Glutathione in Preventing Peripheral Neuropathy Caused by Paclitaxel and Carboplatin in Patients With Ovarian Cancer, Fallopian Tube Cancer, and/or Primary Peritoneal Cancer

Study Overview
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Brief Summary
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This randomized phase III trial is studying glutathione to see how well it works in preventing peripheral neuropathy caused by paclitaxel and carboplatin in patients with ovarian cancer, fallopian tube cancer, and/or primary peritoneal cancer. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Chemoprotective drugs, such as glutathione, may help prevent peripheral neuropathy caused by paclitaxel and carboplatin. It is not yet known whether glutathione is more effective than a placebo in preventing peripheral neuropathy.

Detailed Description
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PRIMARY OBJECTIVES: I. To compare TAXOL (paclitaxel)/carboplatin (CBDCA) induced peripheral neuropathy as measured by European Organization for Research and Treatment of Cancer (EORTC)- Quality of Life (QOL)-chemotherapy induced peripheral neuropathy 20 (CIPN20) between glutathione (GSH) and placebo arms. SECONDARY OBJECTIVES: I. To compare the incidences of grade 2+ and grade 3+ TAXOL/CBDCA induced peripheral neuropathy measured by Common Terminology Criteria for Adverse Events (CTCAE) neuropathy scale between GSH and placebo arms. II. To compare the time to onset of grade 2+ and grade 3+ TAXOL/CBDCA induced peripheral neuropathy between GSH and placebo arms, measured by CTCAE neuropathy scale. III. To compare the proportion of patients requiring chemotherapy dose reductions secondary to TAXOL/CBDCA induced peripheral neuropathy between GSH and placebo arms. IV. To compare the proportion of patients stopping TAXOL/CBDCA secondary to peripheral neuropathy between GSH and placebo arms. V. To assess the toxicity profile of GSH in this situation. VI. To evaluate whether GSH influences the anti-tumor activity of TAXOL/CBDCA. VII. To evaluate patient quality of life (QOL) measured by Functional Assessment of Cancer Therapy-Ovarian (FACT-O) (ovarian/fallopian tube/primary peritoneal cancer patients only) and patient daily symptom questionnaires over time between GSH and placebo arms. TERTIARY: I. To explore the association of genetic variations in genes involved in taxane/platinum metabolism with incidence of grade 2+ TAXOL/CBDCA induced peripheral neuropathy. II. As part of ongoing research for North Central Cancer Treatment Group (NCCTG) studies, we are banking blood products for future studies. OUTLINE: Patients are stratified according to baseline neuropathy (none vs grade 1), debulked status (no gross residual disease [no clinically apparent residual lesions at the completion of primary surgery] vs optimal [largest residual lesion < 1 cm at primary surgery] vs sub-optimally debulked [residual lesion > 1 cm] or not operated upon), and cancer type (ovarian/fallopian tube/primary peritoneal cancers vs lung cancer vs other). Patients are randomized to 1 of 2 treatment arms. Patients are grouped based on, Planned paclitaxel dose cycle length (Weekly vs. every 3 weeks vs. every 4 weeks). The stratification factors listed include demographic, prognostic factors and medication that can potentially impact the primary or secondary outcomes, so they need to be distributed evenly among the two arms. The 18 level combinations involved in these four stratification factors are within the maximum recommended of one half of the group sample size for the study. Ideally, patients begin receiving glutathione before their first dose of chemotherapy, but must begin glutathione before their second dose of chemotherapy. ARM I: Patients receive glutathione intravenously (IV) over 15 minutes, paclitaxel* IV over 1 or 3 hours depending on planned dose cycle length and carboplatin IV over 30 minutes. ARM II: Patients receive placebo IV over 15 minutes, paclitaxel* IV over 1 or 3 hours depending on planned dose cycle length and carboplatin IV over 30 minutes. NOTE: *Alternatively, patients may receive paclitaxel IV over 1 hour and glutathione/placebo IV over 15 minutes weekly and carboplatin every 21 days for 12 weeks. Blood samples are collected periodically for pharmacogenomic and other biomarker analyses. Patients complete questionnaires periodically, including quality-of-life assessments. After completion of study treatment, patients are followed up every 3 months for 1 year.

