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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT00741260




Registration number
NCT00741260
Ethics application status
Date submitted
22/08/2008
Date registered
26/08/2008
Date last updated
5/09/2018

Titles & IDs
Public title
Study Evaluating The Combination Of Neratinib And Capecitabine In Solid Tumors And Breast Cancer
Scientific title
A Phase 1/2, Open-Label Study Of Neratinib (HKI-272) In Combination With Capecitabine In Subjects With Solid Tumors And ErbB-2 Positive Metastatic Or Locally Advanced Breast Cancer
Secondary ID [1] 0 0
3144A1-2206 / B1891017
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Breast Cancer 0 0
Condition category
Condition code
Cancer 0 0 0 0
Breast

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Neratinib
Treatment: Drugs - Capecitabine

Experimental: Neratinib and Capecitabine (Dose Level 1) - Neratinib 160 mg and Capecitabine 1500 mg/m^2

Experimental: Neratinib and Capecitabine (Dose Group 2) - Neratinib 240 mg and Capecitabine 1500 mg/m^2

Experimental: Neratinib and Capecitabine (Dose Group 3) - Neratinib 240 mg and Capecitabine 2000 mg/m^2

Experimental: Neratinib and Capecitabine (Dose Group 4) - Neratinib 200 mg and Capecitabine 2000 mg/m^2

Experimental: Neratinib and Capecitabine (Dose Group 5) - Neratinib 160 mg and Capecitabine 2000 mg/m^2

Experimental: Neratinib and Capecitabine MTD (Dose Group 6) - Neratinib and Capecitabine Maximum Tolerated Dose without prior lapatinib

Experimental: Neratinib and Capecitabine MTD (Dose Group 7) - Neratinib and Capecitabine Maximum Tolerated Dose with prior lapatinib


Treatment: Drugs: Neratinib
Neratinib orally once daily continually

Treatment: Drugs: Capecitabine
Capecitabine orally on days 1-14 of each 21 day cycle

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Number of Participants With Dose Limiting Toxicities - Number of participants reporting Adverse Events Causing Dose Limiting Toxicities (DLT).
Timepoint [1] 0 0
From first dose date to day 21
Primary outcome [2] 0 0
Maximum Tolerated Dose (MTD) of Neratinib - MTD reflects the highest dose of neratinib plus capeciteabine that did not cause a selected Grade 3 toxicity in >= 2 participants, which is any of 1) Grade 3 or 4 non-hematologic toxicity (Grade 3 asthenia was not considered a DLT unless lasting >3 days, 2) Grade 3 diarrhea lasting >2 days on optimal medical therapy or associated with fever or dehydration. 3) Grade 4 neutropenia lasting = 3 days or Grade 4 febrile neutropenia, 4) Grade 4 thrombocytopenia lasting =3 days or associated with bleeding or requiring platelet transfusion, 5) Delayed recovery [to = National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or baseline] from one of the above listed toxicities that were related to neratinib and/or capecitabine that delayed the initiation of the next dose by more than 3 weeks.
Timepoint [2] 0 0
From first dose date to day 21.
Primary outcome [3] 0 0
Maximum Tolerated Dose (MTD) of Capecitabine - MTD reflects the highest dose of capecitabine in combination with neratinib that did not cause a selected Grade 3 toxicity in >= 2 participants, which is any of 1) Grade 3 or 4 non-hematologic toxicity (Grade 3 asthenia was not considered a DLT unless lasting >3 days, 2) Grade 3 diarrhea lasting >2 days on optimal medical therapy or associated with fever or dehydration. 3) Grade 4 neutropenia lasting = 3 days or Grade 4 febrile neutropenia, 4) Grade 4 thrombocytopenia lasting =3 days or associated with bleeding or requiring platelet transfusion, 5) Delayed recovery [to = National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or baseline] from one of the above listed toxicities that were related to neratinib and/or capecitabine that delayed the initiation of the next dose by more than 3 weeks.
Timepoint [3] 0 0
From first dose date to day 21.
Secondary outcome [1] 0 0
Overall Response Rate - Number of Subjects with Complete or Partial Response 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.
Timepoint [1] 0 0
From first dose date to progression or last tumor assessment, up to three years.
Secondary outcome [2] 0 0
Clinical Benefit Rate - The percentage of subjects with Complete Response, Partial Response, or Stable Disease at least 24 weeks per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v1.0: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Timepoint [2] 0 0
From first dose date to progression or last tumor assessment, up to three years.
Secondary outcome [3] 0 0
Duration of Response - Duration of response was measured from the time at which response criteria were met for complete response (CR) or partial response (PR) (whichever status was recorded first) until the first date of recurrence or progressive disease (PD) or death per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v1.0: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions.
Timepoint [3] 0 0
From start date of response to first PD/death, up to three years.

Eligibility
Key inclusion criteria
INCLUSION CRITERIA

PART 1:

- confirmed pathologic diagnosis of a solid tumor not curable with available therapies
for which neratinib plus capecitabine is a reasonable treatment option.

PART 2:

- confirmed histologically and/or cytologically confirmed diagnosis of breast cancer,
metastatic or locally advanced.

- erbB-2 gene amplified tumor (FISH or CISH) or erbB-2 overexpression (IHC 3+, or IHC2+
with FISH or CISH confirmation), based on local testing, or based on centralized FISH
testing prior to day 1.

