A Study Of Neratinib (HKI-272) And Capecitabine In Japane... | NCT01128842

NCT01128842

Protocol Section

Identification Module

Results Section

Participant Flow Module

Annotation Section

No data available

No data is available for this block.

Document Section

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No data is available for this block.

Derived Section

Miscellaneous Info Module

Status Module

Label	Type	Description	Intervention Names
Neratinib + Capecitabine	Experimental	Neratinib + Capecitabine	Drug: Neratinib Drug: Capecitabine

Name	Type	Description	Arm Group Labels	Other Names
Neratinib	Drug	240 mg once daily by mouth.	Neratinib + Capecitabine

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Dose Limiting Toxicity (DLT) - Percentage of Participants With DLT Events	DLT was defined as 1. Grade 3 or 4 non-hematologic toxicity (exceptions listed below as a.-c.), a. Grade 3 asthenia was NOT considered to be a DLT UNLESS it lasted >3 days. b. Grade 3 nausea or vomiting was NOT considered to be a DLT UNLESS the subject was already receiving optimal medical therapy. c. Grade 3 or 4 infection was NOT considered to be a DLT UNLESS it is associated with grade 3 or 4 neutropenia. 2. Grade 3 diarrhea that lasted >2 days while the subject was on optimal medical therapy or that was associated with fever (greater than or equal 38.0 ºC) or grade 3 dehydration. 3. Grade 4 neutropenia lasting ≥3 days or grade 4 febrile neutropenia. 4. Grade 4 thrombocytopenia lasting ≥3 days or complicated with bleeding or requiring platelet transfusion. 5. Delayed recovery (to National Cancer Institute [NCI] grade 1 or less, or baseline) from any of the toxicities listed above (items 1-4), that was related to study drug, and that delayed the next dose by more than 3 weeks.	From first dose date to day 21.
Tolerated Dose	Six subjects will be initially enrolled (neratinib 240 mg/day; capecitabine 1500 mg/m²/day on days 1 through 14). AEs and DLTs will be assessed from the first dose of investigational product through day 21. Based on the DLT rate in these first 6 subjects, dose tolerability will be confirmed as follows: If ≤1 of the first 6 evaluable subjects experience a DLT by day 21, then this dose is considered tolerable, and enrollment will stop. If ≥3 of the first 6 evaluable subjects experience a DLT by day 21, this dose is considered intolerable. If 2 of the first 6 evaluable subjects experience a DLT by day 21, then an additional 4 subjects will be enrolled at the same dose level. If a total of 10 subjects are enrolled, then the tolerability will be confirmed as follows: If ≤3 of the total 10 subjects experience a DLT by day 21, then this dose will be considered tolerable. If ≥4 of the total 10 subjects experience a DLT by day 21, then the dose will be considered intolerable.	From first dose date to day 21.

Secondary Outcomes

Measure	Description	Time Frame
Best Overall Response	Number of participants with Partial Response (PR) or Complete Response (CR) per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) (v1.0) criteria. CR: Disappearance of all lesions; PR: at least a 30% decrease in the sum of longest diameters (SLD) of target lesions, taking as reference the baseline SLD; Progressive Disease (PD): at least a 20% increase in the SLD of target lesions, taking as reference the nadir longest diameter, meaning the smallest SLDs recorded since the treatment started, or the appearance of 1 or more new lesions, or unequivocal progression of existing nontarget lesions; and stable disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SLD since treatment started.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Male and female subjects 20 years and older
Confirmed pathologic diagnosis of a solid tumor not curable with currently available therapies, for which neratinib plus capecitabine is a reasonable treatment option.
At least 1 measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria (Please note: ascites, pleural or pericardial effusion, osteoblastic bone metastases, and carcinomatous lymphangitis of the lung will not be considered measurable lesions).
Subjects with skin lesions that are measurable by computed tomography (CT) scans or magnetic resonance imaging (MRI) as the only site of measurable disease are allowed.
Recovery from all clinically significant adverse events (AEs) related to prior therapies (excluding alopecia).
Left ventricular ejection fraction (LVEF) within institutional range of normal as measured by multi-gated acquisition (MUGA) or echocardiogram (ECHO).
Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 (not declining within 2 weeks before signing the informed consent form [ICF]).

