A Study Of Neratinib (HKI-272) And Capecitabine In Japanese With Solid Tumor

• Sponsor: Puma Biotechnology, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01128842
• Collaborator: (none)
• Enrollment: 7
• Locations: 2
• Arm: 1
• Actual Duration (Months): 11
• Patients Per Site: 3.5
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This is an open-label, phase 1 study of a single cohort of neratinib (HKI-272) in combination with capecitabine.

Condition or Disease	Intervention/Treatment	Phase
Advanced Malignant Solid Tumors	Drug: Neratinib; Drug: Capecitabine	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 7 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1, Open-Label Study Of Neratinib (HKI-272) In Combination With Capecitabine In Japanese Subject With Solid Tumors
• Actual Study Start Date: Apr 1, 2010
• Actual Primary Completion Date: Mar 1, 2011
• Actual Study Completion Date: Mar 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Neratinib + Capecitabine Neratinib + Capecitabine	Drug: Neratinib; 240 mg once daily by mouth.; Drug: Capecitabine; 1500 mg/m^2 twice daily by mouth.

Outcome Measures

Primary Outcome Measures

1. Dose Limiting Toxicity (DLT) - Percentage of Participants With DLT Events [From first dose date to day 21.]

   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.

2. Tolerated Dose [From first dose date to day 21.]

   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.

Secondary Outcome Measures

1. Best Overall Response [From first dose date to progression or last tumor assessment, up to 41 weeks.]

   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.

2. Objective Response Rate [From first dose date to progression or last tumor assessment, up to 41 weeks.]

   Percentage of participants with partial response (PR) or complete response (CR) 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 Progressive Disease (PD) for non-target lesions, and no new lesions.

3. Progression Free Survival [From first dose date to PD or death, up to 41 weeks.]

   Number of weeks between the date of the first dose of test article and the first date of disease recurrence or disease progression (PD), 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.

4. Area Under the Curve (AUC) of Neratinib in Combination With Capecitabine [At 1, 2, 4, 6, 8 and 21-24 hours after dose on day 14.]

   AUC of Neratinib at day 14 following Administration of Neratinib 240 mg in combination with Capecitabine 1500 mg/m^2 per day to Japanese Subjects with Cancer.

5. Maximum Plasma Concentration of Neratinib in Combination With Capecitabine [Measured at 1, 2, 4, 6, 8 and 21-24 hours after dose on day 14.]

   Maximum plasma concentration (nanograms/milliliter) of Neratinib at day 14 following Administration of Neratinib 240 mg in combination with Capecitabine 1500 mg/m^2 per day to Japanese Subjects with Cancer.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Investigational Site	Shizuoka		Japan
2	Investigational Site	Tokyo		Japan

Sponsors and Collaborators

• Puma Biotechnology, Inc.

Investigators

• Study Director: Puma, Biotechnology

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Puma Biotechnology, Inc.
• ClinicalTrials.gov Identifier: NCT01128842
• Other Study ID Numbers: 3144A1-1122 / B1891018
• First Posted: May 24, 2010
• Last Update Posted: Dec 19, 2018
• Last Verified: Dec 1, 2018

• Keywords provided by Puma Biotechnology, Inc.: Neratinib; Capecitabine; Combination; Solid Tumor
• Additional relevant MeSH terms: Neoplasms; Capecitabine

Study Results

Participant Flow

Arm/Group Title	Neratinib + Capecitabine
Arm/Group Description	Neratinib: 240 mg once daily by mouth, Capecitabine: 1500 mg/m^2 twice daily.
Period Title: Overall Study
STARTED	7
COMPLETED	0
NOT COMPLETED	7

Baseline Characteristics

Arm/Group Title	Neratinib + Capecitabine
Arm/Group Description	Neratinib: 240 mg, continuous once daily by mouth Capecitabine: 1500 mg/m^2 twice daily by mouth
Overall Participants	7
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	6 85.7%
>=65 years	1 14.3%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	52.43 (11.27)
Sex: Female, Male (Count of Participants)
Female	4 57.1%
Male	3 42.9%
Race/Ethnicity, Customized (Count of Participants)
Japanese	7 100%

Outcome Measures

1. Primary Outcome

Title	Dose Limiting Toxicity (DLT) - Percentage of Participants With DLT Events
Description	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.
Time Frame	From first dose date to day 21.

