Breast CancerPhase 1/2NCT03190967
T-DM1 Alone Versus T-DM1 and Metronomic Temozolomide in Secondary Prevention of HER2-Positive Breast Cancer Brain Metastases Following Stereotactic Radiosurgery
A Phase 1/2 study testing T-DM1 and TMZ in people with Breast Cancer and Brain Metastasis, run by National Cancer Institute (NCI) at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Breast Cancer, Brain Metastasis, Brain Cancer
- What is being tested?
- T-DM1 and TMZ
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 12 participants
- Where
- 1 siteUnited States
- Study dates
- 18 Apr 2018to 13 Jun 2023
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Phase 1 Inclusion Criteria
- 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)
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- 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.
- Phase 2 Inclusion Criteria
- Patients must have histologically confirmed 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 1-10 brain metastases, by contrast magnetic resonance imaging (MRI), treated within 12 weeks of study entry with SRS and/or resection. A minimum interval of 3 weeks between completion of brain SRS and/or resection 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 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 to 18 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.
- ECOG performance status less than or equal to 2 (Karnofsky greater than or equal to 60%)
- 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
- AST(SGOT)/ALT(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.
Who cannot join
- Phase 1 Exclusion Criteria
- 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.
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- 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.
- Patients with breast tissue expanders must have those removed before enrollment.
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to temozolomide or T-DM1. Patients who are tolerating TDM1 successfully with pre-medications and slower infusion will be allowed.
- Patients receiving medications that are strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers are ineligible. In vitro studies indicate that DM1, the cytotoxic component of T-DM1, is metabolized mainly by CYP3A4 and to a lesser extent by cytochrome P450 3A5 (CYP3A5). Concomitant use of strong CYP3A4 inhibitors with T-DM1 should be avoided due to the potential for an increase in DM1 exposure and toxicity. Consider an alternate medication with no or minimal potential to inhibit CYP3A4. Lists including medications and substances known or with the potential to interact with CYP3A4 isoenzymes are provided in Appendix B.
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, that would limit compliance with study requirements.
- Pregnant women are excluded from this study because temozolomide is an alkylating agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with temozolomide and/or T-DM1, breastfeeding should be discontinued if the mother is treated with either of those agents. These potential risks may also apply to other agents used in this study.
- human immunodeficiency virus (HIV)-positive patients are excluded because these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy.
- Patients with any other concomitant invasive malignancies are ineligible. Prior invasive cancers treated with curative intent, and with no evidence of recurrent disease, may be eligible after principal investigator (PI) evaluation. Patients with treated limited stage basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the breast or cervix are eligible.
- Phase 2 Exclusion Criteria
- 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 previously treated with whole brain radiation therapy (WBRT).
- Patients with major symptoms or impairments related to brain metastases, such as aphasia or severe confusion, will be excluded per 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).
- HBV (HBs Ag positive) or 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 (NCI 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 LVEF (<50%).
- Patients with inability to complete brain MRI studies with contrast.
- Patients with breast tissue expanders must have those removed before enrollment.
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to temozolomide or T-DM1. Patients who are tolerating TDM1 successfully with pre-medications and slower infusion will be allowed.
- Patients receiving medications that are strong CYP3A4 inhibitors or inducers are ineligible. In vitro studies indicate that DM1, the cytotoxic component of T-DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5. Concomitant use of strong CYP3A4 inhibitors with T-DM1 should be avoided due to the potential for an increase in DM1 exposure and toxicity. Consider an alternate medication with no or minimal potential to inhibit CYP3A4. Lists including medications and substances known or with the potential to interact with CYP3A4 isoenzymes are provided in Appendix B.
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, that would limit compliance with study requirements.
- Pregnant women are excluded from this study because temozolomide is an alkylating agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with temozolomide and/or T-DM1, breastfeeding should be discontinued if the mother is treated with either of those agents. These potential risks may also apply to other agents used in this study.
- HIV-positive patients are excluded because these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy.
