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A Study of HER2+ Breast Cancer Patients With Active Brain Metastases Treated With Afatinib & T-DM1 vs. T-DM1 Alone (HER2BAT)

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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04158947
Recruitment Status : Not yet recruiting
First Posted : November 12, 2019
Last Update Posted : November 12, 2019
Sponsor:
Information provided by (Responsible Party):
xuexin he, Second Affiliated Hospital, School of Medicine, Zhejiang University

Brief Summary:

This study is being done for the following reasons:

The study has two parts. The purpose of the first part (Phase I) of the study is to find out the highest dose of Afatinib that can be given safely with T-DM1.

The purpose of the second part of the study (Phase II) is to find out whether the dose of Afatinib with T-DM1 determined in Phase I will keep breast cancer from getting worse for a period of time.


Condition or disease Intervention/treatment Phase
HER2-positive Breast Cancer Brain Metastases Drug: Afatinib Drug: T-DM1 Phase 2

Detailed Description:
This is a prospective, randomized, 2-arm, multicenter study to compare the safety and efficiency of T-DM1 + Afatinib versus T-DM1 in HER2-positive breast cancer patients with active refractory brain metastases. This study will be divided into two phases. The purpose of Phase I is to find out the highest dose of Afatinib that can be given safely with T-DM1. 3 ~ 24 eligible subjects will be enrolled in the study. The purpose of Phase II is to find out whether the dose of Afatinib with T-DM1 determined in Phase I will keep subjects from getting worse for a period of time. The estimated ORR is 17.9 percent in the control group, hypothesis Afatinib can improve the prognosis of subjects, so objective respond rate (ORR) of experimental group is increased by 30 percent, with alpha = 0.025 (unilateral), beta = 0.1. The ratio of the experimental group and control group is 1:1, assuming a 5 percent loss rate. As a result, calculating by PASS 11 software, approximately 106 subjects will be enrolled, with 53 cases in the experimental group, and 53 cases in the control group.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 130 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized Study of HER2+ Breast Cancer Patients With Active Refractory Brain Metastases Treated With Afatinib in Combination With T-DM1 vs. T-DM1 Alone
Estimated Study Start Date : January 1, 2020
Estimated Primary Completion Date : December 31, 2023
Estimated Study Completion Date : March 31, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: T-DM1 + Afatinib

Trastuzumab emtansine (T-DM1) : 3.6 mg/kg IV Day 1 every 21 days.

Afatinib: the highest dose of Afatinib with T-DM1 found in Phase I, po every day

Drug: Afatinib

Dose-escalation Phase (Phase I) - Afatinib Dose-escalation will proceed on the basis of dose limiting toxicity (DLT) during Cycle 1 starting at 20 mg/day.

Dose level 1: 20 mg/day; Dose level 2: 30 mg/day; Dose level 3: 40 mg/day; Dose level 4: 50 mg/day.

Dose-evaluation Phase (Phase II) - Patients will receive the highest dose of Afatinib with T-DM1 found in Phase I as study therapy

Other Name: BIBW 2992

Drug: T-DM1

Dose-escalation Phase (Phase I) - Trastuzumab emtansine (T-DM1) will be given at 3.6 mg/kg IV Day 1 every 21 days.

Dose-evaluation Phase (Phase II) - Trastuzumab emtansine (T-DM1) will be given at 3.6 mg/kg IV Day 1 every 21 days.

Other Name: Trastuzumab emtansine

Active Comparator: T-DM1
Trastuzumab emtansine (T-DM1) :3.6 mg/kg IV Day 1 every 21 days.
Drug: T-DM1

Dose-escalation Phase (Phase I) - Trastuzumab emtansine (T-DM1) will be given at 3.6 mg/kg IV Day 1 every 21 days.

Dose-evaluation Phase (Phase II) - Trastuzumab emtansine (T-DM1) will be given at 3.6 mg/kg IV Day 1 every 21 days.

Other Name: Trastuzumab emtansine




Primary Outcome Measures :
  1. Safety and tolerability of T-DM1 and Afatinib to determine the recommended Phase II dose (RP2D) [ Time Frame: 21 days ]
    If 1 of 3 patients in this cohort experiences a dose limiting toxicity (DLT), 3 more patients will be added at the same dose level. If 0 of 3 initial patients or 1 of 6 patients in an expanded cohort experiences a DLT, the dose for the next cohort will be escalated to dose level 2; otherwise, the combination will be considered too toxic.

  2. Objective Response Rate(ORR) [ Time Frame: From the start of study therapy through study therapy stops, approximately 3 months ]
    The sum of complete response (CR) rate and partial response (PR) rate by measurement of target lesions


Secondary Outcome Measures :
  1. Progression-free Survival (PFS) [ Time Frame: From the start of study therapy through study therapy stops, approximately 3 months ]
    PFS is defined as time from randomization to disease progression or death, whichever occurs first, including central nervous system lesions and external central nervous system lesions



