Carcinoma, Non-Small-Cell Lung, Lung Neoplasms
Conditions
Keywords
Lung Cancer, HKI-272, Neratinib, Nerlynx
Brief summary
The purpose of this study is to learn whether HKI-272 is safe and effective in treating non-small cell lung cancer.
Interventions
DRUGHKI-272
320mg or 240mg daily by mouth. The starting dose was reduced from 320mg to 240mg per amendment #1 to the protocol for subject safety and tolerability.
Sponsors
Puma Biotechnology, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Pathologic diagnosis of NSCLC and current stage IIIB (with pleural effusion) or IV, not curable with conventional therapy. For Arm C, less than or equal to 20 pack-years smoking history and current non smoker. A pack year = number of packs of cigarettes smoked per day x years smoked. * Progression following at least 12 weeks of treatment with Tarceva or Iressa. (Arms A and B only) * ECOG (Eastern Cooperative Oncology Group) performance status of 0, 1, or 2 (not declining within past 2 weeks). * Tumor sample available and adequate for analysis. * At least one measurable target lesion. * Adequate cardiac, kidney, and liver function * Adequate blood counts
Exclusion criteria
* More than 3 prior cytotoxic chemotherapy treatments for relapsed or metastatic disease. * Significant cardiac disease or dysfunction. * Prior treatment with anthracyclines with cumulative dose of \>400 mg/m\^2. * Active central nervous system metastases, as indicated by clinical symptoms and/or progressive growth. * Use of Tarceva or Iressa within 14 days of treatment day 1 (Arms A and B only). * Major surgery, chemotherapy, radiotherapy, investigational drugs, or other cancer therapy within 3 weeks of treatment day 1. * Significant chronic or recent acute gastrointestinal disorder with diarrhea as a major symptom. * Inability or unwillingness to swallow HKI-272 capsules. * Pregnant or breastfeeding women.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate for Neratinib in Patients With Non-small Cell Lung Cancer | From first dose date to progression/death or last tumor assessment, up to three years. | Objective response rate as reported by Independent Assessment (radiographic review by independent radiologists) 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Benefit Rate for Neratinib in Patients With Non-small Cell Lung Cancer | From first dose date to progression/death or last tumor assessment, up to three years. | Clinical benefit rate is the percentage of patients with Partial or Complete Response, or with Stable Disease \>= 12 Weeks 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; Stable Disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. |
| Duration of Response for Neratinib in Patients With Non-small Cell Lung Cancer | From start date of response to first PD, assessed up to three years after the first randomization. | Measured from the time at which measurement criteria were first met for CR or PR (whichever status was recorded first), until the date of first recurrence, PD, or death was objectively documented, taking as a reference for PD the smallest measurements recorded since enrollment, 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. |
| Progression Free Survival for Neratinib in Patients With Non-small Cell Lung Cancer | From first dose date to progression/death, assessed up to three years. | Defined as the interval from the date of randomization until the first date on which recurrence or progression, or death due to any cause, is documented, censored at the last assessable evaluation or at the initiation of new anticancer therapy. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v 1.0 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. |
Countries
France, Hungary, Poland, Spain, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Prior Tarceva or Iressa With EGFR Mutation Patients whose disease has progressed following \> or = 12 weeks of treatment with Tarceva or Iressa and who have a tumor with an EGFR mutation demonstrated at screening
HKI-272: 320mg or 240mg daily by mouth. The starting dose was reduced from 320mg to 240mg per amendment #1 to the protocol for subject safety and tolerability. | 91 |
| Prior Tarceva or Iressa w/o EGFR Mutation Patients whose disease has progressed following \> or = 12 weeks of treatment with Tarceva or Iressa and who have a tumor without an EGFR mutation demonstrated at screening
HKI-272: 320mg or 240mg daily by mouth. The starting dose was reduced from 320mg to 240mg per amendment #1 to the protocol for subject safety and tolerability. | 48 |
| No Prior EGFR Tyrosine Kinase Inhibitor Treatment Patients with no prior EGFR tyrosine kinase inhibitor treatment, adenocarcinoma, \< or = 20 pack-year smoking history, and current non-smoker (no requirement for EGFR mutation)
HKI-272: 320mg or 240mg daily by mouth. The starting dose was reduced from 320mg to 240mg per amendment #1 to the protocol for subject safety and tolerability. | 28 |
