Study Evaluating The Effects Of Neratinib After Adjuvant Trastuzumab In Women With Early Stage Breast Cancer (ExteNET)

• ClinicalTrials.gov Identifier: NCT00878709
• Recruitment Status: Completed
• First Posted: April 9, 2009
• Results First Posted: October 9, 2017
• Last Update Posted: June 11, 2021
• Sponsor: Puma Biotechnology, Inc.
• Information provided by (Responsible Party): Puma Biotechnology, Inc.

Tracking Information

• First Submitted Date: April 8, 2009
• First Posted Date: April 9, 2009
• Results First Submitted Date: August 10, 2017
• Results First Posted Date: October 9, 2017
• Last Update Posted Date: June 11, 2021
• Actual Study Start Date: July 9, 2009
• Actual Primary Completion Date: August 21, 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 19, 2020)

• Invasive Disease-free Survival (iDFS) in Neratinib Arm Compared to Placebo Arm at Year 2 [ Time Frame: From randomization until time of event up to 2 years ]
  Invasive disease-free survival time is defined as the time from date of randomization until the first disease recurrence of the following events: invasive ipsilateral breast tumor recurrence, invasive contralateral breast cancer, local/regional invasive recurrence, distant recurrence and death from any cause.
• Kaplan-Meier Estimates of Invasive Disease-free Survival (iDFS) at Year 2 by Treatment Arms [ Time Frame: From randomization until time of event up to 2 years ]

• Original Primary Outcome Measures (submitted: April 8, 2009): disease free survival [ Time Frame: five years ]

Current Secondary Outcome Measures (submitted: November 19, 2020)

• Overall Survival (OS) [ Time Frame: Randomization until death due to any cause (up to 119 Months) ]
  OS was defined as the time from randomization to death due to any cause, censored at the last date known alive.
• Disease-free Survival Including Ductal Carcinoma in Situ (DFS-DCIS) in Neratinib Arm Compared to Placebo Arm at Year 2 [ Time Frame: From randomization until time of event up to 2 years ]
  Disease-free survival including DCIS time is defined as the time from date of randomization until the first occurrence of DCIS or an iDFS event (an iDFS event including invasive ipsilateral breast tumor recurrence, invasive contralateral breast cancer, local/regional invasive recurrence, or distant recurrence and death from any.
• Kaplan-Meier Estimates of Disease-free Survival Including Ductal Carcinoma in Situ (DFS-DCIS) at Year 2 by Treatment Arms [ Time Frame: From randomization until time of event up to 2 years ]
• Distant Disease-free Survival (DDFS) in Neratinib Arm Compared to Placebo Arm at Year 2 [ Time Frame: From randomization until time of event up to 2 years ]
  Distant disease-free survival time is defined as the time from date of randomization until the first occurrence of distant recurrence or death from any cause.
• Kaplan-Meier Estimates of Distant Disease-free Survival (DDFS) at Year 2 by Treatment Arms [ Time Frame: From randomization until time of event up to 2 years ]
• Percentage of Participants With Time to Distant Recurrence (TTDR) Event in Neratinib Arm Compared to Placebo Arm at Year 2 [ Time Frame: From randomization until time of event up to 2 years ]
  Percentage of Participants with TTDR events is reported. TTDR is defined as the time from date of randomization until the first occurrence of distant recurrence or death from breast cancer.
• Kaplan-Meier Estimates of Time to Distant Recurrence (TTDR) Survival at Year 2 by Treatment Arms [ Time Frame: From randomization until time of event up to 2 years ]
• Central Nervous System Recurrence in Neratinib Arm Compared to Placebo Arm at Year 2 [ Time Frame: From randomization until time of event up to 2 years ]
  CNS recurrence is defined as the time from randomization to CNS as the first distant recurrence. Competing events include distant recurrence at other sites as the first distant recurrence and death from any cause prior to distant recurrence.
• Cumulative Incidence of Central Nervous System Recurrence (CNS) at Year 2 [ Time Frame: From randomization until time of event up to 2 years ]
  Cumulative incidence of Central Nervous System Recurrence (CNS) is estimated by Gray's method (Gray,1988).

• Original Secondary Outcome Measures (submitted: April 8, 2009): Common Terminology for Adverse Events (CTCAE) version 3 [ Time Frame: duration of subject's participation on active portion of study ]

Current Other Pre-specified Outcome Measures (submitted: November 19, 2020)