Official Title
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The Use of Glutathione (GSH) for Prevention of Paclitaxel/Carboplatin (TAXOL/CBDCA) Induced Peripheral Neuropathy: A Phase III Randomized, Double-Blind Placebo Controlled Study

Conditions
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Chemotherapeutic Agent Toxicity, Neuropathy, Neurotoxicity Syndrome, Pain, Stage IIIA Fallopian Tube Cancer, Stage IIIA Ovarian Cancer, Stage IIIA Primary Peritoneal Cancer, Stage IIIB Fallopian Tube Cancer, Stage IIIB Ovarian Cancer, Stage IIIB Primary Peritoneal Cancer, Stage IIIC Fallopian Tube Cancer, Stage IIIC Ovarian Cancer, Stage IIIC Primary Peritoneal Cancer, Stage IV Fallopian Tube Cancer, Stage IV Ovarian Cancer, Stage IV Primary Peritoneal Cancer

Intervention / Treatment
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* Drug: Carboplatin
* Drug: Glutathione
* Other: Laboratory Biomarker Analysis
* Drug: Paclitaxel
* Other: Placebo
* Other: Quality-of-Life Assessment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Scheduled to undergo treatment with TAXOL at 150-200 mg/m2 and CBDCA at area under the curve (AUC) = 5-7 every 21 or 28 days for at least 12 weeks; alternatively, paclitaxel can be prescribed at 80 mg/m2 weekly for at least 12 weeks, with the same CBDCA dose of AUC = 5-7 every 21 days; additional chemotherapy agents are allowed (bevacizumab, etoposide, etc) per physician discretion, as long as they are not known to be neurotoxic; Note: patients ideally will begin GSH therapy prior to their first dose of this chemotherapy, but must begin GSH therapy prior to their second dose of chemotherapy Ability to sign informed consent and understand the nature of a placebo-controlled trial Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Ability to complete English language questionnaire(s) by themselves or with assistance Life expectancy >= 6 months Negative pregnancy test done =< 7 days prior to registration, for women of childbearing potential only, per clinician discretion Willingness to provide blood specimens as required by the protocol White blood cell (WBC) >= 3400 Absolute neutrophil count (ANC) >= 1500 Platelet (PLT) >= 100,000 Hemoglobin (HgB) > 10.0 Creatinine =< 1.5 x upper limit of normal (ULN) Exclusion Criteria: Pre-existing history of peripheral neuropathy > grade 1 (National Cancer Institute [NCI] CTCAE version [v] 4.0) due to any cause (e.g., chemotherapy, diabetes, alcohol, toxin, or heredity) Other medical conditions, which in the opinion of the treating physician/allied health professional would make this protocol unreasonably hazardous for the patient Any of the following: Pregnant women Nursing women Women of childbearing potential who are unwilling to employ adequate contraception Prior TAXOL and/or CBDCA chemotherapy treatment (other than the current treatment regimen) Concurrent use of any agent being used specifically to prevent or treat neuropathy, including but not limited to the following: Gabapentin Glutamine powder or glutamine tablets Vitamin B6 or E

