Advanced Malignant Solid Tumors, Breast Cancer
Conditions
Keywords
Metastatic breast cancer, HKI-272, Neratinib, Nerlynx, PB-272
Brief summary
The purpose of this study is to identify the highest tolerable dose of neratinib (HKI-272) in combination with vinorelbine and to assess the safety of the combination of the two drugs as well as to obtain preliminary information on whether the combination of the two drugs has any effect on solid tumors. The study will be conducted in two parts. In the first part, testing will be done on up to 12 subjects to determine the highest tolerable dose of HKI-272 and vinorelbine in patients with advanced solid tumors. In the second part of the study, approximately 60 additional subjects with metastatic ErbB-2-positive breast cancer, with no prior exposure to lapatinib, are planned to be added to better define the tolerability and preliminary activity of HKI-272 in combination with vinorelbine. Up to 20 additional subjects with ErbB-2-positive breast cancer with prior lapatinib exposure are also planned to be enrolled in part 2 for exploratory analyses.
Interventions
DRUGneratinib
DRUGvinorelbine
Sponsors
Puma Biotechnology, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Confirmed pathologic diagnosis of a solid tumor that is not curable with available therapies for which HKI-272 plus vinorelbine is a reasonable treatment option (part 1 only) or Confirmed pathologic diagnosis of ErbB-2-positive breast cancer (current stage IV) in female subjects for which vinorelbine plus HKI-272 is a reasonable treatment option (part 2 only). * At least 1 prior antineoplastic chemotherapy treatment regimen for metastatic disease and at least 1 prior treatment with a trastuzumab-containing regimen for at least 6 weeks, for metastatic disease or subject relapsing under adjuvant treatment (part 2 only). * At least 1 measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST).
Exclusion criteria
* More than 2 prior antineoplastic treatment regimens (excluding hormonotherapy) for metastatic disease. Subjects who relapsed under adjuvant treatment shouldn't have received more than one line of chemotherapy for metastatic disease (part 2 only). * Prior treatment with vinorelbine for metastatic setting, or prior treatment with any ErbB-2 targeted agents except trastuzumab (part 2 only). Up to 20 subjects with ErbB-2-overexpressing metastatic breast cancer who have been previously exposed to lapatinib but are not refractory to lapatinib may be enrolled in part 2. * Prior treatment with anthracyclines with a cumulative dose of doxorubicin of greater than 400 mg/m2, or of epirubicin dose of greater than 800 mg/m2, or the equivalent dose for other anthracyclines or derivatives (part 2 only).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate | From first dose date to progression or last tumor assessment, up to four years and six months. | Overall Response Rate (ORR), subjects with CR or PR by independent review in subjects with ErbB-2-positive breast cancer treated at the MTD of neratinib in combination with vinorelbine per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v1.0: 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. |
| Maximum Tolerated Dose | From Day 1 to Day 21. | Maximum Tolerated Dose (MTD) of Neratinib in combination with vinorelbine in subjects with advanced solid tumors. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Benefit Rate | From first dose date to progression or last tumor assessment, up to four years and six months. | Percentage of participants with partial response (PR) or complete response (CR) or stable disease \> 24 weeks by independent assessment for subjects with ErbB-2-positive breast cancer treated at the MTD of neratinib in combination with vinorelbine, 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. |
| Progression-Free Survival | From first dose date to progression or death, up to four years and six months. | Number of weeks between the date of the first dose of test article and the first date of disease recurrence or progression, or death due to any cause, was documented, censored at the last evaluation, investigator assessment. Progression is defined using Response Evaluation Criteria in Solid Tumors Criteria (v1.0), as at least a 20% increase in the sum of the longest diameters (LD) of target lesions, taking as reference the nadir LD, meaning the smallest sum of the LDs recorded since the treatment started; or unequivocal progression of existing nontarget lesions; or the appearance of any new lesions. |
| Duration Of Response | From start date of response to first PD/death, up to four years and six months. | Duration of response for subjects who had complete or partial response from first response to disease progression, death or last assessment per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v1.0: 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. |
Countries
Belgium, China, France, Hong Kong, Netherlands, Poland, Spain, Sweden, Taiwan, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Neratinib 160 mg + Vinorelbine 25 mg/m² Neratinib 160 mg qd + Vinorelbine 25 mg/m² IV on days 1 and 8 every 3 weeks | 6 |
| Neratinib 240 mg + Vinorelbine 25 mg/m² Neratinib 240 mg qd + Vinorelbine 25 mg/m² IV on days 1 and 8 every 3 weeks | 6 |
| Neratinb 240 mg + Vinorelbine 25 mg/m² - No Prior Lapatinib Neratinib 240 mg qd + Vinorelbine 25 mg/m² IV on days 1 and 8 every 3 weeks, with no prior lapatinib exposure | 64 |
