ASLAN001 in Patients With Advanced or Metastatic Cholangiocarcinoma Who Progressed on at Least 1 Line of Systemic Therapy

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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