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

September 26, 2023 updated by: Baptist Health South Florida

Phase 1 Trial of Tucatinib, Trastuzumab, and Capecitabine With Stereotactic Radiosurgery (SRS) in Patients With Brain Metastases From HER-2 Positive Breast Cancer

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Estimated)

40

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Histologically confirmed HER-2 -positive breast cancer with newly-diagnosed brain metastases.
  2. ECOG Performance Status (PS) of 0, 1, 2
  3. 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
  4. 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
  5. Life expectancy at least 12 weeks
  6. Any number of prior systemic therapies will be allowed, except tucatinib and capecitabine.
  7. Hemoglobin ≥9g/dL, White blood count ≥3.0 x 10^9/ L , Absolute Granulocyte count ≥1.5x 10^9/ L and platelet count ≥100 × 10^9/ L.
  8. Serum bilirubin ≤ 1.5 x ULN
  9. AST and / or ALT <= 2 ULN (≤ 5 x ULN when clearly attributable to the presence of liver metastases)
  10. Serum creatinine ≤ 1.5 ULN or calculated creatinine clearance > 60ml/min
  11. Ability to comply with study procedures and monitoring
  12. For women of childbearing potential, a negative pregnancy test should be obtained within one week prior to the start of therapy
  13. 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 120 days after last dose of tucatinib, capecitabine and trastuzumab.

Highly effective and acceptable forms of contraception are:

  • Male condom plus spermicide
  • Cap plus spermicide
  • Diaphragm plus spermicide
  • Copper T
  • Progesterone T
  • Levonorgestrel-releasing intrauterine system (e.g., Mirena®)
  • Implants
  • Hormone shot or injection
  • Combined pill
  • Mini-pill
  • Patch

Postmenopausal woman on the study (that will not need contraception) is defined as:

  • Amenorrhoeic for 1 year or more following cessation of exogenous hormonal treatments
  • LH and FSH levels in the postmenopausal range for women under 50
  • Radiation-induced oophorectomy with last menses > 1 year ago
  • Chemotherapy-induced menopause with >1 year interval since last menses
  • Surgical sterilization (bilateral oophorectomy or hysterectomy).

Men and women and members of all races and ethnic groups are eligible for this trial.

Exclusion Criteria:

  1. Patients with leptomeningeal metastases documented by MRI or CSF evaluation
  2. Evidence of intra-tumoral or peri-tumoral hemorrhage deemed significant by the treating physician
  3. Brain metastases within 5 mm of the optic chiasm or optic nerve
  4. Metastases in the brainstem (midbrain, pons, or medulla)
  5. 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
  6. 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
  7. Unable to undergo brain MRI
  8. Known human immunodeficiency virus (HIV) infection or chronic Hepatitis B or C
  9. All toxicities from prior therapies must have resolved to CTCAE v 5.0 grade 1 or better by the time of study enrollment
  10. 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
  11. Currently receiving other investigational cancer therapy within 4 weeks prior to start of study treatment with the exception of continuing therapy with GnRH analogues
  12. Mean QT interval corrected heart rate (QTc) ≥ 470ms calculated from 3 electrocardiograms using Frediricia's Correction
  13. Left ventricular ejection fraction (LVEF) <50%
  14. Concomitant use of strong cytochrome P450 (CYP)2C8 inhibitor within 5 half-lives of the inhibitor
  15. 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
  16. Concomitant use of potent CYP2C8 inhibitors within 5 days prior to the first dose of study treatment
  17. History of hypersensitivity to tucatinib, capecitabine, and trastuzumab any of its excipients
  18. History and/or confirmed corneal ulceration
  19. Pregnant or breast feeding

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Investigational Treatment
Combination product: Combined use of SRS with Tucatinib, Trastuzumab, and Capecitabine

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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence of dose-limiting toxicities (DLTs)
Time Frame: During first 4 weeks following SRS

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
Time Frame: 30 days of progression or last dose of drug

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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
Progression-free survival (PFS)
Time Frame: Six months
Time from first dose of study drug until the first date of disease progression or death due any cause. The date of disease progression will be defined as the earliest date of disease progression based on central review. For participants whose disease has not progressed at the time of the analysis, censoring will be performed using the date of the last valid disease assessment. The data will be analyzed by the Kaplan-Meier method. PFS will be considered when there is progression just intracranially, as well as when there is progression intracranially or extracranially.
Six months
Overall survival
Time Frame: One year
Time from the beginning of study drug treatment until death due to any cause. For participants who have not died at the time of the analysis, censoring will be performed using the date the patient was last known to be alive. The data will be analyzed by the Kaplan-Meier method.
One year
Overall response rate (ORR)
Time Frame: One year
Proportion of participants with a complete response (CR) or partial response (PR) as defined by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1. For ORR analysis in all the treated population, participants with an CR or PR will be counted as successes and all other participants (including those with missing response information) will be counted as failures. ORR will be considered for intracranial and extracranial tumors.
One year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Baptist Health South Florida

Collaborators

Seagen Inc.

Investigators

  • Principal Investigator: Manmeet Ahluwalia, M.D., MBA, Miami Cancer Institute/Baptist Health South Florida

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 18, 2023

Primary Completion (Estimated)

November 1, 2024

Study Completion (Estimated)

November 1, 2025

Study Registration Dates

First Submitted

September 16, 2022

First Submitted That Met QC Criteria

September 22, 2022

First Posted (Actual)

September 23, 2022

Study Record Updates

Last Update Posted (Actual)

September 28, 2023

Last Update Submitted That Met QC Criteria

September 26, 2023

Last Verified

September 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2020-AHL-001

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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