Nilotinib in Preventing Paclitaxel-Induced Peripheral Neuropathy in Patients With Stage I-III Breast Cancer

Study Overview
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Brief Summary
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This phase Ib/II trial studies the side effects and best dose of nilotinib in preventing paclitaxel-induced peripheral neuropathy in stage I-III breast cancer patients who are receiving paclitaxel therapy. Chemotherapy is the usual or ?standard? treatment for breast cancer. It kills cancer cells and lowers the chance that the cancer will come back. Sometimes, this treatment can cause numbness and tingling, especially in the hands and feet. This is called chemotherapy-induced peripheral neuropathy. This study aims to test the safety and effectiveness, both good and bad, of taking nilotinib in preventing chemotherapy-induced peripheral neuropathy.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the recommended phase 2 dose (RP2D) of nilotinib hydrochloride monohydrate (nilotinib) in combination with paclitaxel. (Phase Ib) II. To determine the toxicity profile (based on Common Terminology Criteria for Adverse Events [CTCAE] version [v.] 5.0) of nilotinib in combination with paclitaxel. (Phase Ib) III. To assess the efficacy of nilotinib versus (vs.) placebo in preventing paclitaxel-induced neuropathy when administered in combination with paclitaxel, as measured by patient reported outcomes using Chemotherapy-Induced Peripheral Neuropathy (CIPN)-20 and Brief Pain Inventory (BPI)-20. (Phase II) SECONDARY OBJECTIVES: I. To determine the effect of paclitaxel on pharmacokinetics (PK) of nilotinib in the study population. (Phase Ib) II. To determine the effect of nilotinib on PK of paclitaxel in the study population. (Phase Ib) III. To evaluate the effect of paclitaxel on PK of nilotinib in the study population. (Phase II) OUTLINE: This is a phase Ib, dose-escalation study of nilotinib hydrochloride monohydrate followed by phase a II study. PHASE Ib: Paclitaxel will be given weekly on days 1, 8, 15, of every 21 days, at a starting dose of 80mg/m2. Nilotinib will be given orally on cycle 1 Days 7, 14 once a day 24 hours prior to the paclitaxel infusion and again 30 minutes prior to the paclitaxel infusion on days 8, 15. During the cycle 1, PK will be obtained at baseline, during, and up to 24 hours after paclitaxel or nilotinib administration on the days 1, 7, 8. Patients will continue paclitaxel without nilotinib after cycle 1 as part of standard of care at the discretion of the treating investigator PHASE II: Patients are randomized to 1 of 2 groups. GROUP I: Patients receive paclitaxel IV on days 1, 8, and 15. Patients also receive nilotinib hydrochloride monohydrate PO on days 7, 8, 14, and 15 of cycle 1 and days -1, 1, 7, 8, 14, and 15 of cycle 2. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. GROUP II: Patients receive paclitaxel IV on days 1, 8, and 15. In cycle 1. Patients also receive placebo PO on days 7, 8, 14, and 15 of cycle 1 and days -1, 1, 7, 8, 14, and 15 of cycle 2. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 3 and 6 months.

Official Title
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A Phase Ib/II Study of the Safety and Pharmacology of Nilotinib to Prevent Paclitaxel-Induced Peripheral Neuropathy in Patients With Breast Cancer

