T-DM1 Alone Versus T-DM1 and Metronomic Temozolomide in Secondary Prevention of HER2-Positive Breast Cancer Brain Metastases Following Stereotactic Radiosurgery

NCT03190967 | Terminated Phase 1 Results DMC FDA Drug

• 2 other identifiers: 17011517-C-0115
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief Summary

Background: Sometimes breast cancer spreads (metastasizes) to the brain. Researchers want to study new treatments for brain metastases. The drug Temozolomide is approved to treat brain tumors. Researchers want to see if combining it with the drug trastuzumab emtansine (T-DMI) prevents the formation of new metastases in the brain. Objective: To study if Temozolomide with T-DM1 lowers the chance of having new metastases in the brain. Eligibility: Adults at least 18 years old with a human epidermal growth factor receptor 2 (HER2)-positive breast cancer that has spread to the brain and was recently treated with stereotactic radiation or surgery. Design: Participants will be screened with

• Medical history
• Physical exam
• Heart tests
• A scan (computed tomography (CT) that makes a picture of the body using a small amount of radiation
• A scan (magnetic resonance imaging (MRI) that uses a magnetic field to make an image of the brain
• Blood tests.
• Pregnancy test. The study will be done in 3-week cycles. All participants will get T-DM1 on Day 1 of every cycle through a small plastic tube inserted in an arm vein. Some participants will also take Temozolomide capsules by mouth every day. Participants will keep a medication diary. During the study, participants will also:
• Repeat most of the screening tests.
• Answer questions about their general well-being and functioning. Participants will have lumbar puncture at least 2 times. A needle is inserted into the spinal canal low in the back and cerebrospinal fluid is collected. This will be done with local anesthesia and with the help of images. Participants will be asked to provide tumor samples when available. Participants will have a follow-up visit about 1 month after stopping the study drug. They will be contacted by telephone or email every 3 months after that.

Conditions

Breast Cancer; Brain Metastasis; Brain Cancer

Keywords

Ado-trastuzumab Emtansine; Systemic Control of Disease; Maximum Tolerated Dose; Preventing the Formation of a Metastasis

Outcome Measures

Primary Outcomes (2)

• Phase I: Maximum Tolerated Dose (MTD) of Temozolomide (TMZ) When Used With T-DM1 (Ado-trastuzumab)

  Maximum tolerated dose of TMZ when used in combination with T-DM1. MTD is defined as the dose level at which 0 or 1 participant in 6 has a dose limiting toxicity (DLT). A DLT is defined as grade 3 or higher non-hematologic adverse events excluding grade 3 hypertension controlled with anti-hypertensive therapy; or grade 3 asymptomatic electrolytes imbalance; grade 3 endocrinopathy; grade 3 asymptomatic increase in aspartate aminotransferase or alanine aminotransferase; and transient (lasting less than \<48 hours) nausea, emesis, or diarrhea if corrected with conservative measures within 24-48 hours. A hematologic grade 4 neutropenia of ≥ 7 days duration, grade ≥ 3 thrombocytopenia, and all other grade 4 hematologic toxicities excluding grade 4 lymphopenia, or leukopenia in the absence of grade 3 or higher neutropenia. Grade 3 is severe. Grade 4 is life-threatening.

  first 21 days of treatment

• Phase II: Median Amount of Time Participant Survives Without New Brain Lesions After Starting Treatment

  Median time to progression. Progression was assessed using the Response Assessment in Neuro-oncology Brain Metastases (RANO-BM) Criteria for evaluation of brain lesions, and the Response Evaluation Criteria in Solid Tumors (RECIST) for systemic evaluation. Progression is a 25% increase in the sum of products of all measurable lesions observed over baseline if no decrease. Or appearance of new lesions, or failure to return for evaluation due to death or deteriorating condition.

  From the start of treatment until new brain lesions

Secondary Outcomes (6)

• Phase I: Number of Participants With Grade 3 and/or Grade 4 Adverse Events

  Evaluated at the beginning of every cycle while on study, for an average of 9.6 months (range 2.8-33.9 months).

• Phase I: Number of Participants With Dose Limiting Toxicity (DLTs) at Each Dose Level

  After first cycle of treatment, up to 30 days

• Phase II: Time to Whole Brain Irradiation

  At progression

• Phase I: Median Survival

  From date of first therapy until death, an average of 40.79 months

• Phase I: Standard Time to Progression (TTP)

  From first day of treatment to the day of disease progression, an average of 15 months.

Other Outcomes (1)

• Phase I: Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)

  Date treatment consent signed to date off study, approximately 44 months and 27 days for level 1, 28 months and 10 days for level 2, and 40 months and 8 days for level 3.

