• BTCs are heterogeneous and highly lethal malignancies includinga spectrum of invasive carcinomas arising in the gallbladder andbile ducts (intrahepatic and extrahepatic), and variably,ampullary carcinoma. These tumors are very uncommon,representing less than 1% of all cancers in the developedcountries.

• BTCs are often diagnosed at advanced stage with limitedtreatment options and the 5-year overall survival rates are 10%to 40% for cholangiocarcinomas (CCAs) and 5% to 10% forgallbladder cancers.

• Overexpression of epidermal growth factor receptor (EGFR),human epidermal growth factor receptor (HER)2, HER3, andHER4 vary from 23-57%, 4-13%, 12-23% and 59-60% of BTCs,respectively. Blockade of EGFR and HER2 by lapatinib leads togrowth inhibition of intrahepatic CCA in the pre-clinical ratmodel if administered early. Thus, co-inhibition of EGFR andHER2 represents a new therapeutic approach for BTCs.

• Varlitinib is a small molecular tyrosine kinase inhibitor of EGFR,HER2 and HER4 with potent antitumor effect in preclinical BTCmodels. Varlitinib also demonstrated tumor shrinkage responsesand durable disease stabilization in BTC patients in Phase IBstudy.

TREETOPP: A phase 2/3 study of varlitinib plus capecitabine versus placebo plus capecitabine as second-line treatment in patients with advanced or metastatic biliary tract cancers (BTCs).

Milind M. Javle, Do-Youn Oh, Masafumi Ikeda, Shukui Qin, Wei-Peng Yong, Yee Chao, Nicola McIntyre, Chih-Yi Hsieh, Lilian Chow, Alyssa Chang, Mark McHale, Bertil Lindmark

• The study is intended to recruit approximately 490 patients inaround 70 centers

• Patient enrolment is in progress, the first patient was enrolledin June 2017.

• Topline data will be available in 2019.

Acknowledgement

1. Valle J, Wasan H, Palmer DH, et al; ABC-02 Trial Investigators. CisplatinplusGemcitabine versus Gemcitabine for biliary tract cancer. N Engl J Med. 2010Apr8;362(14):1273-81.

2. Ciombor KK, Goff LW. Advances in the management of biliary tract cancers. ClinAdvHematol Oncol. 2013 Jan;11(1):28-34.

3. Ghosn M, Kourie HR, El Rassy E, eEt al. Optimum chemotherapy for themanagementof advanced biliary tract cancer. World J Gastroenterol. 2015 Apr14;21(14):4121-5.

4. Mitsunaga S, Kojima M, Ikeda M, Ochiai. Et al. Membranous expressions of ErbBfamily in biliary tract cancer [Abstract]. The 76th Annual Meeting of the JapaneseCancer Association, Japan

5. Yang X, Wang W, Wang C, et al. Characterization of EGFR family gene aberrations incholangiocarcinoma. Oncol Rep. 2014;32(2):700-8

6. Pignochino Y, Sarotto I, Peraldo-Neia C, et al. Targeting EGFR/HER2 pathwaysenhances the antiproliferative effect of gemcitabine in biliary tract and gallbladdercarcinomas. BMC Cancer. 2010;10:631.

7. Yoshikawa D, Ojima H, Iwasaki M, et al. Clinicopathological and prognostic significanceof EGFR, VEGF, and HER2 expression in cholangiocarcinoma. Br J Cancer.2008;98(2):418-25.

8. Zhang Z, Oyesanya RA, Campbell DJ, et al. Preclinical assessment of simultaneoustargeting of epidermal growth factor receptor (ErbB1) and ErbB2 as a strategy forcholangiocarcinoma therapy. Hepatology. 2010 ;52(3):975-86.

This study was sponsored by ASLAN Pharmaceuticals.

Background

References

University of Texas MD Anderson Cancer Center, Houston, TX, USA; Seoul National University Hospital, Seoul, Korea, Republic of (South); National Cancer Center Hospital East, Kashiwa, Japan; People's Liberation Army 81 Hospital, Nanjing, China; National University Cancer Institute, Singapore, Singapore; Taipei Veterans General Hospital, Taipei, Taiwan; ASLAN Pharmaceuticals, Singapore, Singapore; ASLAN Pharmaceuticals, Taipei, Taiwan

• Clinical trial identification: ClinicalTrials.gov NCT03093870 • Contact information:

• mjavle@mdanderson.org• Chih-Yi.Hsieh@aslanpharma.com

Study Design

� Failed from 1st line systemic treatment which must contain gemcitabine� Treatment will continue until disease progression or development of unacceptable

toxicity or consent withdrawal or death.