| Total | 167 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 6 | 4 | 1 |
| Overall Study | Concomitant Radiotherapy | 0 | 1 | 0 |
| Overall Study | Death | 1 | 1 | 1 |
| Overall Study | Disease Progression | 72 | 37 | 23 |
| Overall Study | Hospitalization | 1 | 0 | 0 |
| Overall Study | Physician Decision | 2 | 1 | 1 |
| Overall Study | Symptomatic Deterioration | 6 | 3 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 1 | 1 |
Baseline characteristics
| Characteristic | Prior Tarceva or Iressa With EGFR Mutation | Prior Tarceva or Iressa w/o EGFR Mutation | No Prior EGFR Tyrosine Kinase Inhibitor Treatment | Total |
|---|---|---|---|---|
| Age, Customized < 60 years | 45 Participants | 24 Participants | 13 Participants | 82 Participants |
| Age, Customized >= 60 years | 46 Participants | 24 Participants | 15 Participants | 85 Participants |
| Sex: Female, Male Female | 74 Participants | 26 Participants | 18 Participants | 118 Participants |
| Sex: Female, Male Male | 17 Participants | 22 Participants | 10 Participants | 49 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 | 91 / 91 | 46 / 48 | 26 / 28 |
| serious Total, serious adverse events | 33 / 91 | 21 / 48 | 14 / 28 |
Outcome results
Primary
Objective Response Rate for Neratinib in Patients With Non-small Cell Lung Cancer
Objective response rate as reported by Independent Assessment (radiographic review by independent radiologists) 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/death or last tumor assessment, up to three years.
Population: modified ITT: Subjects who were randomized and who had taken at least 1 dose of neratinib; equivalent to the safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Prior Tarceva or Iressa With EGFR Mutation | Objective Response Rate for Neratinib in Patients With Non-small Cell Lung Cancer | 3.3 percentage of participants |
| Prior Tarceva or Iressa w/o EGFR Mutation | Objective Response Rate for Neratinib in Patients With Non-small Cell Lung Cancer | 0 percentage of participants |
| No Prior EGFR Tyrosine Kinase Inhibitor Treatment | Objective Response Rate for Neratinib in Patients With Non-small Cell Lung Cancer | 3.6 percentage of participants |
Secondary
Clinical Benefit Rate for Neratinib in Patients With Non-small Cell Lung Cancer
Clinical benefit rate is the percentage of patients with Partial or Complete Response, or with Stable Disease \>= 12 Weeks 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; Stable Disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Time frame: From first dose date to progression/death or last tumor assessment, up to three years.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Prior Tarceva or Iressa With EGFR Mutation | Clinical Benefit Rate for Neratinib in Patients With Non-small Cell Lung Cancer | 9.9 percentage of participants |
| Prior Tarceva or Iressa w/o EGFR Mutation | Clinical Benefit Rate for Neratinib in Patients With Non-small Cell Lung Cancer | 6.3 percentage of participants |
| No Prior EGFR Tyrosine Kinase Inhibitor Treatment | Clinical Benefit Rate for Neratinib in Patients With Non-small Cell Lung Cancer | 10.7 percentage of participants |
Secondary
Duration of Response for Neratinib in Patients With Non-small Cell Lung Cancer
Measured from the time at which measurement criteria were first met for CR or PR (whichever status was recorded first), until the date of first recurrence, PD, or death was objectively documented, taking as a reference for PD the smallest measurements recorded since enrollment, 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, assessed up to three years after the first randomization.
Population: Number of subjects with PR or higher response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Prior Tarceva or Iressa With EGFR Mutation | Duration of Response for Neratinib in Patients With Non-small Cell Lung Cancer | 54.1 weeks |
| No Prior EGFR Tyrosine Kinase Inhibitor Treatment | Duration of Response for Neratinib in Patients With Non-small Cell Lung Cancer | 28.7 weeks |
Secondary
Progression Free Survival for Neratinib in Patients With Non-small Cell Lung Cancer
Defined as the interval from the date of randomization until the first date on which recurrence or progression, or death due to any cause, is documented, censored at the last assessable evaluation or at the initiation of new anticancer therapy. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v 1.0 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/death, assessed up to three years.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Prior Tarceva or Iressa With EGFR Mutation | Progression Free Survival for Neratinib in Patients With Non-small Cell Lung Cancer | 15.3 weeks |
| Prior Tarceva or Iressa w/o EGFR Mutation | Progression Free Survival for Neratinib in Patients With Non-small Cell Lung Cancer | 16.1 weeks |
| No Prior EGFR Tyrosine Kinase Inhibitor Treatment | Progression Free Survival for Neratinib in Patients With Non-small Cell Lung Cancer | 9.3 weeks |