Clinical Trials /

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

NCT02154529

Description:

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

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Terminated

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of the Combination of KD019 and Trastuzumab in Subjects With HER2-Positive Metastatic Breast Cancer
  • Official Title: A Phase 1b/2a Study of the Combination of KD019 and Trastuzumab in Subjects With HER2-Positive Metastatic Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: KD019-204
  • NCT ID: NCT02154529

Conditions

  • HER-2 Positive Breast Cancer
  • Metastatic Malignant Neoplasm to Brain

Interventions

DrugSynonymsArms
Tesevatinib in combination with TrastuzumabKD019, XL647, HerceptinPhase 1b, Arm 1

Purpose

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

Trial Arms

NameTypeDescriptionInterventions
Phase 1b, Arm 1ExperimentalTesevatinib in combination with Trastuzumab. Tesevatinib will be orally administered to subjects at 150mg once daily in combination with Trastuzumab 8mg/kg every 3 weeks.
  • Tesevatinib in combination with Trastuzumab
Phase 1b, Arm 2ExperimentalTesevatinib in combination with Trastuzumab. Tesevatinib will be orally administered to subjects at 250mg once daily in combination with Trastuzumab 8mg/kg every 3 weeks.
  • Tesevatinib in combination with Trastuzumab
Phase 1b, Arm 3ExperimentalTesevatinib in combination with Trastuzumab. Tesevatinib will be orally administered to subjects at 300mg once daily in combination with Trastuzumab 8mg/kg every 3 weeks.
  • Tesevatinib in combination with Trastuzumab
Phase 1b, Arm 4ExperimentalTesevatinib in combination with Trastuzumab. Tesevatinib will be orally administered to subjects at 350mg once daily in combination with Trastuzumab 8mg/kg every 3 weeks.
  • Tesevatinib in combination with Trastuzumab
Phase 1b, Arm 5ExperimentalTesevatinib in combination with Trastuzumab. Tesevatinib will be orally administered to subjects at 400mg once daily in combination with Trastuzumab 8mg/kg every 3 weeks.
  • Tesevatinib in combination with Trastuzumab
Phase 2a, Group 1ExperimentalTesevatinib 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.
  • Tesevatinib in combination with Trastuzumab
Phase 2a, Group 2ExperimentalTesevatinib 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 metastatic breast cancer who do not have brain metastases, or who have asymptomatic brain metastases, or who have minimally symptomatic brain metastases that do not require immediate radiation therapy or neurosurgery.
  • Tesevatinib in combination with Trastuzumab
Phase 2a, Group 3ExperimentalTesevatinib 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 be limited to those with HER2-positive metastatic breast cancer with pathologically confirmed leptomeningeal metastases with or without brain metastases. Brain metastases do not have to have progressed after radiation therapy in this group.
  • Tesevatinib in combination with Trastuzumab

Eligibility Criteria

        Key Inclusion Criteria:

          -  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/CEP17 ratio ≥ 2.0

          -  Metastatic disease that has progressed on previous therapy or previous therapy was not
             tolerated

          -  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)

               -  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

               -  If the subject has ER+ breast cancer, prior therapy must have included at least 1
                  hormonal therapy

               -  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

               -  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

          -  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

               -  Subjects in Group 3 are not required to have measurable disease but must have
                  cytologic confirmation of leptomeningeal disease

          -  No increase in steroid dose during the week prior to screening brain MRI

          -  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

          -  Adequate organ and bone marrow functions

          -  Serum potassium and magnesium levels within normal limits

          -  Cardiac ejection fraction within normal limits as measured by echocardiogram

          -  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

        Key Exclusion Criteria:

          -  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

          -  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

          -  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

          -  Has an active infectious process

          -  Has marked prolongation of QTc interval at screening or baseline using the Fridericia
             method of correction for heart rate

          -  History of gastrointestinal condition that might interfere with drug absorption
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of Subjects Experiencing Adverse Events as a Measure of Safety and Tolerability and MTD
Time Frame:27 months
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Response Rate
Time Frame:27 months
Safety Issue:
Description: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.
Measure:Pharmacokinetics
Time Frame:27 months
Safety Issue:
Description: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.
Measure:Median Progression-Free Survival
Time Frame:27 months
Safety Issue:
Description:To determine the median progression-free survival (PFS) and the percentage of subjects without disease progression after 2, 4, and 6 months of dosing.
Measure:Median Overall Survival
Time Frame:30 months
Safety Issue:
Description:To determine the median overall survival (OS).

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Terminated
Lead Sponsor:Kadmon Corporation, LLC

Last Updated

August 28, 2017