Advanced Malignant Solid Tumors
Conditions
Keywords
HKI-272, Paclitaxel, Combination, Solid Tumor
Brief summary
This is an open-label, phase 1 study of ascending multiple oral doses of HKI-272 in combination with paclitaxel.
Interventions
DRUGNeratinib
Administered orally, continuous, once daily.
DRUGPaclitaxel
Administered IV, on days 1, 8, 15 of 28 day cycle.
Sponsors
Puma Biotechnology, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subjects must have confirmed pathologic diagnosis of a solid tumor that is not curable with available therapy for which HKI-272 plus paclitaxel is a reasonable treatment option. * At least 1 measurable lesion as defined by RECIST criteria. * Eastern Cooperative Oncology Group (ECOG) 0 to 1 * LVEF within institutional limits of normal (by MUGA or ECHO). * Screening laboratory values within the following parameters: * ANC: greater than or equal to 1.5 x 10E9 /L (1,500 /mm3) * Platelet count: 10 x 10E10 /L (100,000 /mm3) * Hemoglobin: greater than or equal to 9.0 g/dL * Serum creatinine: less than or equal to 1.5 x upper limit of normal (ULN) * Total bilirubin: less than or equal to 1.5 xULN · AST and ALT: less than or equal to 2.5 xULN (less than or equal to 5 x ULN if liver metastases are present) * For women of child bearing potential, a negative urine or serum pregnancy test result before study entry. A woman of childbearing potential is one who is biologically capable of becoming pregnant. This includes women who are using contraceptives or other means of birth control or whose sexual partners are either sterile or using contraceptives. * All subjects who are not surgically sterile or postmenopausal 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.
Exclusion criteria
* Prior treatment with anthracyclines with a cumulative dose of doxorubicin of greater than 400 mg/m\^2, epirubicin dose of greater than 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 2 weeks of treatment day 1 or non-recovery from all clinically significant acute adverse effects of prior therapies (excluding alopecia). * Subjects with bone or skin as the only site of disease. * Active central nervous system (CNS) 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 have been clinically stable for at least three months, and off steroids or anticonvulsants, before first dose of test article). * QTc interval greater than 0.47 second or known history of QTc prolongation or Torsade de Pointes (TdP). * Known hypersensitivity to paclitaxel or Cremophor EL (polyoxyethylated castor oil). * Pregnant or breast feeding women. * Significant chronic or recent acute gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn's disease, malabsorption, or Grade greater than or equal to 2 diarrhea of any etiology at baseline). * Inability or unwillingness to swallow the HKI-272. * Treatment with a taxane within 3 months of treatment day 1. * Pre-existing grade 2 or greater motor or sensory neuropathy. * 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. * Presence of clinically significant or uncontrolled cardiac disease, including congestive heart failure (New York Heart Association \[NYHA\] functional classification of greater than or equal to 2), angina requiring treatment, myocardial infarction within the past 12 months, or any clinically significant supraventricular arrhythmia or ventricular arrhythmia requiring treatment or intervention. * 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), uncontrolled major seizure disorder, or significant pulmonary disorder (e.g. interstitial pneumonitis, pulmonary hypertension).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Limiting Toxicity (DLT) - Percentage of Participants With DLT Events | From first dose day through day 28. | The incidence of DLTs in subjects with advanced solid tumors, treated with neratinib in combination with paclitaxel 80 mg/m\^2. DLT was defined as any neratinib plus paclitaxel related Grade 3 or 4 nonhematologic toxicity or Grade 4 hematologic toxicity with few exceptions. |
| Maximum Tolerated Dose | From first dose day through day 28. | The maximum tolerated dose of neratinib, as determined by the incidence of DLTs, in combination with paclitaxel 80 mg/m\^2, in subjects with advanced solid tumors. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate | From first dose date to progression/death or last tumor assessment, up to 78 weeks. | 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. |
