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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02154529
Recruitment Status : Terminated (Sponsor closed the study due to lack of response.)
First Posted : June 3, 2014
Results First Posted : March 24, 2022
Last Update Posted : April 27, 2022
Sponsor:
Information provided by (Responsible Party):
Kadmon Corporation, LLC

Brief Summary:
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

Condition or disease Intervention/treatment Phase
HER-2 Positive Breast Cancer Metastatic Malignant Neoplasm to Brain Drug: Tesevatinib Drug: Trastuzumab Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 17 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: A phase 1b ascending dose-finding study for establishing the maximum tolerated dose (MTD) of tesevatinib (with trastuzumab).
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1b/2a Study of the Combination of KD019 and Trastuzumab in Subjects With HER2-Positive Metastatic Breast Cancer
Study Start Date : May 2014
Actual Primary Completion Date : September 13, 2015
Actual Study Completion Date : September 13, 2015

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer
Drug Information available for: Trastuzumab

Arm Intervention/treatment
Experimental: Arm 1: Tesevatinib 150 mg PO QD + Trastuzumab 8 mg/kg IV
Tesevatinib in combination with Trastuzumab: tesevatinib 150 mg PO QD in combination with trastuzumab 8 mg/kg IV initially then 6 mg/kg IV every 3 weeks thereafter.
Drug: Tesevatinib
Other Names:
  • KD019
  • XL647

Drug: Trastuzumab
Experimental: Arm 2: Tesevatinib 250 mg PO QD + Trastuzumab 8 mg/kg IV
Tesevatinib in combination with Trastuzumab: tesevatinib 250 mg PO QD in combination with trastuzumab 8 mg/kg IV initially then 6 mg/kg IV every 3 weeks thereafter.
Drug: Tesevatinib
Other Names:
  • KD019
  • XL647

Drug: Trastuzumab
Experimental: Arm 3: Tesevatinib 300 mg PO QD + Trastuzumab 8 mg/kg IV
Tesevatinib in combination with Trastuzumab: tesevatinib 300 mg PO QD in combination with trastuzumab 8 mg/kg IV initially then 6 mg/kg IV every 3 weeks thereafter.
Drug: Tesevatinib
Other Names:
  • KD019
  • XL647

Drug: Trastuzumab
Experimental: Arm 4: Tesevatinib 350 mg PO QD + Trastuzumab 8 mg/kg IV
Tesevatinib in combination with Trastuzumab: tesevatinib 350 mg PO QD in combination with trastuzumab 8 mg/kg IV initially then 6 mg/kg IV every 3 weeks thereafter.
Drug: Tesevatinib
Other Names:
  • KD019
  • XL647

Drug: Trastuzumab



Primary Outcome Measures :
  1. Safety and Tolerability: Percentage of Subjects With Treatment Emergent Adverse Events (TEAEs) by Severity and/or Relationship to Tesevatinib [ Time Frame: Up to 8 months: 1 month (28 days) Screening + 6 months treatment + 1 month follow-up ]
    Percentage of subjects with at least 1 treatment-emergent adverse event of Grade 3 or greater or relationship with tesevatinib. TEAE grading was by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) where Grade 3 is severe and Grade 4 is life-threatening. TEAEs were considered related to study drug if the investigator assessed them as possibly related, probably related, or related.

  2. Safety and Tolerability: Percentage of Subjects With Serious Adverse Event (SAE) Related to Tesevatinib [ Time Frame: Up to 8 months: 1 month (28 days) Screening + 6 months treatment + 1 month follow-up ]
    Percentage of subjects with at least 1 serious adverse event considered related to study drug. SAEs were considered related to tesevatinib drug if the investigator assessed them as possibly related, probably related, or related.


Secondary Outcome Measures :
  1. Pharmacokinetics (PK): Mean Serum Cmax After 1 Cycle of Treatment With Tesevatinib + Trastuzumab [ Time Frame: PK samples taken pre-dose, and 1, 2, 4, 6, 8, and 24 hours post-dose on Cycle 1 Day 1 and Cycle 2 Day 1 ]
    The mean of the maximum serum concentration (Cmax) for the combination of tesevatinib and trastuzumab after 1 cycle (Cycle 2 Day 1).

