Randomized, double-blind, phase 3 study of tucatinib or placebo in combination with ado-trastuzumab emtansine (T-DM1) for subjects with unresectable locally-advanced or metastatic HER2+ breast cancer
(HER2CLIMB-02)

1. Histologically confirmed HER2+ breast carcinoma, as determined by sponsor-
designated central laboratory testing on tumor tissue submitted prior to
randomization (see Section 7.1.1), from either:
a. Archival tissue (most recent tumor tissue sample preferred)
b. If archival tissue is not available, then a newly-obtained baseline biopsy
of an
accessible tumor lesion that has not been previously irradiated is required
2. History of prior treatment with a taxane and trastuzumab in any setting,
separately or in
combination. Prior pertuzumab therapy is allowed, but not required.
3. Have progression of unresectable LA/M breast cancer after last systemic
therapy (as
confirmed by investigator), or be intolerant of last systemic therapy
4. Measureable or non-measurable disease assessable by RECIST v1.1
5. HR (estrogen receptor [ER]/ progesterone receptor [PR]) status must be known
prior to
randomization
6. Age >=18 years at time of consent or >= the age of majority in the geographic
location
7. ECOG performance status score of 0 or 1 (see APPENDIX B for conversion of
performance status using Karnofsky scale, if applicable)
8. Life expectancy >=6 months, in the opinion of the investigator
9. Adequate hepatic function as defined by the following:
a. Total bilirubin <= 1.5 X upper limit of normal (ULN), except for subjects
with known
Gilbert*s disease, who may enroll if the conjugated bilirubin is <=1.5 X ULN
b. Transaminases (aspartate aminotransferase/serum glutamic oxaloacetic
transaminase
[AST/SGOT] and alanine aminotransferase/serum glutamic pyruvic transaminase
[ALT/SGPT]) <= 2.5 X ULN (<= 5 X ULN if liver metastases are present)
10. Adequate baseline hematologic parameters as defined by:
a. Absolute neutrophil count >=1.5 X 103/µL
b. Platelet count >=100 X 103/µL
c. Hemoglobin >=9 g/dL
d. In subjects transfused before study entry, transfusion must be >=14 days
prior to start
of therapy to establish adequate hematologic parameters independent from
transfusion support
11. Estimated glomerular filtration rate (GFR) >=50 mL/min/1.73 m2 using the
Modification
of Diet in Renal Disease (MDRD) study equation (see Section 7.8.4).
12. International normalized ratio (INR) and partial thromboplastin time
(PTT)/activated
partial thromboplastin time (aPTT) <= 1.5 X ULN, unless on medication known to
alter INR and PTT/aPTT.
13. Left ventricular ejection fraction (LVEF) >=50% as assessed by
echocardiogram (ECHO)
or multi-gated acquisition scan (MUGA) documented within 4 weeks prior to first
dose of study treatment (see Section 6.2.2 for exceptions)
14. For subjects of childbearing potential, as defined in Section 4.3, the
following
stipulations apply:
a. Must have a negative serum or urine pregnancy test (minimum sensitivity of
25 mIU/mL or equivalent units of beta human chorionic gonadotropin [β-hCG])
result within 7 days prior to the first dose of study treatment. A subject with
a false positive result and documented verification that the subject is not
pregnant is eligible for participation.
b. Must agree not to try to become pregnant during the study and for at least 7
months
after the final dose of study drug administration
c. Must agree not to breastfeed or donate ova, starting at time of informed
consent and
continuing through 7 months after the final dose of study drug administration
d. If sexually active in a way that could lead to pregnancy, must consistently
use 2 highly
effective methods of birth control (as defined in Appendix K) starting at the
time of informed consent and continuing throughout the study and for at least 7
months after the final dose of study drug administration.

15. For subjects who can father children, the following stipulations apply:
a. Must agree not to donate sperm starting at time of informed consent and
continuing
throughout the study period and for at least 7 months after the final study
drug administration
b. If sexually active with a person of childbearing potential in a way that
could lead to
pregnancy, must consistently use 2 highly effective methods of birth control
(as defined in Appendix K) starting at time of informed consent and continuing
throughout the study and for at least 7 months after the final dose of study
drug administration
c. If sexually active with a person who is pregnant or breastfeeding, must
consistently
use 1 of 2 highly effective methods of birth control (as defined in Appendix K)
starting at time of informed consent and continuing throughout the study and
for at least 7 months after the final dose of study drug administration
16. The subject must provide written informed consent
17. Subject must be willing and able to comply with study procedures
18. CNS Inclusion - Based on screening contrast brain magnetic resonance
imaging (MRI),
subjects must have at least one of the following:
a. No evidence of brain metastases
b. Untreated brain metastases not needing immediate local therapy. For subjects
with
untreated CNS lesions >2.0 cm in diameter on screening contrast brain MRI,
approval from the medical monitor is required prior to enrollment.
c. Previously treated brain metastases
i. Brain metastases previously treated with local therapy may either be stable
since
treatment or may have progressed since prior local CNS therapy, provided that
there is no clinical indication for immediate re-treatment with local therapy
in the opinion of the investigator
ii. Subjects treated with CNS local therapy for newly identified lesions or
previously
treated and progressing lesions found on
contrast brain MRI performed during screening for this study may be eligible to
enroll if all of the following criteria are met:
* Time since SRS is >=7 days prior to first dose of study treatment, time since
whole-brain radiation therapy (WBRT) is >=14 days prior to first dose of study
treatment, or time since surgical resection is >=28 days
* Other sites of evaluable disease are present
iii. Relevant records of any CNS treatment must be available to allow for
classification of target and non-target lesions

