Tucatinib, Trastuzumab, and Capecitabine With SRS for Brain Metastases From HER-2 Positive Breast Cancer

NCT05553522 | Terminated Phase 1 DMC FDA Drug

• 1 other identifier: 2020-AHL-001
• Study Type: interventional
• Target: 1
• Locations: 1 country
• Sites: 1

Brief Summary

This research study will evaluate how well brain metastases associated with HER-2 positive breast cancer can be controlled using a type of radiation known as stereotactic radiosurgery (SRS) when combined with three therapeutic agents, tucatinib, capecitabine, and trastuzumab. The combined use of SRS with the three drugs is considered investigational.

Conditions

HER2-positive Breast Cancer; Brain Metastases

Keywords

brain metastases; HER2-positive breast cancer

Outcome Measures

Primary Outcomes (2)

• Incidence of dose-limiting toxicities (DLTs)

  Toxicities will be graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0). DLTs are defined as any of the following events: 1. Grade 3 or 4 thrombocytopenia 2. Grade 4 anemia 3. Grade 4 neutropenia lasting more than 7 days 4. Febrile neutropenia 5. Any non-hematologic toxicity of grade 3 or greater (excluding alopecia) despite maximal medical therapy 6. Grade 4 radiation-induced skin changes 7. Any episode of noninfectious pneumonitis.

  During first 4 weeks following SRS

• Incidence of radiation-related toxicities

  Toxicities presumed to be due to radiation are defined as: 1. Acute, \< 90 days from treatment start: Expected toxicities include hair loss (for lesions abutting skull), erythema of the scalp (for lesions abutting skull), headache, nausea, and vomiting. Reactions in the ear canals and on the ear should be observed and treated symptomatically. Pin site infection, pin site pain, facial swelling/bruising, and scalp numbness are other common acute effects. Acute toxicity is defined by CTCAE v5.0. 2. Both acute and delayed, \> or = 90 days from treatment start (lethargy, transient worsening of existing neurological deficits) or late (radiation necrosis, cognitive dysfunction, accelerated atherosclerosis, radiation-induced neoplasms) effects of radiotherapy are to be recorded and included in the toxicity evaluation. Late or delayed toxicity is defined by CTCAE v5.0.

  30 days of progression or last dose of drug

Secondary Outcomes (3)

• Progression-free survival (PFS)

  Six months

• Overall survival

  One year

• Overall response rate (ORR)

  One year

Study Arms (1)

Investigational Treatment

EXPERIMENTAL

Combination Product: Combined use of SRS with Tucatinib, Trastuzumab, and Capecitabine

Interventions

Combined use of SRS with Tucatinib, Trastuzumab, and Capecitabine COMBINATION_PRODUCT

SRS and oral tucatinib for 2 wk, followed by oral tucatinib, oral capecitabine, and intravenous (IV) trastuzumab maintenance during 21-d cycles until tumor progression, participant withdrawal, a severe adverse event deemed related to the study drug, or the treating physician discontinues the drug. There are three dosing levels of tucatinib (Dose Level 0, Dose Level -1, or Dose Level -2) using a dose de-escalation scheme. Dosing of capectabine (1000 mg/m2 BID Days 1-14) and trastuzumab (6 mg/kg once per 21 days; 8 mg/kg initial loading dose) per cycle will remain the same regardless of tucatinib dosing. Dose Level 0: 300 mg twice a day (BID) continuously for 2 wk post SRS, then 300 mg BID continuously per cycle. Dose Level -1: 250 mg twice a day (BID) continuously for 2 wk post SRS, then 250 mg BID continuously per cycle. Dose Level -2: 200 mg twice a day (BID) continuously for 2 wk post SRS, then 200 mg BID continuously per cycle.

