Phase 1b of ASLAN001 (Varlitinib) in Patients With Advanced/ Metastatic Hepatocellular Carcinoma (HCC)

Study Overview
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Brief Summary
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This is a single-arm, allocation open label study. Phase 1 is a dose-finding phase in patients with advanced/ metastatic hepatocellular carcinoma (HCC) who have progressed on first line Sorafenib or Lenvatinib. The primary objective of this study will be to establish the maximal tolerable dose (MTD) of ASLAN001 (Varlitinib) in the study population The secondary objectives include: To evaluate the efficacy of ASLAN001 (Varlitinib), as measured by duration of response (DoR), progression free survival (PFS), overall survival (OS) and disease control rate (DCR) To assess the ORR, DoR, PFS, DCR and OS by tumor EGFR/HER2/HER3/HER4 status To identify tumor and host biomarkers predictive of treatment response or toxicity to ASLAN001.

Detailed Description
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There are currently no effective and approved second line treatment options for advanced/ metastatic HCC. ASLAN001 (Varlitinib) is a small molecule tyrosine kinase inhibitor against HER1 (EGFR), HER2, and HER4. In vivo studies on HER2/3 expressing HCC PDX models suggest inhibition of pERB B2/3, pERK1 and pERK 2 with treatment with ASLAN001 (Varlitinib). Dose dependent inhibition of Cdc2 and pAKT in HCC PDX models treated with ASLAN001 (Varlitinib) also suggest robust inhibition of the PI3K pathway. EGFR overexpression in HCC and matched non tumor tissues were detected in (32.5%) and (28.6%), respectively. Moreover, missense and silent mutations were detected in (39.4%) and (33.3%) of HCC tissues, respectively. Determine the maximum tolerable dose (MTD) of ASLAN001 (Varlitinib) in advanced/metastatic HCC patients. After the recommended dose is determined, the Phase Ib portion of the study will evaluate the efficacy of ASLAN001 (Varlitinib) in HCC patients who have progressed on Sorafenib.

Official Title
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Phase 1b Open Label Dose Assessment Study of ASLAN001 (Varlitinib) in Patients With Advanced/ Metastatic Hepatocellular Carcinoma (HCC) With an Expansion Cohort in HCC Patients Expressing HER3 Who Have Progressed on First Line Sorafenib or Lenvatinib

Conditions
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Advanced/ Metastatic Hepatocellular Carcinoma

Intervention / Treatment
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* Drug: ASLAN001


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient must have unresectable or metastatic HCC with Childs Pugh status A with histologic confirmation. i) Subjects with only a radiologic diagnosis of HCC may be enrolled for screening in the study but histological confirmation is mandatory prior to the start of study therapy. ii) Evaluable tumor tissue (formalin-fixed, paraffin embedded archival or recent acquisition) must have 15 unstained slides for correlative studies. If archived samples are not available, subjects must consent to a pre-treatment fresh biopsy as a condition of protocol participation. Patients must have failed Sorafenib or Lenvatinib due to disease progression or intolerance. Presence of radiographically measurable disease based on RECIST v1.1. No evidence of biliary duct obstruction, unless obstruction is controlled by local treatment or, in whom the biliary tree can be decompressed by endoscopic or percutaneous stenting with subsequent reduction in bilirubin to below 1.5 x upper level of normal (ULN). Patients age ≥ 21 years at the time of written informed consent. Patients with Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Patient must be able to understand and willing to sign the informed consent form and donate tumor tissue (archival or fresh) for evaluation of relevant exploratory endpoints. Patient with adequate organ and hematological function: a. Hematological function, as follows: i. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L ii. Platelet count ≥ 80 x 10^9/L b. Renal functions, as follows: i. Serum creatinine ≤ 1.5x ULN or eGFR > 60 mL/min/1.73m2 c. Hepatic function in addition to Childs Pugh score A: i. Total bilirubin ≤ 1.5 x ULN ii. AST and ALT ≤ 2.5 x ULN Expansion cohort Patients must agree to a post treatment biopsy HER3 expression on IHC Other inclusion criteria as above Exclusion Criteria: Patient with radiation or local treatment within the past 6 weeks for the target lesion(s). Patients with major surgical procedures within 21 days prior to study entry. Patient with brain lesion, known brain metastases (unless previously treated and well controlled for a period of at least 3 months). Patient with malabsorption syndrome, diseases significantly affecting gastrointestinal function, resection of the stomach or small bowel, or difficulty in swallowing and retaining oral medications. 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. Patients with any history of other malignancy unless in remission for more than 1 year. (Non-melanoma skin carcinoma and carcinoma-in-site of uterine cervix treated with curative intent is not exclusionary). Female patients who are pregnant or breast feeding. Patients who were previously treated with ASLAN001 (Varlitinib). Patients who have received any investigational drug (or have used an investigational device) within the last 14 days before receiving the first dose of study medication. Patient with unresolved or unstable serious toxicity ( ≥ CTCAE 4.03 Grade 2) from prior administration of another investigational drug and/or prior cancer treatment. Patients with a known history of HIV, decompensated cirrhosis, chronic active hepatitis or chronic persistent hepatitis. Patients who need continuous treatment with proton pump inhibitors during the study period. Any history or presence of clinically significant cardiovascular, respiratory, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic or psychiatric disease or any other condition which in the opinion of the Investigator could jeopardize the safety of the patient or the validity of the study results

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ASLAN001<br>A 3+3 study de-escalating dose design will be employed for dose determination. Subjects will receive treatment in 21-day cycles until disease progression, intolerable toxicities or withdrawal of consent. | Drug: ASLAN001<br>* Starting dose at 300mg BD Dose level +1: 400mg BD (which is the target dose for this study) Dose reduction of ASLAN001 in event of adverse events grade 2 and above: Dose level -1: 200mg BD Dose level -2: 100mg BD<br>* Other names: Varlitinib;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Definition of MTD (maximum tolerable dose) | The maximum tolerable dose is defined as the highest evaluated dose where < 1/6 patients experiences DLT during the DLT evaluation window. | up to 1 year since the start of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate | Defined as the proportion of patients with a response of Partial Response or Complete Response, as defined by RECIST v1.1 criteria. Measurable disease: Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the plane of measurement is to be recorded) with a minimum size of 10mm on CT scan Malignant lymph node: ≥15mm in short axis on CT scan Non-measurable disease: All other lesions, including small lesions (longest diameter <10mm or pathological lymph nodes with >10 to <15mm short axis) as well as truly non-measurable lesions | up to 1 year since the start of treatment | 
| Progression Free Survival | Defined as the time from the start of treatment until the date of objective disease progression or death (by any cause in the absence of progression). Progression is defined in accordance with RECIST v1.1 criteria. | up to 1 year since the start of treatment |