Study of the Combination of KD019 and Trastuzumab in Subjects With HER2-Positive Metastatic Breast Cancer

To evaluate the safety and tolerability and determine the MTD of the combination of tesevatinib and trastuzumab in subjects with HER2-positive metastatic breast cancer

To evaluate the safety and tolerability and determine the MTD of the combination of tesevatinib and trastuzumab in subjects with HER2-positive metastatic breast cancer.

15 months

27 months

67

80

<p>Key Inclusion Criteria:</p><ul><li>Females with histologically or cytologically confirmed HER2-positive breast cancer.
HER2-positive is defined as 3+ staining by immunohistochemistry, or HER2 gene amplification by fluorescent in situ hybridization or silver in situ hybridization with HER2&#x2F;CEP17 ratio ≥ 2.0</li><li>Metastatic disease that has progressed on previous therapy or previous therapy was not tolerated</li><li><p>Subjects in the Phase 1b portion of the study and in Group 1 of the Phase 2a portion of the study may have received any number of prior therapies for breast cancer.
Subjects in Group 2 of the Phase 2a portion of the study may have received up to 3 lines of therapy in the metastatic setting (not including adjuvant or neoadjuvant therapy)</p><ul><li>These must have included trastuzumab, pertuzumab, and trastuzumab emtansine.
Subjects starting initial systemic therapy for HER2-positive breast cancer prior to June 2012, when pertuzumab was approved for initial treatment of patients with HER2-positive breast cancer, are not required to have had pertuzumab</li><li>If the subject has ER+ breast cancer, prior therapy must have included at least 1 hormonal therapy</li><li>Subjects with asymptomatic brain metastases found on screening MRI may be entered into Phase 1b or into Group 2 of the Phase 2a without prior radiation therapy to the brain.
Subjects with minimally symptomatic brain metastases found on screening MRI may be entered into Phase 1b or into Group 2 of the Phase 2a without prior radiation therapy to the brain if they do not require immediate surgical or radiation therapy</li></ul></li><li>At least 1 measurable breast cancer lesion that is ≥ 10mm in one dimension (or ≥15mm in shortest axis for lymph nodes) by spiral CT scan or by brain MRI</li><li>No increase in steroid dose during the week prior to screening brain MRI</li><li>No history of another malignancy in the past 5 years, except treated non-melanoma skin cancer or superficial bladder cancer or carcinoma-in-situ of the cervix</li><li>Adequate organ and bone marrow functions</li><li>Serum potassium and magnesium levels within normal limits</li><li>Cardiac ejection fraction within normal limits as measured by echocardiogram</li><li>Women of childbearing potential must have negative urine pregnancy test.
Sexually active women must agree to use two forms of accepted methods of contraception during the course of the study and for 3 months after their last dose of study drug.
Effective birth control includes (a) IUD plus one barrier method; (b) on stable doses of hormonal contraception for at least 3 months (eg, oral, injectable, implant, transdermal) plus one barrier method; (c) 2 barrier methods.
Effective barrier methods are male or female condoms, diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm); or (d) vasectomized partner</li></ul><p>Key Exclusion Criteria:</p><ul><li>Cerebrospinal fluid cytology positive for malignant cells or symptomatic leptomeningeal carcinomatosis</li><li>Taking any medication known to inhibit the CYP3A4 isozyme or any drugs that are CYP3A4 inducers (including phenytoin), or any drugs associated with torsades de pointes or known to prolong the QTc(f) interval within 2 weeks prior to Day 1 of treatment on study.
A stable regimen of antidepressants of the SSRI class is allowed</li><li>Has evidence of active heart disease within the 3 months prior to study entry; symptomatic coronary insufficiency or heart block; congestive heart failure; moderate or severe pulmonary dysfunction, torsades de pointes, ventricular tachycardia or fibrillation, pathologic sinus bradycardia, heart block, or congenital long QT syndrome</li><li>Has an active infectious process</li><li>Has marked prolongation of QTc interval at screening or baseline using the Fridericia method of correction for heart rate</li><li>History of gastrointestinal condition that might interfere with drug absorption</li></ul>

