A Study of Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in Patients With HER2+ Metastatic Breast Cancer Who Have Received Two or More Prior HER2 Directed Regimens in the Metastatic Setting (NALA)

• ClinicalTrials.gov Identifier: NCT01808573
• Recruitment Status: Completed
• First Posted: March 11, 2013
• Results First Posted: December 11, 2019
• Last Update Posted: June 11, 2021
• Sponsor: Puma Biotechnology, Inc.
• Information provided by (Responsible Party): Puma Biotechnology, Inc.

Tracking Information

• First Submitted Date: March 4, 2013
• First Posted Date: March 11, 2013
• Results First Submitted Date: September 27, 2019
• Results First Posted Date: December 11, 2019
• Last Update Posted Date: June 11, 2021
• Actual Study Start Date: March 29, 2013
• Actual Primary Completion Date: September 28, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 3, 2020)

• Centrally Assessed Progression Free Survival [ Time Frame: From randomization date to recurrence, progression or death, assessed up to 38 months. The result is based on primary analysis data cut. ]
  Progression Free Survival (PFS), Measured in Months, for Randomized Subjects of the Central Assessment. The time interval from the date of randomization until the first date on which recurrence, progression (per Response Evaluation Criteria in Solid Tumors Criteria (RECIST) v1.1), or death due to any cause, is documented. For subjects without recurrence, progression or death, it is censored at the last valid tumor assessment. Progression is defined using Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Here, the time to event was reported as the restricted mean survival time. The restricted mean survival time was defined as the area under the curve of the survival function up to 24 months.
• Overall Survival [ Time Frame: From randomization date to death, assessed up to 59 months.The result is based on primary analysis data cut. ]
  Overall survival (OS) is defined as the time from randomization to death due to any cause, censored at the last date known alive on or prior to the data cutoff employed for the analysis, whichever was earlier. Here, the time to event was reported as the restricted mean survival time. The restricted mean survival time was defined as the area under the curve of the survival function up to 48 months.

Original Primary Outcome Measures (submitted: March 7, 2013)

• Independently assessed Progression Free Survival [ Time Frame: Estimated 10 months ]
• Overall Survival [ Time Frame: Estimated 28 months ]

Current Secondary Outcome Measures (submitted: March 3, 2020)

• Intervention for Symptomatic Metastatic Central Nervous System Disease [ Time Frame: From randomization date to first intervention for symptomatic metastatic CNS disease, assessed up to 59 months.The result is based on primary analysis data cut. ]
  Intervention for symptomatic metastatic central nervous system disease is defined as the time from randomization to the first start date of an intervention for symptomatic metastatic CNS disease. Subjects that do not have an intervention for symptomatic metastatic CNS and do not die will be censored at the last date known alive on or prior to the data cutoff. Deaths are treated as competing events. Percentage of participants with intervention for CNS, estimated by cumulative incidence methods. Cumulative incidence methods are the standard way to estimate incidence of an endpoint in the presence of competing risks and censoring.
• Objective Response Rate (ORR) - Central Assessment (ITT Population With Measurable Disease at Screening) [ Time Frame: From randomization date to first confirmed Complete or Partial Response, whichever came earlier, up to 42 months.The result is based on primary analysis data cut. ]
  Objective response rate is defined as the percentage of participants demonstrating an objective response during the study. Objective response includes confirmed complete responses (CR) and partial responses (PR) as defined in the RECIST criteria included in the study protocol. The ORR is for Central Assessment for subjects that had measurable disease at screening. Per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
• Clinical Benefit Rate (CBR) - Central Assessment (ITT Population With Measurable Disease at Screening) [ Time Frame: From randomization date to either first confirmed CR or PR or Stable Disease, whichever came earlier, up to 42 months.The result is based on primary analysis data cut. ]
  Clinical benefit rate is the percentage of participants who achieve overall tumor response (confirmed CR or PR) or stable disease (SD) lasting for at least 24 weeks from randomization. The CBR was for Central Assessment for subjects who had Measurable Disease at Screening.
• Duration of Response (DOR) - Central Assessment (Population That Had a Response With Measurable Disease at Screening) [ Time Frame: From start date of response after randomization to first PD, up to 33 months.The result is based on primary analysis data cut. ]
  The Duration of Response (DOR) is for Central Assessment for the Population that Had a Response with Measurable Disease at Screening. Duration of response is measured from the time at which measurement criteria are first met for CR or PR (whichever status is recorded first) until the first date of recurrence or progressive disease (PD) or death is objectively documented, taking as a reference for PD the smallest measurements recorded since enrollment, per RECIST v1.1. This value is censored at the last valid tumor assessment if PD or death has not been documented.
• Percentage of Participants With Treatment-Emergent Adverse Events (Adverse Events and Serious Adverse Events) [ Time Frame: From first dose through last dose + 28 days, up to 41 months. The result is based on final data cut. ]
  Adverse Events to be measured are Treatment-Emergent and Serious AEs that occurred on or after first dose of investigational product and up to 28 days after the last dose

