Duloxetine to Prevent Oxaliplatin-Induced Peripheral Neuropathy in Patients With Stage II-III Colorectal Cancer

Study Overview
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Brief Summary
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This phase II/III trial studies the best dose of duloxetine and how well it works in preventing pain, tingling, and numbness (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.

Detailed Description
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The primary and secondary objectives of the study: 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). (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. (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) 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. (Phase II) II. To compare the serially measured OIPN total sensory neuropathy scores calculated from the six individual Quality of Life Questionnaire - Chemotherapy-Induced Peripheral Neuropathy 20 (QLQ-CIPN20) questions that quantify numbness, tingling, and pain in the fingers (or hands) and toes (or feet), measured on day 1 of each cycle of oxaliplatin treatment and at 1 month post-oxaliplatin treatment between the most promising dosage of duloxetine identified in the Phase II component and placebo. (Phase III) III. To compare the serially measured Brief Pain Inventory Short Form (BPI-SF) patient-reported on the average pain scores, measured on day 1 of each cycle of oxaliplatin treatment and at 1 month post-oxaliplatin treatment between the most promising dosage of duloxetine identified in the Phase II component and placebo. IV. 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. (Phase III) OUTLINE: PHASE II: Patients are randomized to 1 of 3 arms. ARM I: Patients in Phase II receive duloxetine hydrochloride 30 mg (1 duloxetine capsule) orally (PO) once daily (QD) during week 1, duloxetine hydrochloride 30 mg (1 duloxetine capsule) PO QD and placebo (1 placebo capsule) PO QD during weeks 2-16, followed by duloxetine hydrochloride 30 mg (1 duloxetine capsule) PO QD during week 17 in the absence of unacceptable toxicity. ARM II: Patients in Phase II receive duloxetine hydrochloride 30 mg (1 duloxetine capsule) orally (PO) once daily (QD) during week 1, duloxetine hydrochloride 60 mg (2 duloxetine capsules) PO QD during weeks 2-16, followed by duloxetine hydrochloride 30 mg (1 duloxetine capsule) PO QD during week 17 in the absence of unacceptable toxicity. ARM III: Patients in Phase II receive placebo (1 placebo capsule) orally (PO) once daily (QD) during week 1, placebo (2 placebo capsules) PO QD weeks 2-16, followed by placebo (1 placebo capsule) PO QD during week 17 in the absence of unacceptable toxicity. PHASE III: Patients are randomized to 1 of 2 arms. ARM I: Patients in Phase III receive most promising dose of duloxetine hydrochloride from Phase II PO QD in the absence of unacceptable toxicity. ARM II: Patients in Phase III receive placebo PO QD in the absence of unacceptable toxicity. NOTE: Patients in all arms receive standard of care 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.

Official Title
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Duloxetine to Prevent Oxaliplatin-Induced Chemotherapy-Induced Peripheral Neuropathy: A Randomized, Double-Blind, Placebo-Controlled Phase II to Phase III Study

Conditions
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Stage II Colorectal Cancer AJCC v8, Stage III Colorectal Cancer AJCC v8

Intervention / Treatment
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* Drug: Oxaliplatin
* Drug: Duloxetine Hydrochloride
* Drug: Duloxetine
* Other: Quality-of-Life Assessment
* Other: Questionnaire Administration
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Stage II-III colorectal cancer patients scheduled to receive oxaliplatin 510 mg/m^2 (cumulative dose) over 12 weeks as a component of adjuvant leucovorin calcium (calcium folinate), 5-fluorouracil and oxaliplatin (FOLFOX) treatment, in which patients are scheduled to receive oxaliplatin 85 mg/m^2 every 2 weeks for 12 weeks (i.e., 6 cycles), or adjuvant capecitabine and oxaliplatin (CAPOX) treatment, in which patients are scheduled to receive oxaliplatin 135 mg/m^2 every 3 weeks for 12 weeks (i.e., 4 cycles) No prior neurotoxic chemotherapy No pre-existing clinical or pre-clinical peripheral neuropathy from any cause. No history of seizure disorder, No history of narrow-angle glaucoma. No symptoms of or history of schizophrenia, bipolar disease, suicidal thoughts and/or a major depression. No serious eating disorder such as bulimia or anorexia. No 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 anticipated or concurrent use of any antidepressant or serotonin-altering agent known to interact with duloxetine, due to concern regarding cumulative toxicity and potential drug interactions. Use of a monoamine oxidase inhibitor (MAOI) or other antidepressants must be discontinued at least 14 days prior to start of protocol treatment. No concomitant treatment with strong CYP1A2 and CYP2D6 inhibitors. 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. No use of warfarin or heparin products. 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 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)

