An Open-label Randomized Phase 3 Study of Tucatinib in Combination with Trastuzumab and mFOLFOX6 versus mFOLFOX6 given with or without either Cetuximab or Bevacizumab as First-line Treatment for Subjects with HER2+ Metastatic Colorectal Cancer

Subjects must meet the following criteria to be eligible for the study:

1. Have histologically and/or cytologically documented adenocarcinoma of the
colon or rectum, which is locally advanced unresectable or metastatic.
2. Subjects must be willing and able to provide the most recently available
formalin-fixed paraffin-embedded tumor tissue blocks (or freshly sectioned
slides, see laboratory manual for details), obtained prior to treatment
initiation, to a sponsor-designated central laboratory for biomarker analysis.
If archival tissue is not available, then a newly-obtained baseline biopsy of
an accessible tumor lesion is required within 35 days prior to the Cycle 1 Day
1 timeframe. Biopsy must provide adequate tissue for analysis; the following
biopsy types are acceptable: resection, excision, punch (skin lesions only) and
core needle biopsies.
3. Have HER2+ disease as determined by tissue-based investigational HER2 IHC
and ISH assays performed at a sponsor-defined central laboratory. HER2
amplification will be determined using ASCO/CAP guidelines for gastric and
gastroesophageal cancer with IHC 3+ or IHC 2+/ISH+ result.
4. Have RAS WT disease as determined by local or central testing (if local
testing is unavailable or is not preferred). For central RAS analysis, tissue
sample must be analyzed within 1 year of biopsy date.
5. Age >=18 years at time of consent and >= the age of majority per regional
requirements
6. Have radiographically measurable disease per RECIST v1.1 according to INV
assessment, with at least one site of disease that is measurable and that has
not been previously irradiated; or, if the subject has had previous radiation
to the target lesion(s), there must be evidence of progression since the
radiation
7. Have an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of
0 or 1
8. Life expectancy of >=3 months, in the opinion of the investigator
9. Have adequate hematological, hepatic, renal, coagulation, and cardiac
function, as defined below, obtained <=7 days prior to enrollment (Cycle 1 Day
1):
a. Absolute neutrophil count (ANC) >=1.5 × 103/µL
b. Platelet count >=100 × 103/µL
c. Hemoglobin >=9.0 g/dL
d. Total bilirubin <=1.5 × upper limit of normal (ULN). Subjects with known
history of Gilbert*s Syndrome may enroll if direct bilirubin is <=1.5 × ULN
e. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <=3 × ULN
(<=5 × ULN if liver metastases are present)
f. Creatinine level <=1.5 × institutional ULN or estimated creatinine clearance
>=60 mL/min for subjects with creatinine levels >1.5 × institutional ULN
g. International normalized ratio (INR) and activated partial thromboplastin
time (aPTT) <=1.5 × ULN unless on medication known to alter INR and/or aPTT
h. Left ventricular ejection fraction (LVEF) >=50% as assessed by echocardiogram
(ECHO) or multiple-gated acquisition (MUGA) scan documented <=28 days prior to
study treatment
10. For subjects of childbearing potential, the following stipulations apply:
a. Must have a negative serum 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 treatment administration
c. Must agree not to breastfeed or donate ova, starting at time of main
informed consent and continuing through 7 months after the final dose of study
treatment administration
d. May choose to practice complete abstinence, if consistent with the subject*s
preferred lifestyle, as an acceptable form of contraception
e. If sexually active in a way that could lead to pregnancy, must consistently
use 2 methods of birth control, as defined in Appendix B, starting at the time
of main informed consent and continuing throughout the study and for at least 7
months after the final dose of any study treatment administration
11. For subjects who can father children, the following stipulations apply:
a. Must agree not to donate sperm starting at time of main informed consent and
continuing throughout the study period and for at least 7 months after the
final study treatment administration
b. If sexually active with a person of childbearing potential in a way that
could lead to pregnancy, must consistently use 2 methods of birth control, as
defined in Appendix B, starting at time of main informed consent and continuing
throughout the study and for at least 7 months after the final dose of study
treatment administration.
c. If sexually active with a person who is pregnant or breastfeeding, must
consistently use one of 2 contraception options, as defined in Appendix B,
starting at time of main informed consent and continuing throughout the study
and for at least 7 months after the final dose of study treatment
administration.
d. May choose to practice complete abstinence, if consistent with the subject*s
preferred lifestyle, as an acceptable form of contraception
12. Subject must provide signed informed consent that has been approved by an
institutional review board/independent ethics committee (IRB/IEC) prior to
initiation of any study-related tests or procedures.
13. Subject must be willing and able to comply with study procedures.
14. Subject must be willing and able to adhere to mandatory antidiarrheal
prophylaxis.
15. CNS Inclusion*Based on screening contrast brain magnetic resonance imaging
(or CT with contrast if MRI is contraindicated), subjects may have any of the
following:
a. No evidence of brain metastases
b. Previously treated brain metastases which are asymptomatic
- Brain metastases previously treated with local therapy must not have
progressed since treatment
* Time since whole brain radiation therapy (WBRT) is >= 14 days prior to
enrollment, time since stereotactic radiosurgery (SRS) is >= 7 days prior to
enrollment, or time since surgical resection is >= 28 days prior to enrollment
- Relevant records of any CNS treatment must be available to allow for
classification of target and non-target lesions

