Advanced Malignant Solid Tumors
Conditions
Keywords
HKI-272, Vinorelbine, Combination, Solid Tumor, Neratinib, Nerlynx, PB-272
Brief summary
The purposes of this study are to evaluate the safety and tolerability of neratinib in combination with vinorelbine at the maximum tolerated dose (MTD) determined in a previous study, or to determine a lower MTD 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 in Japanese patients.
Interventions
DRUGNeratinib
DRUGVinorelbine
Sponsors
Puma Biotechnology, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 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 neratinib plus vinorelbine is a reasonable treatment option. * At least 1 measurable lesion as defined by Response Evaluation Criteria in Solid Tumors. * Eastern Cooperative Oncology Group performance status of 0 to 2 (not declining within 2 weeks before signing the informed consent form). * Recovery from all clinically significant AEs related to prior therapies (excluding alopecia). * Left ventricular ejection fraction within the study site's limits of normal. * Screening laboratory values within the following parameters: * Absolute neutrophil count: 1.5 × 109/L * Platelet count: 100 × 109/L * Hemoglobin: 9.0 g/dL * Serum creatinine: 1.5 × upper limit of normal * Total bilirubin: 1.5 × ULN * Aspartate aminotransferase and alanine aminotransferase: 2.5 × ULN (\<= 5 × ULN if liver metastases are present). * For women of childbearing potential, a negative urine or serum pregnancy test result before study entry. * All female and male subjects who are biologically capable of having children must agree and commit to the use of a reliable method of birth control for the duration of the study and for 28 days after the last dose of test article. A subject is biologically capable of having children if he or she is using contraceptives or if his or her sexual partner is sterile or using contraceptives.
Exclusion criteria
* Prior treatment with anthracyclines with a cumulative dose of doxorubicin of \>400 mg/m\^2, or of epirubicin \>800 mg/m\^2, or the equivalent dose for other anthracyclines or derivatives. * Major surgery, chemotherapy, radical (curative intent) radiotherapy, investigational agents, or other cancer therapy within at least 2 weeks before treatment day 1. * Bone as the only site of disease. * Active central nervous system metastases, as indicated by clinical symptoms, cerebral edema, and/or progressive growth. (Subjects with a history of CNS metastases or cord compression are allowable if they have been definitively treated and are off anticonvulsants and steroids for at least 4 weeks before cycle 1 day 1) . * QT (QTc) interval \> 0.47 s or a known history of QTc prolongation or Torsades de Pointes. * Presence of clinically significant or uncontrolled cardiac disease, including congestive heart failure (New York Heart Association functional classification of =2), angina requiring treatment, myocardial infarction within the past 12 months, or any clinically significant supraventricular arrhythmia or ventricular arrhythmia requiring treatment or intervention. * Pregnant or breastfeeding women. Significant chronic or recent acute gastrointestinal disorder with diarrhea as a major symptom (eg, Crohn disease, malabsorption, or grade 2 diarrhea of any etiology at baseline). * Inability or unwillingness to swallow tablets (neratinib). * Preexisting grade 2 or greater motor or sensory neuropathy. * Subject known to be human immunodeficiency virus seropositive and/or have acute or chronic hepatitis B infection (hepatitis B surface antigen \[HBsAg\] positive) or hepatitis C infection (anti-HCV positive). * History of known hypersensitivity to vinorelbine and any of its components. * Any other cancer within 5 years prior to screening with the exception of contralateral breast carcinoma, adequately treated cervical carcinoma in situ, or adequately treated basal or squamous cell carcinoma of the skin. * Clinically significant ongoing or recent infection within 2 weeks before treatment day 1. * Evidence of significant medical illness or abnormal laboratory finding that would, in the investigator's judgment, make the subject inappropriate for this study. Examples include, but are not limited to, serious active infection (ie, requiring intravenous antibiotic or antiviral agent) or uncontrolled major seizure.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Limiting Toxicity (DLT) | From first dose date to 21st day | Number of participants experiencing DLT of neratinib in combination with vinorelbine in Japanese patients. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Terminal-phase Elimination Half-life | Predose, and hour 1, 2, 4, 6, 8 and 24 on day 8. | Terminal-phase elimination half-life of Neratinib at day 8 following Administration of Neratinib 240 mg in combination with Vinorelbine 25 mg/m\^2 to Japanese Subjects with Cancer. |
| Duration of Objective Response | From first response date to PD/death, up to 40 weeks. | The duration of objective response was measured from the time at which measurement criteria were met for Complete Response (CR) or Partial Response (PR) (whichever status was recorded first) until the first date on which recurrence or Progressive Disease (PD) was objectively documented, taking as reference for PD the smallest measurements recorded since the treatment started. |
| Best Overall Response | From first dose date to progression or last tumor assessment, up to 40 weeks. | Best Overall Response in Evaluable Population per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. |
| Progression Free Survival | From first dose to last evaluation, up to 40 weeks. | 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. Disease Progression (PD) is defined using Response Evaluation Criteria in Solid Tumors Criteria (v1.0), 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. |
| Area Under the Curve (AUC) Tau | Predose, and hour 1, 2, 4, 6, 8 and 24 on day 8. | AUC of Neratinib at day 8 following administration of Neratinib 240 mg in combination with Vinorelbine 25 mg/m\^2 to Japanese Subjects with Cancer. |
| Objective Response Rate (ORR) | From first dose date to progression or last tumor assessment, up to 40 weeks. | Proportion of subjects who achieved complete response or partial response per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Nera 240 + Vino 25 Neratinib 240 mg + Vinorelbine 25 mg/m\^2 | 6 |
| Total | 6 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Disease Progression | 6 |
Baseline characteristics
| Characteristic | Nera 240 + Vino 25 |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants |
| Age, Continuous | 54 years STANDARD_DEVIATION 13.37 |
| Race/Ethnicity, Customized Japanese | 6 Participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 6 / 6 |
| serious Total, serious adverse events | 1 / 6 |
Outcome results
Primary
Dose Limiting Toxicity (DLT)
Number of participants experiencing DLT of neratinib in combination with vinorelbine in Japanese patients.