Outcome Measure Data

Analysis Population Description

The safety population was defined as all subjects who received at least 1 dose of investigational product (neratinib and/or capecitabine).

Arm/Group Title	Neratinib + Capecitabine
Arm/Group Description	Neratinib: 240 mg once daily by mouth, Capecitabine: 1500 mg/m^2 twice daily by mouth.
Measure Participants	7
Count of Participants [Participants]	1 14.3%

2. Secondary Outcome

Title	Best Overall Response
Description	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.
Time Frame	From first dose date to progression or last tumor assessment, up to 41 weeks.

Outcome Measure Data

Analysis Population Description

All subjects who met Inclusion and Exclusion criteria, received at least 2 weeks of Investigational Product, and underwent at least 1 Follow Up (FU) tumor assessment at approximately cycle 2 (week 6). Subjects who died or had PD including symptomatic deterioration before the scheduled FU tumor assessment were included in the evaluable population.

Arm/Group Title	Neratinib + Capecitabine
Arm/Group Description	Neratinib: 240 mg once daily by mouth, Capecitabine: 1500 mg/m^2 twice daily by mouth.
Measure Participants	7
Partial Response	1 14.3%
Stable Disease	4 57.1%
Progressive Disease	2 28.6%

3. Secondary Outcome

Title	Objective Response Rate
Description	Percentage of participants with partial response (PR) or complete response (CR) 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 Progressive Disease (PD) for non-target lesions, and no new lesions.
Time Frame	From first dose date to progression or last tumor assessment, up to 41 weeks.

Outcome Measure Data

Analysis Population Description

All subjects who met Inclusion and Exclusion criteria, received at least 2 weeks of Investigational Product, and underwent at least 1 Follow Up (FU) tumor assessment at approximately cycle 2 (week 6). Subjects who died or had PD including symptomatic deterioration before the scheduled FU tumor assessment were included in the evaluable population.

Arm/Group Title	Neratinib + Capecitabine
Arm/Group Description	Neratinib: 240 mg once daily by mouth, Capecitabine: 1500 mg/m^2 twice daily by mouth.
Measure Participants	7
Number (95% Confidence Interval) [percentage of participants]	14.3 204.3%

4. Secondary Outcome

Title	Progression Free Survival
Description	Number of weeks between the date of the first dose of test article and the first date of disease recurrence or disease progression (PD), 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 PD or death, up to 41 weeks.

Outcome Measure Data

Analysis Population Description

All subjects who met Inclusion and Exclusion criteria, received at least 2 weeks of Investigational Product, and underwent at least 1 Follow Up (FU) tumor assessment at approximately cycle 2 (week 6). Subjects who died or had PD including symptomatic deterioration before the scheduled FU tumor assessment were included in the evaluable population.

Arm/Group Title	Neratinib + Capecitabine
Arm/Group Description	Neratinib: 240 mg once daily by mouth, Capecitabine: 1500 mg/m^2 twice daily by mouth.
Measure Participants	7
Median (95% Confidence Interval) [weeks]	15.6

5. Secondary Outcome

Title	Area Under the Curve (AUC) of Neratinib in Combination With Capecitabine
Description	AUC of Neratinib at day 14 following Administration of Neratinib 240 mg in combination with Capecitabine 1500 mg/m^2 per day to Japanese Subjects with Cancer.
Time Frame	At 1, 2, 4, 6, 8 and 21-24 hours after dose on day 14.

Outcome Measure Data

Analysis Population Description

The pharmacokinetic population was defined as all subjects who received at least 1 dose of investigational product (neratinib and/or capecitabine).

Arm/Group Title	Neratinib + Capecitabine
Arm/Group Description	Neratinib: 240 mg once daily by mouth, Capecitabine: 1500 mg/m^2 twice daily by mouth.
Measure Participants	7
Mean (Standard Deviation) [ng*hr/mL]	1070 (619)

6. Secondary Outcome

Title	Maximum Plasma Concentration of Neratinib in Combination With Capecitabine
Description	Maximum plasma concentration (nanograms/milliliter) of Neratinib at day 14 following Administration of Neratinib 240 mg in combination with Capecitabine 1500 mg/m^2 per day to Japanese Subjects with Cancer.
Time Frame	Measured at 1, 2, 4, 6, 8 and 21-24 hours after dose on day 14.