• Invasive Disease-free Survival (iDFS) in Neratinib Arm Compared to Placebo Arm at Year 5 [ Time Frame: From randomization until time of event up to 5 years ]
  Invasive disease-free survival time is defined as the time from date of randomization until the first disease recurrence of the following events: invasive ipsilateral breast tumor recurrence, invasive contralateral breast cancer, local/regional invasive recurrence, distant recurrence and death from any cause.
• Kaplan-Meier Estimates of Invasive Disease-free Survival (iDFS) at Year 5 by Treatment Arms [ Time Frame: From randomization until time of event up to 5 years ]
• Disease-free Survival Including Ductal Carcinoma in Situ (DFS-DCIS) in Neratinib Arm Compared to Placebo Arm at Year 5 [ Time Frame: From randomization until time of event up to 5 years ]
  Disease-free survival including DCIS time is defined as the time from date of randomization until the first occurrence of DCIS or an iDFS event (an iDFS event including invasive ipsilateral breast tumor recurrence, invasive contralateral breast cancer, local/regional invasive recurrence, or distant recurrence and death from any.
• Distant Disease-free Survival (DDFS) in Neratinib Arm Compared to Placebo Arm at Year 5 [ Time Frame: From randomization until time of event up to 5 years ]
  Distant disease-free survival time is defined as the time from date of randomization until the first occurrence of distant recurrence or death from any cause.
• Percentage of Participants With Time to Distant Recurrence (TTDR) Event in Neratinib Arm Compared to Placebo Arm at Year 5 [ Time Frame: From randomization until time of event up to 5 years ]
  Percentage of Participants with TTDR events is reported. TTDR is defined as the time from date of randomization until the first occurrence of distant recurrence or death from breast cancer.
• Cumulative Incidence of Central Nervous System Recurrence (CNS) at Year 5 [ Time Frame: From randomization until time of event up to 5 years ]
  Cumulative incidence of Central Nervous System Recurrence (CNS) is estimated by Gray's method (Gray,1988).

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study Evaluating The Effects Of Neratinib After Adjuvant Trastuzumab In Women With Early Stage Breast Cancer
• Official Title: A Randomized, Double-Blind, Placebo-Controlled Trial Of Neratinib (HKI-272) After Trastuzumab In Women With Early-Stage HER-2/Neu Overexpressed/Amplified Breast Cancer
• Brief Summary: The purpose of this study is to investigate whether neratinib can further reduce the risk of recurrence from previously diagnosed HER-2 positive breast cancer after adjuvant treatment with trastuzumab.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Breast Cancer

Intervention

• Drug: neratinib
  Other Names:

  • HKI-272
  • Nerlynx
• Other: placebo

Study Arms

• Experimental: Neratinib
  240 mg orally daily for one year
  Intervention: Drug: neratinib
• Placebo Comparator: Placebo
  orally daily for one year
  Intervention: Other: placebo

Publications *

• Iwata H, Masuda N, Kim SB, Inoue K, Rai Y, Fujita T, Chiu J, Ohtani S, Takahashi M, Miyaki T, Lu YS, Xu B, Yap YS, Bustam A, Yao B, Zhang B, Bryce R, Chan A. Neratinib after trastuzumab-based adjuvant therapy in patients from Asia with early stage HER2-positive breast cancer. Future Oncol. 2019 Jul;15(21):2489-2501. doi: 10.2217/fon-2019-0143. Epub 2019 May 29.
• Chia SKL, Martin M, Holmes FA, Ejlertsen B, Delaloge S, Moy B, Iwata H, von Minckwitz G, Mansi J, Barrios CH, Gnant M, Tomasevic Z, Denduluri N, Separovic R, Kim SB, Jakobsen EH, Harvey V, Robert N, Smith J 2nd, Harker G, Zhang B, Eli LD, Ye Y, Lalani AS, Buyse M, Chan A. PIK3CA alterations and benefit with neratinib: analysis from the randomized, double-blind, placebo-controlled, phase III ExteNET trial. Breast Cancer Res. 2019 Mar 11;21(1):39. doi: 10.1186/s13058-019-1115-2.
• Mortimer J, Di Palma J, Schmid K, Ye Y, Jahanzeb M. Patterns of occurrence and implications of neratinib-associated diarrhea in patients with HER2-positive breast cancer: analyses from the randomized phase III ExteNET trial. Breast Cancer Res. 2019 Feb 27;21(1):32. doi: 10.1186/s13058-019-1112-5.
• Delaloge S, Cella D, Ye Y, Buyse M, Chan A, Barrios CH, Holmes FA, Mansi J, Iwata H, Ejlertsen B, Moy B, Chia SKL, Gnant M, Smichkoska S, Ciceniene A, Martinez N, Filipovic S, Ben-Baruch NE, Joy AA, Langkjer ST, Senecal F, de Boer RH, Moran S, Yao B, Bryce R, Auerbach A, Fallowfield L, Martin M. Effects of neratinib on health-related quality of life in women with HER2-positive early-stage breast cancer: longitudinal analyses from the randomized phase III ExteNET trial. Ann Oncol. 2019 Apr 1;30(4):567-574. doi: 10.1093/annonc/mdz016.
• Martin M, Holmes FA, Ejlertsen B, Delaloge S, Moy B, Iwata H, von Minckwitz G, Chia SKL, Mansi J, Barrios CH, Gnant M, Tomasevic Z, Denduluri N, Separovic R, Gokmen E, Bashford A, Ruiz Borrego M, Kim SB, Jakobsen EH, Ciceniene A, Inoue K, Overkamp F, Heijns JB, Armstrong AC, Link JS, Joy AA, Bryce R, Wong A, Moran S, Yao B, Xu F, Auerbach A, Buyse M, Chan A; ExteNET Study Group. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1688-1700. doi: 10.1016/S1470-2045(17)30717-9. Epub 2017 Nov 13.
• Chan A, Delaloge S, Holmes FA, Moy B, Iwata H, Harvey VJ, Robert NJ, Silovski T, Gokmen E, von Minckwitz G, Ejlertsen B, Chia SKL, Mansi J, Barrios CH, Gnant M, Buyse M, Gore I, Smith J 2nd, Harker G, Masuda N, Petrakova K, Zotano AG, Iannotti N, Rodriguez G, Tassone P, Wong A, Bryce R, Ye Y, Yao B, Martin M; ExteNET Study Group. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2016 Mar;17(3):367-377. doi: 10.1016/S1470-2045(15)00551-3. Epub 2016 Feb 10.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 20, 2015): 2840
• Original Estimated Enrollment (submitted: April 8, 2009): 3850
• Actual Study Completion Date: October 4, 2019
• Actual Primary Completion Date: August 21, 2014 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Stage II through IIIC HER-2/erbB-2 positive breast cancer with node positive disease.
• Been treated for early breast cancer with standard of care duration of trastuzumab.
• Could have been treated neoadjuvantly but have not reached pathologic complete response.

