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HER2 Positive Breast CancersPhase 1NCT01983501

A Study of Tucatinib (ONT-380) Combined With Ado-trastuzumab Emtansine (T-DM1) in Patients With HER2+ Breast Cancer

A Phase 1 study testing Tucatinib (ONT-380) and T-DM1 in people with HER2 Positive Breast Cancers, run by Seagen Inc. at 11 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

The purpose of this study is to determine the maximal tolerated dose (MTD) or recommended dose (RD) and to assess the safety and tolerability of tucatinib (ONT-380) combined with ado-trastuzumab emtansine (T-DM1) in patients with HER2+ breast cancer. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
HER2 Positive Breast Cancers
What is being tested?
Tucatinib (ONT-380) and T-DM1
Could I receive a placebo?
No, everyone receives an active treatment
How many people
57 participants
Where
11 sitesin 2 countries
Study dates
28 Feb 2014to 3 Sep 2020
Phase
Phase 1
Are there results?
None posted in the registry

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

  • HER2+ metastatic breast cancer, documented as HER2+ by FISH and/or 3+ staining by immunohistochemistry.
  • History of prior therapy with trastuzumab and a taxane, separately or in combination. For patients in dose escalation and MTD expansion cohorts, prior therapy with trastuzumab and a taxane must have been for metastatic disease. For patients in CNS disease expansion cohorts, trastuzumab and taxane (together or separately) may have been given at any time prior to study enrollment as part of neoadjuvant therapy, adjuvant therapy, or therapy for metastatic disease.
  • If female and of child-bearing potential, has negative pregnancy test within 14 days prior to treatment.
  • If a sexually active male or a sexually active female of child-bearing potential, agrees to use dual (two concurrent) forms of medically accepted contraception from the time of consent until 6 months after the last dose of either tucatinib (ONT-380) or T-DM1, whichever is longer.
  • Signed an informed consent document that has been approved by an institutional review board or independent ethics committee (IRB/IEC).
  • Must have target or non-target lesions as per RECIST 1.1.
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  • All toxicity related to prior cancer therapies must have resolved to ≤ Grade 1, with the following exceptions: alopecia; neuropathy, which must have to resolved to ≤ Grade 2; and congestive heart failure (CHF), which must have been ≤ Grade 1 in severity and must have resolved completely.
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at screening.
  • In the opinion of the Investigator, life expectancy > 6 months.
  • Adequate hematologic function as defined by:
  • Hemoglobin ≥ 9 g/dL
  • Absolute neutrophil count (ANC) ≥ 1000 cells/µL
  • Platelets ≥ 100,000/µL
  • Adequate hepatic function as defined by the following:
  • Total bilirubin ≤ 1.5 X upper limit of normal (ULN)
  • Transaminases (aspartate aminotransferase/serum glutamic oxaloacetic transaminase [AST/SGOT] and alanine aminotransferase/serum glutamic pyruvic transaminase [ALT/SGPT]) ≤ 1.5 X ULN (< 2.5 X ULN if liver metastases are present)
  • INR and aPTT < 1.5 X ULN unless on medication known to alter INR and aPTT.
  • Calculated creatinine clearance ≥ 60 mL/min.
  • Left ventricular ejection fraction (LVEF) must be within institutional limits of normal as assessed by echocardiogram or multigated acquisition scan (MUGA) documented within 4 weeks prior to first dose of study drug.

