Breast Neoplasms
Conditions
Keywords
Tumors, Neratinib, HKI-272, Nerlynx
Brief summary
The purpose of this study is to evaluate the safety and tolerability as well as find the maximum tolerated dose (MTD) for HKI-272. In addition, this study will examine the effects of the study drug on your tumor, and how your body uses and eliminates HKI-272.
Interventions
DRUGneratinib
HKI-272
Sponsors
Puma Biotechnology, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This trial was an open-label, phase 1, ascending single and multiple oral dose study of HKI-272 administered to subjects with erbB-2- or erbB-1-positive tumors. Each subject participated in only 1 dose group and received a single dose of test article, followed by a 1-week observation period, and then received the test article administered once daily by mouth for up to 6 months (6 cycles). Daily dose administration could continue beyond 6 cycles at the same dose level if HKI-272 was well tolerated and there was no evidence of progressive disease.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Her2/neu or Her1/EGFR positive cancer * Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 * Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST)
Exclusion criteria
* Prior treatment with anthracyclines with a cumulative dose of doxorubicin or equivalent of greater than 300 mg/m\^2 * Patients with significant cardiac risk factors * Active central nervous system metastasis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Limiting Toxicity (DLT) | From first dose date to day 14 | DLT is defined as any neratinib-related nonhematologic grade 3 or any grade 4 adverse event (AE) according to the National Cancer Institute (NCI) common terminology criteria (CTC) for AEs version 3.0. DLTs were assessed from the first single dose to 14 days of continuous daily administration. |
| Maximum Tolerated Dose (MTD) | From first dose date to day 14 | If 2 or more, of 3 to 6 subjects, at a dose level had an neratinib-related dose limiting toxicity (DLT) by day 14 of continuous daily dose administration, dose escalation stopped and the prior dose level was considered the MTD. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | From first dose date to progression or death, up to 39 weeks. | Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. |
| Number of Participants With Best Overall Response | From first dose date to progression or last tumor assessment, up to 39 weeks. | Best Overall response by tumor type, evaluable population per Response Evaluation Criteria In Solid Tumors Criteria v1.0 for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in sum of the longest diameter (LD) of target lesions in reference to baseline sum of LD of target lesions; Progressive Disease (PD), \>=20% increase in sum of LD of target lesions, taking as reference the smallest sum of recorded LD of target lesions since treatment started or appearance of 1 or more new lesions; Stable disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of LD of target lesions since the treatment start. The best overall response was the best response recorded from start of treatment until PD/recurrence. In general, the subject's best response assignment depended on achievement of both measurement and confirmation criteria. |
| Clinical Benefit Rate | From first dose date to progression/death or last assessment, up to 39 weeks. | Patients with PR or higher responses or SD\>=24 weeks, evaluable population |
| Objective Response Rate | From first dose date to progression/death or last assessment, up to 39 weeks | Patients with PR or higher responses, evaluable population |
| Duration of Response | From start date of response to first PD, up to 39 weeks. | Duration of response of responders (PR+) by Kaplan-Meier estimate |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Neratinib 40 mg Neratinb 40 mg qd | 3 |
| Neratinib 80 mg Neratinib 80 mg qd | 4 |
| Neratinib 120 mg Neratinib 120 mg qd | 4 |
| Neratinib 180 mg Neratinib 180 mg qd | 6 |
| Neratinib 240 mg Neratinib 240 mg qd | 3 |
| Neratinib 320 mg Neratinib 320 mg qd | 7 |
| Neratinib 400 mg Neratinib 400 mg qd | 6 |
