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A Phase 1/2 Study Of HKI-272 (Neratinib) in Combination With Trastuzumab (Herceptin) In Subjects With Advanced Breast Cancer

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ClinicalTrials.gov Identifier: NCT00398567
Recruitment Status : Completed
First Posted : November 10, 2006
Results First Posted : April 13, 2018
Last Update Posted : July 24, 2018
Sponsor:
Information provided by (Responsible Party):
Puma Biotechnology, Inc.

Study Description
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Brief Summary:
The purpose of this study is to determine the safety and efficacy of HKI-272 (neratinib) in combination with trastuzumab in patients with advanced breast cancer.

Condition or disease Intervention/treatment Phase
Advanced Breast Cancer Drug: HKI-272 Drug: trastuzumab Phase 1 Phase 2

Detailed Description:
Open label phase 1/2 study of ascending multiple oral doses of HKI-272 in combination with IV trastuzumab in subjects with advanced human epidermal growth factor receptor 2 positive (HER2+) breast cancer. Three to six subjects will be enrolled in each dose group. Adverse events and dose limiting toxicities will be assessed from the first dose of study drug though day 21. When the maximum tolerated dose (MTD) of HKI-272 plus trastuzumab is determined, an additional 30 subjects will be enrolled at that dose level, and followed for progression free survival for approximately 1 year.

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 45 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Study of HKI-272 in Combination With Trastuzumab (Herceptin) in Subjects With Advanced Breast Cancer
Actual Study Start Date : April 4, 2007
Actual Primary Completion Date : July 31, 2009
Actual Study Completion Date : March 2, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arms and Interventions
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Arm Intervention/treatment
Experimental: Part 1 - dose level 1 (160 mg)
All subjects receiving HKI-272 dose level 1 in combination with trastuzumab
 Drug: HKI-272
HKI-272 by mouth
Other Name: neratinib

Drug: trastuzumab
trastuzumab 4 mg/kg IV as a loading dose followed by trastuzumab 2 mg/kg weekly thereafter
Other Name: Herceptin
Experimental: Part 1 - dose level 2 (240 mg)
All subjects receiving HKI-272 dose level 2 in combination with trastuzumab
 Drug: HKI-272
HKI-272 by mouth
Other Name: neratinib

Drug: trastuzumab
trastuzumab 4 mg/kg IV as a loading dose followed by trastuzumab 2 mg/kg weekly thereafter
Other Name: Herceptin
Experimental: Part 2 - expanded MTD cohort
All subjects receiving HKI-272 in combination with trastuzumab
 Drug: HKI-272
HKI-272 by mouth
Other Name: neratinib

Drug: trastuzumab
trastuzumab 4 mg/kg IV as a loading dose followed by trastuzumab 2 mg/kg weekly thereafter
Other Name: Herceptin


Outcome Measures
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Primary Outcome Measures :
  1. 16-week Progression-free Survival (PFS) Rate [ Time Frame: From first dose date to progression status (PD or death) at 16-week ]
    16-week progression-free survival (PFS) rate for subjects with advanced breast cancer who receive neratinib at the maximum tolerated dose (MTD) in combination with trastuzumab, evaluable population.


Secondary Outcome Measures :
  1. Objective Response Rate (ORR) [ Time Frame: From first dose date to progression or last tumor assessment, up to five and a half years. ]
    Percentage of participants with partial response (PR) or complete response (CR) 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.

  2. Duration of Response (DOR) [ Time Frame: From start date of response to first PD, assessed up to five and half years after the first subject was randomized ]
    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 on which recurrence or PD was objectively documented, taking as the reference for PD the smallest measurements recorded since the test article administration started.

  3. Progression Free Survival (PFS) [ Time Frame: From first dose date to progression or death, assessed up to five and half years. ]
    Progression Free Survival was measured from the date of the first dose of test article until the first date on which recurrence or progression, or death due to any cause, was documented, censored at the last evaluation, investigator assessment.

  4. Clinical Benefit Rate (CBR) [ Time Frame: From first dose date to progression or last tumor assessment, assessed up to five and half years. ]
    The percentage of participants with a best overall response of a complete response (CR) or partial response (PR) or stable disease (SD) >=24 weeks.

