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

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.

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)