Brief Title
ASLAN001 in Patients With Advanced or Metastatic Cholangiocarcinoma Who Progressed on at Least 1 Line of Systemic Therapy
Official Title
A Phase 2A, Single Arm, Multicentre, Study of ASLAN001 in Patients With Advanced or Metastatic Cholangiocarcinoma Who Progressed on at Least 1 Line of Systemic Therapy
Brief Summary
This is a single arm, multicentre, Phase 2 study to assess efficacy and safety of ASLAN001 in
patients with advanced or metastatic cholangiocarcinoma who progressed on at least 1 line of
systemic therapy.
25 evaluable patients will be enrolled in the study. After evaluation of initial response in
the first 10 evaluable patients, Sponsor will make a decision on recruitment of an additional
15 evaluable patients. If no response is observed, the study will stop.
The primary objective is to assess efficacy of varlitinib (also known as ASLAN001) as
measured by ORR (based on RECIST v1.1). The secondary objectives are to (1) evaluate the
efficacy of varlitinib, as measured by DoR, PFS, OS and DCR, (2) assess ORR, DoR, PFS, DCR
and OS by tumor EGFR/HER2 status, (3) assess safety and tolerability of ASLAN001 monotherapy.
Exploratory objectives are to explore possible relationships between response to ASLAN001 and
the protein expression levels and gene mutational status of the proteins and genes via IHC
and PCR/Sequencing.
Detailed Description
Cholangiocarcinoma (CCA) is a malignancy arising from the biliary epithelium characterized by
poor prognosis and poor response to current treatments. Emerging at any portion of the
biliary tree, it includes a group of tumours with epidemiologic, morphologic, biologic, and
clinical heterogeneity. Despite recent medical advances, the long-term outcomes and
recurrence rates for CCA are poor. The 5-year survival rate following surgical resection is
11-40%. Tumour recurrence rates are as high as 50-65%, with a median time to recurrence
between 12-43 months.
In the United States, the incidence and mortality of CCA have increased over the last 30
years without clear underlying etiological reasons. The only curative therapy is surgical;
however this is not an option for many patients given the stage of the disease at
presentation and metastasis. While improvements in diagnostic modalities and neoadjuvant
chemotherapy have allowed for detection at earlier stages and greater survival rates, the
prognosis is still unfavorable. Therapies that can decrease tumour growth, improve resection
outcomes, increase survival rates, and decrease recurrence would make a great impact on the
quality of life of CCA patients and are urgently needed.
Currently, the Food and Drug Administration (FDA)-approved agents used in unresectable CCA
include gemcitabine, capecitabine, cisplatin, oxaliplatin, fluoropyrimidines (including
5-fluorouracil), or a combination of these. However, none are FDA-approved primarily for use
in CCA specifically. Gemcitabine and cisplatin combination therapy, along with
fluoropyrimidine-based or other gemcitabine-based regimens are part of the guidelines for
unresectable cancer per the National Comprehensive Cancer Network. To date, the most
effective chemotherapy regimen is administration of gemcitabine with cisplatin or
oxaliplatin, which have now become the standard of care for systemic therapy. Even this most
efficacious treatment has been found to only modestly increase overall survival (11.7 months
vs 8.3 months for patients receiving gemcitabine alone) and progression-free survival (8.4 vs
6.5 months). Standard treatment as second-line chemotherapy for CCA is unclear as there is no
significant evidence for specific therapy which indicates that further chemotherapy beyond
progression on first-line chemotherapy improves survival.
CCA involves mutations in members of the ErbB family, including EGFR and HER2 mutations. EGFR
is overexpressed in both intrahepatic and extrahepatic CCA (30.8% and 20.9%, respectively)
and is an independent prognostic factor in intrahepatic cases, per Yang et al 2014. While
this study found overexpression of HER2 exclusively in extrahepatic samples (and only in 4.5%
of these), previous studies have implicated this protein in both extra- and intrahepatic
tumours. Settakorn et al (2005) showed HER2 expression is correlated with high histological
grade in intrahepatic CCA. Kim et al. (2007) found HER2 (gene and protein levels) are
overexpressed in approximately 30% of extrahepatic CCA patients and is a prognostic factor
for survival in those with lymph node metastasis.