- disease progression on or following at least 1 prior trastuzumab containing treatment
regimen (at least 6 weeks) for metastatic or locally advanced disease. (Prior adjuvant
trastuzumab is allowed but not required). A 2 week period is required between the last
dose of trastuzumab treatment and first dose of the test article.

- Prior treatment with a taxane in the neoadjuvant, adjuvant, locally advanced, and/or
metastatic disease treatment setting.

PARTS 1 and 2:

- At least 1 measurable lesion as defined by RECIST criteria.

- LVEF within institutional range of normal as measured by multi-gated acquisition
(MUGA) or echocardiogram (ECHO).

EXCLUSION CRITERIA

PART 2:

- prior treatment with capecitabine, lapatinib (20 subjects with prior lapatinib
exposure will be enrolled) or any erbB-2 targeted agents except trastuzumab. Treatment
with erbB-2 targeted therapy must exceed 2 weeks (14 days) in order to be
exclusionary.

- prior treatment with anthracyclines with a cumulative dose of doxorubicin of greater
than 400 mg/m², epirubicin dose of greater than 800 mg/m², or the equivalent dose for
other anthracyclines.

PARTS 1 and 2:

- Subjects with bone as the only site of disease.

- Active uncontrolled or symptomatic 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
considered definitively treated and are off anticonvulsants and steroids for at least
4 weeks before the first dose of test article.

- Any other cancer within 5 years prior to screening with the exception of adequately
treated cervical carcinoma in situ, or adequately treated basal or squamous cell
carcinoma of the skin.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Phase
Phase 1/Phase 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD,VIC
Recruitment hospital [1] 0 0
Mater Private Centre for HOCA - South Brisbane
Recruitment hospital [2] 0 0
Border Medical Oncology - Wodonga
Recruitment postcode(s) [1] 0 0
4101 - South Brisbane
Recruitment postcode(s) [2] 0 0
3690 - Wodonga
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Alabama
Country [2] 0 0
United States of America
State/province [2] 0 0
California
Country [3] 0 0
United States of America
State/province [3] 0 0
Florida
Country [4] 0 0
United States of America
State/province [4] 0 0
Idaho
Country [5] 0 0
United States of America
State/province [5] 0 0
Indiana
Country [6] 0 0
United States of America
State/province [6] 0 0
Missouri
Country [7] 0 0
United States of America
State/province [7] 0 0
New York
Country [8] 0 0
United States of America
State/province [8] 0 0
Ohio
Country [9] 0 0
United States of America
State/province [9] 0 0
Pennsylvania
Country [10] 0 0
United States of America
State/province [10] 0 0
Texas
Country [11] 0 0
Brazil
State/province [11] 0 0
RS - Brazil
Country [12] 0 0
Brazil
State/province [12] 0 0
RS
Country [13] 0 0
China
State/province [13] 0 0
Beijing
Country [14] 0 0
China
State/province [14] 0 0
Jiangsu
Country [15] 0 0
Croatia
State/province [15] 0 0
Zagreb
Country [16] 0 0
Hong Kong
State/province [16] 0 0
Hong Kong
Country [17] 0 0
Hungary
State/province [17] 0 0
Budapest
Country [18] 0 0
Hungary
State/province [18] 0 0
Nyiregyhaza
Country [19] 0 0
Korea, Republic of
State/province [19] 0 0
Seoul
Country [20] 0 0
Russian Federation
State/province [20] 0 0
Kazan
Country [21] 0 0
Russian Federation
State/province [21] 0 0
Perm
Country [22] 0 0
Russian Federation
State/province [22] 0 0
Saint Petersburg
Country [23] 0 0
Singapore
State/province [23] 0 0
Singapore
Country [24] 0 0
Spain
State/province [24] 0 0
Barcelona
Country [25] 0 0
Spain
State/province [25] 0 0
Madrid
Country [26] 0 0
Spain
State/province [26] 0 0
Valencia

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Puma Biotechnology, Inc.
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
This is a world wide phase 1/2, open-label, study of neratinib in combination with
capecitabine, conducted in 2 parts.

In Part 1, 3 to 9 subjects with solid tumors will be enrolled in each dose group of the
combination of neratinib and capecitabine. Each subject will participate in only 1 dose
group.

Additional subjects may be included at any dose level to further assess the safety and
tolerability at that dose level.

In Part 2, up to 60 subjects with erbB-2 positive metastatic breast cancer will receive
treatment with the combination of neratinib and capecitabine at the maximum tolerated dose
level, as determined in Part 1. In addition 20 subjects with prior lapatinib exposure will be
enrolled in Part 2.

Depending on the safety and activity profile observed during the dose escalation phase, the
dose selected for Part 2 may be adjusted, if appropriate. In case one test article of the
combination is discontinued due to intolerance the other test article can be administered
alone.

The primary objectives of Part 1 are to assess the safety and tolerability, and to define the
maximum tolerated dose (MTD) of neratinib in combination with capecitabine in subjects with
advanced solid tumors.

The primary objective of Part 2 of this study is to confirm the MTD determined in Part 1.

The secondary objective of Part 1 is to collect information on preliminary anti-tumor
activity of the combination of neratinib and capecitabine.

Secondary objectives for Part 2 are to collect pharmacokinetic information and to obtain
additional efficacy data, such as Objective Response Rate, for subjects with erbB-2 positive
breast cancer treated at the MTD of neratinib + capecitabine.
Trial website
https://clinicaltrials.gov/show/NCT00741260
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Puma
Address 0 0
Biotechnology
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications