Phase II Study to Assess the Efficacy of ASLAN001 Plus Capecitabine in CNS Metastases for HER2+ Breast Cancer

A Phase II Single Arm Trial to Assess the Efficacy of ASLAN001 Plus Capecitabine in Previously Irradiated, Progressing Central Nervous System (CNS) Metastases for HER2 Positive Breast Cancer Patients

This study is designed to study the efficacy of ASLAN 001 plus capecitabine for previously irradiated, progressing CNS metastases for HER2+ breast cancer patients.

Brain metastasis in breast cancer (BMBC) has very poor prognosis. The focus for this group of patients is on palliation as well as therapeutics that offer meaningful clinical benefits. Treatment options generally involve local control using either whole brain radiotherapy (WBRT) or neurosurgery/radiosurgery or combination of both. Subsequent to local treatment, systemic control can be re-initiated via systemic chemotherapy/targeted therapies or trial participation.

This is a single arm, single center, phase 2 study. A total of 29 eligible HER2 positive breast cancer patients with irradiated, progressing brain metastasis will be enrolled to receive ASLAN001 400 mg orally BID with capecitabine 1000 mg/m2 orally BID for days 1-14 of a 21-day cycle. Treatment will continue until disease progression or unacceptable toxicity.

Baseline brain imaging using either magnetic resonance imaging (MRI) or computed tomography (CT) scans will be performed; non-brain imaging will also be performed in the same settings. Radiological imaging to assess disease status will be performed at baseline and every 2 cycles until disease progression.

Inclusion Criteria:

1. Patients with documented histological confirmation of breast cancer with HER-2 overexpression or gene amplification (immunohistochemistry 3+ or immunohistochemistry 2+ with fluorescent / chromogenic / silver in situ hybridization +) prior to study entry.

2. Patients with HER-2-positive breast cancer with brain metastasis (BMBC) who received either radiosurgery and/or WBRT and progressing in CNS.

3. Presence of more than one radiographically measurable brain metastasis.

4. Patients must complete radiation treatment with either whole brain radiotherapy (WBRT) and/or radiosurgery at least 30 days 30 days prior to study entry. (No washout period for other antineoplastic treatment)

5. Patients must be of legal age of more than 21 years old at the time of written informed consent.

6. Patients of childbearing potential to use adequate contraception prior to, during the study, and 12 weeks after the last dose of therapy.

7. Patients able to understand and willing to sign the informed consent form.

8. Patients with Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.

9. Patients with acceptable organ and hematological function:

   1. Hematological function:

      • Absolute neutrophil count ≥1.5 × 10**9/L.
      • Platelet count ≥100 × 10**9/L.
      • Hemoglobin ≥9 g/L.

   2. Renal functions:

      - Serum creatinine ≤1.5 × upper limit of normal (ULN).

   3. Hepatic function:

      • Total bilirubin ≤1.5 × ULN.
      • AST and ALT ≤2.5 × ULN (≤5 × ULN if liver metastases are present).

Exclusion Criteria:

1. Patients with malabsorption syndrome, diseases significantly affecting gastrointestinal function, resection of the stomach or small bowel, or difficulty in swallowing and retaining oral medications.
2. Patients with an uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, unstable angina pectoris, cardiac arrhythmia, diabetes, hypertension, or psychiatric illness/social situations that would limit compliance with study requirements.
3. Patients with any history of other malignancy unless in remission for more than 1 year. (Nonmelanoma skin carcinoma and carcinoma-in-situ of uterine cervix treated with curative intent is not exclusionary).
4. Patients who are pregnant or breast-feeding.
5. Patients who were previously treated with ASLAN001 and/or with lapatinib and/or with capecitabine.
6. Patient with known active infection on hepatitis B and hepatitis C and dihydropyrimidine dehydrogenase (DPD) deficiency. (Screening tests not required.)
7. Patients with non-measurable disease alone (i.e. leptomeningeal disease)
8. Patients who need continuous treatment with proton pump inhibitors during the study period.