Who cannot join

  • Medical, social, or psychosocial factors that, in the opinion of the Investigator, could impact safety or compliance with study procedures.
  • Patient is breastfeeding.
  • Patient was treated with any experimental agent within 14 days or five half-lives of study treatment, whichever is greater.
  • Patient was treated with trastuzumab or other antibody based therapy within three weeks of starting study treatment or with chemotherapy or hormonal cancer therapy within two weeks of starting study treatment.
  • Patient had prior exposure to a cumulative dose of doxorubicin that exceeded 360 mg/m2 or its equivalent.
  • Previous treatment with T-DM1 at any time; or previous treatment with any small molecule HER2 inhibitors including (but not limited to) lapatinib, neratinib, or afatinib within the last 4 weeks prior to initiation of study therapy.
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  • CNS disease:
  • Patients with leptomeningeal disease are excluded
  • Dose escalation and MTD/RP2D expansion cohort: Patients with symptomatic CNS metastases are excluded. Patients with treated CNS metastases or untreated asymptomatic CNS metastases not requiring immediate local therapy may be eligible. Enrollment of patients with metastases must be approved by the study medical monitor.
  • Optional CNS disease expansion cohort: Patients with asymptomatic untreated CNS metastases not needing immediate local therapy or patients with progressive CNS disease following local therapy may be eligible with medical monitor approval.
  • History of allergic reactions to compounds of similar chemical or biological composition to T-DM1 or tucatinib (ONT-380), except for a history of Grade 1 or Grade 2 Infusion Related Reaction to trastuzumab which has been successfully managed.
  • Patients with uncorrectable electrolyte abnormalities.
  • Known to be HIV positive. HIV testing is not required for those patients who are not known to be positive.
  • Known carrier of Hepatitis B and / or Hepatitis C (whether active disease or not).
  • Known liver disease, autoimmune hepatitis, or sclerosing cholangitis.
  • Inability to swallow pills or any significant gastrointestinal diseases, which would preclude adequate absorption of oral medications.
  • Use of a strong CYP3A4 inhibitor within three elimination half-lives of the inhibitor prior to the start of study treatment.
  • Use of a strong CYP2C8 inducer or inhibitor within three elimination half-lives of the inducer or inhibitor prior to the start of study treatment.
  • Radiotherapy within 14 days of study treatment; patient must have recovered from acute effects of radiotherapy to baseline.
  • Known impaired cardiac function or clinically significant cardiac disease such as ventricular arrhythmia requiring therapy, congestive heart failure and uncontrolled hypertension (defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure > 100 mmHg on antihypertensive medications).
  • Myocardial infarction or unstable angina within 6 months prior to the first dose of study drug.

Trial locations and contacts

11 sites in 2 countries.

11 sites in 2 countries

United States7 sites

  • University of Colorado Cancer Center

    Aurora, Colorado, 80045

  • University of Alabama

    Birmingham, Alabama, 35294

  • Dana Farber Cancer Institute

    Boston, Massachusetts, 02215

  • University of Kansas

    Kansas City, Kansas, 66160

  • Sarah Cannon Research Institute

    Nashville, Tennessee, 37203

  • Providence Cancer Center

    Portland, Oregon, 97213

  • Northwest Medical Specialties

    Tacoma, Washington, 98045

Other trials in United States

Canada4 sites

  • Hospital de la Cite-de-la-Sante

    Laval, Quebec, H7M 3L9

  • London Health Sciences Centre

    London, Ontario, N6A 5W9

  • Jewish General Hospital

    Montreal, Quebec, H3T 1E2

  • Princess Margaret Cancer Centre

    Toronto, Ontario, M5T 2M9

Other trials in Canada

About this study

Official title: A Phase 1b, Open-label Study to Assess the Safety and Tolerability of Tucatinib (ONT-380) Combined With Ado-trastuzumab Emtansine (Trastuzumab Emtansine; T-DM1)

The purpose of this study is to determine the maximal tolerated dose (MTD) or recommended dose (RD) and to assess the safety and tolerability of tucatinib (ONT-380) combined with ado-trastuzumab emtansine (T-DM1) in patients with HER2+ breast cancer.

Read the detailed description

This is a Phase 1b, open-label study of tucatinib (ONT-380) given in combination with ado-trastuzumab emtansine (T-DM1) to patients with HER2+ breast cancer.

This study will use a 3+3 dose escalation design to evaluate up to four dose levels of tucatinib ONT-380 in order to identify the maximal tolerated dose/recommended dose (MTD/RD) of tucatinib (ONT-380) in combination with T-DM1. T-DM1 will be administered intravenously on day 1 of each cycle (except cycle 1, when it will be administered on day 2 to allow for PK assessments of tucatinib (ONT-380) alone).Tucatinib (ONT-380) will be administered orally, twice per day on days 1-21 of each cycle.

