Advanced Breast Cancer
Conditions
Keywords
HKI-272, neratinib, trastuzumab, breast cancer, Nerlynx, PB-272, HER2
Brief summary
The purpose of this study is to determine the safety and efficacy of HKI-272 (neratinib) in combination with trastuzumab in patients with advanced breast cancer.
Detailed description
Open label phase 1/2 study of ascending multiple oral doses of HKI-272 in combination with IV trastuzumab in subjects with advanced human epidermal growth factor receptor 2 positive (HER2+) breast cancer. Three to six subjects will be enrolled in each dose group. Adverse events and dose limiting toxicities will be assessed from the first dose of study drug though day 21. When the maximum tolerated dose (MTD) of HKI-272 plus trastuzumab is determined, an additional 30 subjects will be enrolled at that dose level, and followed for progression free survival for approximately 1 year.
Interventions
DRUGHKI-272
HKI-272 by mouth
DRUGtrastuzumab
trastuzumab 4 mg/kg IV as a loading dose followed by trastuzumab 2 mg/kg weekly thereafter
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
* Pathologic diagnosis of breast cancer with current stage IIIB, IIIC or IV not curable by available therapy * Progression following at least one Herceptin-containing cytotoxic chemotherapy regimen (neoadjuvant, adjuvant, or metastatic setting) * HER2 positive breast cancer * At least one measurable target lesion * Adequate performance status * Adequate cardiac, kidney, and liver function * Adequate blood counts * Willingness of all subjects who are not surgically sterile or post menopausal to use acceptable methods of birth control
Exclusion criteria
* More than 3 prior cytotoxic chemotherapy regimens for locally advanced or metastatic disease * Major surgery, chemotherapy, radiotherapy, investigational agents, Herceptin or other cancer therapy within 2 weeks of treatment day 1 * Prior treatment with anthracyclines with cumulative dose of \>400 mg/m\^2 * Extensive visceral disease * Active central nervous system metastases * Pregnant or breast feeding women * Significant chronic or recent acute gastrointestinal disorder with diarrhea as a major symptom * Prior exposure to HKI-272 or other HER2 targeted agents (except Herceptin and Tykerb) * Significant cardiac disease or dysfunction * History of life-threatening hypersensitivity to Herceptin * Inability or unwillingness to swallow HKI-272 capsules * Any other cancer within 5 years with the exception of contralateral breast cancer, adequately treated cervical carcinoma in situ, or adequately treated basal or squamous cell carcinoma of the skin
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 16-week Progression-free Survival (PFS) Rate | From first dose date to progression status (PD or death) at 16-week | 16-week progression-free survival (PFS) rate for subjects with advanced breast cancer who receive neratinib at the maximum tolerated dose (MTD) in combination with trastuzumab, evaluable population. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | From first dose date to progression or last tumor assessment, up to five and a half years. | Percentage of participants with partial response (PR) or complete response (CR) per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v.1.0: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; and Non-PD for non-target lesions, and no new lesions. |
| Duration of Response (DOR) | From start date of response to first PD, assessed up to five and half years after the first subject was randomized | Duration of response was measured from the time at which response criteria were met for complete response (CR) or partial response (PR) (whichever status was recorded first) until the first date on which recurrence or PD was objectively documented, taking as the reference for PD the smallest measurements recorded since the test article administration started. |
| Clinical Benefit Rate (CBR) | From first dose date to progression or last tumor assessment, assessed up to five and half years. | The percentage of participants with a best overall response of a complete response (CR) or partial response (PR) or stable disease (SD) \>=24 weeks. |
| Area Under the Curve of Neratinib Concentration | Prior to the first dose, and at hours 1, 2, 4, 6, 8 and 24 on days 22. | Area Under the Curve of Neratinib concentration at day 22 following Administration of Neratinib 240 mg in combination with Trastuzumab 2 mg/kg in Subjects with Cancer. |
| Terminal-phase Elimination Half-life of Neratinib in Combination With Trastuzumab. | Prior to the first dose, on days 22 through 23 of month 1, and on day 1 in months 2 through 6 | Terminal-phase elimination half-life of Neratinib at day 22 following Administration of Neratinib 240 mg in combination with Trastuzumab 2 mg/kg to Subjects with Cancer. |
| Progression Free Survival (PFS) | From first dose date to progression or death, assessed up to five and half years. | Progression Free Survival was measured from the date of the first dose of test article until the first date on which recurrence or progression, or death due to any cause, was documented, censored at the last evaluation, investigator assessment. |
Countries
China, France, Switzerland, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Neratinib 160 mg + Trastuzumab All subjects receiving HKI-272 (neratinib) in combination with trastuzumab (Herceptin) HKI-272: neratinib 160 mg daily by mouth Herceptin: Herceptin 4 mg/kg IV as a loading dose followed by Herceptin 2 mg/kg weekly thereafter | 4 |
| Neratinib 240 mg + Trastuzumab All subjects receiving HKI-272 (neratinib) in combination with trastuzumab (Herceptin) HKI-272: neratinib 160 mg daily by mouth Herceptin: Herceptin 4 mg/kg IV as a loading dose followed by Herceptin 2 mg/kg weekly thereafter | 4 |
| Part 2 - Expanded MTD Cohort All subjects receiving HKI-272 (neratinib) in combination with trastuzumab (Herceptin) HKI-272: neratinib 240 mg daily by mouth Herceptin: Herceptin 4 mg/kg IV as a loading dose followed by Herceptin 2 mg/kg weekly thereafter | 37 |
| Total | 45 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 2 |
| Overall Study | Disease Progression | 3 | 4 | 27 |
| Overall Study | Protocol Violation | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 4 |
Baseline characteristics
| Characteristic | Neratinib 160 mg + Trastuzumab | Neratinib 240 mg + Trastuzumab | Part 2 - Expanded MTD Cohort | Total |
|---|---|---|---|---|
| Age, Continuous | 52.5 years STANDARD_DEVIATION 10.1 | 61.0 years STANDARD_DEVIATION 12.8 | 50.5 years STANDARD_DEVIATION 13 | 51.6 years STANDARD_DEVIATION 12.9 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 21 Participants | 21 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 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 | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 3 Participants | 3 Participants | 15 Participants | 21 Participants |
| Sex: Female, Male Female | 4 Participants | 4 Participants | 37 Participants | 45 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 | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 4 | 4 / 4 | 37 / 37 |
| serious Total, serious adverse events | 1 / 4 | 0 / 4 | 9 / 37 |
Outcome results
Primary
16-week Progression-free Survival (PFS) Rate
16-week progression-free survival (PFS) rate for subjects with advanced breast cancer who receive neratinib at the maximum tolerated dose (MTD) in combination with trastuzumab, evaluable population.