Subjects will be excluded from the study for any of the following reasons:

1. Have previously received any systemic anticancer therapy for CRC in the
metastatic setting or have participated in any interventional clinical trial
for CRC in the metastatic setting.
Note: that subjects may have received a maximum of 2 doses of mFOLFOX6 in the
locally advanced/unresectable or metastatic setting prior to randomization.
Note: Subjects may have received prior chemotherapy for CRC in the adjuvant
setting provided that it was completed >6 months prior to enrollment.
2. Have previously received radiation therapy within 14 days prior to
enrollment (or within 7 days in the setting of SRS). Subjects who have received
prior radiation therapy must have recovered to baseline from any
treatment-related adverse events (AEs). Subjects who have received palliative
radiotherapy for symptomatic metastases may enter the study without a washout
period provided that the subject has recovered from any treatment-related AEs.
3. Have previously been treated with anti-HER2 therapy
4. Have any toxicity related to prior cancer therapies that has not resolved to
<= Grade 1, with the following exceptions:
• Neuropathy, which must have resolved to <= Grade 2
• Alopecia
• Congestive heart failure (CHF), which must have been <= Grade 1 in severity at
the time of occurrence, and must have resolved completely
• Anemia, hemoglobin must have resolved to a level of >=9.0 g/dL
5. Have 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 (Grade 2 or above), symptomatic left
ventricular systolic dysfunction or symptomatic decrease in ejection fraction
• Severe dyspnea at rest (Grade 3 or above) due to complications of advanced
malignancy or hypoxia requiring supplementary oxygen therapy
• Presence of >= Grade 2 corrected QT interval (QTc) prolongation (>480 ms) on
screening electrocardiogram (ECG)
• Interstitial lung disease or pneumonitis
• Have a history of transient ischemic attack, cerebrovascular accident,
myocardial infarction, unstable angina, cardiac or other vascular stenting,
angioplasty, or cardiac surgery within 6 months prior to enrollment (Cycle 1
Day 1)
6. Have a history of a significant bleeding events within 6 months of
enrollment, unless the source of bleeding has been definitively treated
7. Have a history of gastrointestinal (GI) perforation within 12 months of
enrollment
8. Have ongoing >= Grade 2 diarrhea of any etiology
9. Major surgical procedure or significant traumatic injury <=28 days prior to
enrollment (<=56 days for hepatectomy, open thoracotomy, or major neurosurgery)
or anticipation of need for major surgical procedure during the course of the
study
10. Serious, non-healing wound, ulcer, or bone fracture
11. Positive for hepatitis B by surface antigen expression or presence of known
chronic liver disease
12. Have active hepatitis C infection (positive by PCR or on antiviral therapy
for hepatitis C within the last 6 months). Subjects who have been treated for
hepatitis C infection are permitted if they have documented sustained virologic
response of 12 weeks
13. Subjects known to be positive for human immunodeficiency virus (HIV) are
excluded if they meet any of the following criteria:
• CD4+ T-cell count of <350 cells/µL
• Detectable HIV viral load
• History of an opportunistic infection within the past 12 months
• On stable antiretroviral therapy for <4 weeks
14. Subjects who are pregnant, breastfeeding, or planning a pregnancy
15. Inability to swallow pills or any significant GI disease which would
preclude the adequate oral absorption of medications
16. Have used a strong cytochrome p450 (CYP) 2C8 inhibitor within 5 half-lives
of the inhibitor, or have used a strong CYP2C8 or CYP3A4 inducer within 5 days
prior to first dose of study treatment
17. Have any other medical, social, or psychosocial factors that, in the
opinion of the investigator, could impact safety or compliance with study
procedures
18. History of another malignancy within 3 years before the first dose of study
treatment, or any evidence of residual disease from a previously diagnosed
malignancy. Exceptions are malignancies with a negligible risk of metastasis or
death (eg, 5-year OS >=90%), such as adequately treated carcinoma in situ of the
cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal
carcinoma in situ, or Stage I uterine cancer.
19. Subjects with active CNS metastases (irradiated or resected lesions are
permitted, See Inclusion Criteria for details). Subjects with carcinomatous
meningitis are excluded without exception.
20. Have a known hypersensitivity or allergy to any of the study treatments or
any of their excipients, or to required concomitant medications, or to murine
proteins, except for Grade 1 or 2 infusion-related reactions (IRRs) to
oxaliplatin that were successfully managed
21. Have received a live vaccine <30 days prior to enrollment
22. Have known dihydropyrimidine dehydrogenase (DPD) deficiency