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

August 7, 2018 updated by: Puma Biotechnology, Inc.

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

105

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Australia
    • Queensland
      • South Brisbane, Queensland, Australia, 4101
        • Mater Private Centre for HOCA
    • Victoria
      • Wodonga, Victoria, Australia, 3690
        • Border Medical Oncology
  • Brazil
    • RS
      • Porto Alegre, RS, Brazil, 90035-001
        • Associacao Hospitalar Moinhos de Vento Instituto de Edicacao e Pesquisa
    • RS - Brazil
      • Ijui, RS - Brazil, Brazil, 98700-000
        • Associação Hospital de Caridade Ijuí
  • China
      • Beijing, China, 100071
        • The Hospital Affiliated Academy Military Medical Science, Chinese People's Liberation Army
    • Beijing
      • Beijing, Beijing, China, 100021
        • Cancer Hospital, Chinese Academy of Medical Sciences
      • Beijing, Beijing, China, 100032
        • Peking Union Medical College Hospital of Chinese Academy of Medical Sciences
    • Jiangsu
      • Nanjing, Jiangsu, China, 210009
        • Jiangsu Cancer Hospital
  • Croatia
      • Zagreb, Croatia, 10000
        • University Hospital Center Zagreb Department of Oncology
  • Hong Kong
      • Hong Kong, Hong Kong
        • UNIMED Medical Institute, Comprehensive Centre for Breast Diseases
  • Hungary
      • Budapest, Hungary, 1122
        • Országos Onkológiai Intézet "B" Belgyogyaszati osztaly
      • Nyiregyhaza, Hungary, 4400
        • Josa Andras Oktatokorhaz / Onkoradiologiai Osztaly
  • Korea, Republic of
      • Seoul, Korea, Republic of, 120-752
        • Yonsei University Health System-Severance Hospital, Yonsei University College of Medicine
      • Seoul, Korea, Republic of, 135-710
        • Department of Hematology/Oncology, Samsung Medical Center
      • Seoul, Korea, Republic of, 138-736
        • Asan Medical Center Department of Medicine Division of Oncology
  • Russian Federation
      • Kazan, Russian Federation, 420029
        • Republican Clinical Oncology Dispensary
      • Perm, Russian Federation, 614066
        • GUZ Perm Regional Oncology Dispensary
      • Saint Petersburg, Russian Federation, 197022
        • GUZ City Clinical Oncology Dispensary
      • Saint Petersburg, Russian Federation, 188663
        • Leningrad Regional Oncology Dispensary
      • Saint Petersburg, Russian Federation, 197022
        • Saint-Petersburg State Medical University n.a. acad. I.P. Pavlov, Laboratory of Thoracic Oncology of Pulmonology Research Institute
  • Singapore
      • Singapore, Singapore, 308433
        • Johns Hopkins Singapore International Medical Centre
  • Spain
      • Barcelona, Spain, 08035
        • Hospital Vall d'Hebron
      • Madrid, Spain, 28040
        • Hospital Clinico San Carlos
      • Madrid, Spain, 28007
        • Hospital Gregorio Marañón
      • Valencia, Spain, 46010
        • Hospital Clínico Universitario de Valencia
  • United States
    • Alabama
      • Mobile, Alabama, United States, 36604
        • USA Mitchell Cancer Institute
    • California
      • Long Beach, California, United States, 90813
        • Pacific Shores Medical Group
      • Los Angeles, California, United States, 90033
        • University of Southern California
    • Florida
      • Orlando, Florida, United States, 32804
        • Florida Hospital Cancer Institute
    • Idaho
      • Post Falls, Idaho, United States, 83854
        • Kootenai Cancer Center
    • Indiana
      • Lafayette, Indiana, United States, 47905
        • The Care Group, LLC. dba Horizon Oncology Center
    • Missouri
      • Saint Louis, Missouri, United States, 63110
        • Washington University School of Medicine Siteman Cancer Center
    • New York
      • Lake Success, New York, United States, 11042
        • Arena Oncology Associates, PC
    • Ohio
      • Dayton, Ohio, United States, 45420
        • Dayton Clinical Oncology Program
    • Pennsylvania
      • West Reading, Pennsylvania, United States, 19611
        • Berks Hematology Oncology
    • Texas
      • Richardson, Texas, United States, 75080
        • HOPE Oncology
      • San Antonio, Texas, United States, 78229
        • Cancer Therapy and Research Center at The UT Health Science Center Institute for Drug Development