| Neratinib MTD Neratinib maximum tolerated dose (320 mg) from part 2. | 39 |
| Total | 72 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 | 1 | 0 | 2 | 3 | 10 |
| Overall Study | Death | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Disease Progression | 2 | 4 | 2 | 5 | 2 | 2 | 1 | 22 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Symptomatic Deterioration | 1 | 0 | 1 | 0 | 1 | 2 | 0 | 2 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 4 |
Baseline characteristics
| Characteristic | Neratinib 80 mg | Neratinib 120 mg | Neratinib 180 mg | Neratinib 240 mg | Neratinib 320 mg | Neratinib 400 mg | Neratinib 40 mg | Neratinib MTD | Total |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 4 Participants | 0 Participants | 0 Participants | 11 Participants | 18 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 2 Participants | 5 Participants | 3 Participants | 3 Participants | 6 Participants | 3 Participants | 28 Participants | 54 Participants |
| Age, Continuous | 54.00 years STANDARD_DEVIATION 7.66 | 56.25 years STANDARD_DEVIATION 20.43 | 60.67 years STANDARD_DEVIATION 15.31 | 57.00 years STANDARD_DEVIATION 8.89 | 63.71 years STANDARD_DEVIATION 15.7 | 51.33 years STANDARD_DEVIATION 8.91 | 51.33 years STANDARD_DEVIATION 12.5 | 58.18 years STANDARD_DEVIATION 11.05 | 57.68 years STANDARD_DEVIATION 12.06 |
| Sex: Female, Male Female | 4 Participants | 3 Participants | 6 Participants | 2 Participants | 5 Participants | 4 Participants | 2 Participants | 26 Participants | 52 Participants |
| Sex: Female, Male Male | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants | 2 Participants | 1 Participants | 13 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 4 / 4 | 4 / 4 | 6 / 6 | 3 / 3 | 7 / 7 | 6 / 6 | 39 / 39 |
| serious Total, serious adverse events | 3 / 3 | 1 / 4 | 1 / 4 | 2 / 6 | 0 / 3 | 4 / 7 | 2 / 6 | 14 / 39 |
Outcome results
Primary
Dose Limiting Toxicity (DLT)
DLT is defined as any neratinib-related nonhematologic grade 3 or any grade 4 adverse event (AE) according to the National Cancer Institute (NCI) common terminology criteria (CTC) for AEs version 3.0. DLTs were assessed from the first single dose to 14 days of continuous daily administration.
Time frame: From first dose date to day 14
Population: Subjects in the dosing groups 40 mg through 400 mg, excluding the selection of MTD.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Neratinib 40 mg | Dose Limiting Toxicity (DLT) | 0 Participants |
| Neratinib 80 mg | Dose Limiting Toxicity (DLT) | 0 Participants |
| Neratinib 120 mg | Dose Limiting Toxicity (DLT) | 0 Participants |
| Neratinib 180 mg | Dose Limiting Toxicity (DLT) | 1 Participants |
| Neratinib 240 mg | Dose Limiting Toxicity (DLT) | 0 Participants |
| Neratinib 320 mg | Dose Limiting Toxicity (DLT) | 0 Participants |
| Neratinib 400 mg | Dose Limiting Toxicity (DLT) | 4 Participants |
Primary
Maximum Tolerated Dose (MTD)
If 2 or more, of 3 to 6 subjects, at a dose level had an neratinib-related dose limiting toxicity (DLT) by day 14 of continuous daily dose administration, dose escalation stopped and the prior dose level was considered the MTD.
Time frame: From first dose date to day 14
Population: All patients receiving neratinib in the dose escalation part of the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Neratinib 40 mg | Maximum Tolerated Dose (MTD) | 320 mg |
Secondary
Clinical Benefit Rate
Patients with PR or higher responses or SD\>=24 weeks, evaluable population
Time frame: From first dose date to progression/death or last assessment, up to 39 weeks.
Population: Breast, Lung and other solid tumors included in the efficacy evaluable population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Neratinib 40 mg | Clinical Benefit Rate | 36.0 percentage of participants |
| Neratinib 80 mg | Clinical Benefit Rate | 42.9 percentage of participants |
| Neratinib 120 mg | Clinical Benefit Rate | 25.0 percentage of participants |
Secondary
Duration of Response
Duration of response of responders (PR+) by Kaplan-Meier estimate
Time frame: From start date of response to first PD, up to 39 weeks.