Original Secondary Outcome Measures (submitted: March 7, 2013)

• Investigator Assessed Progression Free Survival [ Time Frame: Estimated 10 months ]
• Objective Response Rate (ORR) [ Time Frame: Estimated 10 months ]
• Clinical Benefit Rate (CBR) [ Time Frame: 24 weeks ]
  CBR is defined as Complete Response (CR) or Partial Response (PR) or Stable Disease (SD) for ≥ 24 weeks.
• Duration of Response (DOR) [ Time Frame: Estimated 10 months ]
• Time to intervention for symptomatic metastatic central nervous system disease [ Time Frame: Estimated 10 months ]
• Safety (Adverse Events [AEs] and Serious Adverse Events [SAEs]) [ Time Frame: From consent through 30 days following treatment completion (estimated 11 months) ]
• Health Outcomes Assessments [ Time Frame: Estimated 10 months ]
  Validated Quality of Life Questionnaires; EORTC QLQ-C30, EORTC QLQ-BR23, and EQ-5D-5L

• Current Other Pre-specified Outcome Measures: Not Provided

Original Other Pre-specified Outcome Measures (submitted: March 7, 2013)

Population pharmacokinetics [ Time Frame: 1 month following enrollment ]

To assess the variability of neratinib concentration when administered in combination with capecitabine among individuals in the target population.

Descriptive Information

• Brief Title: A Study of Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in Patients With HER2+ Metastatic Breast Cancer Who Have Received Two or More Prior HER2 Directed Regimens in the Metastatic Setting
• Official Title: A STUDY OF NERATINIB PLUS CAPECITABINE VERSUS LAPATINIB PLUS CAPECITABINE IN PATIENTS WITH HER2+ METASTATIC BREAST CANCER WHO HAVE RECEIVED TWO OR MORE PRIOR HER2-DIRECTED REGIMENS IN THE METASTATIC SETTING (NALA)
• Brief Summary: This is a randomized, multi-center, multinational, open-label, active-controlled, parallel design study of the combination of neratinib plus capecitabine versus the combination of lapatinib plus capecitabine in HER2+ MBC patients who have received two or more prior HER2 directed regimens in the metastatic setting.

Detailed Description

This is a randomized, multi-center, multinational, open-label, active-controlled, parallel design study of the combination of neratinib plus capecitabine versus the combination of lapatinib plus capecitabine in HER2+ MBC patients who have received two or more prior HER2 directed regimens in the metastatic setting. Patients will be randomized in a 1:1 ratio to one of the following treatment arms:

• Arm A: neratinib (240 mg once daily) + capecitabine (1500 mg/m^2 daily, 750 mg/m^2 twice daily [BID])
• Arm B: lapatinib (1250 mg once daily) + capecitabine (2000 mg/m^2 daily, 1000 mg/m^2 BID)

Patients will receive either neratinib plus capecitabine combination or lapatinib plus capecitabine combination until the occurrence of death, disease progression, unacceptable toxicity, or other specified withdrawal criterion.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: HER2+ Metastatic Breast Cancer (MBC)

Intervention

• Drug: neratinib
  Other Name: Nerlynx
• Drug: capecitabine
  Other Name: Xeloda
• Drug: lapatinib
  Other Names:

