Advanced Breast Cancer, Advanced Malignant Solid Tumors, Breast Neoplasms
Conditions
Keywords
cancer, HKI-272, neratinib, paclitaxel, Taxol, breast cancer, Nerlynx
Brief summary
The purpose of this study is to learn whether it is safe and effective to administer HKI-272 (neratinib) in combination with paclitaxel in patients with breast cancer.
Interventions
DRUGHKI-272
DRUGPaclitaxel
Sponsors
Puma Biotechnology, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Inclusion criteria for both parts of clinical trial: * Good performance status * Normal ejection fraction * Adequate cardiac, kidney, and liver function * Adequate blood counts * At least one measurable target lesion * Negative pregnancy test for female subjects Inclusion Criteria for Part 1 Only: \- Pathologically confirmed solid tumor not curable with available standard therapy Inclusion Criteria for Part 2 Only: * Pathologically confirmed breast cancer * HER2 positive tumor * Prior treatment with Herceptin
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate | From first dose date to progression or last tumor assessment, up to 140 weeks | Subjects with partial response (PR) or complete response (CR) with ERBB2 positive breast cancer treated at the maximum tolerated dose (MTD) of neratinib in combination with paclitaxel, per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v.1.0: CR, disappearance of all target lesions; PR, \>=30% decrease in the sum of the longest diameter of target lesions; and no progressive disease (PD) for non-target lesions, and no new lesions. |
| Dose Limiting Toxicity Incidence of Neratinib in Combination With Paclitaxel | From first dose date through day 28 | Dose Limiting Toxicity in subjects with solid tumors treated with neratinib, administered daily, in combination with paclitaxel 80 mg/m² IV on days 1, 8, and 15 of a 28 day cycle. |
| Maximum Tolerated Dose | From first dose date through day 28. | Maximum Tolerated Dose (MTD) of neratinib, daily, in combination with paclitaxel 80 mg/m², intravenous at days 1, 8, and 15, associated with the dose limiting toxicity data. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration of Neratinib | Samples taken at 0 hour and at 1, 2, 4, 6, 8, and 24 hours postdose on Day 15 of Cycle 1, and 1 predose sample on Day 1 in Cycle 1. | Maximum plasma concentration of neratinib; after each dosing of neratinib on Cycle 1 of Day 15, blood samples taken at regular time points. |
| Area Under the Concentration-time Curve 0-24 | Samples taken at 0 hour and at 1, 2, 4, 6, 8, and 24 hours postdose on Day 15 of Cycle 1, and 1 predose sample on Day 1 in Cycle 1. | Area under the concentration-time curve of neratinib; after each dosing of neratinib on Cycle 1 of Day 15, blood samples taken at regular time points. |
Countries
Belgium, Canada, China, Hong Kong, India, Poland, South Korea, Ukraine, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Neratinib 160 mg + Paclitaxel 80 mg/m2 Neratinib 160 mg qd + Paclitaxel 80 mg/m2 IV on days 1, 8, and 15 of a 28 day cycle. | 3 |
| Neratinib 240 mg + Paclitaxel 80 mg/m2 Neratinib 240 mg qd + Paclitaxel 80 mg/m2 IV on days 1, 8, and 15 of a 28 day cycle. | 5 |
| Arm A Neratinib (MTD) + Paclitaxel Neratinib (MTD) + Paclitaxel 80 mg/m2 on days 1, 8, and 15 of a 28 day cycle for subjects with not more than 1 prior cytotoxic chemotherapy treatment regimen for metastatic disease | 71 |
| Arm B Neratinib (MTD) + Paclitaxel Neratinib (MTD) + Paclitaxel 80 mg/m2 on days 1, 8, and 15 of a 28 day cycle for subjects with not more than 3 prior cytotoxic chemotherapy treatment regimen for metastatic disease | 31 |
| Total | 110 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 3 | 0 |
| Overall Study | Death | 0 | 1 | 2 | 0 |
| Overall Study | Disease Progression | 3 | 4 | 54 | 27 |
| Overall Study | Physician Decision | 0 | 0 | 1 | 1 |
| Overall Study | Surgery | 0 | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 7 | 0 |
Baseline characteristics
| Characteristic | Neratinib 160 mg + Paclitaxel 80 mg/m2 | Total | Arm B Neratinib (MTD) + Paclitaxel | Arm A Neratinib (MTD) + Paclitaxel | Neratinib 240 mg + Paclitaxel 80 mg/m2 |
|---|---|---|---|---|---|
| Age, Continuous | 56.3 years STANDARD_DEVIATION 14.57 | 50.0 years STANDARD_DEVIATION 9.82 | 51.4 years STANDARD_DEVIATION 8.5 | 49.2 years STANDARD_DEVIATION 10.1 | 49.6 years STANDARD_DEVIATION 11.72 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 77 Participants | 25 Participants | 48 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 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 | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 30 Participants | 5 Participants | 22 Participants | 3 Participants |
| Sex: Female, Male Female | 1 Participants | 105 Participants | 31 Participants | 71 Participants | 2 Participants |
| Sex: Female, Male Male | 2 Participants | 5 Participants | 0 Participants | 0 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 5 / 5 | 70 / 71 | 31 / 31 |
| serious Total, serious adverse events | 1 / 3 | 4 / 5 | 27 / 71 | 4 / 31 |
Outcome results
Primary
Dose Limiting Toxicity Incidence of Neratinib in Combination With Paclitaxel
Dose Limiting Toxicity in subjects with solid tumors treated with neratinib, administered daily, in combination with paclitaxel 80 mg/m² IV on days 1, 8, and 15 of a 28 day cycle.