Study Arms (3)

1/Phase I: Ado-trastuzumab (T-DMI) + Temozolomide (TMZ) Dose Escalation

EXPERIMENTAL

T-DM1 + TMZ in dose escalation

Drug: T-DM1; Drug: TMZ

2A /Phase II: Arm A, Ado-trastuzumab (T-DMI) Alone

ACTIVE COMPARATOR

T-DM1

Drug: T-DM1

2B/Phase II /Arm B, Ado-trastuzumab (T-DMI) + Temozolomide (TMZ)

EXPERIMENTAL

T-DM1 + TMZ at recommended phase 2 dose (RP2D)

Drug: T-DM1; Drug: TMZ

Interventions

T-DM1 DRUG

T-DM1 3.6 mg/kg intravenous (IV) every 21 days

Also known as: Ado-trastuzumab

1/Phase I: Ado-trastuzumab (T-DMI) + Temozolomide (TMZ) Dose Escalation; 2A /Phase II: Arm A, Ado-trastuzumab (T-DMI) Alone; 2B/Phase II /Arm B, Ado-trastuzumab (T-DMI) + Temozolomide (TMZ)

TMZ DRUG

Phase I: TMZ 30, 40 or 50 mg/m\^2 daily Phase II: TMZ at recommended phase 2 dose (RP2D) estimated in Phase I dose escalation part of the study.

Also known as: Temozolomide

1/Phase I: Ado-trastuzumab (T-DMI) + Temozolomide (TMZ) Dose Escalation; 2B/Phase II /Arm B, Ado-trastuzumab (T-DMI) + Temozolomide (TMZ)

Eligibility Criteria

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

You may qualify if:

• Patients must have histologically confirmed human epidermal growth factor receptor 2 (HER2)-positive breast cancer for which standard curative measures do not exist or are no longer effective. HER2 testing must have been performed in a laboratory accredited by the College of American Pathologists (CAP) or another accrediting entity.
• Patients must have brain metastases, treated within 12 weeks of study entry with stereotactic radiosurgery (SRS), resection or whole brain radiation therapy (WBRT). A minimum interval of 3 weeks between completion of brain SRS and/or resection and 6 weeks for WBRT and the start of treatment in this trial will be observed to allow proper healing. The presence of concomitant extracranial metastatic disease is allowed for enrollment.
• Corticosteroids will be allowed at enrollment and during the first month of treatment with trastuzumab emtansine (T-DM1) after SRS, up to a dose of no more than 10mg of dexamethasone daily or equivalent. Patients that need to continue corticosteroids after the initial month will be allowed to continue in the protocol treatment if no further increase in dose is necessary. Patients that need increase in dose of corticosteroid after initial month will be taken off protocol treatment.
• Age greater than or equal to18 years. Because breast cancer is not commonly found in pediatric population and no dosing or adverse event data are currently available on the use of temozolomide in combination with T-DM1 in patients \<18 years of age, children are excluded from this study, but will be eligible for future pediatric trials.
• Eastern Cooperative Oncology (ECOG) performance status less than or equal to 2 (Karnofsky greater than or equal to 60%, see Appendix A)
• Patients must have normal organ and marrow function as defined below:
• leukocytes greater than or equal to 3,000/mcL
• absolute neutrophil count greater than or equal to 1,000/mcL
• platelets greater than or equal to 100,000/mcL
• total bilirubin within normal institutional limits
• Aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT)/alanine aminotransferase (ALT) serum glutamate pyruvate transaminase (SGPT) \<3.0 X institutional upper limit of normal
• creatinine up to 1.5 upper institutional limits, OR
• creatinine clearance greater than or equal to 60 mL/min/1.73 m(2) for patients with creatinine levels above institutional normal.
• Alkylating agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and for 7 months (women) or 4 months (men) after treatment completion. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
• Ability of subject to understand and the willingness to sign a written informed consent document.

You may not qualify if:

• Patients who are receiving any other investigational agents.
• Patients unable to speak or understand English, since they cannot complete neurocognitive evaluation.
• Patients with known leptomeningeal metastatic disease.
• Patients with major symptoms or impairments related to brain metastases, such as aphasia or severe confusion, will be excluded per principal investigator (PI) discretion when those symptoms preclude proper neurocognitive evaluation during the study treatment.
• Patients who have received previous treatment with T-DM1 and had systemic progression of disease while on it, are ineligible. Patients receiving treatment with T- DM1 whose only site of disease progression was brain are allowed to enroll in this trial.
• Patients who have received chemotherapy in the previous 3 weeks (6 weeks for nitrosoureas or mitomycin).
• Hepatitis B virus (HBV), Hepatitis B surface antigen positive (HBs Ag positive) or hepatitis C virus (HCV) (anti-HCV positive) patients are ineligible because of potential reactivation of hepatitis virus with temozolomide use.
• Grade greater than or equal to 3 peripheral neuropathy according to (National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
• Cerebral Vascular Accident (CVA) or Transitory Ischemic Attack (TIA) in the year before enrollment, or presence of residual symptoms from CVA that happened more than a year before.
• Pulmonary Embolism (PE) in the 3 months before enrollment. Anticoagulation is permitted.
• Impaired cardiac function or clinically significant cardiac disease including the following:
• New York Heart Association grade III or IV congestive heart failure.
• Myocardial infarction within the last 12 months.
• Subjects with impaired left ventricular ejection fraction (LVEF) (\<50%).
• Patients with inability to complete brain MRI studies with contrast.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (5)

