A Phase II Study of Tucatinib and Ado-trastuzumab Emtansine (T-DM1) in Patients With HER2-positive Metastatic Solid Tumors and Metastases to Brain (TUCATEMEB)

Primary Objectives:

● To determine the intracranial antitumor activity of the tucatinib and ado-trastuzumab emtansine (T- bination per the modified Response Evaluation Criteria in Solid Tumors (mRECIST) in patients with huma

Key Secondary Objectives:

• To determine the intracranial antitumor activity of the tucatinib and T-DM1 combination per the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria in patients with HER2-positive metastatic solid tumors and brain metastases.
• To evaluate the duration of intracranial response of the tucatinib and T-DM1 combination in patients with HER2-positive metastatic solid tumors and brain metastases.

Other Secondary Objectives:

• To evaluate the safety and tolerability of the tucatinib and T-DM1 combination in patients with HER2-positive metastatic solid tumors and brain metastases.
• To evaluate the systemic antitumor activity of the tucatinib and T-DM1 combination per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 in patients with HER2-positive metastatic solid tumors and brain metastases.
• To evaluate progression-free survival (PFS) in patients with HER2-positive metastatic solid tumors and brain metastases receiving the tucatinib and T-DM1 combination.
• To evaluate overall survival (OS) in patients with HER2-positive metastatic solid tumors and brain metastases receiving the tucatinib and T-DM1 combination.
• To evaluate the duration of response to the tucatinib and T-DM1 combination per the RECIST v1.1 in patients with HER2-positive metastatic solid tumors and brain metastases.
• To evaluate the clinical benefit rate of the tucatinib and T-DM1 combination per the RECIST v1.1 in patients with HER2-positive metastatic solid tumors and brain metastases.

Exploratory Objectives:

• To assess the effects of the tucatinib and T-DM1 combination on cell proliferation and apoptosis.
• To evaluate predictive and pharmacodynamic (PD) biomarkers of response and resistance to the tucatinib and T-DM1 combination.
• To assess the effects of the tucatinib and T-DM1 combination on circulating-free DNA (cfDNA) dynamics.

Inclusion criteria

• Histologically confirmed HER2-positive metastatic solid tumor. HER2 positivity defined as HER2 overexpression by immunohistochemistry (IHC) 3+ or 2+ and fluorescence in situ hybridization (FISH) positive and/or HER2 amplification by in situ hybridization (ISH) or next generation sequencing (NGS) and/or activating ERBB2 mutation(s) (verified by MDACC Precision Oncology Decision Support).
• Patients must have one of the following on the screening brain MRI:

• Untreated brain metastases not requiring immediate local CNS therapy
• Previously treated brain metastases with progression of previous lesions or new lesions, but not requiring immediate local CNS therapy
• At least one measurable untreated brain lesion ≥0.5 cm and <3.0 cm in the longest axis
• Prior SRS radiosurgery (must be completed within 7 days of study treatment initiation) is allowed as long as the previous treatment volume does not overlap with the current targets.
• Measurable (per the RECIST v1.1) or evaluable extracranial disease.
• Prior treatment with HER2-targeted treatments such as trastuzumab, pertuzumab, T-DM1, neratinib, lapatinib, or tucatinib is allowed, but not required. Patients with breast and gastric cancer must have received at least 1 line of HER2 targeted treatment.
• Age ≥18 years at the time of consent.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (Appendix B).
• Life expectancy ≥3 months, in the opinion of the investigator.
• Adequate hematological and end-organ function, defined by the following laboratory test results, obtained within 28 days prior to study treatment initiation:

• Absolute neutrophil count ≥1,200/μL
• Platelet count ≥100,000/μL
• Hemoglobin ≥9g/dL
• Total bilirubin ≤1.5 × upper limit of normal (ULN), except for patients with known Gilbert's disease, who may enroll if conjugated bilirubin is ≤1.5 × ULN
• Transaminases (AST/ALT) ≤1.5 × ULN (≤5 × ULN if liver metastases are present)
• Creatinine level <1.5 x ULN or estimated glomerular filtration rate (GFR) ≥50 mL/min/1.73 m2 using the Modification of Diet in Renal Disease (MDRD) study equation as applicable.
• International normalized ratio (INR) and partial thromboplastin time (PTT)/activated partial thromboplastin time (aPTT) ≤1.5 × ULN, unless on medication known to alter INR and PTT/aPTT. Proprietary Information of MD Anderson Protocol 2021-0899 v.5.0,04/24/2023 28
• LVEF ≥50% as assessed by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan documented within 3weeks prior to study treatment initiation.
• For patients of childbearing potential, as defined in Section 4.3, the following stipulations apply:

• Must have a negative serum or urine pregnancy test (minimum sensitivity of 25 mIU/mL or equivalent units of beta-human chorionic gonadotropin [β-hCG]) result within 3 days prior to study treatment initiation. A patient with a false positive result and documented verification that the patient is not pregnant will be eligible.
• Must agree not to try to become pregnant during the study and for at least 7 months after the final dose of study treatment
• Must agree not to breastfeed or donate ova starting at the time of informed consent and continuing through the study and for 7 months after the final dose of study treatment
• If sexually active in a way that could lead to pregnancy, must consistently use highly effective methods of birth control (i.e., methods that achieve a failure rate of <1% per year when used consistently and correctly) starting at the time of informed consent and continuing throughout the study and for at least 7 months after the final dose of study treatment.

Highly effective methods of birth control include:

i. Intrauterine device ii. Bilateral tubal occlusion/ligation iii. Vasectomized partner iv. Sexual abstinence when it is the preferred and usual lifestyle choice of the patient.

• For patients who can father children, the following stipulations apply:

• Must agree not to donate sperm starting at the time of informed consent and continuing throughout the study and for at least 7 months after the final dose of study treatment
• 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 the time of informed consent and continuing throughout the study and for at least 7 months after the final dose of study treatment
• If sexually active with a person who is pregnant or breastfeeding, must consistently use a barrier method of birth control starting at the time of informed consent and continuing throughout the study and for at least 7 months after the final dose of study treatment.
• The patient must provide written informed consent.
• Must be willing to undergo biopsy as required by the study, if clinically considered safe and feasible by the investigator.

Exclusion criteria

• Patients must not have any of the following on the screening brain MRI:

• Any untreated brain lesions >3.0 cm in size
• 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 the patient (e.g., brainstem lesions). Patients who undergo local treatment for such lesions may still be eligible for the study based on inclusion criteria #2.
• Ongoing use of systemic corticosteroids for control of symptoms of brain metastases at a total daily dose of >4 mg of dexamethasone (or equivalent).
• Poorly controlled (>1/week) generalized or complex partial seizures, or manifestation of neurologic progression due to brain metastases notwithstanding CNS-directed therapy.
• History of allergic reactions to trastuzumab or compounds chemically or biologically similar to tucatinib, except for Grade 1 or 2 IRRs to trastuzumab that were successfully managed, or known allergy to any of the excipients in the study drugs.
• Treatment with any systemic anticancer therapy or investigational agent within 5 half-lives (of the drug) or within 21 days (whichever is shorter ) prior to study treatment initiation.
• Any toxicity related to prior cancer therapies that has not resolved to ≤ Grade 1, with the following exceptions:

• Alopecia;
• Neuropathy, which must have resolved to ≤ Grade 2;
• Congestive heart failure (CHF), which must have been ≤ Grade 1 in severity at the time of occurrence and must have resolved completely.
• 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, left ventricular systolic dysfunction, or decrease in LVEF
• Severe dyspnea at rest (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] ≥ Grade 3) due to complications of advanced malignancy or hypoxia requiring supplementary oxygen therapy
• Grade 2 or greater corrected QT interval (QTc) prolongation on screening electrocardiogram (ECG).
• Known myocardial infarction or unstable angina within 6 months prior to study treatment initiation.
• Unable for any reason to undergo contrast MRI of the brain.
• Have used a strong cytochrome P450 (CYP)2C8 inhibitor within 5 half-lives of the inhibitor, or a strong CYP3A4 or CYP2C8 inducer within 5 days prior to study treatment initiation. Concomitant use of strong CYP3A4 inducers or CYP2C8 inducers or inhibitors is also prohibited during study treatment and for 2 weeks after discontinuation of study treatment. Use Proprietary Information of MD Anderson of sensitive CYP3A substrates should be avoided 2 weeks prior to study treatment initiation and during study treatment.
• Known carrier of hepatitis B or hepatitis C virus or has other known chronic liver disease.
• Known positive human immunodeficiency virus status.
• Patients who are pregnant, breastfeeding, or planning to become pregnant from the time of informed consent until 7 months after the last dose of study treatment.
• Unable to swallow pills or has significant GI disease that would preclude adequate oral absorption of medication.
• Other medical, social, or psychosocial factors that, in the opinion of the investigator, could impact patient safety or compliance with study procedures.
• Evidence within 1 year of the start of study treatment of another malignancy that required systemic treatment.
• Patients who are eligible for the HER2CLIMB-02 study (NCT03975647) and they can be enrolled in that study.