  2. Pharmacokinetics: Median Serum Tmax After 1 Cycle of Treatment With Tesevatinib + Trastuzumab [ Time Frame: PK samples taken pre-dose, and 1, 2, 4, 6, 8, and 24 hours post-dose on Cycle 1 Day 1 and Cycle 2 Day 1 ]
    The median time of the maximum serum concentration (Tmax) for the combination of tesevatinib and trastuzumab after 1 cycle (Cycle 2 Day 1)

  3. Pharmacokinetics: Mean Serum AUC(0-t) (Area Under Curve) of Treatment With Tesevatinib + Trastuzumab [ Time Frame: PK samples taken pre-dose, and 1, 2, 4, 6, 8, and 24 hours post-dose on Cycle 1 Day 1 and Cycle 2 Day 1 ]
    The mean area under the concentration-time curve during the period from 0 to a given time point 't' in the tesevatinib 150 mg QD, 250 mg QD, and 300 mg QD cohorts.

  4. Pharmacokinetics: Mean AR Cmax After 1 Cycle of Treatment With Tesevatinib + Trastuzumab [ Time Frame: PK samples taken pre-dose, and 1, 2, 4, 6, 8, and 24 hours post-dose on Cycle 1 Day 1 and Cycle 2 Day 1 ]

    The mean of the arithmetic mean accumulation ratio (AR) of the maximum concentration of tesevatinib. The AR is defined as:

    Cmax for Cycle 2 divided by Cmax of Cycle 1.


  5. Pharmacokinetics: Mean AR AUC(0-24hr) After 1 Cycle of Treatment With Tesevatinib + Trastuzumab [ Time Frame: PK samples taken pre-dose, and 1, 2, 4, 6, 8, and 24 hours post-dose on Cycle 1 Day 1 and Cycle 2 Day 1 ]

    The mean of the arithmetic mean accumulation ratio (AR) of the area under the concentration-time curve from 0 to 24 hours. The AR is defined as:

    AUC(0-24hr) for Cycle 2 divided by AUC(0-24hr) for Cycle 1.




Information from the National Library of Medicine

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, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

Subjects will be included if they meet the following criteria:

  1. Female ≥ 18 years old.
  2. 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 (FISH) or silver in situ hybridization (SISH) with HER2/CEP17 ratio ≥ 2.0.
  3. Metastatic disease that has progressed on previous therapy or previous therapy was not tolerated.
  4. Subjects in the Phase 1b portion of the study and in Group 1 and Group 3 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).

    1. Previous therapies must have included trastuzumab, pertuzumab, and trastuzumab emtansine. However, 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.
    2. If the subject has ER+ breast cancer, prior therapy must have included at least 1 hormonal therapy.
    3. 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 in the opinion of the treating investigator and in the opinion of a radiation therapy or neurosurgical consultant.
    4. Subjects with brain metastases that are progressing in the brain after radiation therapy are eligible for enrollment in both Phase 1b and Group 1 of the Phase 2a, provided that there has been no further local therapy for the progressing brain metastases. These subjects must have previously received trastuzumab, pertuzumab (if received initial systemic therapy for HER2-positive breast cancer prior to June 2012 when pertuzumab was approved for initial systemic therapy of HER2-positive, metastatic breast cancer), and trastuzumab emtansine.
    5. 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.
  5. 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.
  6. At least 1 measurable breast cancer lesion that is ≥ 10 mm in one dimension (or

    ≥ 15 mm in shortest axis for lymph nodes) by spiral CT scan or by brain MRI. All brain metastases should be evaluated by T1-weighted, gadolinium-enhanced magnetic resonance imaging (MRI). Subjects with leptomeningeal metastases (Group 3) are not required to have measurable disease but must have cytologic confirmation of leptomeningeal disease.