Population: Subjects responses classified as complete response or partial response in evaluable population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Neratinib 40 mg | Duration of Response | 4.8 months |
| Neratinib 120 mg | Duration of Response | 4.8 months |
Secondary
Number of Participants With Best Overall Response
Best Overall response by tumor type, evaluable population per Response Evaluation Criteria In Solid Tumors Criteria v1.0 for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in sum of the longest diameter (LD) of target lesions in reference to baseline sum of LD of target lesions; Progressive Disease (PD), \>=20% increase in sum of LD of target lesions, taking as reference the smallest sum of recorded LD of target lesions since treatment started or appearance of 1 or more new lesions; Stable disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of LD of target lesions since the treatment start. The best overall response was the best response recorded from start of treatment until PD/recurrence. In general, the subject's best response assignment depended on achievement of both measurement and confirmation criteria.
Time frame: From first dose date to progression or last tumor assessment, up to 39 weeks.
Population: Subjects who had received at least 14 days of continuous dose administration of test article and who had undergone at least 1 follow-up tumor assessment, evaluable population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Neratinib 40 mg | Number of Participants With Best Overall Response | Stable Disease >=8 weeks | 4 Participants |
| Neratinib 40 mg | Number of Participants With Best Overall Response | Stable Disease >=16 weeks | 1 Participants |
| Neratinib 40 mg | Number of Participants With Best Overall Response | Partial Response | 8 Participants |
| Neratinib 40 mg | Number of Participants With Best Overall Response | Stable Disease >=24 weeks | 1 Participants |
| Neratinib 40 mg | Number of Participants With Best Overall Response | Progressive Disease | 11 Participants |
| Neratinib 80 mg | Number of Participants With Best Overall Response | Stable Disease >=16 weeks | 0 Participants |
| Neratinib 80 mg | Number of Participants With Best Overall Response | Partial Response | 0 Participants |
| Neratinib 80 mg | Number of Participants With Best Overall Response | Stable Disease >=24 weeks | 6 Participants |
| Neratinib 80 mg | Number of Participants With Best Overall Response | Stable Disease >=8 weeks | 2 Participants |
| Neratinib 80 mg | Number of Participants With Best Overall Response | Progressive Disease | 6 Participants |
| Neratinib 120 mg | Number of Participants With Best Overall Response | Progressive Disease | 32 Participants |
| Neratinib 120 mg | Number of Participants With Best Overall Response | Stable Disease >=8 weeks | 9 Participants |
| Neratinib 120 mg | Number of Participants With Best Overall Response | Partial Response | 8 Participants |
| Neratinib 120 mg | Number of Participants With Best Overall Response | Stable Disease >=16 weeks | 4 Participants |
| Neratinib 120 mg | Number of Participants With Best Overall Response | Stable Disease >=24 weeks | 7 Participants |
Secondary
Objective Response Rate
Patients with PR or higher responses, evaluable population
Time frame: From first dose date to progression/death or last assessment, up to 39 weeks
Population: Breast, Lung and other solid tumors included in the efficacy evaluable population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Neratinib 40 mg | Objective Response Rate | 32.0 percentage of participants |
| Neratinib 80 mg | Objective Response Rate | 0 percentage of participants |
| Neratinib 120 mg | Objective Response Rate | 13.3 percentage of participants |
Secondary
Progression Free Survival
Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: From first dose date to progression or death, up to 39 weeks.
Population: All subjects who were assigned to treatment, received at least 14 days of continuous dose administration of test article, and who had undergone at least 1 follow-up tumor assessment, evaluable population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Neratinib 40 mg | Progression Free Survival | 3.6 months |
| Neratinib 80 mg | Progression Free Survival | 3.5 months |
| Neratinib 120 mg | Progression Free Survival | 1.9 months |