Tucatinib (ONT-380) and Trastuzumab in Treating Patients With HER2+ Metastatic Colorectal Cancer

PRIMARY OBJECTIVES:

I. To assess the objective response rate (ORR) of tucatinib in combination with trastuzumab
in patients with HER2 positive (+) metastatic CRC.

SECONDARY OBJECTIVES:

I. To assess the clinical benefit rate (CBR) (stable disease [SD] for >= 6 months, or best
response of complete response [CR] or partial response [PR]) of tucatinib in combination with
trastuzumab.

II. To assess the progression free survival (PFS) of tucatinib in combination with
trastuzumab.

III. To assess the duration of response of tucatinib in combination with trastuzumab.

IV. To assess the overall survival (OS) of tucatinib in combination with trastuzumab.

V. To assess the safety and tolerability of tucatinib in combination with trastuzumab.

TERTIARY OBJECTIVES:

I. To determine whether the combination of tucatinib and trastuzumab eliminates HER2
amplified circulating tumor deoxyribonucleic acid (DNA) (ctDNA) from peripheral blood.

II. To explore any correlation between tissue and blood based biomarkers and clinical
outcomes.

OUTLINE:

Patients receive tucatinib orally (PO) twice daily (BID) on days 1-21 and trastuzumab
intravenously (IV) on day 1. Courses repeat every 21 days in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 12
weeks.

Inclusion Criteria:

- Histologically and/or cytologically confirmed and radiographically measurable
adenocarcinoma of the colon or rectum that is metastatic and/or unresectable; subjects
must have been treated with a fluoropyrimidine (e.g., 5-fluorouracil or capecitabine),
oxaliplatin, irinotecan, an anti-VEGF monoclonal antibody (bevacizumab, ramucirumab,
or ziv-aflibercept), and an anti-PD-1 monoclonal antibody (nivolumab or pembrolizumab)
if tumor has deficient mismatch repair proteins or is MSI-High, or contraindication to
such treatment(s)

- Molecular testing result from Clinical Laboratory Improvement Act (CLIA)-certified
laboratory confirming that the tumor tissue has at least one of the following:

- HER2 overexpression (3+ immunohistochemistry [IHC]); Note: HER2 2+ IHC is
eligible if the tumor is amplified by fluorescence in situ hybridization (FISH)

- HER2 (ERBB2) amplification by in situ hybridization assay (FISH or chromogenic in
situ hybridization [CISH] signal ratio >= 2.0 or gene copy number > 6)

- HER2 (ERBB2) amplification by CLIA-certified next generation sequencing (NGS)
sequencing assay

- RAS (KRAS and NRAS) wild-type in primary or metastatic tumor tissue

- At least one site of disease that is measurable by Response Evaluation Criteria in
Solid Tumors (RECIST) criteria that has not been previously irradiated; if the patient
has had previous radiation to the target lesion(s), there must be evidence of
progression since the radiation

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, or 2

- Life expectancy greater than 3 months

- Absolute neutrophil count (ANC) >= 1000/mm^3 obtained =< 7 days prior to registration

- Platelet count >= 75,000/mm^3 obtained =< 7 days prior to registration

- Hemoglobin >= 8.0 g/dL obtained =< 7 days prior to registration

- Total bilirubin =< 1.5 x upper limit of normal (ULN); patients with known history of
Gilbert syndrome and total bilirubin < 3 x ULN and normal aspartate aminotransferase
(AST)/alanine aminotransferase (ALT) are eligible, obtained =< 7 days prior to
registration

- AST and ALT =< 2.5 x ULN (=< 5 x ULN if liver metastases are present) obtained =< 7
days prior to registration

- Calculated creatinine clearance must be >= 50 ml/min using the Cockcroft-Gault formula
obtained =< 7 days prior to registration

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

- Left ventricular ejection fraction (LVEF) >= 50% as assessed by echocardiogram (ECHO)
or multiple-gated acquisition scan (MUGA) documented =< 28 days prior to registration

- Women of child bearing potential and male partners of women of child bearing potential
must agree to use two medically accepted methods of contraception, one of them being a
barrier method during the study and for 7 months after the last study drug
administration

- Note: women of childbearing potential include women who have experienced menarche
and who have not undergone successful surgical sterilization (hysterectomy,
bilateral tubal ligation, or bilateral oophorectomy) or are not postmenopausal;
postmenopause is defined as amenorrhea >= 12 consecutive months

- Negative serum pregnancy test done =< 7 days prior to registration for women of
childbearing potential only

- Capable of understanding and complying with the protocol requirements and has signed
the informed consent document

- Willing to return to enrolling institution for follow-up (during the active monitoring
phase of the study)

- Willing to provide mandatory tissue and blood samples for correlative research
purposes

Exclusion Criteria:

- Radiation therapy, hormonal therapy, biologic therapy, experimental therapy, or
chemotherapy for cancer =< 21 days prior to registration

- Prior anti-HER2 targeting therapy

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Not recovered to baseline or Common Terminology Criteria for Adverse Events (CTCAE) =<
grade 1 from toxicity due to all prior therapies except alopecia and neuropathy;
alopecia and neuropathy must have resolved to =< grade 2; congestive heart failure
(CHF) must have been =< grade 1 in severity at the time of occurrence and must have
resolved completely prior to registration

- Clinically significant cardiac disease such as history of ventricular arrhythmia
requiring therapy, currently uncontrolled hypertension (defined as persistent systolic
blood pressure > 150 mm Hg and/or diastolic blood pressure > 100 mm Hg on
antihypertensive medications), or any history of symptomatic CHF

- Any of the following:

- Pregnant women

- Nursing women

- Men or women of childbearing potential who are unwilling to employ adequate
contraception

- Patient with known active central nervous system (CNS) metastasis (radiated or
resected lesions are permitted, provided the lesions are fully treated and inactive,
patient is asymptomatic, and no steroids have been administered for at least 30 days)

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

- Use of a strong CYP3A4 inducer or inhibitor, or strong CYP2C8 inducer or inhibitor
within 3 elimination half-lives of the inhibitor or inducer prior to first dose of
study treatment

- Major surgical procedure, open biopsy, or significant traumatic injury =< 28 days
prior to registration (=< 56 days for hepatectomy, open thoracotomy, major
neurosurgery) or anticipation of need for major surgical procedure during the course
of the study

- Serious, non-healing wound, ulcer, or bone fracture

- History of myocardial infarction, unstable angina, cardiac or other vascular stenting,
angioplasty, or cardiac surgery =< 6 months prior to registration

- Immunocompromised patients and patients known to be human immunodeficiency virus (HIV)
positive and currently receiving antiretroviral therapy

- NOTE: patients known to be HIV positive, but without clinical evidence of an
immunocompromised state, are eligible for this trial

- Acute or chronic active hepatitis B or C infection, or other serious chronic infection
requiring ongoing treatment

- Known chronic liver disease, autoimmune hepatitis, or sclerosing cholangitis

- Receiving any other investigational agent which would be considered as a treatment for
the primary neoplasm

- Other active malignancy =< 2 years prior to registration which required systemic
treatment

- EXCEPTIONS: non-melanotic skin cancer or carcinoma-in-situ of the cervix

- Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment
of the local investigator, would make the patient inappropriate for entry into this
study or interfere significantly with the proper assessment of safety and toxicity of
the prescribed regimens

- Unable or unwilling to abide by the study protocol or cooperate fully with the
investigator or designee