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
Conditions
Brief summary
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.
Detailed description
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
Interventions
Given PO
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.
Given IV weekly on days 1, 8, 15, of every 21 days, at a starting dose of 80mg/m2
Ancillary studies
Sponsors
Study design
Eligibility
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Adverse Events (Phase Ib) | 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) | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Evaluate Effects of Nilotinib and Paclitaxel (Phase Ib) on Patients Through Pharmacokinetics (PK) for Clinical Significant Interactions. | : 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. | Will explore PK endpoints Area under the plasma concentration versus time curve (AUC) |
Countries
United States
Participant flow
Pre-assignment details
Eleven participants enrolled in the study. One participant withdrew prior to be randomized to a dose level,, leaving ten participants who were randomized to the three dose levels.
Participants by arm
| Arm | Count |
|---|---|
| Dose Level 1 (100mg Nilotinib) 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.
Nilotinib: Given PO
Nilotinib Hydrochloride Monohydrate: 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.
Paclitaxel: Given IV weekly on days 1, 8, 15, of every 21 days, at a starting dose of 80mg/m2
Questionnaire Administration: Ancillary studies | 5 |
| Dose Level 2 (200mg Nilotinib) 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.
Nilotinib: Given PO
Nilotinib Hydrochloride Monohydrate: 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.
Paclitaxel: Given IV weekly on days 1, 8, 15, of every 21 days, at a starting dose of 80mg/m2
Questionnaire Administration: Ancillary studies | 3 |
| Dose Level 3 (300mg Nilotinib) 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.
Nilotinib: Given PO
Nilotinib Hydrochloride Monohydrate: 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.
Paclitaxel: Given IV weekly on days 1, 8, 15, of every 21 days, at a starting dose of 80mg/m2
Questionnaire Administration: Ancillary studies | 2 |
| Total | 10 |
Baseline characteristics
| Characteristic | Dose Level 1 (100mg Nilotinib) | Dose Level 2 (200mg Nilotinib) | Dose Level 3 (300mg Nilotinib) | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 3 Participants | 2 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 3 Participants | 2 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 2 Participants | 2 Participants | 8 Participants |
| Region of Enrollment United States | 5 participants | 3 participants | 2 participants | 10 participants |
| Sex: Female, Male Female | 5 Participants | 3 Participants | 2 Participants | 10 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 3 | 0 / 2 |
| other Total, other adverse events | 5 / 5 | 3 / 3 | 2 / 2 |
| serious Total, serious adverse events | 0 / 5 | 2 / 3 | 0 / 2 |
Outcome results
Number 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.
Time frame: Up to 6 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Otitis externa | 1 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Anemia | 10 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Cardiac disorders - Other, specify | 1 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Ear and labyrinth disorders - Other, specify | 1 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Blurred vision | 1 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Eye pain | 1 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Watering eyes | 1 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Constipation | 1 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Diarrhea | 4 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Gastroesophageal reflux disease | 2 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Gastrointestinal disorders - Other, specify | 1 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Mucositis oral | 4 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Nausea | 3 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Edema limbs | 1 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Fatigue | 4 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Localized edema | 3 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Pain | 1 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Mucosal infection | 2 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Injury, poisoning and procedural complications - Other, specify | 1 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Alkaline phosphatase increased | 1 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Lymphocyte count decreased | 2 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Neutrophil count decreased | 5 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | White blood cell decreased | 4 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Anorexia | 4 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Hyperglycemia | 3 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Hyperphosphatemia | 1 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Arthralgia | 1 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Bone pain | 1 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Musculoskeletal and connective tissue disorder - Other, specify | 1 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Myalgia | 3 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Dysgeusia | 2 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Headache | 4 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Nervous system disorders - Other, specify | 1 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Paresthesia | 1 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Peripheral sensory neuropathy | 5 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Anxiety | 1 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Depression | 3 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Insomnia | 1 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Allergic rhinitis | 4 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Dyspnea | 2 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Alopecia | 1 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Bullous dermatitis | 1 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Nail changes | 1 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Pain of skin | 1 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Palmar-plantar erythrodysesthesia syndrome | 2 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Rash maculo-papular | 1 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Skin and subcutaneous tissue disorders - Other, specify | 5 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Flushing | 1 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Hot flashes | 1 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Hypertension | 1 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Dry mouth | 0 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Alanine aminotransferase increased | 0 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Aspartate aminotransferase increased Aspartate aminotransferase increased | 0 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Weight loss | 0 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Hypokalemia | 0 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Dizziness | 0 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Neuralgia | 0 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Peripheral motor neuropathy | 0 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Dry skin | 0 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Dysuria | 0 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Pruritus | 0 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Skin hyperpigmentation | 0 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Tinnitus | 0 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Abdominal pain | 0 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Vomiting | 0 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Breast infection | 0 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Platelet count decreased | 0 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Back pain | 0 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Joint range of motion decreased | 0 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Muscle cramp | 0 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Scoliosis | 0 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Extrapyramidal disorder | 0 Number of Events |
| Dose Level 1 (100mg Nilotinib) | Number of Adverse Events (Phase Ib) | Sleep apnea | 0 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Aspartate aminotransferase increased Aspartate aminotransferase increased | 1 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Neuralgia | 1 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Hyperglycemia | 3 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Hyperphosphatemia | 0 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Back pain | 0 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Arthralgia | 1 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Peripheral motor neuropathy | 1 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Bone pain | 1 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Musculoskeletal and connective tissue disorder - Other, specify | 0 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Myalgia | 0 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Dry skin | 1 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Dysgeusia | 0 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Headache | 1 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Extrapyramidal disorder | 0 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Nervous system disorders - Other, specify | 0 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Dysuria | 1 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Paresthesia | 1 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Peripheral sensory neuropathy | 1 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Joint range of motion decreased | 0 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Anxiety | 1 