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 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

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KD019 in combination with Trastuzumab.
KD019 will be orally administered to subjects at 150mg once daily in combination with Trastuzumab 8mg/kg every 3 weeks.

Tesevatinib in combination with Trastuzumab.
Tesevatinib will be orally administered to subjects at 150mg once daily in combination with Trastuzumab 8mg/kg every 3 weeks.

Drug: KD019 in combination with Trastuzumab

Drug: Tesevatinib in combination with Trastuzumab

KD019 in combination with Trastuzumab.
KD019 will be orally administered to subjects at 250mg once daily in combination with Trastuzumab 8mg/kg every 3 weeks.

Tesevatinib in combination with Trastuzumab.
Tesevatinib will be orally administered to subjects at 250mg once daily in combination with Trastuzumab 8mg/kg every 3 weeks.

Drug: KD019 in combination with Trastuzumab

Drug: Tesevatinib in combination with Trastuzumab

KD019 in combination with Trastuzumab.
KD019 will be orally administered to subjects at 300mg once daily in combination with Trastuzumab 8mg/kg every 3 weeks.

Tesevatinib in combination with Trastuzumab.
Tesevatinib will be orally administered to subjects at 300mg once daily in combination with Trastuzumab 8mg/kg every 3 weeks.

Drug: KD019 in combination with Trastuzumab

Drug: Tesevatinib in combination with Trastuzumab

Phase 2a

Phase 2a, Group 1

KD019 in combination with Trastuzumab.
In the Phase 2a expansion group, KD019 will be orally administered to all subjects once daily at the MTD dose determined in Phase 1b in combination with Trastuzumab 8mg/kg every 3 weeks.
Subjects will be limited to those with HER2-positive breast cancer and brain metastases that have progressed after radiation therapy.

Tesevatinib in combination with Trastuzumab.
In the Phase 2a expansion group, tesevatinib will be orally administered to all subjects once daily at the MTD dose determined in Phase 1b in combination with Trastuzumab 8mg/kg every 3 weeks.
Subjects will include those with HER2-positive breast cancer and brain metastases that have progressed after radiation therapy.

Drug: KD019 in combination with Trastuzumab

Drug: Tesevatinib in combination with Trastuzumab

KD019 in combination with Trastuzumab

Tesevatinib in combination with Trastuzumab

Phase 2a

Phase 2a, Group 1

<p>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</li><li><p>Subjects may have received any number of prior therapies for breast cancer:</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 brain metastases must have received radiation therapy prior to study entry, except that subjects with asymptomatic brain metastases may be entered into Phase 1b without prior radiation therapy to the brain.</li></ul></li><li>Subjects with disease progression in the brain after prior brain radiation therapy may have extra CNS metastases in any location or may have no extra CNS metastases</li><li>Enrollment in the Phase 2a portion of the study will be limited to subjects with HER2-positive metastatic breast cancer with brain metastases that have progressed after radiation therapy</li><li>At least 1 measurable and new or progressing breast cancer lesion that is ≥ 10mm 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>No coexisting medical problems of sufficient severity to limit compliance with the study</li><li>Women of childbearing potential must have negative urine pregnancy test.
They 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>Exclusion Criteria:</p><ul><li>Any concurrent therapy for breast cancer other than biphosphonates</li><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</li><li>History of 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>Subject who is pregnant or lactating</li><li>Known contraindications to MRI</li><li>Had had major surgery without fully recovery</li><li>Has marked prolongation of QTc interval at screening or baseline using the Fridericia method of correction for heart rate</li><li>Has gastrointestinal tract disease resulting in an inability to take or absorb oral medication</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 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 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>

To evaluate the following pharmacokinetic parameters (Cmax, Tmax, and AUC[0-24hr]) for the combination of KD019 and Trastuzumab.
Plasma concentrations of KD019 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.

2015-08

2015-12

2014-11

2015-01

2014-11-25

2015-01-21

2014-11-26

2015-01-26

Evaluate the safety and tolerability and determine the maximum tolerated dose (MTD) of the combination of KD019 and trastuzumab in subjects with HER2-positive metastatic breast cancer

Evaluate the safety and tolerability and determine the maximum tolerated dose (MTD) of the combination of tesevatinib and trastuzumab in subjects with HER2-positive metastatic breast cancer