  7. Trastuzumab therapy and hormonal therapy for breast cancer treatment started prior to study entry may be continued. However, previous chemotherapy (including antibodies other than trastuzumab) for breast cancer treatment must have been discontinued at least 14 days before the start of study treatment. Surgical procedures other than port placement must have been performed at least 14 days prior to the start of study treatment. Subjects must have recovered from the reversible effects of prior breast cancer treatments, including surgery and radiation therapy (excluding alopecia).
  8. No increase in corticosteroid dose during the week prior to screening brain MRI.
  9. 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.
  10. ECOG (Eastern Cooperative Oncology Group) status of ≤ 1 (see Appendix C). However, subjects in Group 3 (leptomeningeal metastases) require ECOG status of ≤ 2.
  11. Adequate organ and bone marrow functions as follows: (a) Serum creatinine ≤ 1.5 mg/dL; (b) total bilirubin ≤ 1.5 × upper limit of normal (ULN); (c) alanine aminotransferase and aspartate aminotransferase ≤ 3× ULN; (d) white blood cell count > 3000/mm^3; (e) absolute neutrophil count ≥ 1500/mm^3; (f) platelet count > 100,000/mm^3; and (g) hemoglobin > 8 g/dL
  12. Serum potassium and magnesium levels within normal limits (WNL).
  13. Cardiac ejection fraction WNL as measured by echocardiogram, as long as lower limit of normal (LLN) at the institution is ≥ 50%.
  14. No coexisting medical problems of sufficient severity to limit compliance with the study.
  15. Willing and able to sign written informed consent and be able to comply with the study protocol for the duration of the study.
  16. Women of childbearing potential (ie, menstruating women) must have a negative urine pregnancy test (positive urine tests are to be confirmed by serum test). Sexually active women of childbearing potential enrolled in the study must agree to use 2 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) Intrauterine Device (IUD) plus 1 barrier method; (b) on stable doses of hormonal contraception for at least 3 months (eg, oral, injectable, implant, transdermal) plus 1 barrier method; (c) 2 barrier methods where effective barrier methods are male or female condoms, diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm); or (d) a vasectomized partner.

Exclusion Criteria

A subject who meets any of the following criteria is ineligible for entry into the study:

  1. Any concurrent therapy for breast cancer other than the specified treatment in this study. Concurrent treatment with bisphosphonates or denosumab is allowed, if started prior to the start of tesevatinib administration.
  2. Cerebrospinal fluid (CSF) cytology positive for malignant cells or symptomatic leptomeningeal carcinomatosis in the Phase 1b portion of the study. Note: In Group 3 of the Phase 2a portion of the study, subjects are required to have CSF cytology positive for malignant cells.
  3. 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, including anti-arrhythmic medications within 2 weeks prior to Day 1 of treatment in the study. A stable regimen (≥ 4 weeks) of antidepressants of the SSRI(selective serotonin reuptake inhibitor) class is allowed (common SSRIs include escitalopram oxalate, citalopram, fluvoxamine, paroxetine, sertraline, and fluoxetine).
  4. Has evidence of active heart disease such as myocardial infarction within the 3 months prior to study entry; symptomatic coronary insufficiency or heart block; congestive heart failure; moderate or severe pulmonary dysfunction.
  5. History of torsades de pointes, ventricular tachycardia or fibrillation, pathologic sinus bradycardia (< 50 bpm), heart block (excluding first degree block, being PR(partial response) interval only), or congenital long QT syndrome. Subjects with a history of atrial arrhythmias should be discussed with the medical monitor.
  6. Has an active infectious process.
  7. Female subject who is pregnant or lactating.
  8. Known contraindication to MRI, such as cardiac pacemaker, shrapnel, or ocular foreign body.
  9. Has had major surgery without full recovery.
  10. Has marked prolongation of QTc interval at screening or baseline (QTc interval > 470 msec) using the Fridericia method of correction for heart rate.
  11. History of gastrointestinal (GI) condition that might interfere with drug absorption

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02154529


Locations
Layout table for location information
United States, California
UC San Diego Moores Cancer Center
La Jolla, California, United States, 92093
United States, Indiana
Indiana University Health Melvin and Bren Simon Cancer Center
Indianapolis, Indiana, United States, 46202
United States, Massachusetts
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02215
United States, New Mexico
San Juan Oncology
Farmington, New Mexico, United States, 87401
United States, New York
Laura and Isaac Perlmutter Cancer Center @ NYU Langone
New York, New York, United States, 10016
United States, Tennessee
Sarah Cannon Research Institute
Nashville, Tennessee, United States, 37203
Sponsors and Collaborators
Kadmon Corporation, LLC
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Responsible Party: Kadmon Corporation, LLC
ClinicalTrials.gov Identifier: NCT02154529    
Other Study ID Numbers: KD019-204
First Posted: June 3, 2014    Key Record Dates
Results First Posted: March 24, 2022
Last Update Posted: April 27, 2022
Last Verified: April 2022
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Trastuzumab
XL647
Antineoplastic Agents, Immunological
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action