Conditions
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Anatomic Stage IIA Breast Cancer AJCC v8, Anatomic Stage I Breast Cancer AJCC v8, Anatomic Stage IA Breast Cancer AJCC v8, Anatomic Stage IB Breast Cancer AJCC v8, Anatomic Stage II Breast Cancer AJCC v8, Anatomic Stage IIB Breast Cancer AJCC v8, Anatomic Stage III Breast Cancer AJCC v8, Anatomic Stage IIIA Breast Cancer AJCC v8, Anatomic Stage IIIB Breast Cancer AJCC v8, Anatomic Stage IIIC Breast Cancer AJCC v8, Prognostic Stage I Breast Cancer AJCC v8, Prognostic Stage IA Breast Cancer AJCC v8, Prognostic Stage IB Breast Cancer AJCC v8, Prognostic Stage II Breast Cancer AJCC v8, Prognostic Stage IIA Breast Cancer AJCC v8, Prognostic Stage IIB Breast Cancer AJCC v8, Prognostic Stage III Breast Cancer AJCC v8, Prognostic Stage IIIA Breast Cancer AJCC v8, Prognostic Stage IIIB Breast Cancer AJCC v8, Prognostic Stage IIIC Breast Cancer AJCC v8

Intervention / Treatment
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* Drug: Nilotinib
* Drug: Nilotinib Hydrochloride Monohydrate
* Drug: Paclitaxel
* Other: Placebo
* Other: Questionnaire Administration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men or Women with a known diagnosis of breast cancer stages I-III. Be eligible for weekly or dose dense single agent paclitaxel therapy based on physician assessment. Have an Eastern Cooperative Oncology Group (ECOG) performance status =< 2 Patients with ECOG scores of 3 or greater typically do not receive chemotherapeutic intervention. Leukocytes >= 2,000/uL. Absolute neutrophil count >= 1,500/uL. Platelets >= 100,000/uL. Total bilirubin =< upper limit of normal (ULN). Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal. Creatinine within normal institutional limits OR >= 50 mL/min for patients with creatinine levels above institutional normal. Corrected QT interval (QTc) < 450 milliseconds. If a female subject is with child bearing potential, she must have a negative pregnancy test at screening. Female subjects of child-bearing potential and men must agree to use adequate contraception prior to study entry, for the duration of study participation and for 3 months after completion of study treatment administration. Adequate contraception includes methods such as oral contraceptives, double barrier method (condom plus spermicide or diaphragm), or abstaining from sexual intercourse. Be willing and able to understand and sign the written informed consent document. Exclusion Criteria: Known distant metastatic disease. Is HER2+ and is receiving paclitaxel in conjunction with trastuzumab +/- pertuzumab. Has experienced > grade 1 neuropathy during previous therapies for early stage breast cancer. Has experienced prior treatment-related toxicities that have not recovered to grade 1 or less (except for alopecia). Has a history of grade 3-4 immediate hypersensitivity reaction to paclitaxel. Has a history of clinically significant allergic reactions attributed to compounds of similar chemical or biologic composition to nilotinib or paclitaxel. Has uncontrolled intercurrent 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. Is currently pregnant or breast feeding as there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with nilotinib and paclitaxel. Has any other medical or psychiatric condition that in the opinion of the investigator would make the study therapy unsafe for the patient. Has gastrointestinal (GI) disorders or impairment of GI function that is likely to significantly alter the absorption of nilotinib Uses potent CYP3A4 inhibitors (grapefruit juice, cyclosporine, ketoconazole, ritonavir) and if treatment cannot be either safely discontinued or switched to a different medication prior to starting nilotinib. Has a known diagnosis of human immunodeficiency virus (HIV) and is currently taking combination antiretroviral therapy known or suspected to affect paclitaxel pharmacokinetics (PK). Is concurrently using potent OATP1B1 inhibitors, including antibiotics (rifampicin, rifamycin SV, systemic fusidic acid, clarithromycin, erythromycin, roxithromycin, telithromycin), antiretrovirals (indinavir, saquinavir, ritonavir), cyclosporine, and gemfibrozil.