Ages Eligible for Study
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Minimum Age: 25 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: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase II, Arm I (duloxetine hydrochloride, placebo)<br>Patients in Phase II receive duloxetine hydrochloride 30 mg (1 duloxetine capsule) orally (PO) once daily (QD) during week 1, duloxetine hydrochloride 30 mg (1 duloxetine capsule) PO QD and placebo (1 placebo capsule) PO QD during weeks 2-16, followed by duloxetine hydrochloride 30 mg (1 duloxetine capsule) PO QD during week 17 in the absence of unacceptable toxicity. | Drug: Oxaliplatin<br>* Given standard of care oxaliplatin<br>Drug: Duloxetine Hydrochloride<br>* Given PO<br>Drug: Duloxetine<br>* Given PO<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>Other: Questionnaire Administration<br>* Ancillary studies<br>Other: Placebo<br>* Given PO<br>|
| Experimental: Phase II, Arm II (duloxetine hydrochloride)<br>Patients in Phase II receive duloxetine hydrochloride 30 mg (1 duloxetine capsule) orally (PO) once daily (QD) during week 1, duloxetine hydrochloride 60 mg (2 duloxetine capsules) PO QD during weeks 2-16, followed by duloxetine hydrochloride 30 mg (1 duloxetine capsule) PO QD during week 17 in the absence of unacceptable toxicity. | Drug: Oxaliplatin<br>* Given standard of care oxaliplatin<br>Drug: Duloxetine Hydrochloride<br>* Given PO<br>Drug: Duloxetine<br>* Given PO<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>Other: Questionnaire Administration<br>* Ancillary studies<br>|
| Placebo Comparator: Phase II, Arm III (placebo)<br>Patients in Phase II receive placebo (1 placebo capsule) orally (PO) once daily (QD) during week 1, placebo (2 placebo capsules) PO QD weeks 2-16, followed by placebo (1 placebo capsule) PO QD during week 17 in the absence of unacceptable toxicity. | Drug: Oxaliplatin<br>* Given standard of care oxaliplatin<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>Other: Questionnaire Administration<br>* Ancillary studies<br>Other: Placebo<br>* Given PO<br>|
| Experimental: Phase III, Arm I (duloxetine hydrochloride)<br>Patients in Phase III receive most promising dose of duloxetine hydrochloride from Phase II PO QD in the absence of unacceptable toxicity. | Drug: Oxaliplatin<br>* Given standard of care oxaliplatin<br>Drug: Duloxetine Hydrochloride<br>* Given PO<br>Drug: Duloxetine<br>* Given PO<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>Other: Questionnaire Administration<br>* Ancillary studies<br>|
| Placebo Comparator: Phase III, Arm II (placebo)<br>Patients in Phase III receive placebo PO QD in the absence of unacceptable toxicity. | Drug: Oxaliplatin<br>* Given standard of care oxaliplatin<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>Other: Questionnaire Administration<br>* Ancillary studies<br>Other: Placebo<br>* Given PO<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prevention of sensory oxaliplatin-induced peripheral neuropathy (OIPN) response (Phase II) | Will be measured using 6 individual Quality of Life Questionnaire - Chemotherapy-Induced Peripheral Neuropathy 20 (QLQ-CIPN20) questions that quantify numbness, tingling, and pain in the fingers (or hands) and toes (or feet). For each of the 6 individual questions, patients are asked to select 1 of 4 choices regarding how each of the sensory symptoms had affected them during the preceding week: 1 = Not at all, 2 = A little, 3 = Quite a bit, and 4 = Very much. Response will be defined as a patient reporting a highest score of ≤ 2 at any time during oxaliplatin exposure, including 1 month post-oxaliplatin treatment without discontinuing the study due to sensory oxaliplatin-induced peripheral neuropathy. The proportion of responders within each arm will be estimated by the number of responders divided by the total number of evaluable patients. Two-sided 90% exact confidence intervals for the true response proportion will be calculated according to the approach of Clopper and Pearson. | Up to 1 month post-oxaliplatin treatment | 
