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

Sponsor

xuexin he (Other)

Overall Status

Recruiting

CT.gov ID

NCT04158947

Collaborator

(none)

130

Enrollment

Locations

Arms

46.7

Anticipated Duration (Months)

32.5

Patients Per Site

0.7

Patients Per Site Per Month

Study Details

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.

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.

Study Design

Study Type:

Interventional

Anticipated 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

Anticipated Study Start Date :

May 10, 2020

Anticipated Primary Completion Date :

Dec 31, 2023

Anticipated Study Completion Date :

Mar 31, 2024

Arms and Interventions

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 Names: 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 Names: 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 Names: Trastuzumab emtansine

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 Names:

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 Names:

Trastuzumab emtansine

Active Comparator: T-DM1

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

Drug: T-DM1

Other Names:

Trastuzumab emtansine

Outcome Measures

Primary Outcome Measures

Safety and tolerability of T-DM1 and Afatinib to determine the recommended Phase II dose (RP2D) [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.
Objective Response Rate(ORR) [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

Progression-free Survival (PFS) [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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

Female

Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Peking University International Hospital	Beijing	Beijing	China	102206
2	Sun Yat-sen University Cancer Center (SYSUCC)	Guangzhou	Guangdong	China	510000
3	Kiang Wu Hospital	Macao	Macao	China	820002
4	The Second Affiliated Hospital of Zhejiang University School of Medicine (SAHZU)	Hangzhou	Zhejiang	China	310000