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 to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients provided written informed consent
  • Women aged 18-75 years old
  • Histologically or cytologically confirmed HER2-positive (IHC 3+ or ISH+) breast cancer
  • Patients with HER2 positive breast cancer with a documented central nervous system (CNS) recurrence/progression (by imaging) during or after a HER2 inhibitor (Trastuzumab and/or Lapatinib, Pyrotinib, Tucatinib) based therapy
  • At least one measurable and progressive lesion in the CNS (≥10 mm on T1-weighted, gadolinium-enhanced MRI)
  • Previous treatment with HER2 inhibitors to be discontinued prior to first study treatment administration (at least 14 days for trastuzumab and other antibodies, at least 7 days for lapatinib)
  • Previous chemotherapy and hormonal therapy (adjuvant and metastatic regimens) allowed, but chemotherapy must have been discontinued at least 14 days and hormonal therapy at least 7 days prior to first study treatment administration
  • Prior surgery, whole brain radiotherapy or stereotactic radiosurgery allowed provided that there is unequivocal evidence of one or more new and/or progressive brain metastases after completion of whole brain radiotherapy or stereotactic radiosurgery
  • Previous radiotherapy allowed, but radiotherapy must have been discontinued at least 14 days prior to first study treatment administration
  • Patients must have recovered to baseline condition or to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade = 1 from any acute CTCAE v. 5.0 grade =2 side effects of previous treatments
  • Without infection of human immunodeficiency virus (HIV) on central laboratory assay results prior to randomization
  • Alanine aminotransferase (ALT) </= 2.5 × the upper limit of normal (ULN), Aspartate aminotransferase (AST) </= 2.5 × ULN prior to randomization
  • Total bilirubin (TBIL) </= 1.25 × ULN
  • Alkaline phosphatase (ALK) </= 2.5 × ULN
  • Gamma glutamyl transpeptidase (GGT) </= 2.5 × ULN
  • Albumin >/= 30g/L
  • Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 2
  • A life expectancy of at least 1 month
  • Women of child-bearing age should take effective contraceptive measures
  • Serum total bilirubin (TBil) </= 1.5 × ULN
  • Serum creatinine (Scr) </= 1.5 × ULN
  • WBC >/= 3×109/L, Blood neutrophil count >/= 1×109/L, Platelet count >/= 100×109/L, HB >/= 9 g/dL

Exclusion Criteria:

  • Lack of histological or cytological confirmation of HER2-positive (IHC 3+ or ISH-positive) breast cancer
  • Suffering cerebral hernia
  • Only meningeal metastasis
  • Earlier exposure to doxorubicin or pirarubicin at a dosage of more than 360 mg/m2
  • Earlier exposure to epirubicin at a dosage of more than 900 mg/m2
  • Prior treatment with HER2-tyrosine kinase inhibitor other than Lapatinib, Neratinib, Pyrotinib and Tucatinib, such as Afatinib, Erlotinib, Icotinib, Gefitinib and Osimertinib
  • Treatment with trastuzumab emtansine within 6 months
  • Any other current malignancy or malignancy diagnosed within the past five years (other than carcinoma in situ or stage Ia carcinoma of the cervix, skin basal cell carcinoma and papillary thyroid carcinoma at early stage)
  • Active infection with human immunodeficiency virus (HIV) prior to first study treatment administration.
  • History of participating any other clinical trials within 30 days prior to randomization
  • Known hypersensitivity (Grade 3 or 4) to TDM1 or Afatinib or the excipients of any of the trial drugs
  • Significant chronic or recent acute gastrointestinal disorders with diarrhoea as a major symptom e.g. Crohn's disease, malabsorption or Common Terminology Criteria (CTC) grade =2 diarrhoea of any aetiology
  • Pregnancy or lactation
  • Current severe systemic disease (for example, clinically significant cardiovascular, pulmonary, or renal disease)
  • Legal incompetence or limitation.
  • Considered unable to complete the study or sign the informed consent due to a medical or mental disorder by the investigator.

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): NCT04158947


Contacts
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Contact: xuexin he, MD +86-18329139569 xuexinhe@zju.edu.cn

Locations
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China, Beijing
Peking University International Hospital
Beijing, Beijing, China, 102206
Contact: Lingling Zhang, MD    +86-010-69006666      
China, Guangdong
Sun Yat-sen University Cancer Center (SYSUCC)
Guangzhou, Guangdong, China, 510000
Contact: Chengcheng Guo, MD    +86-020-87343088      
China, Macao
Kiang Wu Hospital
Macao, Macao, China, 820002
Contact: Yabing Cao, MD    +86-00853-28371333      
China, Zhejiang
The Second Affiliated Hospital of Zhejiang University School of Medicine (SAHZU)
Hangzhou, Zhejiang, China, 310000
Contact: xuexin he, MD    +86-0571-87784795    xuexinhe@zju.edu.cn   
Principal Investigator: xuexin he, MD         
Sponsors and Collaborators
xuexin he
Investigators
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Study Director: xuexin he, MD The Second Affiliated Hospital of Zhejiang University School of Medicine (SAHZU)

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Responsible Party: xuexin he, MD, Associate chief physician, Second Affiliated Hospital, School of Medicine, Zhejiang University
ClinicalTrials.gov Identifier: NCT04158947    
Other Study ID Numbers: HER2BAT
First Posted: November 12, 2019    Key Record Dates
Last Update Posted: November 12, 2019
Last Verified: November 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by xuexin he, Second Affiliated Hospital, School of Medicine, Zhejiang University:
HER2-positive Breast Cancer
Brain metastases
T-DM1
Afatinib
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasm Metastasis
Neoplasms, Second Primary
Brain Neoplasms
Neoplasms by Site
Neoplasms
Central Nervous System Neoplasms
Nervous System Neoplasms
Central Nervous System Diseases
Breast Diseases
Skin Diseases
Neoplastic Processes
Pathologic Processes
Brain Diseases
Nervous System Diseases
Trastuzumab
Ado-trastuzumab emtansine
Afatinib
Maytansine
Antineoplastic Agents, Immunological
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Phytogenic
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators