Venlafaxine in Preventing Chronic Oxaliplatin-Induced Neuropathy In Patients Receiving Combination Chemotherapy

Study Overview
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Brief Summary
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You are being asked to take part in this research study because you are going to be treated with oxaliplatin chemotherapy as part of your standard care. Oxaliplatin commonly causes neuropathy (numbing, tingling and/or pain).The purpose of this study is to compare the effects, good and/or bad, of venlafaxine with a placebo (an inactive agent) on oxaliplatin-induced neuropathy (numbing, tingling and/or pain)

Detailed Description
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PRIMARY OBJECTIVES: I. To explore whether venlafaxine can prevent or ameliorate chronic, cumulative neurotoxicity associated with oxaliplatin in cancer patients receiving oxaliplatin, fluorouracil, leucovorin calcium (FOLFOX). SECONDARY OBJECTIVES: I. To explore whether venlafaxine can ameliorate acute neuropathy associated with oxaliplatin. TERTIARY OBJECTIVES: I. To explore whether venlafaxine can increase the cumulative oxaliplatin doses that can be delivered without dose-limiting chronic neurotoxicity. II. To explore whether venlafaxine causes adverse events in this setting. III. To explore whether the neuropathy data provided by the Rydel-Seiffer graduated tuning fork is consistent with patient-reported outcome (PRO) measures of chemotherapy-induced peripheral neuropathy (CIPN) and whether this tool might cause different results in patients receiving venlafaxine versus placebo. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive venlafaxine orally (PO) twice daily (BID) beginning on day 1 of and continuing through completion of FOLFOX. ARM II: Patients receive placebo PO BID beginning on day 1 of and continuing through completion of FOLFOX. After completion of study treatment, patients are followed up at 1, 3, 6, 12, and 18 months.

Official Title
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A Pilot Randomized, Placebo-controlled, Double Blind Study of Venlafaxine to Prevent Oxaliplatin-Induced Neuropathy

Conditions
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Peripheral Neuropathy

Intervention / Treatment
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* Drug: venlafaxine
* Drug: placebo
* Other: questionnaire administration
* Other: quality-of-life assessment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Scheduled to receive FOLFOX chemotherapy with individual oxaliplatin doses of 85 mg/m^2 per cycle given in 2 week cycles (e.g. modified [m] FOLFOX6 or FOLFOX4) Adequate complete blood count (CBC) and creatinine values (per attending physician) obtained =< 28 days prior to registration Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0, 1 or 2 Negative pregnancy test done =< 7 days prior to registration, for women of childbearing potential Ability to complete questionnaire(s) by themselves or with assistance Life expectancy >= 4 months Strong inhibitors of CYP3A4: > 5-fold increase in the plasma area under the curve (AUC) values or more than 80 % decrease in clearance Indinavir (Crixivan®) Nelfinavir (Viracept®) Atazanavir (Reyataz®) Ritonavir (Norvir®) Clarithromycin (Biaxin®, Biaxin XL®) Itraconazole (Sporanox®) Ketoconazole (Nizoral®) Nefazodone (Serzone®) Saquinavir (Fortovase®, Invirase®) Telithromycin (Ketek®) Inducers of CYP3A4 Efavirenz (Sustiva®) Nevirapine (Viramune®) Carbamazepine (Carbatrol®, Epitol®, Equetro™, Tegretol®, Tegretol-XR®) Modafinil (Provigil®) Phenobarbital (Luminal®) Phenytoin (Dilantin®, Phenytek®) Pioglitazone (Actos®) Rifabutin (Mycobutin®) Rifampin (Rifadin®) St. John's wort Exclusion Criteria: Any of the following: Pregnant women Nursing women History of an allergic reaction to, or intolerance of, venlafaxine Treatment =< 7 days with other antidepressants, anticonvulsants, monoamine oxidase (MAO) inhibitors, or other neuropathic pain medication agents such as carbamazepine, phenytoin, valproic acid, gabapentin, lamotrigine, topical lidocaine patch or gel, capsaicin cream, or amifostine; in addition, they may not be taking other agents for the treatment of neuropathy, nor other known moderate or strong CYP 2D6 (which consist of Cinacalcet [Sensipar™], quinidine, and Terbinafine [Lamisil®, Lamisil AT®]), nor the strong inducer of CYP 2D6 terbinafine (Lamisil®, Lamisil AT®), nor the following drugs that substantially effect CYP 3A4 Moderate inhibitors of CYP3A4: > 2-fold increase in the plasma AUC values or 50-80% decrease in clearance Aprepitant (Emend®) Erythromycin (Erythrocin®, E.E.S. ®, Ery-Tab®, Eryc®, EryPed®, PCE® Fluconazole (Diflucan®) Grapefruit juice Verapamil (Calan®, Calan SR®, Covera-HS®, Isoptin SR®, Verelan®, Verelan PM®) Diltiazem (Cardizem®, Cardizem CD®, Cardizem LA®, Cardizem SR®, Cartia XT™, Dilacor XR®, Diltia XT®, Taztia XT™, Tiazac®) Other medical conditions which, in the opinion of the treating physician/allied health professional, would make this protocol unreasonably hazardous for the patient Prior neurotoxic chemotherapy Concurrent radiotherapy Current (within the last month) pre-existing peripheral neuropathy of any grade Uncontrolled hypertension (defined as 3 consecutive readings over the past year of over 160 systolic, and over 100 diastolic)

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 (management of therapy complications)<br>Patients receive venlafaxine PO BID beginning on day 1 of and continuing through completion of FOLFOX. | Drug: venlafaxine<br>* Given PO<br>* Other names: VNF;Other: questionnaire administration<br>* Ancillary studies<br>Other: quality-of-life assessment<br>* Ancillary studies<br>* Other names: quality of life assessment;|
| Placebo Comparator: Arm II (placebo)<br>Patients receive placebo PO BID beginning on day 1 of and continuing through completion of FOLFOX. | Drug: placebo<br>* Given PO<br>* Other names: PLCB;Other: questionnaire administration<br>* Ancillary studies<br>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 |
| --- | --- | --- |
| Cycle 1 Sensory Neuropathy Score (Items 31-36, 39, 40 and 48) of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-CIPN20 | The EORTC QLQ-CIPN20 sensory neuropathy score will be calculated using the standard algorithm of EORTC QLQ-CIPN20 and transformed into a 0-100 point scale, where high scores meant less symptom burden. The changes of sensory neuropathy from baseline will be derived by subtracting the baseline score from the sensory neuropathy scores at each cycle of evaluation. | Up to 2 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cycle 1 Acute Neuropathy as Measured by EORTC QLQ CIPN20 Motor Subscale (Items 37, 38, 41-45 and 49), and Autonomic Scale (Items 46, 47, 50) | The EORTC QLQ-CIPN20 motor and autonomic neuropathy scores will be calculated using the standard algorithm of EORTC QLQ-CIPN20 and transformed into a 0-100 point scale, where high scores meant less symptom burden. The changes of sensory neuropathy from baseline will be derived by subtracting the baseline score from the sensory neuropathy scores at each cycle of evaluation. | Up to 2 weeks |