Time frame: From first dose date to 21st day
Population: Safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nera 240 + Vino 25 | Dose Limiting Toxicity (DLT) | 1 participants |
Secondary
Area Under the Curve (AUC) Tau
AUC of Neratinib at day 8 following administration of Neratinib 240 mg in combination with Vinorelbine 25 mg/m\^2 to Japanese Subjects with Cancer.
Time frame: Predose, and hour 1, 2, 4, 6, 8 and 24 on day 8.
Population: Population for pharmacokinetic analyses consisted of all subjects in this study who received at least 1 dose of neratinib and provided samples for pharmacokinetic assessments.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nera 240 + Vino 25 | Area Under the Curve (AUC) Tau | 1330 ng*hr/mL | Standard Deviation 925 |
Secondary
Best Overall Response
Best Overall Response in Evaluable Population per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time frame: From first dose date to progression or last tumor assessment, up to 40 weeks.
Population: Subjects who met eligibility criteria, received at least 2 weeks of continual daily dosing of neratinib, at least 2 doses of vinorelbine, and underwent at least 1 follow-up tumor assessment at 6 weeks, ie, approximately at cycle 2. In the case of disease progression prior to 6 weeks, a clinical assessment of progressive disease was adequate.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Nera 240 + Vino 25 | Best Overall Response | Partial Response | 1 Participants |
| Nera 240 + Vino 25 | Best Overall Response | Stable Disease >= 6 weeks | 5 Participants |
| Nera 240 + Vino 25 | Best Overall Response | Stable Disease >= 24 weeks | 1 Participants |
Secondary
Duration of Objective Response
The duration of objective response was measured from the time at which measurement criteria were met for Complete Response (CR) or Partial Response (PR) (whichever status was recorded first) until the first date on which recurrence or Progressive Disease (PD) was objectively documented, taking as reference for PD the smallest measurements recorded since the treatment started.
Time frame: From first response date to PD/death, up to 40 weeks.
Population: Subjects who had a partial or complete response
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nera 240 + Vino 25 | Duration of Objective Response | 12.0 weeks |
Secondary
Objective Response Rate (ORR)
Proportion of subjects who achieved complete response or partial response per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time frame: From first dose date to progression or last tumor assessment, up to 40 weeks.
Population: Safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nera 240 + Vino 25 | Objective Response Rate (ORR) | 16.7 percentage of participants |
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. Disease Progression (PD) is defined using Response Evaluation Criteria in Solid Tumors Criteria (v1.0), 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 to last evaluation, up to 40 weeks.
Population: Subjects who met eligibility criteria, received at least 2 weeks of continual daily dosing of neratinib and at least 2 doses of vinorelbine, and underwent at least 1 follow-up tumor assessment at 6 weeks, i.e., approximately at cycle 2. In the case of disease progression prior to 6 weeks, a clinical assessment of PD was adequate.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nera 240 + Vino 25 | Progression Free Survival | 18.2 weeks |
Secondary
Terminal-phase Elimination Half-life
Terminal-phase elimination half-life of Neratinib at day 8 following Administration of Neratinib 240 mg in combination with Vinorelbine 25 mg/m\^2 to Japanese Subjects with Cancer.
Time frame: Predose, and hour 1, 2, 4, 6, 8 and 24 on day 8.
Population: Population for pharmacokinetic analyses consisted of all subjects in this study who received at least 1 dose of neratinib and provided samples for pharmacokinetic assessments.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nera 240 + Vino 25 | Terminal-phase Elimination Half-life | 14.37 hr | Standard Deviation 3.41 |