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

Status: Recruiting
Phase: Phase 1
Diagnosis: Breast: Metastatic
NCT ID: NCT01983501 (View complete trial on ClinicalTrials.gov)
DFCI Protocol ID: 13-510


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.


Conducting Institutions:
Dana-Farber Cancer Institute, Brigham and Women's Hospital

Overall PI:
Ian Krop, MD, Dana-Farber Cancer Institute

Site-responsible Investigators:

Dana-Farber Cancer Institute: Breast Cancer Nursing Team, 617-632-3478

Eligibility Criteria

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. Prior therapy with trastuzumab and a taxane must have been 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 received previous treatment with an anthracycline with a total prior exposure > 360 mg/m2. - Previous treatment with T-DM1 or with any small molecule HER2 inhibitors including (but not limited to) lapatinib, neratinib, or afatinib for metastatic disease, with the exception that patients who received lapatinib for adjuvant or neoadjuvant therapy may be included, provided that the last dose of lapatinib was at least 6 months prior to initiation of study therapy. - Patients with untreated CNS metastases are excluded from dose escalation cohorts and the MTD expansion cohort: - Patients with a history of CNS metastases which have been treated prior to enrollment must be stable for four weeks after completion of treatment. These patients must have undergone appropriate imaging studies and currently be on a stable corticosteroid dose that has not been changed for ≥ two weeks. - Following completion of the dose escalation phase of the study, patients with asymptomatic untreated CNS metastases may be eligible for an optional second expansion cohort following discussion with the study medical monitor. - Patients with leptomeningeal disease are excluded - 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.
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