  5. Area Under the Curve of Neratinib Concentration [ Time Frame: Prior to the first dose, and at hours 1, 2, 4, 6, 8 and 24 on days 22. ]
    Area Under the Curve of Neratinib concentration at day 22 following Administration of Neratinib 240 mg in combination with Trastuzumab 2 mg/kg in Subjects with Cancer.

  6. Terminal-phase Elimination Half-life of Neratinib in Combination With Trastuzumab. [ Time Frame: Prior to the first dose, on days 22 through 23 of month 1, and on day 1 in months 2 through 6 ]
    Terminal-phase elimination half-life of Neratinib at day 22 following Administration of Neratinib 240 mg in combination with Trastuzumab 2 mg/kg to Subjects with Cancer.


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Pathologic diagnosis of breast cancer with current stage IIIB, IIIC or IV not curable by available therapy
  • Progression following at least one Herceptin-containing cytotoxic chemotherapy regimen (neoadjuvant, adjuvant, or metastatic setting)
  • HER2 positive breast cancer
  • At least one measurable target lesion
  • Adequate performance status
  • Adequate cardiac, kidney, and liver function
  • Adequate blood counts
  • Willingness of all subjects who are not surgically sterile or post menopausal to use acceptable methods of birth control

Exclusion Criteria:

  • More than 3 prior cytotoxic chemotherapy regimens for locally advanced or metastatic disease
  • Major surgery, chemotherapy, radiotherapy, investigational agents, Herceptin or other cancer therapy within 2 weeks of treatment day 1
  • Prior treatment with anthracyclines with cumulative dose of >400 mg/m^2
  • Extensive visceral disease
  • Active central nervous system metastases
  • Pregnant or breast feeding women
  • Significant chronic or recent acute gastrointestinal disorder with diarrhea as a major symptom
  • Prior exposure to HKI-272 or other HER2 targeted agents (except Herceptin and Tykerb)
  • Significant cardiac disease or dysfunction
  • History of life-threatening hypersensitivity to Herceptin
  • Inability or unwillingness to swallow HKI-272 capsules
  • Any other cancer within 5 years with the exception of contralateral breast cancer, adequately treated cervical carcinoma in situ, or adequately treated basal or squamous cell carcinoma of the skin
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00398567


Locations
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United States, California
City of Hope National Medical Center
Duarte, California, United States, 91010-3000
LAC/USC Medical Center, USC/Norris Comprehensive Cancer Center
Los Angeles, California, United States, 90033
City of Hope National Medical Center
Pasadena, California, United States, 91105
United States, Maryland
University of Maryland, University of Maryland Medical Center
Baltimore, Maryland, United States, 21201
United States, North Carolina
Duke University, Duke University Medical Center
Durham, North Carolina, United States, 27710
United States, Pennsylvania
Fox Chase Cancer Center
Philadelphia, Pennsylvania, United States, 19111
China, Jiangsu
Chinese Nanjing Bayi Hospital
Nanjing, Jiangsu, China, 210002
China, Tianjin
Tianjin Union Medicine Center
Tianjin, Tianjin, China, 300121
China
Cancer Hospital, Academy of Med Science and Peking Union Med
Beijing, China, 100021
307 Hospital of Chinese People's Liberation Army
Beijing, China, 100071
Chinese PLA General Hospital
Beijing, China, 100853
France
Institut Curie
Paris, France, 75005
Centre Rene Gauducheau
Saint-Herblain, France, 44805
Switzerland
Centre Hospitalier Universitaire Vaudois
Lausanne, Switzerland, CH-1011
Sponsors and Collaborators
Puma Biotechnology, Inc.
Investigators
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Study Director: Puma Biotechnology
More Information
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Responsible Party: Puma Biotechnology, Inc.
ClinicalTrials.gov Identifier: NCT00398567     History of Changes
Other Study ID Numbers: 3144A1-202 / B1891013
First Posted: November 10, 2006    Key Record Dates
Results First Posted: April 13, 2018
Last Update Posted: July 24, 2018
Last Verified: June 2018

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Puma Biotechnology, Inc.:
HKI-272
neratinib
trastuzumab
breast cancer
 Nerlynx
PB-272
HER2

Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
 Skin Diseases
Trastuzumab
Antineoplastic Agents, Immunological
Antineoplastic Agents