EGFR, HER2, and HER4 are single-pass transmembrane glycoprotein receptors, members of the
type I receptor tyrosine kinase family. Upon ligand binding, their activation induces the
homo- or heterodimerization and subsequent phosphorylation of intracellular tyrosines, which
lead to both cell proliferation and survival and therefore cancer development and
progression. EGFR and HER2 inhibitors have both demonstrated clinical efficacy in cancer
treatment. The simultaneous inhibition of both represents a new therapeutic approach for
broadly targeting different tumour types that may be more effective than selective inhibition
of each receptor.
Varlitinib, also known as ASLAN001 is a potent, orally active inhibitor of the receptor
tyrosine kinases epidermal growth factor (EGFR) and human epidermal growth factor receptors 2
and 4 (HER2, HER4). In cell-based assays, varlitinib has been shown to potently inhibit the
phosphorylation of EGFR, HER2, and HER4 in a dose-dependent manner. In cell lines
overexpressing HER2, varlitinib also inhibited the phosphorylation of the HER2 downstream
effector AKT.
ASLAN hypothesises that varlitinib will inhibit EGFR, HER2, HER4 as their mutations results
in CCA, thus in turn inhibiting the growth of cancerous cells and development/progression.
ASLAN believes that varlitinib is a compound that may be beneficial to patients with cancer
by simultaneous inhibition of these receptors.
Study Phase
Phase 2
Study Type
Interventional
Primary Outcome
Objective Response Rate (ORR)
Secondary Outcome
Progression Free Survival (PFS)
Condition
Cholangiocarcinoma
Intervention
Varlitinib
Study Arms / Comparison Groups
Treatment Arm A
Description: Varlitinib (ASLAN001) tablets
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
32
Start Date
November 16, 2015
Completion Date
October 11, 2017
Primary Completion Date
July 7, 2017
Eligibility Criteria
Inclusion Criteria:
- Patient must have advanced (unresectable) or metastatic, intra or extra hepatic
adenocarcinoma originated from bile duct. Histologically-confirmed diagnosis is
required for the first 10 evaluable patients. The following patients could be
confirmed histologically or cytologically.
- Patients must have disease progression after failing at least 1 line of systemic drug
regimen for advanced cholangiocarcinoma 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 of respective country's legal age or older at the time of written informed
consent.
- Patients with Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
- Patient must be able to understand and willing to sign the informed consent form and
donate tumour tissue (archival or fresh) for evaluation of relevant exploratory
endpoints. The first 10 evaluable patients need to have adequate archival tissues for
exploratory objectives.
- Patient with adequate organ and hematological function:
- Hematological function, as follows:
- Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L
- Platelet count ≥ 100 x 10^9/L
- Renal functions, as follows:
---Serum creatinine ≤ 1.5x ULN or eGFR > 60 mL/min/1.73m^2
- Hepatic function, as follows:
- Total bilirubin ≤ 1.5 x ULN
- AST and ALT ≤ 5 x ULN
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. (Nonmelanoma 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 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 hepatitis B
with HBV DNA > 2000 IU/ml or persistent abnormal ALT in the past 6 months, chronic
hepatitis C with persistent abnormal ALT in the past 6 months.
- Known History of drug addiction within last 1 year.
- 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.
For additional information regarding investigative sites for this trial, pls contact ASLAN
at [email protected]
Gender
All
Ages
N/A - N/A
Accepts Healthy Volunteers
No
Contacts
Please contact us for more information, ,
Location Countries
Korea, Republic of
Location Countries
Korea, Republic of
Administrative Informations
NCT ID
NCT02609958
Organization ID
ASLAN001-005
Responsible Party
Sponsor
Study Sponsor
Aslan Pharmaceuticals
Study Sponsor
Please contact us for more information, Study Director, ASLAN Pharmaceuticals Pte Ltd
Verification Date
May 2018