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

PRIMARY OBJECTIVES:

I. To determine the recommended phase 2 dose (RP2D) of nilotinib hydrochloride monohydrate (nilotinib) in combination with paclitaxel.

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.

SECONDARY OBJECTIVES:

I. To determine the effect of paclitaxel on pharmacokinetics (PK) of nilotinib in the study population.

II. To determine the effect of nilotinib on PK of paclitaxel in the study population.

OUTLINE: This is a phase Ib, dose-escalation study of nilotinib hydrochloride monohydrate.

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

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.
• Demonstrate adequate electrolyte values as defined below. Hypokalemia and/or hypomagnesemia must be corrected prior to initiating nilotinib:

• Calcium 8.6-10.5mg/dL
• Magnesium 1.6-2.6mg/dL

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
• Has a marked baseline abnormal heart rhythm such as prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc of > 450msec)
• Has a history of additional risk factors for TdP (e.g., heart failure, hypokalemia, hypomagnesemia, family history of Long QT Syndrome)
• 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.