| Neratinib 240 mg + Vinorelbine 25 mg/m² - Prior Lapatinib Neratinib 240 mg qd + Vinorelbine 25 mg/m² IV on days 1 and 8 every 3 weeks, with prior Lapatinib exposure | 15 |
| Total | 91 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 4 | 2 |
| Overall Study | Death | 0 | 0 | 1 | 0 |
| Overall Study | Disease Progression | 4 | 6 | 46 | 12 |
| Overall Study | Failed to return | 0 | 0 | 1 | 0 |
| Overall Study | No treatment received | 0 | 0 | 0 | 1 |
| Overall Study | Not recorded | 0 | 0 | 2 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 2 | 0 |
| Overall Study | Protocol Violation | 0 | 0 | 1 | 1 |
| Overall Study | Symptomatic Deterioration | 0 | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 2 | 0 |
Baseline characteristics
| Characteristic | Neratinib 160 mg + Vinorelbine 25 mg/m² | Neratinib 240 mg + Vinorelbine 25 mg/m² | Neratinb 240 mg + Vinorelbine 25 mg/m² - No Prior Lapatinib | Neratinib 240 mg + Vinorelbine 25 mg/m² - Prior Lapatinib | Total |
|---|---|---|---|---|---|
| Age, Continuous | 53.2 years STANDARD_DEVIATION 14.8 | 54.3 years STANDARD_DEVIATION 13.9 | 51.1 years STANDARD_DEVIATION 10.6 | 52.1 years STANDARD_DEVIATION 9.8 | 51.6 years STANDARD_DEVIATION 10.8 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 18 Participants | 6 Participants | 24 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 2 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 | 2 Participants | 0 Participants | 2 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) White | 4 Participants | 5 Participants | 43 Participants | 9 Participants | 61 Participants |
| Sex: Female, Male Female | 6 Participants | 4 Participants | 64 Participants | 15 Participants | 89 Participants |
| Sex: Female, Male Male | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 2 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 | 6 / 6 | 6 / 6 | 64 / 64 | 15 / 15 |
| serious Total, serious adverse events | 3 / 6 | 3 / 6 | 21 / 64 | 5 / 15 |
Outcome results
Primary
Maximum Tolerated Dose
Maximum Tolerated Dose (MTD) of Neratinib in combination with vinorelbine in subjects with advanced solid tumors.
Time frame: From Day 1 to Day 21.
Population: Safety population of Study Part 1. Treated set including patients eligible for MTD determination.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Neratinb 240 mg + Vinorelbine 25 mg/m² - No Prior Lapatinib | Maximum Tolerated Dose | 240 mg |
Primary
Overall Response Rate
Overall Response Rate (ORR), subjects with CR or PR by independent review in subjects with ErbB-2-positive breast cancer treated at the MTD of neratinib in combination with vinorelbine per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v1.0: 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 four years and six months.
Population: Safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Neratinb 240 mg + Vinorelbine 25 mg/m² - No Prior Lapatinib | Overall Response Rate | 35.9 percentage of participants |
| Neratinib 240 mg + Vinorelbine 25 mg/m² - Prior Lapatinib | Overall Response Rate | 13.3 percentage of participants |
Secondary
Clinical Benefit Rate
Percentage of participants with partial response (PR) or complete response (CR) or stable disease \> 24 weeks by independent assessment for subjects with ErbB-2-positive breast cancer treated at the MTD of neratinib in combination with vinorelbine, 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 four years and six months.
Population: Safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Neratinb 240 mg + Vinorelbine 25 mg/m² - No Prior Lapatinib | Clinical Benefit Rate | 64.1 percentage of participants |
| Neratinib 240 mg + Vinorelbine 25 mg/m² - Prior Lapatinib | Clinical Benefit Rate | 40.0 percentage of participants |
Secondary
Duration Of Response
Duration of response for subjects who had complete or partial response from first response to disease progression, death or last assessment per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v1.0: 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 start date of response to first PD/death, up to four years and six months.
Population: Subjects in evaluable population who had CR or PR according to Independent Assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Neratinb 240 mg + Vinorelbine 25 mg/m² - No Prior Lapatinib | Duration Of Response | 52.7 weeks |
| Neratinib 240 mg + Vinorelbine 25 mg/m² - Prior Lapatinib | Duration Of Response | 77.7 weeks |
Secondary
Progression-Free Survival
Number of weeks between the date of the first dose of test article and the first date of disease recurrence or progression, or death due to any cause, was documented, censored at the last evaluation, investigator assessment. Progression is defined using Response Evaluation Criteria in Solid Tumors Criteria (v1.0), as at least a 20% increase in the sum of the longest diameters (LD) of target lesions, taking as reference the nadir LD, meaning the smallest sum of the LDs recorded since the treatment started; or unequivocal progression of existing nontarget lesions; or the appearance of any new lesions.
Time frame: From first dose date to progression or death, up to four years and six months.
Population: Evaluable population, independent assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Neratinb 240 mg + Vinorelbine 25 mg/m² - No Prior Lapatinib | Progression-Free Survival | 48.0 weeks |
| Neratinib 240 mg + Vinorelbine 25 mg/m² - Prior Lapatinib | Progression-Free Survival | 22.7 weeks |