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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)

Primary Purpose

HER2-positive Breast Cancer, Brain Metastases

Status

Recruiting

Phase

Phase 2

Locations

China

Study Type

Interventional

Intervention

Afatinib

T-DM1

About this trial

This is an interventional treatment trial for HER2-positive Breast Cancer focused on measuring HER2-positive Breast Cancer, Brain metastases, T-DM1, Afatinib

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)FemaleDoes not accept healthy volunteers

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.

Sites / Locations

Peking University International Hospital
Sun Yat-sen University Cancer Center (SYSUCC)
Kiang Wu Hospital
The Second Affiliated Hospital of Zhejiang University School of Medicine (SAHZU)Recruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

T-DM1 + Afatinib

T-DM1

Arm Description

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

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

Outcomes

Primary Outcome Measures

Safety and tolerability of T-DM1 and Afatinib to determine the recommended Phase II dose (RP2D)

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.

Objective Response Rate(ORR)

The sum of complete response (CR) rate and partial response (PR) rate by measurement of target lesions

Secondary Outcome Measures

Progression-free Survival (PFS)

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

Full Information

NCT ID

NCT04158947

First Posted

November 2, 2019

Last Updated

May 9, 2020

Sponsor

xuexin he

1. Study Identification

Unique Protocol Identification Number

NCT04158947

Brief Title

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

Acronym

HER2BAT

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

Study Type

Interventional

2. Study Status

Record Verification Date

May 2020

Overall Recruitment Status

Recruiting

Study Start Date

May 10, 2020 (Anticipated)

Primary Completion Date

December 31, 2023 (Anticipated)

Study Completion Date

March 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

xuexin he

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

5. Study Description

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

HER2-positive Breast Cancer, Brain Metastases

Keywords

HER2-positive Breast Cancer, Brain metastases, T-DM1, Afatinib

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

130 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

T-DM1 + Afatinib

Arm Type

Experimental

Arm Description

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

Arm Title

T-DM1

Arm Type

Active Comparator

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

Afatinib

Other Intervention Name(s)

BIBW 2992

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

T-DM1

Other Intervention Name(s)

Trastuzumab emtansine

Intervention Description

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.

Primary Outcome Measure Information:

Title

Safety and tolerability of T-DM1 and Afatinib to determine the recommended Phase II dose (RP2D)

Description

Time Frame

21 days

Title

Objective Response Rate(ORR)

Description

The sum of complete response (CR) rate and partial response (PR) rate by measurement of target lesions

Time Frame

From the start of study therapy through study therapy stops, approximately 3 months

Secondary Outcome Measure Information:

Title

Progression-free Survival (PFS)

Description

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

Time Frame

From the start of study therapy through study therapy stops, approximately 3 months

10. Eligibility

Sex

Female

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

Eligibility 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.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

xuexin he, MD

Phone

+86-18329139569

xuexinhe@zju.edu.cn

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

xuexin he, MD

Organizational Affiliation

The Second Affiliated Hospital of Zhejiang University School of Medicine (SAHZU)

Official's Role

Study Director

Facility Information:

Facility Name

Peking University International Hospital

City

Beijing

State/Province

Beijing

ZIP/Postal Code

102206

Country

China

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Lingling Zhang, MD

Phone

+86-010-69006666

Facility Name

Sun Yat-sen University Cancer Center (SYSUCC)

City

Guangzhou

State/Province

Guangdong

ZIP/Postal Code

510000

Country

China

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Chengcheng Guo, MD

Phone

+86-020-87343088

Facility Name

Kiang Wu Hospital

City

Macao

State/Province

Macao

ZIP/Postal Code

820002

Country

China

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Yabing Cao, MD

Phone

+86-00853-28371333

Facility Name

The Second Affiliated Hospital of Zhejiang University School of Medicine (SAHZU)

City

Hangzhou

State/Province

Zhejiang

ZIP/Postal Code

310000

Country

China

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

xuexin he, MD

Phone

+86-0571-87784795

xuexinhe@zju.edu.cn

First Name & Middle Initial & Last Name & Degree

xuexin he, MD

12. IPD Sharing Statement

Learn more about this trial

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

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