Evaluate The Efficacy and Safety Of Pregabalin In Prevention, Reduction of Oxaliplatin-Induced Painful Neuropathy

1. OBJECTIVES

1.1. Primary Objectives

The primary objective of this study is to evaluate the efficacy of co-administration of Pregabalin during oxaliplatin infusion in reducing the appearance of both acute and late onset oxaliplatin-induced painful neuropathy in patients with colorectal cancer.

1.2. Secondary Objectives

The secondary objectives of this study are as follows:

• To compare the pain intensity and interference between the two treatment arms
• To compare the safety profile between the two treatment arms
• To compare quality of life between the two treatment arms
• To compare the percentage of patients with neuropathy between the two treatment groups
• To compare the intensity of neuropathy related to oxaliplatin between the two arms
• To compare the small fiber function and positive sensory signs before and after treatment with Pregabalin
• To compare mood (depression and anxiety) before and after treatment with Pregabalin in each treatment arm
• To assess the association between cumulative oxaliplatin dose and time for painful neuropathy and peripheral sensory neuropathy diagnosis, pain intensity, pain interference and small fiber function.

TREATMENT PLAN

2.1 Pregabalin Administration

Treatment will be administered on an outpatient basis. Reported adverse events and potential risks are described in Section 7. Appropriate dose modifications for Pregabalin are described in Section 6. No investigational or commercial agents or therapies other than those described below may be administered with the intent to treat the patient's oxaliplatin-induced painful neuropathy.

Patients will receive either Pregabalin or placebo three days before and three days following the OX infusion (week 1, 3, and 5 from each of the three cycles, in a total of nine sessions).

The total daily dose of Pregabalin will be flexible in the first dose, and then, a fixed dose will be set for each individual. Before the first Ox dose, patients will start on 75mg bid and will be followed by telephone contact by a research nurse who will instruct them to optimize the dose of Pregabalin every two days according to the magnitude and profile of side effects.

The minimum daily dose to allow for entry in the study is 150mg/day upon the first Ox infusion. Such a "guided" dose escalation will only be performed before the first Ox infusion and will last for four days. Thereafter, the maximum tolerated dose used before the first Ox infusion will be used during the three following days and during the rest of the study. The same protocol will be performed in the placebo group.

After signing the informed consent and agreeing to participate in the protocol, patients will undergo the "guided" Pregabalin dose escalation for four days. Then, they will receive Pregabalin for the three days following the first Ox infusion. Thereafter, they will receive this same Pregabalin dosage for six days during the eight next Ox infusions sessions ie., starting three days before and ending on the third day after each Ox infusion session (from D-3 to D+3)

2.2 Duration of Therapy

In the absence of treatment delays due to adverse event(s), treatment may continue for 3 cycles of FLOX (totalizing nine oxaliplatin infusions) or until one of the following criteria applies:

Intercurrent illness that prevents further administration of treatment,

Unacceptable adverse event(s),

Patient decides to withdraw from the study, or

General or specific changes in the patient's condition render the patient unacceptable for further treatment in the judgment of the investigator.

2.3 FLOX administration

Treatment with fluorouracil plus leucovorin and oxaliplatin (FLOX) 28, 29 will be administered on an outpatient basis.

Patients will receive intravenous (IV) treatment weekly for 6 weeks of each 8-week cycle for three cycles. Chemotherapy with FLOX is to be given for 3 cycles in both treatment arms.

FLOX regimen includes:

• Oxaliplatin will be administered at a dose of 85mg/m2 IV on weeks 1, 3, and 5 of each 8-week cycle for three cycles.
• 5-Fluorouracil (5-FU) will be administered at a dose of 500mg/m2 IV bolus weekly for 6 weeks (on weeks 1, 2, 3, 4, 5, and 6).
• Leucovorin 20 mg/m2 IV will be administered on weeks 1, 2, 3, 4, 5, and 6.

Drugs to be administered before chemotherapy:

Dexamethasone 20 mg IV and Ondansetron 8mg IV will be administered before chemotherapy administration. Dexamethasone will be administered on weeks 1, 3, and 5. Ondansetron will be administered on weeks 1, 2, 3, 4, 5, and 6.

Drugs to be administered after chemotherapy:

Patients will also receive dexamethasone 4 mg P.O. BID for three days and ondansetron 8 mg P.O. each 8 hours (if necessary) after each dose of the Oxaliplatin (on weeks 1, 3, and 5).

2.4 Duration of Follow-up

Patients will be followed for 6 months after removal from study or until death, whichever occurs first. Patients removed from study for unacceptable adverse events will be followed until resolution or stabilization of the adverse event.

2.5 Criteria for study withdraw

After fulfilling all the inclusion criteria and not presenting any exclusion criteria, and having started on the protocol, patients will be removed from it if at least one of the conditions bellow is met:

1. Voluntary consent withdraw by the patients, due to any reason;
2. The patient is considered non compliant to the protocol (ie. more than three absences in regular protocol visits or failure to take Pregabalin for two treatment session with oxaliplatin.

In all cases of removal, the patient data and reason for removal will be recorded.

• Pain
• Neuropathic Pain
• Polyneuropathy

• Drug: Pregabalin, Oxaliplatin
  Oxaliplatin will be infused according to the FLOX treatment strategy, as a regular six-month-long adjuvant treatment to colorectal cancer. Pregabalin will be administered P.O. three days before and three days after each of the nine Ox infusions. The dose will be titrated during the first Ox infusion to the highest level tolerated by the patient. The dose used in this first session will be used in the eight following sessions.
• Drug: Placebo , Oxaliplatin
  Oxaliplatin will be infused according to the FLOX treatment strategy, as a regular six-month-long adjuvant treatment to colorectal cancer. Placebo will be administered P.O. three days before and three days after each of the nine Ox infusions. The dose will be titrated during the first Ox infusion to the highest level tolerated by the patient. The dose used in this first session will be used in the eight following sessions.

• Active Comparator: Pregabalin
  Intervention: Drug: Pregabalin, Oxaliplatin
• Placebo Comparator: Placebo
  Intervention: Drug: Placebo , Oxaliplatin

Inclusion Criteria:

• Patient must have histologically or cytologically confirmed colorectal cancer
• Indication of adjuvant chemotherapy regime including oxaliplatin
• Age ? 18 years
• Karnofsky performance status (KPS) ? 50
• Normal neurological examination
• Be able to understand study protocol
• Ability to understand and the willingness to sign a written informed consent document.
• The effects of Pregabalin on the developing human fetus at the recommended therapeutic dose are unknown. For this reason, women of child-bearing and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.

Exclusion Criteria:

• History of exposure to neurotoxic chemotherapy
• Know Concomitant clinical conditions that impair peripheral nerve function,
• Symptoms or signs suggestive of peripheral neuropathy or neuropathic pain.
• Current peripheral neuropathy of NCI-CTCAE, version 3.0 Grade ? 1.
• Inadequate organ function, evidenced by the following laboratory results within 1 week prior to randomization:
• Serum creatinine > 2.0 mg/dL
• Positive blood beta HCG test for women, or women breast feeding
• Assessed by the investigator to be unable or unwilling to comply with the requirements of the protocol
• History of receiving any investigational treatment within 28 days of randomization
• Patients may not be receiving any other investigational agents.
• Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to Pregabalin or known hypersensitivity to the study drug.
• Uncontrolled concurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements