Tucatinib, Palbociclib and Letrozole in Metastatic Hormone Receptor Positive and HER2-positive Breast Cancer

This is a multicenter, single arm, open-label, run-in phase Ib / roll-over phase II study of
novel HER2-targeted tyrosine kinase inhibitor tucatinib in combination with CDK4/6 inhibitor
palbociclib and aromatase inhibitor letrozole in subjects with HR+/HER2+ locally advanced
unresectable or metastatic breast cancer. The study will enroll post-menopausal women and
premenopausal women if on treatment with or willing to be treated with standard ovarian
suppression. The phase Ib part of the study will determine safety and tolerability of the
combination of tucatinib, palbociclib and letrozole to confirm that current RP2D of tucatinib
and FDA approved dosing of palbociclib remains the same in the triplet combination. The dose
of letrozole will be constant through the study period. Once the safety of the combination is
established, we will move to the phase II part of the study in the expansion cohort of
subjects at RP2D for the purpose of assessing efficacy while further refining assessment of
safety of the combination treatment.

Inclusion Criteria:

1. Subjects must have a histologically confirmed diagnosis of HR+/HER2+ positive locally
advanced unresectable or metastatic breast cancer. Estrogen or progesterone receptor
positivity is defined by IHC according to ASCO/CAP guidelines 2010. HER2 positivity is
defined by standard of care fluorescence in situ hybridization (FISH) and/or 3+
staining by IHC according to ASCO/CAP guidelines 2014.

2. Measurable and/or evaluable disease per RECIST 1.1 criteria and/or RANO-BM criteria.
Bone only disease is allowed.

3. CNS inclusion criteria:

- Subjects without CNS metastases are eligible. Note: brain imaging is not required
for asymptomatic subjects without known brain metastatic disease prior to
enrollment into the study

- Subjects with untreated asymptomatic CNS metastases not needing immediate local
therapy in the opinion of investigator are eligible. For subjects with untreated
asymptomatic CNS lesions > 2.0 cm MRI, discussion with and approval from the Lead
PI is required prior to enrollment

- Subjects with stable brain metastases previously treated with radiation therapy
or surgery are allowed to enroll, provided that they are off corticosteroids or
on stable/tapering dose of corticosteroids and stability of CNS metastatic
disease for at least 4 weeks has been demonstrated, with the last MRI taken
within 2 weeks prior to cycle 1 day 1 of the study. Relevant records of any CNS
treatment must be available to allow for classification of target and non-target
lesions

4. Age ≥ 18 years

5. ECOG performance status 0-1

6. Life expectancy of more than 6 months, in the opinion of the investigator

7. Study subjects should be post-menopausal women (premenopausal women are eligible if
they are on or willing to be on mandatory ovarian function suppression)

8. Prior treatments:

- Subjects with newly diagnosed untreated metastatic disease are eligible

- Subjects who have had 1 line of prior endocrine therapy in the metastatic setting
are allowed. Prior adjuvant and/or neoadjuvant endocrine regimens are allowed and
not counted towards this limit

- Subjects may have had up to 1 line of prior chemotherapy, combination of
chemotherapy with HER2-targeted antibodies (trastuzumab, pertuzumab, TDM-1), or
HER2-targeted therapy alone in the metastatic setting. Prior adjuvant and/or
neoadjuvant regimens are allowed and not counted towards this limit

9. Adequate organ and marrow function as defined below:

- Absolute neutrophil count ≥ 1,500/mm3

- Platelets ≥ 75,000/mm3

- Hemoglobin ≥ 9.0 mg/dL without red blood cell transfusion ≤ 7 days prior to Cycle
1 Day 1 of therapy

- Total serum 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
ULN

- AST (SGOT)/ALT (SGPT) ≤2.5 X ULN;

- Serum creatinine ≤ 1.5 mg/dL

- International normalized ratio (INR) and activated partial thromboplastin time
(aPTT) ≤ 1.5 X ULN unless on medication known to alter INR and aPTT

- Left ventricular ejection fraction (LVEF) ≥ 50% (as assessed by ECHO or MUGA)
documented within 4 weeks prior to first dose of study treatment

- Serum or urine pregnancy test (for women of childbearing potential) negative ≤ 7
days of starting treatment

10. Ability to understand and the willingness to sign a written informed consent and
comply with the study scheduled visits, treatment plans, laboratory tests and other
procedures.

11. Subject or legally authorized representative of a subject must provide signed informed
consent document that has been approved by an institutional review board or
independent ethics committee (IRB/IEC) prior to initiation of any study-related tests
or procedures that are not part of standard-of-care for the subject's disease.

Exclusion Criteria:

1. Subjects with previously treated progressing brain metastases are excluded from the
study

2. Subjects with known brain metastases and contraindications to undergo contrast MRI
imaging of the brain are excluded from the study

3. Pregnancy or breast feeding

4. Current active treatment with an investigational agent.

5. Known history of hypersensitivity to aromatase-inhibitor drugs.

6. Any toxicity related to prior cancer therapies that has not resolved to ≤ Grade 1,
with the exception of peripheral neuropathy, which must have resolved to ≤ Grade 2,
and alopecia.

7. Previous treatment with lapatinib, neratinib, afatinib, or other investigational
EGFR-family receptor tyrosine kinase inhibitor or HER2 tyrosine kinase inhibitor.

8. Previous treatment with palbociclib, abemaciclib, ribociclib or other investigational
CDK4/6 inhibitors

9. Any systemic anti-cancer therapy (including hormonal therapy), radiation, or
experimental agent ≤ 2 weeks of first dose of study treatment

10. Active bacterial, fungal or viral infections requiring treatment with IV antibiotic,
IV anti-fungal, or anti-viral.

11. Known active hepatitis B (HBV), hepatitis C (HCV) or human immunodeficiency virus
(HIV) infections. Note: pretesting is not required.

12. Inability to swallow pills or any significant gastrointestinal disease which would
preclude the adequate oral absorption of medications

13. Use of prohibited medications listed in Appendix D (strong CYP3A4 or CYP2C8 inducers
or inhibitors, or moderate CYP2C8 inhibitor trimethoprim) within 3 elimination
half-lives of the inducer or inhibitor prior to first dose of the study treatment

14. Known myocardial infarction, severe/unstable angina, percutaneous transluminal
coronary angioplasty/stenting (PTCA), or coronary artery bypass graft (CABG) within 6
month of the first dose of the study treatment

15. Clinically significant cardio-vascular disease, such as ventricular arrhythmia
requiring therapy, uncontrolled hypertension (defined as persistent systolic blood
pressure > 160 mm Hg and/or diastolic blood pressure > 100 mm Hg on antihypertensive
medications), or any history of symptomatic CHF

16. Other severe acute or chronic medical or psychiatric conditions or laboratory
abnormalities that may increase the risk associated with study participation or study
drug administration, or may interfere with the interpretation of study results, or in
the judgment of the investigator would make the subject inappropriate for entry into
the study.