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)

Inclusion Criteria:

1. Histologically confirmed HER2-positive metastatic solid tumor. HER2 positivitydefined as HER2 overexpression by immunohistochemistry (IHC) 3+ or 2+ andfluorescence in situ hybridization (FISH) positive and/or HER2 amplification by insitu hybridization (ISH) or next generation sequencing (NGS) and/or activating ERBB2mutation(s) (verified by MDACC Precision Oncology Decision Support).

2. 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 newlesions, but not requiring immediate local CNS therapy

• At least one measurable untreated brain lesion ≥0.5 cm and <3.0 cm in thelongest axis

• Prior SRS radiosurgery (must be completed within 7 days of study treatmentinitiation) is allowed as long as the previous treatment volume does notoverlap with the current targets.

3. Measurable (per the RECIST v1.1) or evaluable extracranial disease.

4. Prior treatment with HER2-targeted treatments such as trastuzumab, pertuzumab,T-DM1, neratinib, lapatinib, or tucatinib is allowed, but not required. Patientswith breast and gastric cancer must have received at least 1 line of HER2 targetedtreatment.

5. Age ≥18 years at the time of consent.

6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (Appendix B).

7. Life expectancy ≥3 months, in the opinion of the investigator.

8. Adequate hematological and end-organ function, defined by the following laboratorytest 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 withknown 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) ≥50mL/min/1.73 m2 using the Modification of Diet in Renal Disease (MDRD) studyequation as applicable.

9. International normalized ratio (INR) and partial thromboplastin time (PTT)/activatedpartial thromboplastin time (aPTT) ≤1.5 × ULN, unless on medication known to alterINR and PTT/aPTT. Proprietary Information of MD Anderson Protocol 2021-0899v.5.0,04/24/2023 28

10. LVEF ≥50% as assessed by echocardiogram (ECHO) or multi-gated acquisition (MUGA)scan documented within 3weeks prior to study treatment initiation.

11. For patients of childbearing potential, as defined in Section 4.3, the followingstipulations apply:

• Must have a negative serum or urine pregnancy test (minimum sensitivity of 25mIU/mL or equivalent units of beta-human chorionic gonadotropin [β-hCG]) resultwithin 3 days prior to study treatment initiation. A patient with a falsepositive result and documented verification that the patient is not pregnantwill be eligible.

• Must agree not to try to become pregnant during the study and for at least 7months after the final dose of study treatment

• Must agree not to breastfeed or donate ova starting at the time of informedconsent and continuing through the study and for 7 months after the final doseof study treatment

• If sexually active in a way that could lead to pregnancy, must consistently usehighly effective methods of birth control (i.e., methods that achieve a failurerate of <1% per year when used consistently and correctly) starting at the timeof informed consent and continuing throughout the study and for at least 7months after the final dose of study treatment. Highly effective methods of birth control include: i. Intrauterine device ii. Bilateral tubal occlusion/ligation iii. Vasectomizedpartner iv. Sexual abstinence when it is the preferred and usual lifestyle choice ofthe patient.

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

• Must agree not to donate sperm starting at the time of informed consent andcontinuing throughout the study and for at least 7 months after the final doseof study treatment

• If sexually active with a person of childbearing potential in a way that couldlead to pregnancy, must consistently use a barrier method of birth controlstarting at the time of informed consent and continuing throughout the studyand for at least 7 months after the final dose of study treatment

• If sexually active with a person who is pregnant or breastfeeding, mustconsistently use a barrier method of birth control starting at the time ofinformed consent and continuing throughout the study and for at least 7 monthsafter the final dose of study treatment.

13. The patient must provide written informed consent.

14. Must be willing to undergo biopsy as required by the study, if clinically consideredsafe and feasible by the investigator.

Exclusion Criteria:

1. 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 notlimited to) a lesion in an anatomic site where increase in size or possibletreatment-related edema may pose risk to the patient (e.g., brainstem lesions).Patients who undergo local treatment for such lesions may still be eligible forthe study based on inclusion criteria #2.

2. Ongoing use of systemic corticosteroids for control of symptoms of brain metastasesat a total daily dose of >4 mg of dexamethasone (or equivalent).

3. Poorly controlled (>1/week) generalized or complex partial seizures, ormanifestation of neurologic progression due to brain metastases notwithstandingCNS-directed therapy.

4. History of allergic reactions to trastuzumab or compounds chemically or biologicallysimilar to tucatinib, except for Grade 1 or 2 IRRs to trastuzumab that weresuccessfully managed, or known allergy to any of the excipients in the study drugs.

5. Treatment with any systemic anticancer therapy or investigational agent within 5half-lives (of the drug) or within 21 days (whichever is shorter ) prior to studytreatment initiation.

6. 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 atthe time of occurrence and must have resolved completely.

7. Clinically significant cardiopulmonary disease such as:

• Ventricular arrhythmia requiring therapy

• Symptomatic hypertension or uncontrolled asymptomatic hypertension asdetermined by the investigator

• Any history of symptomatic CHF, left ventricular systolic dysfunction, ordecrease in LVEF

• Severe dyspnea at rest (National Cancer Institute Common Terminology Criteriafor Adverse Events [NCI CTCAE] ≥ Grade 3) due to complications of advancedmalignancy or hypoxia requiring supplementary oxygen therapy

• Grade 2 or greater corrected QT interval (QTc) prolongation on screeningelectrocardiogram (ECG).

8. Known myocardial infarction or unstable angina within 6 months prior to studytreatment initiation.

9. Unable for any reason to undergo contrast MRI of the brain.

10. Have used a strong cytochrome P450 (CYP)2C8 inhibitor within 5 half-lives of theinhibitor, or a strong CYP3A4 or CYP2C8 inducer within 5 days prior to studytreatment initiation. Concomitant use of strong CYP3A4 inducers or CYP2C8 inducersor inhibitors is also prohibited during study treatment and for 2 weeks afterdiscontinuation of study treatment. Use Proprietary Information of MD Anderson ofsensitive CYP3A substrates should be avoided 2 weeks prior to study treatmentinitiation and during study treatment.

11. Known carrier of hepatitis B or hepatitis C virus or has other known chronic liverdisease.

12. Known positive human immunodeficiency virus status.

13. Patients who are pregnant, breastfeeding, or planning to become pregnant from thetime of informed consent until 7 months after the last dose of study treatment.

14. Unable to swallow pills or has significant GI disease that would preclude adequateoral absorption of medication.

15. Other medical, social, or psychosocial factors that, in the opinion of theinvestigator, could impact patient safety or compliance with study procedures.

16. Evidence within 1 year of the start of study treatment of another malignancy thatrequired systemic treatment.

17. Patients who are eligible for the HER2CLIMB-02 study (NCT03975647) and they can beenrolled in that study.