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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01983501
Recruitment Status : Completed
First Posted : November 14, 2013
Last Update Posted : September 21, 2020
Information provided by (Responsible Party):
Seagen Inc.

Brief 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.

Condition or disease Intervention/treatment Phase
HER2 Positive Breast Cancers Drug: Tucatinib (ONT-380) Drug: T-DM1 Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 57 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : February 28, 2014
Actual Primary Completion Date : October 10, 2017
Actual Study Completion Date : September 3, 2020

Arm Intervention/treatment
Experimental: Tucatinib (ONT-380) in combination with T-DM1 Drug: Tucatinib (ONT-380)
Given twice per day, orally

Drug: T-DM1
Given intravenously once every 21 days
Other Name: Kadcyla

Primary Outcome Measures :
  1. Incidence of adverse events [ Time Frame: 12 months ]

Secondary Outcome Measures :
  1. Incidence of clinical lab abnormalities [ Time Frame: 12 months ]
  2. Frequency of dose reductions in tucatinib [ Time Frame: 12 months ]
  3. Frequency of dose reductions in T-DM1 [ Time Frame: 12 months ]
  4. Objective response rate (ORR) [ Time Frame: 12 months ]
  5. Duration of response [ Time Frame: 12 months ]
  6. Disease control rate (DCR) [ Time Frame: 12 months ]
    Defined as best response of complete response (CR), partial response (PR), or stable disease (SD)

  7. Clinical benefit rate (CBR) [ Time Frame: 12 months ]
    Defined as SD for ≥6 months, PR, or CR

  8. Progression-free survival (PFS) [ Time Frame: Up to approximately 6 years ]

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • 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.
  • 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.

Exclusion Criteria:

  • 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.
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01983501

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United States, Alabama
University of Alabama
Birmingham, Alabama, United States, 35294
United States, Colorado
University of Colorado Cancer Center
Aurora, Colorado, United States, 80045
United States, Kansas
University of Kansas
Kansas City, Kansas, United States, 66160
United States, Massachusetts
Dana Farber Cancer Institute
Boston, Massachusetts, United States, 02215
United States, Oregon
Providence Cancer Center
Portland, Oregon, United States, 97213
United States, Tennessee
Sarah Cannon Research Institute
Nashville, Tennessee, United States, 37203
United States, Washington
Northwest Medical Specialties
Tacoma, Washington, United States, 98045
Canada, Ontario
London Health Sciences Centre
London, Ontario, Canada, N6A 5W9
Princess Margaret Cancer Centre
Toronto, Ontario, Canada, M5T 2M9
Canada, Quebec
Hospital de la Cite-de-la-Sante
Laval, Quebec, Canada, H7M 3L9
Jewish General Hospital
Montreal, Quebec, Canada, H3T 1E2
Sponsors and Collaborators
Seagen Inc.
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Study Director: JoAl Mayor, PharmD, BCOP Seagen Inc.
Study Director: Corinna Palanca-Wessels, MD, PhD Seagen Inc.
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: Seagen Inc. Identifier: NCT01983501    
Other Study ID Numbers: ONT-380-004
First Posted: November 14, 2013    Key Record Dates
Last Update Posted: September 21, 2020
Last Verified: September 2020
Keywords provided by Seagen Inc.:
Breast cancer
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Antineoplastic Agents
Molecular Mechanisms of Pharmacological Action
Protein Kinase Inhibitors
Enzyme Inhibitors