1. Prior treatment with tucatinib, afatinib, trastuzumab deruxtecan (DS-8201a),
or
any other investigational anti-HER2, anti-EGFR, or HER2 TKI agent. Prior
treatment with lapatinib or neratinib within 12 months of starting study
treatment (except in cases where they were given for <=21 days and discontinued
for reasons other than disease progression or severe toxicity). Prior treatment
with pyrotinib for recurrent or mBC (except in cases where pyrotinib was given
for <=21 days and discontinued for reasons other than disease progression or
severe toxicity)
2. Prior treatment with T-DM1 in any treatment setting
3. History of allergic reactions to trastuzumab or compounds chemically or
biologically
similar to tucatinib, except for Grade 1 or 2 infusion related reactions to
trastuzumab that were successfully managed, or known allergy to any of the
excipients in the study drugs
4. Treatment with any systemic anti-cancer therapy (including hormonal
therapy), non-CNS
radiation (palliative or therapeutic), experimental agent or participation in
another interventional clinical trial <=3 weeks prior to first dose of study
treatment. An exception for the washout of hormonal therapies is gonadotropin
releasing hormone agonists used for ovarian suppression in premenopausal women,
which are permitted concomitant medications.
5. Any toxicity related to prior cancer therapies that has not resolved to <=
Grade 1, with the
following exceptions:
* Alopecia;
* Neuropathy, which must have resolved to <= Grade 2;
* Congestive heart failure (CHF), which must have been <= Grade 1 in severity at
the
time of occurrence, and must have resolved completely
6. Clinically significant cardiopulmonary disease such as:
* Ventricular arrhythmia requiring therapy
* Symptomatic hypertension or uncontrolled asymptomatic hypertension as
determined
by the investigator
* Any history of symptomatic CHF, symptomatic left ventricular systolic
dysfunction or symptomatic decrease in
ejection fraction
* Severe dyspnea at rest (Common Terminology Criteria for Adverse Events [CTCAE]
Grade 3 or above) due to complications of advanced malignancy or hypoxia
requiring supplementary oxygen therapy
* >= Grade 2 QTc prolongation on screening electrocardiogram (ECG)
7. Known myocardial infarction or unstable angina within 6 months prior to
first dose of
study treatment
8. Known carrier of Hepatitis B or Hepatitis C or has other known chronic liver
disease
9. Subjects known to be positive for human immunodeficiency virus (HIV) if they
meet any
of the following criteria:
* CD4+ T-cell count of <350 cells/uL
* Detectable HIV viral load
* History of an opportunistic infection within the past 12 months
* On stable antiretroviral therapy for <4 weeks
10. Subjects who are pregnant, breastfeeding, or planning to become pregnant
from time of
informed consent until 7 months following the last dose of study drug
11. Unable to swallow pills or has significant gastrointestinal disease which
would preclude
the adequate oral absorption of medications
12. Use of a strong cytochrome P450 (CYP) 3A4 or CYP2C8 inhibitor within 1
week, or use of a strong
CYP3A4 or CYP2C8 inducer within 5 days prior to the first dose of study
treatment (see Appendix C and Appendix D). CYP3A4 or CYP2C8 inducers and
inhibitors are also prohibited as concomitant medications within 1 week of
discontinuation of tucatinib treatment. Use of sensitive CYP3A substrates
(Appendix E:) should be avoided 1 week before enrollment and during study
treatment.
13. Unable to undergo contrast MRI of the brain
14. Other medical, social, or psychosocial factors that, in the opinion of the
investigator,
could impact safety or compliance with study procedures
15. Systemic therapy for another malignancy within 2 years of the start of
study treatment
16. CNS Exclusion - Based on screening brain MRI, subjects must not have any of
the
following:
a. Any untreated brain lesions >2.0 cm in size, unless approved by the medical
monitor
b. Ongoing use of systemic corticosteroids for control of symptoms of brain
metastases
at a total daily dose of >2 mg of dexamethasone (or equivalent). However,
subjects on a chronic stable dose of <=2 mg total daily of dexamethasone (or
equivalent) may be eligible with approval of the medical monitor.
c. Any brain lesion thought to require immediate local therapy, including (but
not
limited to) a lesion in an anatomic site where increase in size or possible
treatment- related edema may pose risk to the subject (e.g., brain stem
lesions). Subjects who undergo local treatment for such lesions identified by
screening contrast brain MRI may still be eligible for the study based on
criteria described under CNS
Inclusion 18c (ii).
d. Known or concurrent leptomeningeal disease as documented by the investigator
e. Poorly controlled (>1/week) generalized or complex partial seizures, or
manifest
neurologic progression due to brain metastases notwithstanding CNS-directed
therapy