| Eligibility |
Inclusion Criteria:
- Patients must meet all of the following inclusion criteria to be eligible for
enrollment into the study:
1. Signed Informed Consent Form (ICF) prior to participation in any study-related
activities.
2. Male or female patients = 18 years of age at the time of signing ICF.
3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
4. Life expectancy of = 16 weeks.
5. Histologically confirmed HER2-positive breast cancer according to American
Society of Clinical Oncology/College of American Pathologists (ASCO/CAP)
guidelines 2018 based on local testing on the most recent analyzed biopsy.
Note: Central confirmation of HER2-positive status is not required for study
entry. However, tissue blocks, or slides, must be submitted to confirm HER2
positivity by a Sponsor-designated central laboratory retrospectively.
6. Tumors may be estrogen receptor (ER)/progesterone receptor (PgR) positive or
negative.
7. Disease progression after last systemic therapy documented by computerized
tomography (CT) scan or magnetic resonance imaging (MRI).
Note: Exclusive tumor marker elevation will not be considered sufficient for
diagnosis of disease progression.
8. Centrally confirmed low affinity CD16A germline genotype (F/F or F/V).
9. Measurable disease as per RECIST v.1.1 criteria.
10. Have received treatment with at least one, and no more than three, HER2-targeting
treatment regimens overall for unresectable locally advanced or MBC. Earlier
adjuvant or neoadjuvant HER2-targeted therapy for more limited disease will be
considered as one of the required prior regimens if the development of
unresectable locally advanced or metastatic disease occurred within a 6-month
period of time after completion of anti-HER2 therapy. In any case, patients must
have received prior treatment with any anti-HER2 antibody drug conjugate (ADC) in
the (neo)adjuvant or metastatic setting.
Note: Eligible patients must have progressed on or following, the most recent
line of therapy. Dose interruptions, delays, pauses during previous therapy, or
changes in therapy to manage toxicity will not constitute a new line of therapy
provided disease progression did not occur.
11. Willingness and ability to provide a tumor biopsy at study entry and after
progression from either metastatic or primary tissues in order to perform
exploratory studies. If not feasible, patient eligibility should be evaluated by
a Sponsor's qualified designee.
Note: Subjects for whom tumor biopsy cannot be obtained (e.g., inaccessible tumor
or subject safety concern) may submit archival pathological material from either
metastatic or primary sites, but the most recent tumor biopsy from the patient
should be obtained when available at both timepoints.
12. Central nervous system (CNS) metastases inclusion; based on screening brain
imaging (CT or MRI), patients must have one of the following:
1. No evidence of brain metastases;
2. Untreated and asymptomatic CNS metastases not needing immediate local
therapy. Patients with untreated lesions >2.0 cm on screening contrast brain
MRI, require analysis and approval from the medical monitor prior to
enrollment.
3. Patients with history of CNS lesions assessable by RECIST v1.1 are eligible
if they have been definitively treated with local therapy, are
non-progressing, and off anticonvulsants and steroids. A specific washout
period from the end of local therapy for CNS lesions to the first dose of
study treatment is mandatory (one week for stereotactic radiosurgery, three
weeks for whole brain radiation therapy, and four weeks for surgical
resection).
13. Resolution of all acute toxic effects of prior anti-cancer therapy to grade = 1
as determined by the National Cancer Institute-Common Terminology Criteria for
Adverse Events (CTCAE) v.5.0 criteria (except for alopecia or other toxicities
not considered a safety risk for the patient at Investigator's discretion).
14. Left ventricular ejection fraction (LVEF) of >50% as assessed by echocardiogram
(ECHO) or multi-gated acquisition scan (MUGA) scan documented within 28 days
prior to first dose of study treatment.
15. Adequate hematologic and organ function within 28 days before the first study
treatment on Cycle 1 Day 1, defined by the following:
1. Hematological: White blood cell (WBC) count > 3.0 x 109/L, absolute
neutrophil count (ANC) > 1.5 x 109/L, platelet count = 100 x 103/µL
(patients with stable platelet count from 75-100 x 103/µL may be included
with approval by the medical monitor), and hemoglobin (Hb) > 9.0 g/dL.
2. Hepatic: Serum albumin = 3 g/dL; Total bilirubin = 1.5 times the upper limit
of normal (× ULN) (= 3 x ULN in the case of Gilbert's disease); aspartate
transaminase (AST) and alanine transaminase (ALT) = 2.5 × ULN (in the case
of liver metastases = 5 × ULN); alkaline phosphatase (ALP) = 2.5 × ULN (= 5
× ULN in the case of liver and/or bone metastases).
3. Renal: Serum creatinine < 1.5 × ULN or creatinine clearance = 50 mL/min
based on Cockcroft-Gault glomerular filtration rate estimation.
4. International normalized ratio (INR) and activated partial thromboplastin
time (aPTT) = 1.5 x ULN unless on medication known to alter INR and/or aPTT.
16. For women of childbearing potential must have a negative serum pregnancy test at
1 week prior to the start of treatment and a further confirmation test on Day 1
(C1D1) before receiving the first dose, and must agree to remain abstinent
(refrain from heterosexual intercourse) or to use a medically acceptable method
of contraception during the study and up to 7 months after the last dose of study
drug, and agree to refrain from donating eggs during this same period.