- Patients with any other concomitant invasive malignancies are ineligible. Prior invasive cancers treated with curative intent, and with no evidence of recurrent disease, may be eligible after PI evaluation.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center
Bethesda, Maryland, 20892
About this study
Official title: Phase I/II Study of T-DM1 Alone Versus T-DM1 and Metronomic Temozolomide in Secondary Prevention of HER2-Positive Breast Cancer Brain Metastases Following Stereotactic Radiosurgery
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.
Read more
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.
Read the detailed description
Background:
- Breast cancer is the most common cancer in women. In the human epidermal growth factor receptor 2 (HER2+) subtype, brain metastases can occur in up to 25-40% of patients.
- The standard therapy for brain metastases continues to be surgery or stereotactic radiosurgery (SRS) and/or whole brain radiation therapy (WBRT).
- Currently, independently of localized or systemic treatment modality, once brain metastases are established, options for treatment are limited, and the disease almost invariably progresses, limiting not only survival but also quality of life in most patients.
- Preclinical literature suggests the hypothesis that preventing the formation of a metastasis by a drug may be more efficacious than attempting to shrink an established lesion.
- Our group has shown in vitro and in vivo in animal models injected with a brain tropic O6-methylguanine DNA methyltransferase (MGMT) + cell line, that even in very low doses temozolomide (TMZ) administered in a prophylactic, metronomic fashion can significantly prevent development of brain metastases.
- We propose a secondary-prevention clinical trial with oral TMZ given to HER2+ breast cancer patients with brain metastases after recent local treatment (SRS or surgical resection) in combination with the anti-HER2 agent T-DM1 for systemic control of disease.
Objectives:
- Phase I (run in): to identify the maximum tolerated dose (MTD) of TMZ when used in combination with T-DM1.
- Phase II: to determine if the combination regimen of trastuzumab emtansine (T-DM1) and temozolomide improves the freedom from distant new brain metastases following stereotactic radiosurgery or surgical resection in HER2-positive breast cancer brain metastases, as compared to T-DM1 alone guided by one-year results as an important benchmark for measuring improvement.
Eligibility:
Phase I:
- Histologically confirmed HER2+ breast cancer.
- Eastern Cooperative Oncology (ECOG) performance status 0-2 and adequate organ and marrow function.
- Brain metastases, treated within 12 weeks of study entry with SRS, resection or WBRT.
- Patients with leptomeningeal metastatic disease are ineligible.
- Patients that are unable to complete a brain MRI with contrast are ineligible.
- Patients with breast tissue expanders must have those removed before enrollment.
- Hepatitis B virus (HBV), hepatitis C virus (HCV) or human immunodeficiency virus (HIV)-positive patients are ineligible.
- Patient with impaired cardiac function or clinically significant cardiac disease are ineligible.
- Corticosteroids will be allowed at enrollment and during the first month of treatment with 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 not be allowed to increase the dose after that period and will be taken off protocol.
Phase II:
- Histologically confirmed HER2+ breast cancer.
- ECOG performance status 0-2 and adequate organ and marrow function.
- 1-10 brain metastases, by contrast MRI, treated within 12 weeks of study entry with SRS and/or resection.
- Patients with leptomeningeal metastatic disease are ineligible.
- Patients with history of WBRT are ineligible.
- Patients that are unable to complete a brain MRI with contrast are ineligible.
- Patients with breast tissue expanders must have those removed before enrollment.
- HBV, HCV or HIV-positive patients are ineligible.
- Patient with impaired cardiac function or clinically significant cardiac disease are ineligible.
- Corticosteroids will be allowed at enrollment and during the first month of treatment with 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 not be allowed to increase the dose after that period and will be taken off protocol.
Design:
- This is a Phase I/II open label study that will evaluate the potential benefit of TMZ in prevention of new brain metastases in patients with limited brain metastases from HER2+ breast cancer, previously treated with SRS or surgical resection of brain metastases.
- All patients will receive the standard second-line therapy for HER2+ metastatic breast cancer: T-DM1. During phase II patients will be randomized between T-DM1 plus TMZ versus T-DM1 alone.
- Phase I run in: T-DM1 3.6 mg/kg intravenous (IV) every 21 days plus TMZ 30, 40 or 50 mg/m^2 daily.
- Phase II: T-DM1 3.6 mg/kg versus T-DM1 3.6mg/kg plus TMZ at recommended phase 2 dose (RP2D).