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Sequential Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Neratinib and Capecitabine (Dose Level 1)
Neratinib 160 mg and Capecitabine 1500 mg/m^2
Drug: Neratinib
Neratinib orally once daily continually
Other Names:
  • HKI-272
Drug: Capecitabine
Capecitabine orally on days 1-14 of each 21 day cycle
Other Names:
  • Xeloda
Experimental: Neratinib and Capecitabine (Dose Group 2)
Neratinib 240 mg and Capecitabine 1500 mg/m^2
Drug: Neratinib
Neratinib orally once daily continually
Other Names:
  • HKI-272
Drug: Capecitabine
Capecitabine orally on days 1-14 of each 21 day cycle
Other Names:
  • Xeloda
Experimental: Neratinib and Capecitabine (Dose Group 3)
Neratinib 240 mg and Capecitabine 2000 mg/m^2
Drug: Neratinib
Neratinib orally once daily continually
Other Names:
  • HKI-272
Drug: Capecitabine
Capecitabine orally on days 1-14 of each 21 day cycle
Other Names:
  • Xeloda
Experimental: Neratinib and Capecitabine (Dose Group 4)
Neratinib 200 mg and Capecitabine 2000 mg/m^2
Drug: Neratinib
Neratinib orally once daily continually
Other Names:
  • HKI-272
Drug: Capecitabine
Capecitabine orally on days 1-14 of each 21 day cycle
Other Names:
  • Xeloda
Experimental: Neratinib and Capecitabine (Dose Group 5)
Neratinib 160 mg and Capecitabine 2000 mg/m^2
Drug: Neratinib
Neratinib orally once daily continually
Other Names:
  • HKI-272
Drug: Capecitabine
Capecitabine orally on days 1-14 of each 21 day cycle
Other Names:
  • Xeloda
Experimental: Neratinib and Capecitabine MTD (Dose Group 6)
Neratinib and Capecitabine Maximum Tolerated Dose without prior lapatinib
Drug: Neratinib
Neratinib orally once daily continually
Other Names:
  • HKI-272
Drug: Capecitabine
Capecitabine orally on days 1-14 of each 21 day cycle
Other Names:
  • Xeloda
Experimental: Neratinib and Capecitabine MTD (Dose Group 7)
Neratinib and Capecitabine Maximum Tolerated Dose with prior lapatinib
Drug: Neratinib
Neratinib orally once daily continually
Other Names:
  • HKI-272
Drug: Capecitabine
Capecitabine orally on days 1-14 of each 21 day cycle
Other Names:
  • Xeloda

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Participants With Dose Limiting Toxicities
Time Frame: From first dose date to day 21
Number of participants reporting Adverse Events Causing Dose Limiting Toxicities (DLT).
From first dose date to day 21
Maximum Tolerated Dose (MTD) of Neratinib
Time Frame: From first dose date to day 21.
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.
Maximum Tolerated Dose (MTD) of Capecitabine
Time Frame: From first dose date to day 21.
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall Response Rate
Time Frame: From first dose date to progression or last tumor assessment, up to three years.
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.
Clinical Benefit Rate
Time Frame: From first dose date to progression or last tumor assessment, up to three years.
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.
Duration of Response
Time Frame: From start date of response to first PD/death, up to three years.
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.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Puma Biotechnology, Inc.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 9, 2008

Primary Completion (Actual)

November 1, 2010

Study Completion (Actual)

June 1, 2018

Study Registration Dates

First Submitted

August 22, 2008

First Submitted That Met QC Criteria

August 22, 2008

First Posted (Estimate)

August 26, 2008

Study Record Updates

Last Update Posted (Actual)

September 5, 2018

Last Update Submitted That Met QC Criteria

August 7, 2018

Last Verified

August 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 3144A1-2206 / B1891017

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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