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

June 26, 2018 updated by: Puma Biotechnology, Inc.

A Phase I/II Study of HKI-272 in Combination With Trastuzumab (Herceptin) in Subjects With Advanced Breast Cancer

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

45

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

  • China
      • Beijing, China, 100853
        • Chinese PLA General Hospital
      • Beijing, China, 100021
        • Cancer Hospital, Academy of Med Science and Peking Union Med
      • Beijing, China, 100071
        • 307 Hospital of Chinese People's Liberation Army
    • Jiangsu
      • Nanjing, Jiangsu, China, 210002
        • Chinese Nanjing Bayi Hospital
    • Tianjin
      • Tianjin, Tianjin, China, 300121
        • Tianjin Union Medicine Center
  • France
      • Paris, France, 75005
        • Institut Curie
      • Saint-Herblain, France, 44805
        • Centre Rene Gauducheau
  • Switzerland
      • Lausanne, Switzerland, CH-1011
        • Centre Hospitalier Universitaire Vaudois
  • United States
    • California
      • Duarte, California, United States, 91010-3000
        • City of Hope National Medical Center
      • Los Angeles, California, United States, 90033
        • LAC/USC Medical Center, USC/Norris Comprehensive Cancer Center
      • Pasadena, California, United States, 91105
        • City of Hope National Medical Center
    • Maryland
      • Baltimore, Maryland, United States, 21201
        • University of Maryland, University of Maryland Medical Center
    • North Carolina
      • Durham, North Carolina, United States, 27710
        • Duke University, Duke University Medical Center
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19111
        • Fox Chase Cancer Center

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:

  • 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

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: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
From first dose date to progression status (PD or death) at 16-week

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
From first dose date to progression or last tumor assessment, up to five and a half years.
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.
From start date of response to first PD, assessed up to five and half years after the first subject was randomized
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.
From first dose date to progression or death, assessed up to five and half years.
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.
From first dose date to progression or last tumor assessment, assessed up to five and half years.
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.
Prior to the first dose, and at hours 1, 2, 4, 6, 8 and 24 on days 22.
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.
Prior to the first dose, on days 22 through 23 of month 1, and on day 1 in months 2 through 6

Collaborators and Investigators

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

Sponsor

Puma Biotechnology, Inc.

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)

April 4, 2007

Primary Completion (Actual)

July 31, 2009

Study Completion (Actual)

March 2, 2018

Study Registration Dates

First Submitted

November 9, 2006

First Submitted That Met QC Criteria

November 9, 2006

First Posted (Estimate)

November 10, 2006

Study Record Updates

Last Update Posted (Actual)

July 24, 2018

Last Update Submitted That Met QC Criteria

June 26, 2018

Last Verified

June 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 3144A1-202 / B1891013

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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