- Phase I will follow a standard 3+3 design. Thus, with 3 dose levels, up to 18 patients may be included in the initial safety evaluation.
- In the phase II portion of the trial, a total of 49 evaluable subjects per arm (98 total) will need to be randomized over a 3-year period and followed for an additional 2 years from the date of entry of the last patient, with occurrence of 79 total relapses in both arms combined, in order to have 80% power to compare the curves.
- Conditions
- Breast Cancer, Brain Metastasis, Brain Cancer
- Being tested
- T-DM1, TMZ
- Keywords
- Ado-trastuzumab Emtansine, Systemic Control of Disease, Maximum Tolerated Dose, Preventing the Formation of a Metastasis
- Medical subject headings
- Breast Neoplasms, Brain Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
T-DM1Drug
Also called Ado-trastuzumab
T-DM1 3.6 mg/kg intravenous (IV) every 21 days
TMZDrug
Also called Temozolomide
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.
| Study group | Role | What they receive |
|---|---|---|
| 1/Phase I: Ado-trastuzumab (T-DMI) + Temozolomide (TMZ) Dose Escalation | Experimental | T-DM1 + TMZ in dose escalation Receives: Drug: T-DM1; Drug: TMZ |
| 2A /Phase II: Arm A, Ado-trastuzumab (T-DMI) Alone | Active comparator | T-DM1 Receives: Drug: T-DM1 |
| 2B/Phase II /Arm B, Ado-trastuzumab (T-DMI) + Temozolomide (TMZ) | Experimental | T-DM1 + TMZ at recommended phase 2 dose (RP2D) Receives: Drug: T-DM1; Drug: TMZ |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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
Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). Grade 3 is severe. Grade 4 is life-threatening.
Measured: 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
Number of participants with DLTs at each dose level 30 days after treatment. 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.
Measured: After first cycle of treatment, up to 30 days
Phase II: Time to Whole Brain Irradiation
Time to whole brain irradiation compared between the two arms and Kaplan-Meier curves constructed with a two-tailed log-rank test used to compare the arms.
Measured: At progression
Phase I: Median Survival
Median amount of time participants survives after therapy. Survival compared between the two arms and Kaplan-Meier curves constructed with a two-tailed log-rank test used to compare the arms.
Measured: From date of first therapy until death, an average of 40.79 months
Phase I: Standard Time to Progression (TTP)
TTP is the time between the first day of treatment to the day of disease progression. Progression was assessed using the Response Evaluation Criteria in Solid Tumors (RECIST). Progression is at least a 25% increase in the sum of products of all measurable lesions over smallest sum observed, clear worsening of any evaluable disease, appearance of any new lesion/site, or failure to return for evaluation due to death or deteriorating condition.
Measured: From first day of treatment to the day of disease progression, an average of 15 months.
Phase II: Median Survival
Median amount of time participants survives after therapy. Survival compared between the two arms and Kaplan-Meier curves constructed with a two-tailed log-rank test used to compare the arms.
Measured: At death
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Jun 2017
- Study start18 Apr 2018
- Primary completion28 Jun 2021
- Study completion13 Jun 2023
Why it stopped: The phase II portion was never started as we could no longer get the drug from the manufacturer.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for Breast CancerStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 12 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Principal investigator, Stanley Lipkowitz, MD, PhD, National Cancer Institute (NCI)
- Investigators
- Stanley Lipkowitz, M.D., Principal investigator, National Cancer Institute (NCI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03190967
- Sponsor's protocol ID
- 170115
- Other IDs
- 17-C-0115
- Status last verified
- Sep 2023
- First submitted
- 16 Jun 2017
- Last updated
- 11 Oct 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request. In addition, all large-scale genomic sequencing data will be shared with subscribers to the database of Genotypes and Phenotypes (dbGaP).
Publications
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.
PubMed 23602601Bartsch 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.
PubMed 26303828Gelmon 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.
PubMed 25779558Jenkins 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.
PubMed 36705597Zimmer 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.
