A Phase 1b Study of ONT-380 Combined With Ado-trastuzumab Emtansine (T-DM1) in Patients With HER2+ Breast Cancer

This study is ongoing, but not recruiting participants.
Information provided by (Responsible Party):
Oncothyreon Inc.
ClinicalTrials.gov Identifier:
First received: October 28, 2013
Last updated: September 1, 2015
Last verified: September 2015
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 ONT-380 combined with ado-trastuzumab emtansine (T-DM1) in patients with HER2+ breast cancer.

Condition Intervention Phase
HER2 Positive Breast Cancers
Drug: ONT-380
Drug: T-DM1
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 1b, Open-label Study to Assess the Safety and Tolerability of ONT-380 Combined With Ado-trastuzumab Emtansine (Trastuzumab Emtansine;T-DM1)

Resource links provided by NLM:

Further study details as provided by Oncothyreon Inc.:

Primary Outcome Measures:
  • Incidence and severity of adverse events [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
  • incidence and severity of clinical lab abnormalities [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • anti-tumor activity of ONT-380 given at the MTD/RD in combination with T-DM1 [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]

Enrollment: 57
Study Start Date: February 2014
Estimated Study Completion Date: May 2016
Primary Completion Date: March 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Dose Escalation of ONT-380 in combination with T-DM1 Drug: ONT-380
Phase 1b dose escalation: 21-day cycles of ONT-380 (administered twice per day, orally) and T-DM1 (administered intravenously once every 21 days) until disease progression or unacceptable toxicity.
Drug: T-DM1
Phase 1b dose escalation: 21-day cycles of ONT-380 (administered twice per day, orally) and T-DM1 (administered intravenously once every 21 days) until disease progression or unacceptable toxicity.
Other Name: Kadcyla

Detailed Description:

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

Phase 1 will use a 3+3 dose escalation design to evaluate up to four dose levels of ONT-380 in order to identify the maximal tolerated dose/recommended dose (MTD/RD) of 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 ONT-380 alone). 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.


Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
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.
  • ≥ 18 years at time of consent.
  • 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 ONT-10 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 is 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 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. (See Appendix E).
  • 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. (See Appendix F).
  • 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.
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01983501

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
Oncothyreon Inc.
  More Information

No publications provided

Responsible Party: Oncothyreon Inc.
ClinicalTrials.gov Identifier: NCT01983501     History of Changes
Other Study ID Numbers: ONT-380-004
Study First Received: October 28, 2013
Last Updated: September 1, 2015
Health Authority: United States: Institutional Review Board
United States: Food and Drug Administration

Keywords provided by Oncothyreon Inc.:
HER2 positive breast cancer
Breast cancer

Additional relevant MeSH terms:
Breast Neoplasms
Breast Diseases
Neoplasms by Site
Skin Diseases
Ado-trastuzumab emtansine
Antimitotic Agents
Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses
Tubulin Modulators

ClinicalTrials.gov processed this record on November 25, 2015