Description:
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.
Title
- Brief Title: A Study of HER2+ Breast Cancer Patients With Active Brain Metastases Treated With Afatinib & T-DM1 vs. T-DM1 Alone
- 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
Clinical Trial IDs
- ORG STUDY ID:
HER2BAT
- NCT ID:
NCT04158947
Conditions
- HER2-positive Breast Cancer
- Brain Metastases
Interventions
| Drug | Synonyms | Arms |
|---|
| Afatinib | BIBW 2992 | T-DM1 + Afatinib |
| T-DM1 | Trastuzumab emtansine | T-DM1 |
Purpose
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.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| T-DM1 + Afatinib | Experimental | 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 | |
| T-DM1 | Active Comparator | Trastuzumab emtansine (T-DM1) :3.6 mg/kg IV Day 1 every 21 days. | |
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.
| Maximum Eligible Age: | 75 Years |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | Female |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Safety and tolerability of T-DM1 and Afatinib to determine the recommended Phase II dose (RP2D) |
| Time Frame: | 21 days |
| Safety Issue: | |
| Description: | 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. |
Secondary Outcome Measures
| Measure: | Progression-free Survival (PFS) |
| Time Frame: | From the start of study therapy through study therapy stops, approximately 3 months |
| Safety Issue: | |
| 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 |
Details
| Phase: | Phase 2 |
| Primary Purpose: | Interventional |
| Overall Status: | Recruiting |
| Lead Sponsor: | xuexin he |
Trial Keywords
- HER2-positive Breast Cancer
- Brain metastases
- T-DM1
- Afatinib
Last Updated
May 12, 2020
