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)

Summary

This is a randomized, multi-center, multinational, open-label, active-controlled, parallel design study of the combination ofneratinib 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:i 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, i 000 mg/m 2 BiD)

Following a 21-day screening period (Section 9.i), eligible patients will be randomized to arm a or arm B. Baseline assessments will be performed prior to randomization and Cycle 1/Day 1 dosing. Patients will then participate in the active treatment phase, consisting of 21-day treatment cycles (Section 9.2). investigational products will be administered orally by patients as described in Section 6.1. neratinib and lapatinib are to be taken continuously, in 21-day cycles, with no rest between cycles. Capecitabine will be taken on Days i to 14 of each 21-day cycle.

There are 2 co-primary endpoints in this study: independently-adjudicated PFS (Progression Free Survival) and oS (overall survivor) . all patients randomized will be evaluated.

The secondary efficacy endpoints include investigator-assessed PFS,(Progression Free0, oRR (objective Response Rate), DoR (Duration of Response) , and CBR (clinical benefit rate)

Progression-free Survival
Progression-free survival is determined programmatically from adjudicated PD, defined as the interval from the date of randomization until the first date on which recurrence, progression (per ReCiST v1.1 [appendix 7]) or death due to any cause, is documented, censored at the last assessable evaluation, or at the initiation of new anticancer therapy. it is not necessary to confirm disease progression.

overall Survival
overall survival is defined as the time from randomization to death due to any cause

objective Response Rate
The oRR is defined as the proportion of patients demonstrating either a CR or PR per ReCiST v1.1 (appendix 7) as their best overall response during the study.

Duration of Response
The DoR 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 on which recurrence or PD or death is objectively documented, taking as a reference for PD the smallest measurements recorded since enrollment,

Clinical Benefit Rate
The CBR is defined as the proportion of patients who achieved overall tumor response (CR or PR) or SD for at least 24 weeks. Stable disease is measured from enrollment until the criteria for disease progression or response are met,

Time to intervention for Symptomatic CnS Disease
Time to intervention for symptomatic metastatic CnS disease is defined as the date of initiation of intervention or therapy for symptomatic CnS disease determined by the investigator to be due to CnS metastasis. This may include brain, leptomeningeal and epidural metastases including epidural spinal cord compression arising from tumor growth in the epidural spac

Participant Eligibility

Each patient will be entered into this study only if she/he meets all of the following criteria:
1. Aged >=18 years at signing of informed consent.
2. Histologically confirmed MBC, current stage IV.
3. Documented HER2 overexpression or gene-amplified tumor (immunohistochemistry
[IHC] 3+; or IHC 2+ with confirmatory fluorescence in situ hybridization [FISH]+). (Note:
Patients who are IHC 0 or 1+ are not eligible to participate in the study). Tumor samples will
be evaluated for HER2 expression by IHC (Herceptest(TM)) and if required for gene
amplification by FISH analysis (Abbott/Vysis).
4. Prior treatment with at least two HER2-directed regimens for metastatic breast cancer. A new
regimen is defined as a modification in a planned course of therapy to include other treatment
agents (alone or in combination) as a result of disease progression, relapse, or toxicity [61]. A
new regimen also starts when a planned period of observation off therapy is interrupted by a
need for additional treatment for the disease.
5. At least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors
(RECIST v1.1 [62], see Appendix 7). Specifically, no ascites, pleural or pericardial effusions,
osteoblastic bone metastases, or carcinomatous lymphangitis of the lung as the only lesion
are allowed.
6. Left ventricular ejection fraction (LVEF) >=50% measured by multiple-gated acquisition scan
(MUGA) or echocardiogram (ECHO).
7. Eastern Cooperative Oncology Group (ECOG) status of 0 to 1 (see Appendix 3).
8. Negative [BETA]-human chorionic gonadotropin (hCG) pregnancy test for premenopausal women
of reproductive capacity (those who are biologically capable of having children) and for
women less than 12 months after menopause.
9. Women of childbearing potential must agree and commit to the use of a highly effective
method of contraception, as determined to be acceptable by the Investigator, from the time of
informed consent until 28 days after the last dose of the investigational products. Men must
agree and commit to use a barrier method of contraception while on treatment and for
3 months after last dose of investigational products.
10. Provide written, informed consent to participate in the study and follow the study procedures.