Outcome Measure Data

Analysis Population Description

The pharmacokinetic population was defined as all subjects who received at least 1 dose of investigational product (neratinib and/or capecitabine).

Arm/Group Title	Neratinib + Capecitabine
Arm/Group Description	Neratinib: 240 mg once daily by mouth, Capecitabine: 1500 mg/m^2 twice daily by mouth
Measure Participants	7
Mean (Standard Deviation) [ng/mL]	61.9 (32.0)

7. Primary Outcome

Title	Tolerated Dose
Description	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.
Time Frame	From first dose date to day 21.

Outcome Measure Data

Analysis Population Description

The safety population was defined as all subjects who received at least 1 dose of investigational product (neratinib and/or capecitabine).

Arm/Group Title	Neratinib + Capecitabine
Arm/Group Description	Neratinib: 240 mg once daily by mouth, Capecitabine: 1500 mg/m^2 twice daily by mouth.
Measure Participants	7
Number [mg]	240

Adverse Events

Time Frame	From first dose through 28 days after last dose, up to 41 weeks.
Arm/Group Title	Neratinib + Capecitabine
Arm/Group Description	Neratinib: 240 mg once daily by mouth, Capecitabine: 1500 mg/m^2 twice daily by mouth.
All Cause Mortality
	Neratinib + Capecitabine
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Neratinib + Capecitabine
	Affected / at Risk (%)	# Events
Total	1/7 (14.3%)
Gastrointestinal disorders
Diarrhoea	1/7 (14.3%)
Nausea	1/7 (14.3%)
Other (Not Including Serious) Adverse Events
	Neratinib + Capecitabine
	Affected / at Risk (%)	# Events
Total	7/7 (100%)
Blood and lymphatic system disorders
Anaemia	1/7 (14.3%)
Neutropenia	2/7 (28.6%)
Thrombocytopenia	1/7 (14.3%)
Gastrointestinal disorders
Abdominal pain upper	1/7 (14.3%)
Cheilitis	2/7 (28.6%)
Diarrhoea	7/7 (100%)
Nausea	4/7 (57.1%)
Oesophagitis	1/7 (14.3%)
Proctalgia	1/7 (14.3%)
Stomatitis	2/7 (28.6%)
Vomiting	2/7 (28.6%)
General disorders
Asthenia	1/7 (14.3%)
Fatigue	5/7 (71.4%)
Mucosal inflammation	1/7 (14.3%)
Hepatobiliary disorders
Hyperbilirubinaemia	1/7 (14.3%)
Infections and infestations
Cystitis	1/7 (14.3%)
Nasopharyngitis	1/7 (14.3%)
Paronychia	4/7 (57.1%)
Tinea infection	1/7 (14.3%)
Upper respiratory tract infection	1/7 (14.3%)
Investigations
Alanine aminotransferase increased	1/7 (14.3%)
Aspartate aminotransferase increased	1/7 (14.3%)
Electrocardiogram QT prolonged	1/7 (14.3%)
Weight decreased	5/7 (71.4%)
Metabolism and nutrition disorders
Decreased appetite	5/7 (71.4%)
Dehydration	1/7 (14.3%)
Hypokalaemia	1/7 (14.3%)
Hypophosphataemia	1/7 (14.3%)
Musculoskeletal and connective tissue disorders
Pain in extremity	1/7 (14.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain	1/7 (14.3%)
Nervous system disorders
Neuropathy peripheral	1/7 (14.3%)
Peripheral sensory neuropathy	1/7 (14.3%)
Psychiatric disorders
Anxiety	2/7 (28.6%)
Insomnia	2/7 (28.6%)
Renal and urinary disorders
Haematuria	1/7 (14.3%)
Proteinuria	1/7 (14.3%)
Respiratory, thoracic and mediastinal disorders
Cough	2/7 (28.6%)
Productive cough	2/7 (28.6%)
Respiratory tract haemorrhage	1/7 (14.3%)
Skin and subcutaneous tissue disorders
Dry skin	1/7 (14.3%)
Palmar-plantar erythrodysaesthesia syndrome	4/7 (57.1%)
Rash	6/7 (85.7%)
Skin exfoliation	1/7 (14.3%)
Skin hyperpigmentation	1/7 (14.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.