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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase III Randomized, Placebo-Controlled, Double-Blind Study of Intravenous Calcium/Magnesium in Two Different Versions to Prevent Oxaliplatin-Induced Sensory Neurotoxicity

Conditions
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Chemotherapeutic Agent Toxicity, Colorectal Cancer, Neuropathy, Neurotoxicity

Intervention / Treatment
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* Drug: calcium gluconate
* Drug: magnesium sulfate
* Other: placebo
* Drug: oxaliplatin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>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). | Drug: calcium gluconate<br>* Given IV<br>Drug: magnesium sulfate<br>* Given IV<br>Drug: oxaliplatin<br> <br> |
| Placebo Comparator: Arm II<br>Patients receive placebo IV over 30 minutes immediately before and after oxaliplatin administration (part of FOLFOX chemotherapy). | Other: placebo<br>* Given IV<br>Drug: oxaliplatin<br> <br> |
| Experimental: Arm III<br>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). | Drug: calcium gluconate<br>* Given IV<br>Drug: magnesium sulfate<br>* Given IV<br>Other: placebo<br>* Given IV<br>Drug: oxaliplatin<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sensory Area Under the Curve(AUC) Score. Oxaliplatin-induced Sensory Neuropathy as Repeatedly Measured by the EORTC QLQ-CIPN20 Sensory Subscale During Chemotherapy | The oxaliplatin-induced sensory neuropathy as repeatedly measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire of Chemotherapy-induced peripheral neuropathy (EORTC QLQ-CIPN20) sensory subscale during the chemotherapy. This is a multivariate repeated measurement of CIPN with possibly variable cycles for every patient. The CIPN sensory subscale will be calculated by standard scoring algorithm and converted to 0-100 scale, where higher scores represent a higher quality of life. Rather than choosing the CIPN20 sensory subscale at a fixed cycle of chemotherapy, we will adopt a summary measure, area under the curve (AUC) of CIPN20 sensory subscale as the primary endpoint. This AUC will be prorated by the number of chemotherapy cycles patients received. | Up to 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve (AUC) of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire of Chemotherapy-induced Peripheral Neuropathy (EORTC QLQ-CIPN20) Autonomic Neuropathy Subscale Scores | The oxaliplatin-induced autonomic neuropathy as repeatedly measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire of Chemotherapy-induced peripheral neuropathy (EORTC QLQ-CIPN20) autonomic subscale during the chemotherapy. This is a multivariate repeated measurement of CIPN with possibly variable cycles for every patient. The CIPN autonomic subscale will be calculated by standard scoring algorithm and converted to 0-100 scale, where higher scores represent a higher quality of life. Rather than choosing the CIPN20 autonomic subscale at a fixed cycle of chemotherapy, we will adopt a summary measure, area under the curve (AUC) of CIPN20 autonomic subscale as the endpoint. This AUC will be prorated by the number of chemotherapy cycles patients received. | Up to 18 months | 
| Area Under the Curve (AUC) of European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire of Chemotherapy-induced Peripheral Neuropathy (EORTC QLQ-CIPN20) Motor Neuropathy Subscale Scores | The oxaliplatin-induced motor neuropathy as repeatedly measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire of Chemotherapy-induced peripheral neuropathy (EORTC QLQ-CIPN20) motor neuropathy subscale during the chemotherapy. This is a multivariate repeated measurement of CIPN with possibly variable cycles for every patient. The CIPN motor neuropathy subscale will be calculated by standard scoring algorithm and converted to 0-100 scale, where higher scores represent a higher quality of life. Rather than choosing the CIPN20 motor neuropathy subscale at a fixed cycle of chemotherapy, we will adopt a summary measure, area under the curve (AUC) of CIPN20 motor neuropathy subscale as the endpoint. This AUC will be prorated by the number of chemotherapy cycles patients received. | Up to 18 Months | 
| Percentage of Patients Experiencing Grade 2+ and Grade 3+ Chronic Cumulative Neurotoxicity. | Grades are determined by the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE version 4.0) and oxaliplatin-specific neurotoxicity scale, during and after chemotherapy. Higher grades symbolize greater severity of the adverse event. | Up to 18 months | 
| Time to Onset of Grade 2+ and Grade 3+ Chronic Cumulative Neurotoxicity and the Duration of the Chronic Cumulative Neurotoxicity During and After Chemotherapy | Time to onset of grade 2+ and grade 3+ chronic cumulative neurotoxicity, the duration of the chronic cumulative neurotoxicity during and after the adjuvant oxaliplatin-based chemotherapy. Grades are determined by the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE version 4.0) and oxaliplatin-specific neurotoxicity scale, during and after chemotherapy. Higher grades symbolize greater severity of the adverse event. | Up to 18 months | 
| Cumulative Oxaliplatin Doses That Can be Administered Without Dose-limiting Chronic Neurotoxicity | A patient has a dose-limiting chronic neurotoxicity when they discontinue oxaliplatin-based chemotherapy because of neurotoxicity. | Up to 18 months | 
| Percentage of Patients Discontinuing Oxaliplatin-based Chemotherapy Because of Neurotoxicity |  | Up to 18 months | 
| Percentage of Patients With Acute Neuropathy Associated With Oxaliplatin | This is the percent of patients who scored >=50 in all sequences of all cycles by arm for side effect Q1: Sensitivity to touching cold. This is a> repeated measurement of CIPN with possibly variable cycles for every patient. The CIPN subscale will be calculated by standard scoring algorithm and converted to 0-100 scale. Where 0 is no sensitivity and 100 is as bad as it can be. | Up to 18 months | 
| Incidence of Calcium Gluconate and Magnesium Sulfate-induced Adverse Events as Measured by CTCAE Version 4.0 |  | Up to 18 months | 
| Area Under the Curve (AUC) of Patient-reported Quality of Life (QOL) as Measured by the Supplemental QOL Questionnaire | This is a multivariate repeated measurement of CIPN with possibly variable cycles for every patient. The supplemental quality of life (QOL) subscale will be calculated by standard scoring algorithm and converted to 0-100 scale, where higher scores represent a higher quality of life. Rather than choosing the subscale at a fixed cycle of chemotherapy, we will adopt a summary measure, area under the curve (AUC) . This AUC will be prorated by the number of chemotherapy cycles patients received. | Up to 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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neurotoxicity, neuropathy, chemotherapeutic agent toxicity, stage II colon cancer, stage III colon cancer, stage IV colon cancer, stage II rectal cancer, stage III rectal cancer, stage IV rectal cancer, adenocarcinoma of the colon, adenocarcinoma of the rectum