<p>Key Inclusion Criteria:</p><ul><li>Females with histologically or cytologically confirmed HER2-positive breast cancer.
HER2-positive is defined as 3+ staining by immunohistochemistry or HER2 gene amplification by fluorescent in situ hybridization or silver in situ hybridization with HER2&#x2F;CEP17 ratio ≥ 2.0</li><li>Metastatic disease that has progressed on previous therapy or previous therapy was not tolerated</li><li><p>Subjects in the Phase 1b portion and in Group 1 and Group 3 of the Phase 2a portion may have received any number of prior therapies for breast cancer.
Subjects in Group 2 of the Phase 2a portion may have received up to 3 lines of therapy in the metastatic setting (not including adjuvant or neoadjuvant therapy)</p><ul><li>Must have included trastuzumab, pertuzumab, and trastuzumab emtansine.
Subjects starting initial systemic therapy for HER2-positive breast cancer prior to June 2012 are not required to have had pertuzumab</li><li>If the subject has ER+ breast cancer, prior therapy must have included at least 1 hormonal therapy</li><li>Subjects with asymptomatic brain metastases found on screening MRI may be entered into Phase 1b or into Group 2 of the Phase 2a without prior radiation therapy to the brain.
Subjects with minimally symptomatic brain metastases found on screening MRI may be entered into Phase 1b or into Group 2 of the Phase 2a without prior radiation therapy to the brain if they do not require immediate surgical or radiation therapy</li><li>Subjects with leptomeningeal metastases may or may not have brain metastases.
When brain metastases are present, they do not need to have progressed after radiation therapy</li></ul></li><li><p>At least 1 measurable breast cancer lesion that is ≥ 10mm in one dimension (or ≥15mm in shortest axis for lymph nodes) by spiral CT scan or by brain MRI</p><ul><li>Subjects in Group 3 are not required to have measurable disease but must have cytologic confirmation of leptomeningeal disease</li></ul></li><li>No increase in steroid dose during the week prior to screening brain MRI</li><li>No history of another malignancy in the past 5 years, except treated non-melanoma skin cancer or superficial bladder cancer or carcinoma-in-situ of the cervix</li><li>Adequate organ and bone marrow functions</li><li>Serum potassium and magnesium levels within normal limits</li><li>Cardiac ejection fraction within normal limits as measured by echocardiogram</li><li>Women of childbearing potential must have negative urine pregnancy test.
Sexually active women must agree to use two forms of accepted methods of contraception during the course of the study and for 3 months after their last dose of study drug.
Effective birth control includes IUD plus one barrier method; on stable doses of hormonal contraception for at least 3 months plus one barrier method; 2 barrier methods.
Effective barrier methods are male or female condoms, diaphragms, and spermicides; or vasectomized partner</li></ul><p>Key Exclusion Criteria:</p><ul><li>CSF cytology positive for malignant cells or symptomatic leptomeningeal carcinomatosis in the Phase 1b portion.
In Group 3, subjects are required to have CSF cytology positive for malignant cells</li><li>Taking any medication known to inhibit the CYP3A4 isozyme or any drugs that are CYP3A4 inducers (including phenytoin), or any drugs associated with torsades de pointes or known to prolong the QTc(f) interval within 2 weeks prior to Day 1 of treatment on study.
A stable regimen of antidepressants of the SSRI class is allowed</li><li>Evidence of active heart disease within the 3 months prior to study entry; symptomatic coronary insufficiency or heart block; congestive heart failure; moderate or severe pulmonary dysfunction, torsades de pointes, ventricular tachycardia or fibrillation, pathologic sinus bradycardia, heart block, or congenital long QT syndrome</li><li>Has an active infectious process</li><li>Has marked prolongation of QTc interval at screening or baseline using the Fridericia method of correction for heart rate</li><li>History of gastrointestinal condition that might interfere with drug absorption</li></ul>

To determine the response rate (RR) using RECIST for non-CNS disease and by the Response Assessment in Neuro-Oncology (RANO) criteria for CNS disease

To determine the response rate (RR) using RECIST for non-CNS disease and by the Response Assessment in Neuro-Oncology (RANO) criteria for brain metastases.

18 months

27 months

To evaluate the following pharmacokinetic parameters (Cmax, Tmax, and AUC[0-24hr]) for the combination of tesevatinib and Trastuzumab.
Plasma concentrations of Tesevatinib and serum concentrations of trastuzumab will be summarized by dose, sample collection day, and sample collection time for each drug.

To evaluate the following pharmacokinetic parameters (Cmax, Tmax, and AUC[0-24hr]) for the combination of tesevatinib and trastuzumab.
Plasma concentrations of tesevatinib and serum concentrations of trastuzumab will be summarized by dose, sample collection day, and sample collection time for each drug.

15 months

27 months

To determine the median progression-free survival (PFS) and the percentage of subjects without disease progression after 2, 4, and 6 months of dosing

To determine the median progression-free survival (PFS) and the percentage of subjects without disease progression after 2, 4, and 6 months of dosing.

18 months

27 months

To determine the median overall survival (OS)

To determine the median overall survival (OS).

2015-05

2015-06

2015-05-13

2015-06-09

2015-05-14

2015-06-11