PubMed 32270710
Study at a glance
From the registry record, last updated by the sponsor on 11 Oct 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase I/II Study of T-DM1 Alone Versus T-DM1 and Metronomic Temozolomide in Secondary Prevention of HER2-Positive Breast Cancer Brain Metastases Following Stereotactic Radiosurgery
- ClinicalTrials.gov ID
- NCT03190967
- Acronym / sponsor ID
- 170115
- Conditions
- Breast Cancer, Brain Metastasis, Brain Cancer
- Keywords
- Ado-trastuzumab Emtansine, Systemic Control of Disease, Maximum Tolerated Dose, Preventing the Formation of a Metastasis
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: The phase II portion was never started as we could no longer get the drug from the manufacturer.
- Enrolment
- 12 participants (actual)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- 18 Apr 2018 (actual)
- Primary completion
- 28 Jun 2021 (actual)
- Study completion
- 13 Jun 2023 (actual)
- First posted
- 19 Jun 2017 (actual)
- Results
- Posted 11 Oct 2023
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
Background:
- Breast cancer is the most common cancer in women. In the human epidermal growth factor receptor 2 (HER2+) subtype, brain metastases can occur in up to 25-40% of patients.
- The standard therapy for brain metastases continues to be surgery or stereotactic radiosurgery (SRS) and/or whole brain radiation therapy (WBRT).
- Currently, independently of localized or systemic treatment modality, once brain metastases are established, options for treatment are limited, and the disease almost invariably progresses, limiting not only survival but also quality of life in most patients.
- Preclinical literature suggests the hypothesis that preventing the formation of a metastasis by a drug may be more efficacious than attempting to shrink an established lesion.
- Our group has shown in vitro and in vivo in animal models injected with a brain tropic O6-methylguanine DNA methyltransferase (MGMT) + cell line, that even in very low doses temozolomide (TMZ) administered in a prophylactic, metronomic fashion can significantly prevent development of brain metastases.
- We propose a secondary-prevention clinical trial with oral TMZ given to HER2+ breast cancer patients with brain metastases after recent local treatment (SRS or surgical resection) in combination with the anti-HER2 agent T-DM1 for systemic control of disease.
Objectives:
- Phase I (run in): to identify the maximum tolerated dose (MTD) of TMZ when used in combination with T-DM1.
- Phase II: to determine if the combination regimen of trastuzumab emtansine (T-DM1) and temozolomide improves the freedom from distant new brain metastases following stereotactic radiosurgery or surgical resection in HER2-positive breast cancer brain metastases, as compared to T-DM1 alone guided by one-year results as an important benchmark for measuring improvement.
Eligibility:
Phase I:
- Histologically confirmed HER2+ breast cancer.
- Eastern Cooperative Oncology (ECOG) performance status 0-2 and adequate organ and marrow function.
- Brain metastases, treated within 12 weeks of study entry with SRS, resection or WBRT.
- Patients with leptomeningeal metastatic disease are ineligible.
- Patients that are unable to complete a brain MRI with contrast are ineligible.
- Patients with breast tissue expanders must have those removed before enrollment.
- Hepatitis B virus (HBV), hepatitis C virus (HCV) or human immunodeficiency virus (HIV)-positive patients are ineligible.
- Patient with impaired cardiac function or clinically significant cardiac disease are ineligible.
- Corticosteroids will be allowed at enrollment and during the first month of treatment with 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 not be allowed to increase the dose after that period and will be taken off protocol.
Phase II:
- Histologically confirmed HER2+ breast cancer.
- ECOG performance status 0-2 and adequate organ and marrow function.
- 1-10 brain metastases, by contrast MRI, treated within 12 weeks of study entry with SRS and/or resection.
- Patients with leptomeningeal metastatic disease are ineligible.
- Patients with history of WBRT are ineligible.
- Patients that are unable to complete a brain MRI with contrast are ineligible.
- Patients with breast tissue expanders must have those removed before enrollment.
- HBV, HCV or HIV-positive patients are ineligible.
- Patient with impaired cardiac function or clinically significant cardiac disease are ineligible.
- Corticosteroids will be allowed at enrollment and during the first month of treatment with 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 not be allowed to increase the dose after that period and will be taken off protocol.