17. Men with female partners of childbearing potential must remain abstinent or use a
medically acceptable method of contraception during the treatment period and up
to 7 months after the last dose of study drug.
Exclusion Criteria:
- Patients will be excluded from the study if they meet any of the following criteria:
1. Inability to comply with study and follow-up procedures.
2. Prior exposure to margetuximab, capecitabine or other fluoropyrimidine [e.g.,
5-fluorouracil] or any HER2 tyrosine kinase inhibitor (TKI) tucatinib, and/or
dual HER2/epidermal growth factor receptor (EGFR) TKIs (lapatinib, neratinib,
afatinib, etc.) except for the following conditions:
1. Lapatinib at least 12 months prior to starting study treatment (except in
cases where lapatinib was given for = 21 days and was discontinued for
reasons other than disease progression or severe toxicity);
2. Patients who have received capecitabine for adjuvant or neoadjuvant
treatment at least 12 months prior to starting study treatment are eligible
(except in cases where capecitabine was given for = 21 days and was
discontinued for reasons other than disease progression or severe toxicity).
3. Presence of carcinomatous meningitis or leptomeningeal disease.
4. Extracranial radiation therapy within 14 days (seven days for limited-field
palliative radiotherapy) prior to study enrolment, or patients who have not
recovered from radiotherapy-related toxicities to grade = 1.
5. Major surgery (defined as requiring general anesthesia) or significant traumatic
injury within 14 days from the start of study treatment (28 days for brain
surgical resection), or patients who have not recovered from the side effects of
any major surgery.
6. Patients have a concurrent malignancy or malignancy within five years of study
enrollment with the exception of carcinoma in situ of the cervix, non-melanoma
skin carcinoma, or stage I uterine cancer. For other cancers considered to have a
low risk of recurrence, discussion with the Sponsor's Medical Monitor is
required.
7. Treatment with approved or investigational cancer therapy within 14 days prior to
initiation of study drugs.
8. History of prior allogeneic bone marrow, stem-cell, or solid organ
transplantation.
9. Treatment with systemic steroids (e.g., = 10 mg prednisone per day or equivalent)
or other immunosuppressive drugs within 14 days prior to study treatment
initiation. Standard premedication for margetuximab and topical applications of
steroids are allowed.
10. Current known infection with human immunodeficiency virus (HIV), hepatitis B
virus (HBV), or hepatitis C virus (HCV). Patients with past HBV infection or
resolved HBV infection (defined as having a negative hepatitis B surface antigen
[HBsAg] test and a positive hepatitis B core antibody [HBcAb] test, accompanied
by a negative HBV DNA test) are eligible. Patients positive for HCV antibody are
eligible only if polymerase chain reaction (PCR) is negative for HCV ribonucleic
acid (RNA).
11. Active uncontrolled infection at the time of enrollment.
12. Congenital long QT syndrome or screening QT interval corrected using Fridericia's
formula (QTcF) > 480 milliseconds.
13. Patients with clinically significant cardiovascular disease including but not
limited to any of the following:
1. Stroke, transient ischemic attack, unstable angina pectoris, or documented
myocardial infarction within six months prior to study entry.
2. Symptomatic pericarditis or clinically significant pericardial effusion or
myocarditis.
3. Documented congestive heart failure (New York Heart Association functional
classification III- IV).
4. Uncontrolled, persistent hypertension defined as systolic blood pressure >
160 mmHg or diastolic blood pressure > 100 mmHg.
14. Patients have any of the following cardiac conduction abnormalities:
1. Ventricular arrhythmias except for benign premature ventricular
contractions.
2. Supraventricular and nodal arrhythmias requiring a pacemaker or not
controlled with medication.
3. Conduction abnormality requiring a pacemaker.
4. Other cardiac arrhythmia not controlled with medication.
15. Patients have any other concurrent severe and/or uncontrolled medical condition
that would, in the Investigator's judgment contraindicate patient participation
in the clinical study.
16. Patients with pulmonary disease requiring continuous oxygen therapy.
17. History of malabsorption syndrome or other condition that would interfere with
enteral absorption or results in the inability or unwillingness to swallow pills.
18. Vaccination with any live virus vaccine within 28 days prior to study treatment
initiation.
19. Known hypersensitivity to recombinant proteins, or any excipient contained in the
drug formulation for margetuximab, tucatinib, or capecitabine.
20. Use of a strong cytochrome P450 2C8 (CYP2C8) inhibitors within two weeks, or use
of a strong cytochrome P450 3A4 (CYP3A4) or CYP2C8 inducers within five days
prior to the first dose of study treatment. CYP3A4 or CYP2C8 inducers and CYP2C8
inhibitors are also prohibited as concomitant medications within two weeks of
discontinuation of tucatinib treatment. Use of sensitive CYP3A substrates should
be avoided two weeks before enrollment and during study treatment.
21. Require therapy with warfarin or other coumarin derivatives (non-coumarin
anticoagulants are allowed).
22. Have known dihydropyrimidine dehydrogenase deficiency.
23. Pregnant, breastfeeding, or intending to become pregnant during the study or
within 30 days after the last dose of study treatments.
24. Concurrent participation in other clinical trial, except other translational
studies.
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