Study Evaluating Safety And Tolerability, Solid Tumor

Study Overview
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Brief Summary
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This is an open-label, phase 1 study of ascending multiple oral doses of HKI-272 in combination with paclitaxel.

Official Title
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A Phase 1 Study Of Neratinib (HKI-272) In Combination With Paclitaxel In Subjects With Solid Tumors

Conditions
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Advanced Malignant Solid Tumors

Intervention / Treatment
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* Drug: Neratinib
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nera 160 + Pac<br>Neratinib 160 mg + Paclitaxel 80 mg/m^2 | Drug: Neratinib<br>* Administered orally, continuous, once daily.<br>* Other names: HKI-272;Drug: Paclitaxel<br>* Administered IV, on days 1, 8, 15 of 28 day cycle.<br>|
| Experimental: Nera 240 + Pac<br>Neratinib 240 mg + Paclitaxel 80 mg/m^2 | Drug: Neratinib<br>* Administered orally, continuous, once daily.<br>* Other names: HKI-272;Drug: Paclitaxel<br>* Administered IV, on days 1, 8, 15 of 28 day cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From first dose day through day 28. | 
| 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. | From first dose day through day 28. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From first dose date to progression/death or last tumor assessment, up to 78 weeks. | 
| 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. | From first dose date to progression/death, up to 78 weeks. | 
| 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. | From start date of response to first disease progression, up to 71 weeks. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HKI-272, Paclitaxel, Combination, Solid Tumor