Design:
- This is a Phase I/II open label study that will evaluate the potential benefit of TMZ in prevention of new brain metastases in patients with limited brain metastases from HER2+ breast cancer, previously treated with SRS or surgical resection of brain metastases.
- All patients will receive the standard second-line therapy for HER2+ metastatic breast cancer: T-DM1. During phase II patients will be randomized between T-DM1 plus TMZ versus T-DM1 alone.
- Phase I run in: T-DM1 3.6 mg/kg intravenous (IV) every 21 days plus TMZ 30, 40 or 50 mg/m^2 daily.
- Phase II: T-DM1 3.6 mg/kg versus T-DM1 3.6mg/kg plus TMZ at recommended phase 2 dose (RP2D).
- Phase I will follow a standard 3+3 design. Thus, with 3 dose levels, up to 18 patients may be included in the initial safety evaluation.
- In the phase II portion of the trial, a total of 49 evaluable subjects per arm (98 total) will need to be randomized over a 3-year period and followed for an additional 2 years from the date of entry of the last patient, with occurrence of 79 total relapses in both arms combined, in order to have 80% power to compare the curves.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| 1/Phase I: Ado-trastuzumab (T-DMI) + Temozolomide (TMZ) Dose Escalation | Experimental | Drug: T-DM1, Drug: TMZT-DM1 + TMZ in dose escalation |
| 2A /Phase II: Arm A, Ado-trastuzumab (T-DMI) Alone | Active comparator | Drug: T-DM1T-DM1 |
| 2B/Phase II /Arm B, Ado-trastuzumab (T-DMI) + Temozolomide (TMZ) | Experimental | Drug: T-DM1, Drug: TMZT-DM1 + TMZ at recommended phase 2 dose (RP2D) |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (32 listed)
- Phase 1 Inclusion Criteria
- 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.
Key exclusion criteria (47 listed)
- Phase 1 Exclusion Criteria
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| T-DM1Also: Ado-trastuzumabT-DM1 3.6 mg/kg intravenous (IV) every 21 days | Drug | 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) |
| TMZAlso: TemozolomidePhase 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. | Drug | 1/Phase I: Ado-trastuzumab (T-DMI) + Temozolomide (TMZ) Dose Escalation, 2B/Phase II /Arm B, Ado-trastuzumab (T-DMI) + Temozolomide (TMZ) |
Primary outcome
Phase I: Maximum Tolerated Dose (MTD) of Temozolomide (TMZ) When Used With T-DM1 (Ado-trastuzumab)
Time frame: first 21 days of treatment
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.
Phase II: Median Amount of Time Participant Survives Without New Brain Lesions After Starting Treatment
Time frame: From the start of treatment until new brain lesions
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.
6 secondary outcomes
Phase I: Number of Participants With Grade 3 and/or Grade 4 Adverse Events
Time frame: 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
Time frame: After first cycle of treatment, up to 30 days
Phase II: Time to Whole Brain Irradiation
Time frame: At progression
Phase I: Median Survival
Time frame: From date of first therapy until death, an average of 40.79 months
Phase I: Standard Time to Progression (TTP)
Time frame: From first day of treatment to the day of disease progression, an average of 15 months.
Phase II: Median Survival
Time frame: At death
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Oct 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 23602601Swain 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.
- Background: PubMed 26303828Bartsch 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.
- Background: PubMed 25779558Gelmon 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.
- Results publication: PubMed 36705597Jenkins 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.
- Results publication: PubMed 32270710Zimmer 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.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
- Individual participant dataSharing planned: Yes. All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request. In addition, all large-scale genomic sequencing data will be shared with subscribers to the database of Genotypes and Phenotypes (dbGaP).
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Stanley Lipkowitz, M.D. principal investigator
National Cancer Institute (NCI)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing T-DM1 and TMZ in people with Breast Cancer and Brain Metastasis, run by National Cancer Institute (NCI) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 32 inclusion and 47 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 11 Oct 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 11 Oct 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Phase I: Maximum Tolerated Dose (MTD) of Temozolomide (TMZ) When Used With T-DM1 (Ado-trastuzumab) (time frame: first 21 days of treatment). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03190967, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Oct 2023.