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Pruritus | 1 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Depression | 1 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Insomnia | 1 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Allergic rhinitis | 0 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Skin hyperpigmentation | 1 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Dyspnea | 1 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Alopecia | 0 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Bullous dermatitis | 0 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Tinnitus | 0 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Nail changes | 0 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Pain of skin | 0 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Muscle cramp | 0 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Palmar-plantar erythrodysesthesia syndrome | 1 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Abdominal pain | 0 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Rash maculo-papular | 0 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Skin and subcutaneous tissue disorders - Other, specify | 0 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Flushing | 0 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Vomiting | 0 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Hot flashes | 0 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Scoliosis | 0 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Anemia | 2 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Cardiac disorders - Other, specify | 0 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Hypertension | 1 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Ear and labyrinth disorders - Other, specify | 0 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Blurred vision | 0 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Eye pain | 0 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Dry mouth | 1 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Watering eyes | 0 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Constipation | 1 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Breast infection | 0 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Diarrhea | 0 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Alanine aminotransferase increased | 1 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Gastroesophageal reflux disease | 1 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Gastrointestinal disorders - Other, specify | 0 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Mucositis oral | 1 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Anorexia | 0 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Nausea | 2 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Edema limbs | 0 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Fatigue | 2 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Weight loss | 1 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Localized edema | 0 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Pain | 2 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Platelet count decreased | 0 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Mucosal infection | 0 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Otitis externa | 0 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Hypokalemia | 1 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Injury, poisoning and procedural complications - Other, specify | 0 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Alkaline phosphatase increased | 0 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Lymphocyte count decreased | 1 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Dizziness | 1 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Neutrophil count decreased | 0 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | White blood cell decreased | 0 Number of Events |
| Dose Level 2 (200mg Nilotinib) | Number of Adverse Events (Phase Ib) | Sleep apnea | 0 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Nausea | 1 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Anorexia | 0 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Paresthesia | 4 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Aspartate aminotransferase increased Aspartate aminotransferase increased | 0 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Hyperglycemia | 2 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Neuralgia | 0 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Hot flashes | 0 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Hyperphosphatemia | 0 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Lymphocyte count decreased | 3 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Anemia | 2 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Arthralgia | 0 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Vomiting | 4 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Edema limbs | 0 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Bone pain | 0 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Peripheral motor neuropathy | 0 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Cardiac disorders - Other, specify | 0 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Musculoskeletal and connective tissue disorder - Other, specify | 0 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Back pain | 1 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Scoliosis | 1 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Dizziness | 0 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Ear and labyrinth disorders - Other, specify | 0 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Dysgeusia | 0 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Dry skin | 1 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Hypertension | 0 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Headache | 1 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Fatigue | 3 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Blurred vision | 1 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Nervous system disorders - Other, specify | 0 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Sleep apnea | 1 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Injury, poisoning and procedural complications - Other, specify | 0 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Dysuria | 0 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Eye pain | 0 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Peripheral sensory neuropathy | 0 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Hypokalemia | 0 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Localized edema | 0 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Anxiety | 1 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Watering eyes | 0 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Dry mouth | 0 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Depression | 1 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Pruritus | 0 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Weight loss | 0 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Insomnia | 0 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Joint range of motion decreased | 1 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Constipation | 1 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Allergic rhinitis | 0 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | White blood cell decreased | 2 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Pain | 4 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Dyspnea | 3 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Skin hyperpigmentation | 0 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Diarrhea | 4 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Alopecia | 0 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Extrapyramidal disorder | 1 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Alkaline phosphatase increased | 0 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Bullous dermatitis | 0 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Platelet count decreased | 2 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Gastroesophageal reflux disease | 1 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Nail changes | 0 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Tinnitus | 1 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Alanine aminotransferase increased | 1 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Pain of skin | 0 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Mucosal infection | 0 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Gastrointestinal disorders - Other, specify | 0 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Palmar-plantar erythrodysesthesia syndrome | 0 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Breast infection | 2 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Myalgia | 0 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Rash maculo-papular | 3 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Abdominal pain | 1 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Mucositis oral | 1 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Skin and subcutaneous tissue disorders - Other, specify | 0 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Muscle cramp | 1 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Neutrophil count decreased | 0 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Flushing | 0 Number of Events |
| Dose Level 3 (300mg Nilotinib) | Number of Adverse Events (Phase Ib) | Otitis externa | 0 Number of Events |
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.
Time frame: Up to 6 weeks
Population: The 6 participants who completed study treatment were evaluated for this outcome.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Level 1 (100mg Nilotinib) | Recommended Phase II Dose (RP2D) of Nilotinib in Combination With Paclitaxel (Phase Ib) | NA milligrams |
Evaluate Effects of Nilotinib and Paclitaxel (Phase Ib) on Patients Through Pharmacokinetics (PK) for Clinical Significant Interactions.
Will explore PK endpoints Area under the plasma concentration versus time curve (AUC)
Time frame: : 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.