A Phase Ib Study of the Safety and Pharmacology of Nilotinib to Prevent Paclitaxel-Induced Peripheral Neuropathy in Patients With Breast Cancer
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 11
- 试验地点
- 1
- 主要终点
- Number of Adverse Events (Phase Ib)
研究概览
简要总结
This phase Ib 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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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.
研究组 & 干预措施
Dose level 1
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.
干预措施: Nilotinib (Drug)
Dose level 1
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.
干预措施: Nilotinib Hydrochloride Monohydrate (Drug)
Dose level 1
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.
干预措施: Paclitaxel (Drug)
Dose level 1
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.
干预措施: Questionnaire Administration (Other)
Dose level 2
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.
干预措施: Nilotinib (Drug)
Dose level 2
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.
干预措施: Nilotinib Hydrochloride Monohydrate (Drug)
Dose level 2
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.
干预措施: Paclitaxel (Drug)
Dose level 2
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.
干预措施: Questionnaire Administration (Other)
Dose level 3
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.
干预措施: Nilotinib (Drug)
Dose level 3
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.
干预措施: Nilotinib Hydrochloride Monohydrate (Drug)
Dose level 3
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.
干预措施: Paclitaxel (Drug)
Dose level 3
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.
干预措施: Questionnaire Administration (Other)
结局指标
主要结局
Number of Adverse Events (Phase Ib)
时间窗: Up to 6 weeks
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.
Recommended Phase II Dose (RP2D) of Nilotinib in Combination With Paclitaxel (Phase Ib)
时间窗: Up to 6 weeks
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.
次要结局
未报告次要终点
研究者
Nicole Williams
Principal Investigator
Ohio State University Comprehensive Cancer Center