Exclusion Criteria:

• Positive clinical and radiologic assessments for local or regional recurrence of disease at the time of study entry.
• History of heart disease.
• Corrected QT (QTc) interval >0.45 seconds
• History of gastrointestinal disease with diarrhea as the major symptom.

Sex/Gender

• Sexes Eligible for Study: Female
• Gender Based Eligibility: Yes

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Bahamas, Belgium, Brazil, Bulgaria, Canada, China, Colombia, Croatia, Czechia, Denmark, France, Germany, Greece, Hong Kong, Hungary, Israel, Italy, Japan, Korea, Republic of, Lithuania, Malaysia, Malta, Mexico, Netherlands, New Zealand, North Macedonia, Peru, Poland, Romania, Serbia, Singapore, Slovakia, Spain, Sweden, Switzerland, Taiwan, Turkey, United Kingdom, United States
• Removed Location Countries: Argentina, Chile, Czech Republic, Jordan, Lebanon, Macedonia, The Former Yugoslav Republic of, Saudi Arabia

Administrative Information

• NCT Number: NCT00878709
• Other Study ID Numbers: 3144A2-3004 / B1891004
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: Yes

Plan Description

Puma Biotechnology is committed to sharing clinical trial data and information to help physicians and patients make informed treatment decisions, and to help qualified researchers advance scientific knowledge.

In accordance with legal and regulatory requirements, Puma publishes study protocol information and clinical study results on clinical trial registries, including ClinicalTrials.gov and EU Clinical Trials Register. Puma also publishes information about clinical studies in peer-reviewed scientific journals and shares data in scientific meetings.

Puma commits to safeguarding confidentiality and patient privacy throughout the clinical trial data and information sharing process. Any patient-level data will be anonymized to protect personally identifiable information.

Qualified researchers and study participants may submit requests for other study documentation and clinical trial data to clinicaltrials@pumabiotechnology.com for consideration.

• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: Clinical study documents and clinical trial data may be requested by qualified researchers and study participants for studies that have been completed for at least 18 months, and for which the indication of the drug has been approved in the US and/or EU, as applicable. Requests will be accepted for up to 24 months after the criteria described in this section are met.

Access Criteria

Requestors must provide organizational contact information; a detailed research plan, including outcomes; timeline for completion of the research; qualifications of the research team; funding source; and potential conflicts of interest.

Puma will not provide access to patient-level data if there is a reasonable likelihood that individual patients could be identified, or in cases where confidentiality or consent provisions prohibit transfer of data or information to third parties. Additionally, Puma will not disclose information that jeopardizes intellectual property rights or divulges confidential commercial information.

• URL: https://pumabiotechnology.com/data_sharing_policy.html

• Current Responsible Party: Puma Biotechnology, Inc.
• Original Responsible Party: Wyeth (Registry Contact: Clinical Trial Registry Specialist), Wyeth
• Current Study Sponsor: Puma Biotechnology, Inc.
• Original Study Sponsor: Wyeth is now a wholly owned subsidiary of Pfizer
• Collaborators: Not Provided

Investigators

• Study Director: Senior Vice President Clinical Science and Pharmacology; Puma Biotechnology, Inc.

• PRS Account: Puma Biotechnology, Inc.
• Verification Date: May 2021