| Progression Free Survival | From first dose date to progression/death, up to 78 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. 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 disease progression, up to 71 weeks. | Number of weeks from the time at which measurement criteria are met for Complete Response (CR) or Partial Response (PR) (whichever status is recorded first) until the first date on which recurrence or progressive disease (PD) is objectively documented, taking as reference for PD the smallest measurements recorded since the treatment started, for responders only, per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v.1.0: CR, disappearance of all target lesions; 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
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Nera 160 + Pac Neratinib 160 mg + Paclitaxel 80 mg/m\^2 | 3 |
| Nera 240 + Pac Neratinib 240 mg + Paclitaxel 80 mg/m\^2 | 7 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 |
| Overall Study | Disease Progression | 3 | 4 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Nera 240 + Pac | Nera 160 + Pac | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 0 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 3 Participants | 9 Participants |
| Age, Continuous | 53.14 years STANDARD_DEVIATION 8.07 | 49.67 years STANDARD_DEVIATION 10.12 | 52.10 years STANDARD_DEVIATION 8.31 |
| Race/Ethnicity, Customized Japanese | 7 Participants | 3 Participants | 10 Participants |
| Sex: Female, Male Female | 7 Participants | 2 Participants | 9 Participants |
| Sex: Female, Male Male | 0 Participants | 1 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 7 / 7 |
| serious Total, serious adverse events | 0 / 3 | 1 / 7 |
Outcome results
Primary
Dose Limiting Toxicity (DLT) - Percentage of Participants With DLT Events
The incidence of DLTs in subjects with advanced solid tumors, treated with neratinib in combination with paclitaxel 80 mg/m\^2. DLT was defined as any neratinib plus paclitaxel related Grade 3 or 4 nonhematologic toxicity or Grade 4 hematologic toxicity with few exceptions.
Time frame: From first dose day through day 28.
Population: Patients with at least one dose of neratinib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nera 160 + Pac | Dose Limiting Toxicity (DLT) - Percentage of Participants With DLT Events | 0 percentage of participants. |
| Nera 240 + Pac | Dose Limiting Toxicity (DLT) - Percentage of Participants With DLT Events | 0 percentage of participants. |
Primary
Maximum Tolerated Dose
The maximum tolerated dose of neratinib, as determined by the incidence of DLTs, in combination with paclitaxel 80 mg/m\^2, in subjects with advanced solid tumors.
Time frame: From first dose day through day 28.
Population: Patients with at least one dose of neratinib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nera 160 + Pac | Maximum Tolerated Dose | 240 mg |
Secondary
Duration of Response
Number of weeks from the time at which measurement criteria are met for Complete Response (CR) or Partial Response (PR) (whichever status is recorded first) until the first date on which recurrence or progressive disease (PD) is objectively documented, taking as reference for PD the smallest measurements recorded since the treatment started, for responders only, per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v.1.0: CR, disappearance of all target lesions; 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 disease progression, up to 71 weeks.
Population: Patients with Partial Response (PR) or Complete Response (CR) in the evaluable population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nera 160 + Pac | Duration of Response | 70.1 weeks |
| Nera 240 + Pac | Duration of Response | 33.1 weeks |
Secondary
Objective Response Rate
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/death or last tumor assessment, up to 78 weeks.
Population: Subjects who met the eligibility criteria, received at least 2 weeks of neratinib and at least 2 doses of paclitaxel, and underwent at least 1 follow-up tumor assessment at approximately cycle 2 (week 8). In the case of disease progression prior to week 8, a clinical assessment of progressive disease (PD) was adequate.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nera 160 + Pac | Objective Response Rate | 33.3 percentage of participants |
| Nera 240 + Pac | Objective Response Rate | 50.0 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. 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/death, up to 78 weeks.
Population: Subjects who met the eligibility criteria, received at least 2 weeks of neratinib and at least 2 doses of paclitaxel, and underwent at least 1 follow-up tumor assessment at approximately cycle 2 (week 8). In the case of disease progression prior to week 8, a clinical assessment of progressive disease was adequate.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nera 160 + Pac | Progression Free Survival | 15.9 weeks |
| Nera 240 + Pac | Progression Free Survival | 37.1 weeks |