There will be 3-6 evaluable patients enrolled in each cohort in the dose escalation phase, unless that dose is found to be intolerable prior to completion of enrollment. At least 6 evaluable patients are to be treated at a dose level in order for an MTD/RD to be declared. Once an MTD/RD is declared, an additional 24 evaluable patients will be in enrolled in a MTD/RD expansion cohort for a total of 30 evaluable patients to be treated at the MTD/RD.

In addition to the MTD/RD expansion cohort, an optional additional cohort of up to 15 evaluable patients with either untreated, asymptomatic CNS metastases not needing immediate local therapy or progressive CNS metastasis following local therapy may also be enrolled and treated at the MTD/RD. Up to 63 evaluable patients may be treated in this study.

Being tested
Tucatinib (ONT-380), T-DM1
Keywords
ONT-380, T-DM1, Kadcyla, Breast cancer, ARRY-380, Tucatinib
Medical subject headings
Breast Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Tucatinib (ONT-380)Drug

    Given twice per day, orally

  • T-DM1Drug

    Also called Kadcyla

    Given intravenously once every 21 days

Study groups in NCT01983501
Study groupRoleWhat they receive
Tucatinib (ONT-380) in combination with T-DM1ExperimentalNot described
Receives: Drug: Tucatinib (ONT-380); Drug: T-DM1

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Incidence of adverse events

    Measured: 12 months

Secondary outcomes (8)

  1. Incidence of clinical lab abnormalities

    Measured: 12 months

  2. Frequency of dose reductions in tucatinib

    Measured: 12 months

  3. Frequency of dose reductions in T-DM1

    Measured: 12 months

  4. Objective response rate (ORR)

    Measured: 12 months

  5. Duration of response

    Measured: 12 months

  6. Disease control rate (DCR)

    Defined as best response of complete response (CR), partial response (PR), or stable disease (SD)

    Measured: 12 months

  7. Clinical benefit rate (CBR)

    Defined as SD for ≥6 months, PR, or CR

    Measured: 12 months

  8. Progression-free survival (PFS)

    Measured: Up to approximately 6 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted14 Nov 2013 (estimated)
  2. Study start28 Feb 2014
  3. Primary completion10 Oct 2017
  4. Study completion3 Sep 2020

Resources

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
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
57 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01983501
Sponsor's protocol ID
ONT-380-004
Status last verified
Sep 2020
First submitted
28 Oct 2013
Last updated
21 Sep 2020
Results posted
No
Data monitoring committee
Yes

Publications

  • Zhang D, Taylor A, Zhao JJ, Endres CJ, Topletz-Erickson A. Population Pharmacokinetic Analysis of Tucatinib in Healthy Participants and Patients with Breast Cancer or Colorectal Cancer. Clin Pharmacokinet. 2024 Oct;63(10):1477-1487. doi: 10.1007/s40262-024-01412-0. Epub 2024 Oct 5.

    PubMed 39368039

  • Borges VF, Ferrario C, Aucoin N, Falkson C, Khan Q, Krop I, Welch S, Conlin A, Chaves J, Bedard PL, Chamberlain M, Gray T, Vo A, Hamilton E. Tucatinib Combined With Ado-Trastuzumab Emtansine in Advanced ERBB2/HER2-Positive Metastatic Breast Cancer: A Phase 1b Clinical Trial. JAMA Oncol. 2018 Sep 1;4(9):1214-1220. doi: 10.1001/jamaoncol.2018.1812.

    PubMed 29955792

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Tucatinib (ONT-380) and T-DM1 in people with HER2 Positive Breast Cancers, run by Seagen Inc. at 11 sites in 2 countries.

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 19 inclusion and 21 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: finished, as of the sponsor's last update on 21 Sep 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 11 sites in United States, Canada. 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 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.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

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?

Incidence of adverse events (time frame: 12 months). 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 NCT01983501, which also lists 2 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 21 Sep 2020.

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