Investigational Treatment

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically confirmed HER-2 -positive breast cancer with newly-diagnosed brain metastases.
• ECOG Performance Status (PS) of 0, 1, 2
• Patients with 1-10 brain metastases will be candidates for tucatinib, capecitabine, and trastuzumab with SRS at the discretion of the treating radiation oncologist. Intra-cranial brain metastasis must measure 3 cm or less in the greatest dimension
• Age 18 years or greater and being willing and able to sign a written informed consent. A signed informed consent must be obtained prior to any study specific procedures
• Life expectancy at least 12 weeks
• Any number of prior systemic therapies will be allowed, except tucatinib and capecitabine.
• Hemoglobin ≥ 9g/dL, White blood count ≥3.0 × 10\^9/ L , Absolute Granulocyte count ≥1.5x 10\^9/ L and platelet count ≥100 × 10\^9/ L.
• Serum bilirubin ≤ 1.5 × ULN
• AST and / or ALT \<= 2 × ULN (≤ 5 × ULN when clearly attributable to the presence of liver metastases)
• Serum creatinine ≤ 1.5 × ULN or calculated creatinine clearance \> 60mL/min
• Ability to comply with study procedures and monitoring
• For women of childbearing potential, a negative pregnancy test should be obtained within one week prior to the start of therapy
• Male or female patients of reproductive potential need to employ two highly effective and acceptable forms of contraception throughout their participation in the study and for 7 months after last dose of tucatinib, capecitabine and trastuzumab.
• Highly effective and acceptable forms of contraception are:
• Male condom plus spermicide

You may not qualify if:

• Patients with leptomeningeal metastases documented by MRI or CSF evaluation
• Evidence of intra-tumoral or peri-tumoral hemorrhage deemed significant by the treating physician
• Brain metastases within 5 mm of the optic chiasm or optic nerve
• Significant or recent acute gastrointestinal disorders with diarrhea as a major symptom, e.g., Crohn's disease, malabsorption, or CTCAE grade \>2 diarrhea of any etiology at baseline
• History of clinically significant or uncontrolled cardiac disease, including congestive heart failure, angina, myocardial infarction, arrhythmia, New York Heart Association (NYHA) functional classification of 3 or 4
• Unable to undergo brain MRI
• Known human immunodeficiency virus (HIV) infection or chronic Hepatitis B or C
• All toxicities from prior therapies must have resolved to CTCAE v 5.0 grade 1 or better by the time of study enrollment
• Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g., active or uncontrolled infection, uncontrolled diabetes, second active malignancy) that could cause unacceptable safety risks or compromise compliance with the protocol
• Currently receiving other investigational cancer therapy within 4 weeks prior to start of study treatment with the exception of continuing therapy with GnRH analogues
• Mean QT interval corrected heart rate (QTc) ≥ 470ms calculated from 3 electrocardiograms using Frediricia's Correction
• Left ventricular ejection fraction (LVEF) \<50%
• Concomitant use of strong cytochrome P450 (CYP)3A inhibitors including macrolide antibiotics (e.g., Telithromycin), antifungals (e.g., Itraconazole), antivirals (e.g., ritonavir), and Nefazodone
• Concomitant use of strong CYP2C8 inhibitor within 5 half-lives of the inhibitor
• Concomitant use of strong CYP3A4 inducers (e.g., phenytoin, rifampicin, carbamazepine, St. John's Wort) within 5 days prior to the first dose of study treatment

Sponsors & Collaborators

• Baptist Health South Florida: lead
• Pfizer: collaborator

Study Sites (1)

Miami Cancer Institute at Baptist Health, Inc.

Miami, Florida, 33176, United States

Location

Related Publications (17)

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  BACKGROUND

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Related Links

• FDA Drugs development approval process
• Miami Cancer Institute

MeSH Terms

Conditions

Brain Neoplasms

Interventions

tucatinib; Trastuzumab; Capecitabine

Condition Hierarchy (Ancestors)

Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Fluorouracil; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Study Officials

• Manmeet Ahluwalia, M.D., MBA

  Miami Cancer Institute/Baptist Health South Florida

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 16, 2022
• First Posted: September 23, 2022
• Study Start: January 29, 2024
• Primary Completion: December 17, 2025
• Study Completion: December 17, 2025
• Last Updated: December 31, 2025

Record last verified: 2024-12

Locations

US (1)