:

ECOG performance status 0-2
WBC ≥ 3,000/mm^3
ANC ≥ 1,500/mm^3
Platelet count ≥ 100,000/mm^3
Hemoglobin ≥ 10.0 g/dL
Total bilirubin ≤ 1.5 times upper limit of normal (ULN)
Serum creatinine ≤ 1.5 times ULN
Serum calcium ≤ 1.2 times ULN
Serum magnesium ≤ 1.2 times ULN
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
Able to complete questionnaires (alone or with assistance)
Able to comply with study treatment
Willing to return to enrolling institution for follow-up
Willing to provide blood sample for research purposes
No pre-existing peripheral neuropathy of any grade
No family history of a genetic/familial neuropathy
No second or third degree AV heart block or a history of second or third degree heart block
- Bundle branch blocks are allowed.
No other medical conditions that, in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient

PRIOR CONCURRENT THERAPY:

See Disease Characteristics
Central venous access line present, or scheduled to have a central line placed before starting chemotherapy and study treatment
No prior treatment with neurotoxic chemotherapy (e.g., oxaliplatin, cisplatin, taxanes, or vinca alkaloids)
No concurrent digitalis medication
No concurrent treatment with the anticonvulsants carbamazepine (e.g., Tegretol®), phenytoin (e.g., Dilantin®), valproic acid (e.g., Depakene®), gabapentin (Neurontin®), or pregabalin (Lyrica®)
No concurrent neurotropic agents, including venlafaxine (Effexor), desvenlafaxine (Pristiq®), milnacipran (Savella®), or duloxetine (Cymbalta)
No concurrent tricyclic antidepressants (such as amitryptilline), or any other agent specifically being given to prevent or treat neuropathy
No concurrent drugs given as a neuroprotectant

Trial design

Primary purpose

Supportive Care

Allocation

Randomized

Interventional model

Parallel Assignment

Masking

Double Blind

362 participants in 3 patient groups, including a placebo group

Arm I

Experimental group

Description:

Patients receive calcium gluconate and magnesium sulfate IV over 30 minutes immediately before and after oxaliplatin administration (part of FOLFOX chemotherapy comprising leucovorin calcium, fluorouracil, and oxaliplatin).

Treatment:

Drug: calcium gluconate

Drug: oxaliplatin

Drug: magnesium sulfate

Arm II

Placebo Comparator group

Description:

Patients receive placebo IV over 30 minutes immediately before and after oxaliplatin administration (part of FOLFOX chemotherapy).

Treatment:

Drug: oxaliplatin

Other: placebo

Arm III

Experimental group

Description:

Patients receive calcium gluconate and magnesium sulfate IV over 30 minutes immediately before and placebo IV over 30 minutes immediately after oxaliplatin administration (part of FOLFOX chemotherapy).

Treatment:

Drug: calcium gluconate

Drug: oxaliplatin

Other: placebo

Drug: magnesium sulfate