| Prevention of sensory oxaliplatin-induced peripheral neuropathy (OIPN) response (Phase III) | Will be measured using 6 individual Quality of Life Questionnaire - Chemotherapy-Induced Peripheral Neuropathy 20 (QLQ-CIPN20) questions that quantify numbness, tingling, and pain in the distal extremities. For each of the 6 questions, patients are asked to select 1 of 4 choices regarding how each of the sensory symptoms had affected them during the preceding week: 1=Not at all, 2=A little, 3=Quite a bit, and 4=Very much. Response will be defined as a patient reporting a highest score of ≤ 2 at any time during oxaliplatin exposure, including 1 month post-oxaliplatin treatment without discontinuing the study due to sensory OIPN. The analysis population is defined as all randomized patients who received at least 1 dose of oxaliplatin and have completed the 6 QLQCIPN20 sensory symptom items on at least 1 occasion during oxaliplatin treatment, including 1 month post-oxaliplatin treatment. The Fisher exact test will be used for a between-arm comparison of the proportion of responders. | Up to 1 month post-oxaliplatin treatment | 
| Chronic neuropathic pain response (Phase III) | Response will be defined as a 7-day average of chronic neuropathic pain (on the average) ≤ 3 on a 0 (no pain) to 10 (pain as bad as you can imagine) scale 1 month after oxaliplatin treatment, which is obtained from the 7-day chronic neuropathy pain diary. The analysis population is defined as all randomized patients who received at least 1 dose of oxaliplatin and have completed the 7-day chronic neuropathy pain diary on at least 3 of the 7 days 1 month after the last oxaliplatin dose. The Fisher exact test will be used for a between-arm comparison of the proportion of responders. | Up to 1 month after oxaliplatin treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events, including duloxetine side effects of nausea, dry mouth, dizziness, somnolence, fatigue, and insomnia (Phase II) | The constellation of adverse events as scored using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 will be summarized within arms by reporting the number and percentages of patients. The proportion of each of nausea, dry mouth, dizziness, somnolence, fatigue, and insomnia using NCI CTCAE v 5.0 will be estimated within arms with the exact 90% confidence interval. | Up to 1 month post-oxaliplatin treatment | 
| Serially measured total sensory neuropathy scores (Phase III) | The sequence of the total sensory neuropathy scores for each patient will be measured from the Quality of Life Questionnaire - Chemotherapy-Induced Peripheral Neuropathy 20 (QLQ-CIPN20) questionnaire, measured on day 1 of each cycle of oxaliplatin treatment and at 1 month post-oxaliplatin treatment. The corresponding area under the curve will be computed for each arm based on estimated parameters from a repeated-measures (means) mixed model and compared. The analysis population is defined as all randomized patients who received at least 1 dose of oxaliplatin and have a total sensory neuropathy score on at least 1 occasion during oxaliplatin treatment, including 1 month post-oxaliplatin treatment. | Up to 1 month post-oxaliplatin treatment | 
| Serially measured patient reported on the average pain scores (Phase III) | For each patient, the total sensory neuropathy score is calculated by summing the 6 individual Quality of Life Questionnaire - Chemotherapy-Induced Peripheral Neuropathy 20 (QLQ-CIPN20) questions that quantify numbness, tingling, and pain in the fingers (or hands) and toes (or feet) and ranges from 1 to 24, where higher numbers indicate more severe symptoms. The sequence of the total sensory neuropathy scores for each patient will be measured on day 1 of each cycle of oxaliplatin treatment and at 1 month post-oxalipatin treatment. The corresponding area under the curve will be computed for each arm based on estimated parameters from a repeated-measures (means) mixed model and compared. The analysis population is defined as all randomized patients who received at least 1 dose of oxaliplatin and have a total sensory neuropathy score on at least 1 occasion during oxaliplatin treatment, including 1 month post-oxaliplatin treatment. | Up to 1 month post-oxaliplatin treatment | 
| Incidence of adverse events, including duloxetine side effects of nausea, dry mouth, dizziness, somnolence, fatigue, and insomnia (Phase III) | The constellation of adverse events as scored using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 will be summarized within arms by reporting the number and percentages of patients. The proportion of each of nausea, dry mouth, dizziness, somnolence, fatigue, and insomnia using NCI CTCAE v5.0 will be estimated within arms with the exact 95% confidence interval. | Up to 1 month post-oxaliplatin treatment |