Duloxetine to Prevent Oxaliplatin-Induced Peripheral Neuropathy
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.
Inclusion Criteria
- Stage II-III colorectal cancer patients scheduled to receive oxaliplatin via one of the following treatment regimens: * FOLFOX (3-month): 510 mg/m^2 (total planned maximum cumulative dose) over 12 weeks (6 cycles), in which patients are scheduled to receive oxaliplatin 85 mg/m^2 every 2 week * FOLFOX (6-month): 1020 mg/m^2 (total planned maximum cumulative dose) over 24 weeks (12 cycles) in which patients are scheduled to receive oxaliplatin 85 mg/m^2 every 2 weeks * CAPOX (3-month): 520 mg/m^2 (total planned maximum cumulative dose) over 12 weeks (4 cycles) in which patients are scheduled to receive oxaliplatin 130 mg/m^2 every 3 weeks
- No prior neurotoxic chemotherapy
- No pre-existing clinical or pre-clinical peripheral neuropathy from any cause
- Patients with the following comorbid conditions are not eligible: * History of seizure disorder * Narrow-angle glaucoma * History of suicidal thoughts * Symptoms of or a history of schizophrenia, bipolar disease, and/or a major depression * A serious eating disorder such as bulimia or anorexia * Known diagnosis of ethanol (ETOH) addiction/dependence within the past 10 years
- Concomitant medications: * No concomitant use of other adjuvant pharmacologic interventions (e.g., gabapentin, pregabalin, venlafaxine) with known or hypothesized efficacy for peripheral neuropathy. Must be discontinued at least 7 days prior to start of protocol treatment * No concomitant use of non-pharmacologic interventions (known or hypothesized) for CIPN (e.g., cryotherapy, acupuncture) * No anticipated or concurrent use of warfarin or heparin products while patients are receiving study drug. No anticipated or concurrent use of any antidepressant or serotonin-altering agent or other potent CYP2D6 inhibitors (e.g. paroxetine, fluoxetine, quinidine) known to interact with duloxetine, due to concern regarding cumulative toxicity and potential drug interactions. Use of an monoamine oxidase inhibitor (MAOI) or other antidepressants must be discontinued at least 14 days prior to start of protocol treatment * Chronic concomitant treatment with drugs that are extensively metabolized by CYP2D6 and that have a narrow therapeutic index, including certain antidepressants, phenothiazines, and Type 1C antiarrhythmics should be approached with caution ** Concomitant administration of duloxetine and thioridazine should be avoided * Chronic concomitant treatment with strong CYP1A2 inhibitors should be avoided during this trial due to concern regarding cumulative toxicity and potential drug interactions
- Not pregnant and not nursing, because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown. Therefore, for women of childbearing potential, a negative pregnancy test done =< 7 days prior to registration is required
- Age >= 25 years. Duloxetine black box warnings indicate an increased risk of suicide in patients < 25 years of age
- Eastern Cooperative Oncology Group (ECOG) performance status 0-2
- In order to complete the mandatory patient-completed measure, patients must be able to speak and read English
- Calculated creatinine clearance > 30 mL/min
- Aspartate aminotransferases (AST)/serum glutamic-oxaloacetic transaminase (SGOT) =< 3 x upper limit of normal (ULN)
- ePRO-E ELIGIBILITY CRITERIA * Registration to A221805-SI1 (OPEN Step 2) is closed to accrual as of 09/15/2022
- Must be enrolled in A221805
- Participant must own a smartphone or tablet computer, and have access to Wi-Fi
Additional locations may be listed on ClinicalTrials.gov for NCT04137107.
See trial information on ClinicalTrials.gov for a list of participating sites.
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.
Trial PhasePhase II/III
Trial Typesupportive care
Lead OrganizationAlliance for Clinical Trials in Oncology
Principal InvestigatorEllen M. Lavoie Smith
- Primary IDA221805
- Secondary IDsNCI-2019-04727
- ClinicalTrials.gov IDNCT04137107