Ages Eligible for Study
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Minimum Age: 18 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group I (paclitaxel, nilotinib hydrochloride monohydrate)<br>Patients receive paclitaxel IV on days 1, 8, and 15. Patients also receive nilotinib hydrochloride monohydrate PO on days 7, 8, 14, and 15 of cycle 1 and days -1, 1, 7, 8, 14, and 15 of cycle 2. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. | Drug: Nilotinib<br>* Given PO<br>* Other names: AMN 107 Base Form;Drug: Nilotinib Hydrochloride Monohydrate<br>* Given PO on cycle 1 Days 7, 14, 15 once a day 24 hours prior to the paclitaxel infusion and again 30 minutes prior to the paclitaxel infusion on days 8, 15.<br>* Other names: Tasigna;Drug: Paclitaxel<br>* Given IV weekly on days 1, 8, 15, of every 21 days, at a starting dose of 80mg/m2<br>* Other names: Taxol Konzentrat;Other: Questionnaire Administration<br>* Ancillary studies<br>|
| Placebo Comparator: Group II (paclitaxel, placebo)<br>Patients receive paclitaxel IV on days 1, 8, and 15. Patients also receive placebo PO on days 7, 8, 14, and 15 of cycle 1 and days -1, 1, 7, 8, 14, and 15 of cycle 2. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. | Drug: Paclitaxel<br>* Given IV weekly on days 1, 8, 15, of every 21 days, at a starting dose of 80mg/m2<br>* Other names: Taxol Konzentrat;Other: Placebo<br>* Given PO<br>* Other names: sham therapy;Other: Questionnaire Administration<br>* Ancillary studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events (Phase Ib) | Will be classified and attributed using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version (v)5.0 and will be summarized within and across dose levels using descriptive statistics. The overall number and percentage of patients experiencing adverse events (AEs) and toxicities will be summarized and reported as across all event types, non-hematologic AEs, hematologic AEs, and for each type. Specific focus will be in summarizing any neuropathy-related AEs by dose level and how this corresponds to our measures of OATP1B1 inhibition. All patients who have received at least one dose of the therapeutic agents will be evaluable for toxicity and tolerability. | Up to 6 weeks | 
| Recommended phase II dose (RP2D) of nilotinib in combination with paclitaxel (Phase Ib) | The RP2D will be derived from an adaptive Bayesian method for dose-finding based on trade-offs between the probabilities of treatment efficacy and toxicity. In this design, treatment efficacy is defined as significant inhibition of OATP1B1 activity by nilotinib, without causing changes in the pharmacokinetic profiles of paclitaxel. Efficacy in this setting will be OATP1B1 inhibition as defined by a >= 5-fold increase in the area under the curve (AUC) of GCDCA-S from pre- to post-treatment and/or detectable CDCA-24G levels post-treatment. | Up to 6 weeks | 
| Total sensory neuropathy scores (Phase II) | Assessed with Chemotherapy-Induced Peripheral Neuropathy (CIPN)-20 questionnaire. The AUC, approximated with the trapezoid method, can be used to summarize the sequence of repeated total sensory neuropathy scores for each evaluable patient and this summary measure tends to be approximately normally distributed. Total sensory neuropathy score measured as composite of sensory questions in CIPN 20 (i.e., prior to randomization) and at least one corresponding total score obtained during exposure to paclitaxel. | Up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Severity and onset of all six sensory symptoms on CIPN 20 (Phase II) | A composite response will be defined reflecting the severity and onset time of all six sensory symptoms. For each patient, the worst patient-reported sensory score obtained during paclitaxel exposure, including 1 week after the final paclitaxel dose, will be calculated. Response is defined as a patient reporting a worst score of =< 2 (i.e. ?Not at all? or ?A little?) on an ordinal scale of 1-4 without discontinuing the study due to paclitaxel-induced sensory neuropathy symptoms. | Up to 6 months | 
| Incidence of adverse events (Phase II) | The percentage of patients experiencing NCI CTCAE v5.0 grade >= 3 toxicity will be compared between the arms using a Fisher?s exact test as well as the percentage of patients experiencing peripheral neuropathy associated with paclitaxel. Additionally, the time of onset of peripheral neuropathy (from randomization) will be examined using Kaplan-Meier survival curves and log-rank testing. | Up to 6 months |