Patients with advanced BTC*

Varlitinib + Capecitabine300 mg BID,

every day1000 mg/m2 BID

d1-14, q21d

Part 1 endpoints:Primary: ORR, PFSSecondary: OS, DoR, DCR, ORR, tumor size, sparse PK, ECG parameters, safety and tolerabilityExploratory: Biomarkers

Part 2 endpoints:Primary: OSSecondary: ORR, DoR, PFS, DCR, sparse PK, safety and tolerability.Exploratory: Biomarkers

#

Placebo + CapecitabineBID,

every day1000 mg/m2 BID

d1-14, q21d

1:1 Randomization

Study Objectives

Major Criteria

Study Progress

Statistical Analysis

• Have histologically or cytologically confirmed advanced(unresectable) or metastatic BTC, including intrahepatic orextrahepatic CCA, gallbladder cancer and carcinoma ofAmpulla of Vater. . This includes clinical diagnosis of BTC withhistological confirmation of adenocarcinoma.

• A two-part randomized multicenter study: United States, Japan,South Korea, Singapore, Taiwan, China, multiple countries inEurope, and the rest of world.

• Part 1 of the study is a double-blind, randomized, placebocontrolled study to assess the efficacy and safety of varlitinib(300 mg BID) plus capecitabine (1000 mg/m2 BID for 14 days outof 21 days) in comparison with placebo plus capecitabine in BTCpatients. Eligible patients will be randomized to varlitinib orplacebo in a 1:1 ratio.

Other Information

Primary objectives:• Part 1

To assess the efficacy of varlitinib in combination withcapecitabine as measured by co-primary endpoints ofobjective response rate (ORR) and progression-free survival(PFS), both assessed by an Independent Central Review (ICR).

• Part 2To assess the efficacy of varlitinib in combination withcapecitabine as measured by overall survival (OS).

Secondary objectives:• Part 1

1. To evaluate the efficacy of varlitinib in combination withcapecitabine, as measured by duration of response (DoR),and disease control rate (DCR) as assessed by ICR, and OSand ORR as assessed by the site

2. To assess the safety and tolerability of varlitinib whencombined with capecitabine

3. To explore exposure-response relationships for varlitinib(and any relevant circulating metabolites) for measures ofefficacy, safety, and pharmacological responses

4. To examine the effects of varlitinib, when added tocapecitabine on electrocardiography (ECG) parametersincluding QTcF, QTcB, HR (heart or ventricular rate), PRand QRS

• Part 21. To evaluate the efficacy of varlitinib in combination with

capecitabine, as measured by ORR, DoR, DCR and PFS, allbased on site assessment

2. To assess the safety and tolerability of varlitinib whencombined with capecitabine

3. To explore exposure-response relationships for varlitinib(and any relevant circulating metabolites) for measures ofefficacy, safety, and pharmacological responses via sparsepharmacokinetics (PK) sampling and population PKanalyses

Exploratory objectives:• Part 1

1. To explore the role of HER family status as a predictor ofbenefit to varlitinib

2. To explore possible relationships between HER family anddownstream signaling protein and phospho-proteinexpression levels and clinical outcomes

3. To explore possible relationships between genemutational status and clinical outcomes

• Part 2If a relationship is found between biomarker(s) expressionand clinical outcomes in Part 1 of the study, the biomarker(s)could be prospectively evaluated in Part 2 of the study.

• Co-primary endpoints of Part 1, ORR, and PFS, will be analyzedusing data from an ICR of radiological data. A Hochbergprocedure will be used to control the familywise type I errorrate for Part 1 at the 10% level (one-sided).

• The primary endpoint of Part 2, OS, will be tested at the two-sided 5% significance level

Abstract Number: TPS4143

• Have received and failed one and only one prior line ofsystemic treatment for advanced or metastatic disease withradiologic evidence of disease progression. This prior line ofsystemic treatment must also contain gemcitabine

• Have received at least 6 doses of gemcitabine containingtreatment in first line (Adjuvant therapy is not regarded as 1stline therapy)

• Have radiographically measurable disease based on ResponseEvaluation Criteria in Solid Tumours (RECIST) v1.1 as assessedby ICR (For Part 1)

• Have no evidence of biliary duct obstruction, unlessobstruction is controlled by local treatment or, in whom thebiliary tree can be decompressed by endoscopic orpercutaneous stenting with subsequent reduction in bilirubinto below or equal to 1.5 × upper level of normal

• Have no known metastatic brain lesion(s), includingasymptomatic and well controlled lesion(s)

• Have no evidence of multiple (≥ 2) peritoneal metastases orascites at baseline as assessed by ICR (For Part 1). (Asciteswhich can be attributed by non-malignant causes is notexcluded.)About Varlitinib

• Part 2 of the study is a double-blind, randomized, placebocontrolled study to confirm the efficacy of varlitinib pluscapecitabine compared to capecitabine in BTC patients. Part 2will follow the same design and treatment schedule as Part 1.This part of the study will commence following review of the Part1 results.