Study Evaluating The Combination Of Neratinib And Capecitabine In Solid Tumors And Breast Cancer

Breast Cancer Clinical Trial

Official 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00741260
• Other study ID #: 3144A1-2206 / B1891017
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: December 9, 2008
• Est. completion date: June 2018

Study information

• Verified date: August 2018
• Source: Puma Biotechnology, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 105
• Est. completion date: June 2018
• Est. primary completion date: November 2010
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

Drug:
• Neratinib
Neratinib orally once daily continually
• Capecitabine
Capecitabine orally on days 1-14 of each 21 day cycle

Locations

Country	Name	City	State
Australia	Mater Private Centre for HOCA	South Brisbane	Queensland
Australia	Border Medical Oncology	Wodonga	Victoria
Brazil	Associacao Hospital de Caridade Ijui	Ijui	RS - Brazil
Brazil	Associacao Hospitalar Moinhos de Vento Instituto de Edicacao e Pesquisa	Porto Alegre	RS
China	Cancer Hospital, Chinese Academy of Medical Sciences	Beijing	Beijing
China	Peking Union Medical College Hospital of Chinese Academy of Medical Sciences	Beijing	Beijing
China	The Hospital Affiliated Academy Military Medical Science, Chinese People's Liberation Army	Beijing
China	Jiangsu Cancer Hospital	Nanjing	Jiangsu
Croatia	University Hospital Center Zagreb Department of Oncology	Zagreb
Hong Kong	UNIMED Medical Institute, Comprehensive Centre for Breast Diseases	Hong Kong
Hungary	Orszagos Onkologiai Intezet "B" Belgyogyaszati osztaly	Budapest
Hungary	Josa Andras Oktatokorhaz / Onkoradiologiai Osztaly	Nyiregyhaza
Korea, Republic of	Asan Medical Center Department of Medicine Division of Oncology	Seoul
Korea, Republic of	Department of Hematology/Oncology, Samsung Medical Center	Seoul
Korea, Republic of	Yonsei University Health System-Severance Hospital, Yonsei University College of Medicine	Seoul
Russian Federation	Republican Clinical Oncology Dispensary	Kazan
Russian Federation	GUZ Perm Regional Oncology Dispensary	Perm
Russian Federation	GUZ City Clinical Oncology Dispensary	Saint Petersburg
Russian Federation	Leningrad Regional Oncology Dispensary	Saint Petersburg
Russian Federation	Saint-Petersburg State Medical University n.a. acad. I.P. Pavlov, Laboratory of Thoracic Oncology of Pulmonology Research Institute	Saint Petersburg
Singapore	Johns Hopkins Singapore International Medical Centre	Singapore
Spain	Hospital Vall d'Hebron	Barcelona
Spain	Hospital Clinico San Carlos	Madrid
Spain	Hospital Gregorio Maranon	Madrid
Spain	Hospital Clínico Universitario de Valencia	Valencia
United States	Dayton Clinical Oncology Program	Dayton	Ohio
United States	The Care Group, LLC. dba Horizon Oncology Center	Lafayette	Indiana
United States	Arena Oncology Associates, PC	Lake Success	New York
United States	Pacific Shores Medical Group	Long Beach	California
United States	University of Southern California	Los Angeles	California
United States	USA Mitchell Cancer Institute	Mobile	Alabama
United States	Florida Hospital Cancer Institute	Orlando	Florida
United States	Kootenai Cancer Center	Post Falls	Idaho
United States	HOPE Oncology	Richardson	Texas
United States	Washington University School of Medicine Siteman Cancer Center	Saint Louis	Missouri
United States	Cancer Therapy and Research Center at The UT Health Science Center Institute for Drug Development	San Antonio	Texas
United States	Berks Hematology Oncology	West Reading	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
Puma Biotechnology, Inc.

Countries where clinical trial is conducted

United States,  Australia,  Brazil,  China,  Croatia,  Hong Kong,  Hungary,  Korea, Republic of,  Russian Federation,  Singapore,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Dose Limiting Toxicities	Number of participants reporting Adverse Events Causing Dose Limiting Toxicities (DLT).	From first dose date to day 21
Primary	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.	From first dose date to day 21.
Primary	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.	From first dose date to day 21.
Secondary	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.	From first dose date to progression or last tumor assessment, up to three years.
Secondary	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.	From first dose date to progression or last tumor assessment, up to three years.
Secondary	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.	From start date of response to first PD/death, up to three years.