Screening lab values within the following parameters: Absolute neutrophil count (ANC): 1.5×109/L (1500/mm3) Platelet count: 100×109/L (100,000/mm3) Hemoglobin: 9.0 g/dL (90 g/L) Serum creatinine: 01.5×upper limit of normal (ULN) Total bilirubin: 1.5×ULN (<3 ULN if Gilbert's disease) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT): 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 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 investigational product. 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 >400 mg/m², or of epirubicin >800 mg/m², or the equivalent dose for other anthracyclines or derivatives.
Major surgery, chemotherapy, radiotherapy, any investigational agents, or other cancer therapy within at least 2 weeks before administration of the first dose of investigational product.
Bone 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 permitted if they have been definitively treated and are off anticonvulsants and steroids for at least 4 weeks before cycle 1 day 1).

QT (corrected QT (QTc)) interval >0.47seconds 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 [NYHA] functional classification of 02), 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's disease, malabsorption, or grade 2 or higher diarrhea of any etiology at baseline).
Inability or unwillingness to swallow tablets (neratinib and capecitabine).
Subjects with active or uncontrolled renal insufficiency, in whom medication dose adjustments are indicated.
Subject known to be human immunodeficiency virus (HIV) seropositive and/or have acute or chronic hepatitis B infection (hepatitis B surface antigen [HBsAg] positive) or hepatitis C infection (anti-HCV positive).
Known history of hypersensitivity to capecitabine or any of it components, including 5-FU.
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 administration of the first dose of investigational product.
Evidence of significant medical illness or abnormal laboratory findings that in the investigator's judgment will substantially increase the risk associated with the subject's participation in and completion of the study, or preclude the evaluation of the subject's response. Examples include, but are not limited to, serious active infection, (ie, requiring intravenous antibiotic or antiviral agent) or uncontrolled major seizure disorder, significant pulmonary disorder (eg, interstitial pneumonitis, pulmonary hypertension), or psychiatric disorder that would interfere with subject safety or informed consent.

Name	Affiliation	Role
Puma	Biotechnology	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Investigational Site		Shizuoka			Japan
Investigational Site

ID	Title	Description
FG000	Neratinib + Capecitabine	Neratinib: 240 mg once daily by mouth, Capecitabine: 1500 mg/m^2 twice daily.

ID	Title	Description
BG000	Neratinib + Capecitabine	Neratinib: 240 mg, continuous once daily by mouth Capecitabine: 1500 mg/m^2 twice daily by mouth

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Categorical			Count of Participants

Outcome Measures Module

Outcome Measures

Type	Title	Description	Population Description	Reporting Status	Anticipated Posting Date	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Time Frame	Units Analyzed	Denominator Units Selected	Arm/Group Information	Denominators	Classes	Analyses
Primary	Dose Limiting Toxicity (DLT) - Percentage of Participants With DLT Events	DLT was defined as 1. Grade 3 or 4 non-hematologic toxicity (exceptions listed below as a.-c.), a. Grade 3 asthenia was NOT considered to be a DLT UNLESS it lasted >3 days. b. Grade 3 nausea or vomiting was NOT considered to be a DLT UNLESS the subject was already receiving optimal medical therapy. c. Grade 3 or 4 infection was NOT considered to be a DLT UNLESS it is associated with grade 3 or 4 neutropenia. 2. Grade 3 diarrhea that lasted >2 days while the subject was on optimal medical therapy or that was associated with fever (greater than or equal 38.0 ºC) or grade 3 dehydration. 3. Grade 4 neutropenia lasting ≥3 days or grade 4 febrile neutropenia. 4. Grade 4 thrombocytopenia lasting ≥3 days or complicated with bleeding or requiring platelet transfusion. 5. Delayed recovery (to National Cancer Institute [NCI] grade 1 or less, or baseline) from any of the toxicities listed above (items 1-4), that was related to study drug, and that delayed the next dose by more than 3 weeks.	The safety population was defined as all subjects who received at least 1 dose of investigational product (neratinib and/or capecitabine).	Posted		Count of Participants		Participants		From first dose date to day 21.

ID	Term
D003841	Deoxycytidine
D003562	Cytidine
D011741	Pyrimidine Nucleosides
D011743	Pyrimidines

ID	Term
C487932	neratinib
D000069287	Capecitabine