Summary

This phase II/III trial studies the best dose of duloxetine and how well it works in preventing pain, tingling, numbness, and muscle weakness (peripheral neuropathy) caused by treatment with oxaliplatin in patients with stage II-III colorectal cancer. Duloxetine increases the amount of certain chemicals in the brain that help relieve depression and pain. Giving duloxetine in patients undergoing treatment with oxaliplatin for colorectal cancer may help prevent peripheral neuropathy.

Objectives

PRIMARY OBJECTIVES:
I. To determine the dosage of duloxetine hydrochloride (duloxetine) (30 mg or 60 mg daily) that appears most promising in preventing oxaliplatin-induced peripheral neuropathy (OIPN), as assessed on day 1 of each oxaliplatin treatment cycle as well as 2 weeks (14 days) after day 1/cycle 4 (capecitabine and oxaliplatin [CAPOX]) or day 1/cycle 6 (5-fluorouracil, oxaliplatin, and leucovorin calcium [FOLFOX]), regardless of the oxaliplatin treatment regimen received (3- or 6- month FOLFOX or 3-month CAPOX). (Phase II)
II. To demonstrate that the most promising dosage of duloxetine identified in the Phase II component is more effective than placebo at preventing OIPN sensory symptoms, as assessed on day 1 of each oxaliplatin treatment cycle as well as 2 weeks (14 days) after day 1/cycle 4 (CAPOX) or day 1/cycle 6 (FOLFOX), regardless of the oxaliplatin treatment regimen received (3-or 6-month FOLFOX or 3-month CAPOX). (Phase III)
III. To demonstrate that the most promising dosage of duloxetine identified in the Phase II component is more effective than placebo at preventing oxaliplatin-induced chronic neuropathic pain. (Phase III)
IV. Compare electronic pateint-reported outcome (ePRO) uptake in patients who do and do not have access to ePRO-E. (Correlative study)

SECONDARY OBJECTIVES:
I. To characterize toxicity in each arm, including duloxetine side effects of nausea, dry mouth, dizziness, somnolence, fatigue, and insomnia using Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0 as well as characterizing the toxicity profile within the two distinct patient cohorts: those receiving 3- or 6-month oxaliplatin regimens. (Phase II)
II. To compare the serially measured OIPN total sensory neuropathy scores calculated from the six individual Quality of Life Questionnaire (QLQ)-Chemotherapy-Induced Peripheral Neuropathy (CIPN) 20 questions that quantify numbness, tingling, and pain in the fingers (or hands) and toes (or feet), assessed on day 1 of each oxaliplatin treatment cycle as well as 2 weeks (14 days) after day 1/cycle 4 (CAPOX) or day 1/cycle 6 (FOLFOX) regardless of oxaliplatin treatment regimen received (3- or 6- month FOLFOX or 3-month CAPOX) between the most promising dosage of duloxetine identified in the Phase II component and placebo. (Phase III)
III. To characterize toxicity in each arm, including duloxetine side effects of nausea, dry mouth, dizziness, somnolence, fatigue, and insomnia using the CTCAE v 5.0 as well as characterizing the toxicity profile within the two distinct patient cohorts: those receiving 3- or 6-month oxaliplatin regimens. (Phase III)
IV. Compare ePRO data submission patterns in patients who do and do not have access to ePRO-E. (Correlative study)

EXPLORATORY OBJECTIVES:
I. To explore differences in the response profile by arm of the patient-reported outcomes obtained from the QLQ-CIPN20, Brief Pain Inventory - short form (BPI-SF), including the BPI-SF interference subscale, and the 7-day average of chronic (worse and average) neuropathic pain obtained from the 7-day chronic neuropathy pain diary, measured through 18 months post-oxaliplatin treatment, in two separate patient cohorts: those receiving 3- and 6-month oxaliplatin regimens, separately. (Phase III)
II. To explore between-arm differences in the time to initial onset of sensory OIPN (numbness [N], tingling [T], and pain) in two separate patient cohorts: those receiving 3- and 6-month oxaliplatin regimens, separately. (Phase III)
III. To explore between-arm differences in the pattern of acute, more transient neuropathy symptoms reported with oxaliplatin therapy, in two separate patient cohorts: those receiving 3- and 6-month oxaliplatin regimens, separately. (Phase III)
IV. To explore between-arm differences in the percentages of patients receiving full planned oxaliplatin doses per cycle, in two separate patient cohorts: those receiving 3- and 6-month oxaliplatin regimens, separately. (Phase III)
V. To characterize the frequency and severity of patient-reported pain, numbness, and tingling as measured by the Patient Reported Outcomes (PRO)-CTCAE, measured through 18 months post oxaliplatin treatment, in patients receiving 3- and 6-month oxaliplatin regimens, separately. (Phase III)
VI. To document the reasons why a patient chose not to use the electronic patient-reported outcome (ePRO) tool to complete the study questionnaires. (Phase III)
VII. Using a quantitative and qualitative data collection methods, describe the demographic and clinical characteristics, and technology attitudes and experiences of all A221805 participants (control and intervention group patients) who do and do not elect to use ePRO as their preferred method for submitting PRO study questionnaires. (Correlative study)

OUTLINE: This is a phase II study followed by a phase III study.

PHASE II: Patients are randomized to 1 of 3 arms.

ARM I: Patients receive duloxetine hydrochloride orally (PO) once daily (QD) during week 1, duloxetine hydrochloride PO QD and placebo PO QD during weeks 2-16, followed by duloxetine hydrochloride PO QD during week 17 in the absence of unacceptable toxicity. Patients also receive standard of care (SOC) oxaliplatin during weeks 1-12.

ARM II: Patients receive duloxetine hydrochloride PO QD during weeks 1-17 in the absence of unacceptable toxicity. Patients also receive SOC oxaliplatin during weeks 1-12.

ARM III: Patients receive placebo PO QD during weeks 1-17 in the absence of unacceptable toxicity. Patients also receive SOC oxaliplatin during weeks 1-12.

PHASE III: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive most promising dose of duloxetine hydrochloride from Phase II PO QD during weeks 1-16 in the absence of unacceptable toxicity. Patients also receive SOC oxaliplatin during weeks 1-12.

ARM II: Patients receive placebo PO QD during weeks 1-16 in the absence of unacceptable toxicity. Patients also receive SOC oxaliplatin during weeks 1-12.

After completion of study, patients are followed up at 30 days and at 3, 6, 12, and 18 months after last oxaliplatin treatment.