Clinical trial NCT04205903: Nilotinib in Preventing Paclitaxel-Induced Peripheral Neuropathy in Patients with Stage I-III Breast Cancer
Official title: A Phase Ib/II Study of the Safety and Pharmacology of Nilotinib to Prevent Paclitaxel-Induced Peripheral Neuropathy in Patients with Breast Cancer
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: 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 IIA 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
Lead sponsor: Ohio State University Comprehensive Cancer Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2019-12-20
Enrollment: 11
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Incidence of adverse events (Phase Ib)
timeFrame: Up to 6 weeks
measure: Recommended phase II dose (RP2D) of nilotinib in combination with paclitaxel (Phase Ib)
timeFrame: Up to 6 weeks
measure: Total sensory neuropathy scores (Phase II)
timeFrame: Up to 6 months
Secondary outcomes:
measure: Severity and onset of all six sensory symptoms on CIPN 20 (Phase II)
timeFrame: Up to 6 months
measure: Incidence of adverse events (Phase II)
timeFrame: Up to 6 months
Other outcomes:
measure: Evaluate effects of nilotinib and paclitaxel (Phase Ib) on patients through Pharmacokinetics (PK) for clinical significant interactions.
timeFrame: : Pre-dose, prior to starting paclitaxel (day 1, day 8), prior to starting nilotinib (day 8 only), immediately prior to end of paclitaxel, after paclitaxel on days 1 and 8 and pre-dose, after nilotinib on day 7.
Locations:
city: Columbus
country: United States
facility: Ohio State University Comprehensive Cancer Center
state: Ohio
Study officials:
affiliation: Ohio State University Comprehensive Cancer Center
name: Nicole Williams, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Stage TB, Hu S, Sparreboom A, Kroetz DL. Role for Drug Transporters in Chemotherapy-Induced Peripheral Neuropathy. Clin Transl Sci. 2021 Mar;14(2):460-467. doi: 10.1111/cts.12915. Epub 2020 Nov 9.