  • Tykerb
  • Tyverb

Study Arms

• Experimental: neratinib plus capecitabine
  neratinib 240 mg orally, once daily with food, continuously in 21 day cycles, and capecitabine 1500 mg/m^2 daily in 2 evenly divided doses, orally with water within 30 minutes after a meal, taken on days 1 to 14 of each 21 day cycle.
  Interventions:

  • Drug: neratinib
  • Drug: capecitabine
• Active Comparator: lapatinib plus capecitabine
  lapatinib 1250 mg orally, once daily, continuously in 21 day cycles, and capecitabine 2000 mg/m^2 daily in 2 evenly divided doses, orally with water within 30 minutes after a meal, taken on days 1 to 14 of each 21 day cycle.
  Interventions:

  • Drug: capecitabine
  • Drug: lapatinib

Publications *

• Dai MS, Feng YH, Chen SW, Masuda N, Yau T, Chen ST, Lu YS, Yap YS, Ang PCS, Chu SC, Kwong A, Lee KS, Ow S, Kim SB, Lin J, Chung HC, Ngan R, Kok VC, Rau KM, Sangai T, Ng TY, Tseng LM, Bryce R, Bebchuk J, Chen MC, Hou MF. Analysis of the pan-Asian subgroup of patients in the NALA Trial: a randomized phase III NALA Trial comparing neratinib+capecitabine (N+C) vs lapatinib+capecitabine (L+C) in patients with HER2+metastatic breast cancer (mBC) previously treated with two or more HER2-directed regimens. Breast Cancer Res Treat. 2021 Oct;189(3):665-676. doi: 10.1007/s10549-021-06313-5. Epub 2021 Sep 23.
• Saura C, Oliveira M, Feng YH, Dai MS, Chen SW, Hurvitz SA, Kim SB, Moy B, Delaloge S, Gradishar W, Masuda N, Palacova M, Trudeau ME, Mattson J, Yap YS, Hou MF, De Laurentiis M, Yeh YM, Chang HT, Yau T, Wildiers H, Haley B, Fagnani D, Lu YS, Crown J, Lin J, Takahashi M, Takano T, Yamaguchi M, Fujii T, Yao B, Bebchuk J, Keyvanjah K, Bryce R, Brufsky A; NALA Investigators. Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in HER2-Positive Metastatic Breast Cancer Previously Treated With >/= 2 HER2-Directed Regimens: Phase III NALA Trial. J Clin Oncol. 2020 Sep 20;38(27):3138-3149. doi: 10.1200/JCO.20.00147. Epub 2020 Jul 17.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: October 9, 2017): 621
• Original Estimated Enrollment (submitted: March 7, 2013): 600
• Actual Study Completion Date: December 9, 2019
• Actual Primary Completion Date: September 28, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Aged ≥18 years at signing of informed consent.
• Histologically confirmed MBC, current stage IV.
• Documented HER2 overexpression or gene-amplified tumor immunohistochemistry 3+ or 2+, with confirmatory fluorescence in situ hybridization (FISH) +.
• Prior treatment with at least two (2) HER2-directed regimens for metastatic breast cancer.

Exclusion Criteria:

• Received previous therapy with capecitabine, neratinib, lapatinib, or any other HER2 directed tyrosine kinase inhibitor.

Note: There are additional inclusion and exclusion criteria. The study center will determine if you meet all of the criteria.

Sex/Gender

• Sexes Eligible for Study: All

• 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: Argentina, Australia, Austria, Belgium, Brazil, Canada, Czechia, Denmark, Finland, France, Germany, Hong Kong, Ireland, Israel, Italy, Japan, Korea, Republic of, Netherlands, Portugal, Russian Federation, Singapore, Spain, Sweden, Switzerland, Taiwan, Turkey, United Kingdom, United States
• Removed Location Countries: Czech Republic

Administrative Information

• NCT Number: NCT01808573
• Other Study ID Numbers: PUMA-NER-1301; 2012-004492-38 ( EudraCT Number ); UTN U1111-1161-1603 ( Other Identifier: WHO )
• 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: Same as current
• Current Study Sponsor: Puma Biotechnology, Inc.
• Original Study Sponsor: Same as current
• 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