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (glutathione, carboplatin)<br>Patients receive glutathione intravenously (IV) over 15 minutes, paclitaxel* IV over 1 or 3 hours depending on planned dose cycle length and carboplatin IV over 30 minutes. | Drug: Carboplatin<br>* Given IV, over 30 minutes per planned chemotherapy regimen<br>* Other names: Ribocarbo;Drug: Glutathione<br>* Given IV, over 15 minutes, immediately before chemotherapy administration<br>* Other names: Reduced Glutathione;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Paclitaxel<br>* Given IV, over 1 or 3 hours, per planned chemotherapy regimen<br>* Other names: Taxol Konzentrat;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|
| Placebo Comparator: Arm II (placebo, paclitaxel)<br>Patients receive placebo IV over 15 minutes, paclitaxel* IV over 1 or 3 hours depending on planned dose cycle length and carboplatin IV over 30 minutes. | Drug: Carboplatin<br>* Given IV, over 30 minutes per planned chemotherapy regimen<br>* Other names: Ribocarbo;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Paclitaxel<br>* Given IV, over 1 or 3 hours, per planned chemotherapy regimen<br>* Other names: Taxol Konzentrat;Other: Placebo<br>* Given IV<br>* Other names: sham therapy;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Paclitaxel/Carboplatin (PC) Induced Peripheral Neuropathy as Assessed by EORTC QLQ-CIPN20 (European Organization for Research and Treatment of Cancer (EORTC), Quality of Life (QLQ), Chemotherapy Induced Peripheral Neuropathy 20 (CIPN20)). | The CIPN sensory subscale will be calculated by standard scoring algorithm and converted to 0-100 scale (higher scores indicated less symptoms and better quality of life). Generalized linear models (repeated measures analysis of variance [ANOVA] if data are complete) will be used to compare the CIPN between Glutathione (GSH) and placebo arms. | Every 28 day cycle, up to 6 cycles. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrence-free Survival (for Patients Without Clinical Evidence of Disease) | A log-rank test and a Kaplan-Meier curve will be used to compare the recurrence free survival between GSH and placebo arms (for ovarian/fallopian tube/primary peritoneal patients only). | Up to 1 year | 
| Change in Patient Reported Quality of Life as Assessed by Functional Assessment of Cancer Therapy-Ovarian (FACT-O) and Patient Daily-symptom Questionnaires Over Time. | Quality of life was measured by FACT-O (on a 0 to 100 scale, higher scores represent better life quality) from baseline and at the end of TAXOL/CBDCA. The change in Quality of Life was calculated as the difference between baseline measure and end of treatment measure (with range from -100 to 100). A negative change represents a worsening in QOL from baseline to one year. Abbreviations used: Change from Baseline (chg from bsl) | Baseline to 1 year | 
| Paclitaxel Acute Pain Syndrome Incidence and Severity Between GSH and Placebo Arms | Descriptive statistics will be used to describe TAXOL/CBDCA acute pain syndrome incidence/severity between GSH and placebo arms. Pain was scored on a scale from 0-10, where 0 = 'No aches or pains' and 10 = 'Aches or pains as bad as can be.' | Up to 1 year | 
| Percentage of Patients Delaying PC Chemotherapy Secondary to PN | Patients delaying TAXOL/CBDCA secondary to peripheral neuropathy between GSH and placebo arms. | Up to 1 year | 
| Percentage of Patients Undergoing Dose Reductions Secondary to PCI PN | Proportion of patients requiring chemotherapy dose reductions secondary to TAXOL/CBDCA induced peripheral neuropathy between GSH and placebo arms. | Up to 1 year | 
| Percentage of Patients With Grade 2+ and Grade 3+ Paclitaxel/Carboplatin-induced (PCI) Peripheral Neuropathy (PN) According to the Common Terminology Criteria for Adverse Events (CTCAE) Neuropathy Scale | Proportion of grade 2+ and grade 3+ chemotherapy induced peripheral neuropathy (CIPN) at any time during or at the end of the TAXOL/CBDCA based chemotherapy between GSH and placebo arms. Neuropathy scale has grades 1 through 5 (1-mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening and Grade 5 Death related to AE). | Up to 1 year | 
| Times to Onset of CTCAE Grade 2+ PN | Compare time to grade 2+ CIPN between GSH and placebo arms. | Up to 1 year | 
| Times to Onset of CTCAE Grade 3+ PN | Time to grade 3+ CIPN between GSH and placebo arms. | Up to 5 years from registration |