Time frame: From first dose date to progression status (PD or death) at 16-week
Population: The evaluable population was defined as the subjects who met the eligibility criteria for study enrollment, received at least 1 week of neratinib and at least 2 doses of trastuzumab, and had a baseline tumor assessment and at least 1 follow-up tumor assessment approximately 8 weeks after starting test article administration.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 2 - Expanded MTD Cohort | 16-week Progression-free Survival (PFS) Rate | 44.8 percentage of population |
Secondary
Area Under the Curve of Neratinib Concentration
Area Under the Curve of Neratinib concentration at day 22 following Administration of Neratinib 240 mg in combination with Trastuzumab 2 mg/kg in Subjects with Cancer.
Time frame: Prior to the first dose, and at hours 1, 2, 4, 6, 8 and 24 on days 22.
Population: Subjects for whom complete blood samples at day 22 were available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 2 - Expanded MTD Cohort | Area Under the Curve of Neratinib Concentration | 1110 ng*hr/mL | Standard Deviation 430 |
Secondary
Clinical Benefit Rate (CBR)
The percentage of participants with a best overall response of a complete response (CR) or partial response (PR) or stable disease (SD) \>=24 weeks.
Time frame: From first dose date to progression or last tumor assessment, assessed up to five and half years.
Population: The evaluable population was defined as the subjects who met the eligibility criteria for study enrollment, received at least 1 week of neratinib and at least 2 doses of trastuzumab, and had a baseline tumor assessment and at least 1 follow-up tumor assessment approximately 8 weeks after starting test article administration.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 2 - Expanded MTD Cohort | Clinical Benefit Rate (CBR) | 35.7 percentage of participants |
Secondary
Duration of Response (DOR)
Duration of response was measured from the time at which response criteria were met for complete response (CR) or partial response (PR) (whichever status was recorded first) until the first date on which recurrence or PD was objectively documented, taking as the reference for PD the smallest measurements recorded since the test article administration started.
Time frame: From start date of response to first PD, assessed up to five and half years after the first subject was randomized
Population: The subjects who had a complete response or partial response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 2 - Expanded MTD Cohort | Duration of Response (DOR) | 44.2 weeks |
Secondary
Objective Response Rate (ORR)
Percentage of participants with partial response (PR) or complete response (CR) per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v.1.0: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; and Non-PD for non-target lesions, and no new lesions.
Time frame: From first dose date to progression or last tumor assessment, up to five and a half years.
Population: The evaluable population was defined as the subjects who met the eligibility criteria for study enrollment, received at least 1 week of neratinib and at least 2 doses of trastuzumab, and had a baseline tumor assessment and at least 1 follow-up tumor assessment approximately 8 weeks after starting test article administration.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 2 - Expanded MTD Cohort | Objective Response Rate (ORR) | 28.6 percentage of participants |
Secondary
Progression Free Survival (PFS)
Progression Free Survival was measured from the date of the first dose of test article until the first date on which recurrence or progression, or death due to any cause, was documented, censored at the last evaluation, investigator assessment.
Time frame: From first dose date to progression or death, assessed up to five and half years.
Population: The evaluable population was defined as the subjects who met the eligibility criteria for study enrollment, received at least 1 week of neratinib and at least 2 doses of trastuzumab, and had a baseline tumor assessment and at least 1 follow-up tumor assessment approximately 8 weeks after starting test article administration.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 2 - Expanded MTD Cohort | Progression Free Survival (PFS) | 15.9 weeks |
Secondary
Terminal-phase Elimination Half-life of Neratinib in Combination With Trastuzumab.
Terminal-phase elimination half-life of Neratinib at day 22 following Administration of Neratinib 240 mg in combination with Trastuzumab 2 mg/kg to Subjects with Cancer.
Time frame: Prior to the first dose, on days 22 through 23 of month 1, and on day 1 in months 2 through 6
Population: Subjects for whom complete blood samples at day 22 were available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 2 - Expanded MTD Cohort | Terminal-phase Elimination Half-life of Neratinib in Combination With Trastuzumab. | 21.22 hr | Standard Deviation 10.16 |