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)
- Conditions
- Interventions
- Registration Number
- NCT05673928
- Lead Sponsor
- M.D. Anderson Cancer Center
- Brief Summary
To learn if the study drugs, tucatinib and adotrastuzumab emtansine (T-DM1), can help to control solid tumors that have spread to the brain.
- Detailed Description
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:
...
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 30
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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).
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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.
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Measurable (per the RECIST v1.1) or evaluable extracranial disease.
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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.
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Age ≥18 years at the time of consent.
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Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (Appendix B).
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Life expectancy ≥3 months, in the opinion of the investigator.
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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.
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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
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LVEF ≥50% as assessed by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan documented within 3weeks prior to study treatment initiation.
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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.
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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.
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The patient must provide written informed consent.
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Must be willing to undergo biopsy as required by the study, if clinically considered safe and feasible by the investigator.
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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.
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Ongoing use of systemic corticosteroids for control of symptoms of brain metastases at a total daily dose of >4 mg of dexamethasone (or equivalent).
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Poorly controlled (>1/week) generalized or complex partial seizures, or manifestation of neurologic progression due to brain metastases notwithstanding CNS-directed therapy.
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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.
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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.
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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.
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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).
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Known myocardial infarction or unstable angina within 6 months prior to study treatment initiation.
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Unable for any reason to undergo contrast MRI of the brain.
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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.
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Known carrier of hepatitis B or hepatitis C virus or has other known chronic liver disease.
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Known positive human immunodeficiency virus status.
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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.
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Unable to swallow pills or has significant GI disease that would preclude adequate oral absorption of medication.
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Other medical, social, or psychosocial factors that, in the opinion of the investigator, could impact patient safety or compliance with study procedures.
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Evidence within 1 year of the start of study treatment of another malignancy that required systemic treatment.
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Patients who are eligible for the HER2CLIMB-02 study (NCT03975647) and they can be enrolled in that study.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Tucatinib and Adotrastuzumab Emtansine (T-DM1) Trastuzumab emtansine Each study cycle is 21 days (3 weeks) Participants will take tablets of tucatinib two (2) times a day, about 8-12 hours apart. Participants will receive T-DM1 by vein over about 30 minutes on Day 1 of each cycle Tucatinib and Adotrastuzumab Emtansine (T-DM1) Tucatinib Each study cycle is 21 days (3 weeks) Participants will take tablets of tucatinib two (2) times a day, about 8-12 hours apart. Participants will receive T-DM1 by vein over about 30 minutes on Day 1 of each cycle
- Primary Outcome Measures
Name Time Method Incidence of Adverse Events, Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version (v) 5.0 through study completion; an average of 1 year.
- Secondary Outcome Measures
Name Time Method
Trial Locations
- Locations (1)
M D Anderson Cancer Center
🇺🇸Houston, Texas, United States