This phase I/II study will assess the recommended dosing of tucatinib in combination with
trastuzumab and either vinorelbine or gemcitabine in patients with advanced, HER2+ breast
cancer. The study will be conducted as a parallel cohort study looking at optimal dose and
safety and efficacy.
Arm 1 Gemcitabine + Tucatinib + Trastuzumab: Gemcitabine (1000 mg/m2) will be administered
intravenously on Days 1 and 8. The investigational study drug (tucatinib) will be
administered as 300mg by mouth taken twice a day of every day in each cycle. Trastuzumab will
be administered per package insert on Day 1 of each cycle.
Arm 2 Vinorelbine + Tucatinib + Trastuzumab: Vinorelbine (25 mg/m2) will be administered
intravenously on Days 1 and 8 of each cycle. The investigational study drug (tucatinib) will
be administered as 300mg by mouth twice a day of every day in each cycle. Trastuzumab will be
administered per package insert on Day 1 of each 2 cycle.
Note: Cycle length is 21 days.
1. Age >18, with metastatic breast cancer, documented Her2+ by FISH/Dual-ISH, and/or IHC
3+ staining, local determination of Her2+ allowed
2. Progressive disease with history of prior treatment with trastuzumab and capecitabine
for metastatic disease (unless deemed intolerable or ineligible for capecitabine by
3. Prior treatment with T-DM1 in any setting unless deemed intolerable or ineligible for
T-DM1 by the investigator.
4. Target or non-target lesions per RECIST 1.1.
5. ECOG 0 or 1.
6. In the opinion of the investigator, life expectancy >6 months.
7. LVEF > 50% by ECHO or MUGA within 4 weeks prior to first study treatment.
8. Cr Clearance > 50mL/min per institutional guidelines.
9. Negative serum pregnancy test for women of child bearing potential within 14 days of
first study treatment and must agree to use effective contraception through 30 days
after last treatment.
For subjects who can father children:
- Must agree not to donate sperm starting at time of informed consent and
continuing throughout the study period and for at least 30 days after the final
study drug administration.
- If sexually active with a person of childbearing potential in a way that could
lead to pregnancy, must consistently use a barrier method of birth control
starting at time of informed consent and continuing throughout the study and for
at least 30 days after the final dose of study drug administration.
- If sexually active with a person who is pregnant or breastfeeding, must
consistently use a barrier method of birth control starting at time of informed
consent and continuing throughout the study and for at least 30 days after the
final dose of study drug administration.
10. Willing and able to provide written Informed consent.
11. All toxicities related to prior cancer therapies must have resolved to < grade 1, with
following exceptions: alopecia, neuropathy, which must have resolved to <Grade 2;
congestive heart failure which must have been <grade 1 in severity at the time of
occurrence and resolved completely.
12. Adequate hematologic and hepatic function as defined by:
- Hemoglobin >9g/dL
- Absolute neutrophil count (ANC)>1000 cells/uL
- Platelets >100,000/uL
- 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
- 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)
13. CNS Inclusion - Based on screening contrast brain MRI, patients must have one of the
- No evidence of brain metastases
- Untreated brain metastases not needing immediate local therapy. For patients with
untreated CNS lesions > 2.0 cm on screening contrast brain MRI, discussion with
and approval from the medical monitor is required prior to enrollment
- Previously treated brain metastases
A. 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
B. Patients treated with CNS local therapy for newly identified 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:
i. Time since WBRT is ≥ 21 days prior to first dose of treatment, time since SRS is ≥ 7
days prior to first dose of treatment, or time since surgical resection is ≥ 28 days ii.
Other sites of disease assessable by RECIST 1.1 are present C. Relevant records of any CNS
treatment must be available to allow for classification of target and non-target lesions
1. Having previous treatment with vinorelbine and gemcitabine for metastatic disease.
2. History of allergic reactions to trastuzumab except for grade 1/2 infusion reactions.
3. History of allergic reactions to tucatinib.
4. Any systemic anti-cancer therapy <14 days of first study treatment, including any
5. Clinically significant cardiopulmonary disease including ventricular arrhythmia
- Uncontrolled hypertension (defined as persistent systolic blood pressure >
150mmHG and/or diastolic blood pressure >100mm Hg on antihypertensive medication)
or any history of symptomatic CHF
6. Known history of HIV, Hep B/C or known chronic liver disease.
7. Known MI or unstable angina in last 6 months prior to first study treatment
8. Inability to swallow pills or significant GI disease, in the opinion of the
Investigator that would preclude oral absorption of the medication.
9. Are pregnant, breastfeeding, or planning pregnancy.
10. CNS Exclusion - Based on screening brain MRI, patients must not have any of the
A. Any untreated brain lesions > 2.0 cm in size, unless discussed with medical monitor
and approval for enrollment is given.
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, patients on
a chronic stable dose of ≤ 2 mg total daily of dexamethasone (or equivalent) may be
eligible with discussion and approval by 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 patient (e.g. brain stem lesions). Patients
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
D. Known or suspected LMD as documented by the investigator. E. Have poorly controlled
(> 7days) generalized or complex partial seizures, or manifest neurologic progression
due to brain metastases notwithstanding CNS-directed therapy
11. Use of a strong CYP3A4 or CYP2C8 inhibitor within ≤14days, or use of a strong CYP3A4
or CYP2C8 inducer within ≤5 days prior to the first study treatment. CYP3A4 or CYP2C8
inducers and inhibitors are also prohibited as concomitant medications within ≤14 days
of initiating Tucatinib treatment. . Use of sensitive CYP3A substrates should be
avoided two weeks before enrollment and during study treatment. See Appendices C, D, E
for references. (See Section 7.6 for additional prohibited concomitant medications)
12. Prior radiation therapy less than 7 days from start of treatment.
13. Other medical, social, or psychosocial factors that, in the opinion of the
investigator, could impact safety or compliance with study procedures.