Time frame: From first dose date through day 28
Population: Safety population of Study Part 1. Treated set including patients eligible for MTD determination.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Neratinib 160 mg + Paclitaxel 80 mg/m² | Dose Limiting Toxicity Incidence of Neratinib in Combination With Paclitaxel | 0 Participants |
| Neratinib 240 mg + Paclitaxel 80 mg/m² | Dose Limiting Toxicity Incidence of Neratinib in Combination With Paclitaxel | 0 Participants |
Primary
Maximum Tolerated Dose
Maximum Tolerated Dose (MTD) of neratinib, daily, in combination with paclitaxel 80 mg/m², intravenous at days 1, 8, and 15, associated with the dose limiting toxicity data.
Time frame: From first dose date through day 28.
Population: Safety population of Study Part 1. Treated set including patients eligible for MTD determination.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Neratinib 160 mg + Paclitaxel 80 mg/m² | Maximum Tolerated Dose | 240 mg |
Primary
Objective Response Rate
Subjects with partial response (PR) or complete response (CR) with ERBB2 positive breast cancer treated at the maximum tolerated dose (MTD) of neratinib in combination with paclitaxel, per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v.1.0: CR, disappearance of all target lesions; PR, \>=30% decrease in the sum of the longest diameter of target lesions; and no progressive disease (PD) for non-target lesions, and no new lesions.
Time frame: From first dose date to progression or last tumor assessment, up to 140 weeks
Population: All subjects, in Study part 2 evaluable population, who met the inclusion/exclusion criteria, received at least 2 weeks of neratinib and at least 2 doses of paclitaxel, and underwent at least 1 post-Baseline tumor assessment. Subjects who died or had symptomatic deterioration before the first scheduled post-Baseline tumor assessment were included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Neratinib 160 mg + Paclitaxel 80 mg/m² | Objective Response Rate | 70.6 percentage of participants |
| Neratinib 240 mg + Paclitaxel 80 mg/m² | Objective Response Rate | 77.4 percentage of participants |
Secondary
Area Under the Concentration-time Curve 0-24
Area under the concentration-time curve of neratinib; after each dosing of neratinib on Cycle 1 of Day 15, blood samples taken at regular time points.
Time frame: Samples taken at 0 hour and at 1, 2, 4, 6, 8, and 24 hours postdose on Day 15 of Cycle 1, and 1 predose sample on Day 1 in Cycle 1.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Neratinib 160 mg + Paclitaxel 80 mg/m² | Area Under the Concentration-time Curve 0-24 | 684 h*ng/mL | Geometric Coefficient of Variation 92 |
| Neratinib 240 mg + Paclitaxel 80 mg/m² | Area Under the Concentration-time Curve 0-24 | 1274 h*ng/mL | Geometric Coefficient of Variation 61 |
Secondary
Maximum Plasma Concentration of Neratinib
Maximum plasma concentration of neratinib; after each dosing of neratinib on Cycle 1 of Day 15, blood samples taken at regular time points.
Time frame: Samples taken at 0 hour and at 1, 2, 4, 6, 8, and 24 hours postdose on Day 15 of Cycle 1, and 1 predose sample on Day 1 in Cycle 1.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Neratinib 160 mg + Paclitaxel 80 mg/m² | Maximum Plasma Concentration of Neratinib | 66.78 ng/mL | Geometric Coefficient of Variation 25 |
| Neratinib 240 mg + Paclitaxel 80 mg/m² | Maximum Plasma Concentration of Neratinib | 80.42 ng/mL | Geometric Coefficient of Variation 55 |