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

Advanced Breast Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00398567
• Other study ID #: 3144A1-202 / B1891013
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: April 4, 2007
• Est. completion date: March 2, 2018

Study information

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

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 45
• Est. completion date: March 2, 2018
• Est. primary completion date: July 31, 2009
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Advanced Breast Cancer
• Breast Neoplasms

Intervention

Drug:
• HKI-272
HKI-272 by mouth
• trastuzumab
trastuzumab 4 mg/kg IV as a loading dose followed by trastuzumab 2 mg/kg weekly thereafter

Locations

Country	Name	City	State
China	307 Hospital of Chinese People's Liberation Army	Beijing
China	Cancer Hospital, Academy of Med Science and Peking Union Med	Beijing
China	Chinese PLA General Hospital	Beijing
China	Chinese Nanjing Bayi Hospital	Nanjing	Jiangsu
China	Tianjin Union Medicine Center	Tianjin	Tianjin
France	Institut Curie	Paris
France	Centre Rene Gauducheau	Saint-Herblain
Switzerland	Centre Hospitalier Universitaire Vaudois	Lausanne
United States	University of Maryland, University of Maryland Medical Center	Baltimore	Maryland
United States	City of Hope National Medical Center	Duarte	California
United States	Duke University, Duke University Medical Center	Durham	North Carolina
United States	LAC/USC Medical Center, USC/Norris Comprehensive Cancer Center	Los Angeles	California
United States	City of Hope National Medical Center	Pasadena	California
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
Puma Biotechnology, Inc.

Countries where clinical trial is conducted

United States,  China,  France,  Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	16-week Progression-free Survival (PFS) Rate	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	Objective Response Rate (ORR)	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.
Secondary	Duration of Response (DOR)	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
Secondary	Progression Free Survival (PFS)	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.
Secondary	Clinical Benefit Rate (CBR)	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.
Secondary	Area Under the Curve of Neratinib Concentration	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.
Secondary	Terminal-phase Elimination Half-life of Neratinib in Combination With Trastuzumab.	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