breast cancer breast carcinoma
Conditions
Interventions
Subjects will be randomized in a 1:1 manner to receive study treatment on a
21-day cycle, either:
* Control arm: Placebo given orally twice a day (PO BID)
T-DM1 3.6 mg/kg given
intravenously (IV) every 21 days
* Experimental arm: Tucatinib 300 mg PO BID
T-DM1 3.6 mg/kg IV every 21 days
Duration of Treatment
Study treatment will continue until unacceptable toxicity, disease progression,
withdrawal of consent, or study closure. In the absence of clea
Sponsors
Seagen Inc.
Eligibility
Age
18 Years to 64 Years
Inclusion criteria
Inclusion criteria: 1. Histologically confirmed HER2+ breast carcinoma, as determined by sponsor- designated central laboratory testing on tumor tissue submitted prior to randomization (see Section 7.1.1), from either: a. Archival tissue (most recent tumor tissue sample preferred) b. If archival tissue is not available, then a newly-obtained baseline biopsy of an accessible tumor lesion that has not been previously irradiated is required 2. History of prior treatment with a taxane and trastuzumab in any setting, separately or in combination. Prior pertuzumab therapy is allowed, but not required. 3. Have progression of unresectable LA/M breast cancer after last systemic therapy (as confirmed by investigator), or be intolerant of last systemic therapy 4. Measureable or non-measurable disease assessable by RECIST v1.1 5. HR (estrogen receptor [ER]/ progesterone receptor [PR]) status must be known prior to randomization 6. Age >=18 years at time of consent or >= the age of majority in the geographic location 7. ECOG performance status score of 0 or 1 (see APPENDIX B for conversion of performance status using Karnofsky scale, if applicable) 8. Life expectancy >=6 months, in the opinion of the investigator 9. Adequate hepatic function as defined by the following: a. Total bilirubin =1.5 X 103/µL b. Platelet count >=100 X 103/µL c. Hemoglobin >=9 g/dL d. In subjects transfused before study entry, transfusion must be >=14 days prior to start of therapy to establish adequate hematologic parameters independent from transfusion support 11. Estimated glomerular filtration rate (GFR) >=50 mL/min/1.73 m2 using the Modification of Diet in Renal Disease (MDRD) study equation (see Section 7.8.4). 12. International normalized ratio (INR) and partial thromboplastin time (PTT)/activated partial thromboplastin time (aPTT) =50% as assessed by echocardiogram (ECHO) or multi-gated acquisition scan (MUGA) documented within 4 weeks prior to first dose of study treatment (see Section 6.2.2 for exceptions) 14. For subjects of childbearing potential, as defined in Section 4.3, the following stipulations apply: a. 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 7 days prior to the first dose of study treatment. A subject with a false positive result and documented verification that the subject is not pregnant is eligible for participation. b. Must agree not to try to become pregnant during the study and for at least 7 months after the final dose of study drug administration c. Must agree not to breastfeed or donate ova, starting at time of informed consent and continuing through 7 months a
Exclusion criteria
Exclusion criteria: 1. Prior treatment with tucatinib, afatinib, trastuzumab deruxtecan (DS-8201a), or any other investigational anti-HER2, anti-EGFR, or HER2 TKI agent. Prior treatment with lapatinib or neratinib within 12 months of starting study treatment (except in cases where they were given for = Grade 2 QTc prolongation on screening electrocardiogram (ECG) 7. Known myocardial infarction or unstable angina within 6 months prior to first dose of study treatment 8. Known carrier of Hepatitis B or Hepatitis C or has other known chronic liver disease 9. Subjects known to be positive for human immunodeficiency virus (HIV) if they meet any of the following criteria: * CD4+ T-cell count of <350 cells/uL * Detectable HIV viral load * History of an opportunistic infection within the past 12 months * On stable antiretroviral therapy for <4 weeks 10. Subjects who are pregnant, breastfeeding, or planning to become pregnant from time of informed consent until 7 months following the last dose of study drug 11. Unable to swallow pills or has significant gastrointestinal disease which would preclude the adequate oral absorption of medications 12. Use of a strong cytochrome P450 (CYP) 3A4 or CYP2C8 inhibitor within 1 week, or use of a strong CYP3A4 or CYP2C8 inducer within 5 days prior to the first dose of study treatment (see Appendix C and Appendix D). CYP3A4 or CYP2C8 inducers and <
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Efficacy Assessments Disease response per RECIST v1.1 (Eisenhauer 2009) will be assessed by both investigator assessment and BICR. Response assessments will include measurement of all known sites of unresectable LA/M disease (including at a minimum the chest, abdomen, and pelvis), preferably by high quality spiral contrast computed tomography (CT), at baseline, every 6 weeks for the first 24 weeks, and every 9 weeks thereafter, irrespective of dose interruptions. Positron emission tomography (PET)/CT (if high quality CT scan included), and/or MRI scan may also be done as appropriate, as well as additional imaging of any other known sites of disease (e.g., skin lesion photography for skin lesions, nuclear bone scan imaging for bone lesions). Contrast MRI of the brain will be required on this same schedule only in those subjects with prior history of brain metastases or brain metastases found at screening. Additional contrast MRIs of the brain may also be performed in subjects without known brain metastases if there is clinical suspicion of new brain lesions. Treatment decisions will be made based upon local assessment of radiologic scans. Response assessments for each subject will continue until a PFS event per RECIST v1.1 by investigator assessment has been documented. Follow-up for survival will continue until study closure or withdrawal of consent. Safety Assessments Safety assessments will include surveillance and recording of AEs, physical examination findings, and laboratory tests. Assessment of cardiac ejection fraction will be performed by multi-gated acquisition (MUGA) scan or echocardiogram (ECHO). | — |
Secondary
| Measure | Time frame |
|---|---|
| Pharmacokinetic Assessments PK assessments will be performed from Cycle 3 to Cycle 6 in all subjects to assess the steady state PK of tucatinib and DM1. In the US only, approximately 50 subjects (25 from each treatment arm) will participate in a PK sub-study with additional PK sampling on Days 1, 2, 3, and 5 in Cycle 2 to assess any effects of tucatinib on the PK of DM1. Other Assessments - Quality of Life Health-related QoL will be assessed at protocol-specified time points using standardized assessment tools including the European Quality of Life 5Dimension 3Level (EQ-5D-3L) instrument, the European Organization for Research and Treatment of Cancer (EORTC) quality-of-life questionnaire (QLQ-C30), National Cancer Institute's patient-reported outcomes version of the Common Terminology Criteria for Adverse Events (NCIPRO-CTCAE) questionnaire customized to focus on adverse events (AEs) or symptoms of interest, and the Functional Assessment of Cancer Therapy - Breast (FACTB). | — |
Countries
Netherlands
Outcome results
None listed