• Swain SM, Kim SB, Cortes J, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Knott A, Clark E, Ross G, Benyunes MC, Baselga J. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2013 May;14(6):461-71. doi: 10.1016/S1470-2045(13)70130-X. Epub 2013 Apr 18.

  PMID: 23602601 BACKGROUND

• Bartsch R, Berghoff AS, Vogl U, Rudas M, Bergen E, Dubsky P, Dieckmann K, Pinker K, Bago-Horvath Z, Galid A, Oehler L, Zielinski CC, Gnant M, Steger GG, Preusser M. Activity of T-DM1 in Her2-positive breast cancer brain metastases. Clin Exp Metastasis. 2015 Oct;32(7):729-37. doi: 10.1007/s10585-015-9740-3. Epub 2015 Aug 25.

  PMID: 26303828 BACKGROUND

• Gelmon KA, Boyle FM, Kaufman B, Huntsman DG, Manikhas A, Di Leo A, Martin M, Schwartzberg LS, Lemieux J, Aparicio S, Shepherd LE, Dent S, Ellard SL, Tonkin K, Pritchard KI, Whelan TJ, Nomikos D, Nusch A, Coleman RE, Mukai H, Tjulandin S, Khasanov R, Rizel S, Connor AP, Santillana SL, Chapman JA, Parulekar WR. Lapatinib or Trastuzumab Plus Taxane Therapy for Human Epidermal Growth Factor Receptor 2-Positive Advanced Breast Cancer: Final Results of NCIC CTG MA.31. J Clin Oncol. 2015 May 10;33(14):1574-83. doi: 10.1200/JCO.2014.56.9590. Epub 2015 Mar 16.

  PMID: 25779558 BACKGROUND

• Jenkins S, Zhang W, Steinberg SM, Nousome D, Houston N, Wu X, Armstrong TS, Burton E, Smart DD, Shah R, Peer CJ, Mozarsky B, Arisa O, Figg WD, Mendoza TR, Vera E, Brastianos P, Carter S, Gilbert MR, Anders CK, Connolly RM, Tweed C, Smith KL, Khan I, Lipkowitz S, Steeg PS, Zimmer AS. Phase I Study and Cell-Free DNA Analysis of T-DM1 and Metronomic Temozolomide for Secondary Prevention of HER2-Positive Breast Cancer Brain Metastases. Clin Cancer Res. 2023 Apr 14;29(8):1450-1459. doi: 10.1158/1078-0432.CCR-22-0855.

  PMID: 36705597 RESULT

• Zimmer AS, Steinberg SM, Smart DD, Gilbert MR, Armstrong TS, Burton E, Houston N, Biassou N, Gril B, Brastianos PK, Carter S, Lyden D, Lipkowitz S, Steeg PS. Temozolomide in secondary prevention of HER2-positive breast cancer brain metastases. Future Oncol. 2020 May;16(14):899-909. doi: 10.2217/fon-2020-0094. Epub 2020 Apr 9.

  PMID: 32270710 RESULT

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Breast Neoplasms; Brain Neoplasms

Interventions

Ado-Trastuzumab Emtansine; Temozolomide

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Central Nervous System Neoplasms; Nervous System Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Maytansine; Macrolides; Lactones; Organic Chemicals; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds; Trastuzumab; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Dacarbazine; Triazenes; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Dr. Stanley Lipkowitz, PhD
• Organization: National Cancer Institute

lipkowis@navmed.nci.nih.gov

240-760-6129

Study Officials

• Stanley Lipkowitz, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: June 16, 2017
• First Posted: June 19, 2017
• Study Start: April 18, 2018
• Primary Completion: June 28, 2021
• Study Completion: June 13, 2023
• Last Updated: October 11, 2023
• Results First Posted: October 11, 2023

Record last verified: 2023-09

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Clinical data are available during the study and indefinitely. Genomic data are available once genomic data are uploaded per protocol Genomic Data Sharing (GDS) plan for as long as database is active.
• Access Criteria: Clinical data will be made available via subscription to Biomedical Translational Research Information System (BTRIS) and with the permission of the study principal investigator (PI). Genomic data are made available via the database of Genotypes and Phenotypes (dbGaP) through requests to the data custodians.

Locations

US (1)