Brief Title
Varlitinib in Combination With Gemcitabine and Cisplatin for Treatment naïve Advanced or Metastatic BTC
Official Title
A Multicentre, Phase 1B/2 Study of Varlitinib in Combination With Gemcitabine and Cisplatin for Treatment naïve Advanced or Metastatic Biliary Tract Cancer.
Brief Summary
The study intends to evaluate the following objectives in patients with advanced or
metastatic biliary tract cancer who have not received systemic therapy for
advanced/metastatic disease.
Primary Objectives:
Phase 1B
- To determine the maximum tolerated dose (MTD), as determined by dose-limiting toxicities
(DLTs), and to characterise the safety profile of Varlitinib in combination with
Gemcitabine and Cisplatin.
Phase 2A
- To further evaluate the safety and tolerability of Varlitinib in combination with
Gemcitabine and Cisplatin at the recommended phase 2 dose (RP2D).
- To provide a preliminary assessment of the clinical activity of Varlitinib in
combination with Gemcitabine and Cisplatin at the RP2D as measured by Objective Response
Rate (ORR) and progression-free survival (PFS) (based on RECIST v1.1)
Phase 2B
- To compare the efficacy of Varlitinib in combination with Gemcitabine and Cisplatin to
placebo in combination with Gemcitabine and Cisplatin as measured by progression-free
survival (based on RECIST v1.1).
Detailed Description
In phase 1B part, patients will receive Varlitinib plus Gemcitabine and Cisplatin, and follow
a modified 3+3+3 study dose escalation scheme starting from Varlitinib 200 mg BID. The
primary objective of the phase 1B part is to determine the MTD of Varlitinib when given in
combination with Gemcitabine and Cisplatin, and to characterise the safety profile of the
study treatment regimen.
Based on the determined MTD and clinical information obtained from phase 1B part of the
study, the DSMB will review the safety data and other clinical data, together with the
sponsor, determine the MTD as well as the recommended phase 2 dose (RP2D). The sponsor will
make a decision when to proceed with the phase 2A part of the study.
The phase 2A part of the study is designed as a single arm expansion, enrolling a further 20
patients at the RP2D. The purpose of the phase 2A expansion study is to confirm the safety
and tolerability of the RP2D in a larger number of patients, and to provide preliminary
estimates of the clinical activity of Varlitinib in combination with Gemcitabine and
Cisplatin, prior to embarking on the larger, randomised phase 2B part of the trial.
The phase 2B part will be a two-arm, double-blinded, placebo controlled study. Patients will
be randomised into 2 arms to receive Varlitinib plus Gemcitabine and Cisplatin, or placebo
plus Gemcitabine and Cisplatin. The primary endpoint of the phase 2B part is progression-free
survival (PFS). The randomisation will be stratified by primary tumour location (gall bladder
or non-gall bladder).
Patient screening activities including informed consent and study eligibility verification
will be performed within 21 days prior to first dose of the study medication. Radiological
imaging to assess the disease status will be performed at baseline and every 6 weeks from
Cycle 1 Day 1. Blood samples will be taken during the screening phase, treatment period until
end of treatment. Patients will be required to complete safety follow-up within 28 days after
the last administration of study medication.
Study Phase
Phase 1/Phase 2
Study Type
Interventional
Primary Outcome
Phase 1B: Maximum tolerated dose (MTD) of Varlitinib
Secondary Outcome
Objective Response Rate (ORR)(Phase 1B)
Condition
Biliary Tract Cancer
Intervention
Varlitinib
Study Arms / Comparison Groups
Phase 1B
Description: Varlitinib (starting dose at 200 mg BID) Cisplatin Gemcitabine
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
204
Start Date
December 13, 2016
Completion Date
November 24, 2020
Primary Completion Date
June 16, 2020
Eligibility Criteria
Inclusion Criteria:
1. Patient of respective country's legal age or older at the time of written informed
consent.
2. Patient must be able to understand and willing to provide informed consent for
participation in the study and donation of tumour tissue (archival or fresh) for
evaluation of relevant exploratory endpoints.
3. Patient must have histologically or cytologically confirmed advanced (unresectable) or
metastatic biliary tract cancer, including intrahepatic or extrahepatic
cholangiocarcinoma, gallbladder cancer, or carcinoma of the Ampulla of Vater, with no
prior systemic therapy for advanced/metastatic disease. This includes clinical
diagnosis of biliary tract cancer with histological confirmation of adenocarcinoma.
4. For phase 1B and 2A only: Presence of radiologically measured disease with at least
one, not previously irradiated, measurable lesion according to RECIST v.1.1.
5. No evidence of clinically significant 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 or
equal to 1.5 x upper level of normal (ULN).
6. Patients with Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
7. Patient with adequate organ and haematological function prior to first dose of study
medication:
a. Haematological function, as follows: i. Absolute neutrophil count (ANC) ≥ 1.5 x
109/L ii. Platelet count ≥ 100 x 109/L iii. Haemoglobin level ≥ 10 g/dl b. Renal
functions, as follows: i. Serum creatinine ≤ 1.5x ULN or eGFR > 60 ml/min/1.73m2 c.
Hepatic function, as follows: i. Total bilirubin ≤ 1.5 x ULN ii. AST and ALT ≤ 5 x ULN
Exclusion Criteria:
1. Patients with radiation or local treatment 6 weeks prior to screening for the target
lesion(s).
2. Patients with major surgical procedures within 21 days prior to screening.
3. Patients with known brain metastases.
4. Patients with malabsorption syndrome, diseases significantly affecting
gastrointestinal function, resection of the stomach or small bowel, or difficulty in
swallowing and retaining oral medications which in the opinion of the Investigator
could jeopardize the validity of the study results. Any extent of stomach resection
will be excluded.
5. Pre-existing peripheral sensory neuropathy ≥ grade 2 according to CTCAE (v.4.03).
6. 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.
7. Patients with any history of other malignancy unless in remission for more than 1 year
prior to screening (Non-melanoma skin carcinoma and carcinoma-in-situ of uterine
cervix treated with curative intent is not exclusionary).
8. Patients with a known history of HIV, decompensated cirrhosis, HCV infection, and for
phase 1B: HBV infection with detectable HBV deoxyribonucleic acid (DNA) or abnormal
transaminase; for phase 2A & 2B: HBV infection with HBV DNA exceeding 2000 IU/mL.
9. Any history or presence of clinically significant cardiovascular, respiratory,
hepatic, renal, haematologic, gastrointestinal, endocrine, immunologic, dermatologic,
neurologic or psychiatric disease or any other condition, which, in the opinion of the
investigator, could jeopardise the safety of the patient or the validity of the study
results.
10. Patients with known history of drug addiction within last 1 year.
11. Patients who may need continuous treatment with proton pump inhibitors or strong
CYP3A4 inhibitors during the study period.
12. Female patients who are pregnant or breast-feeding.
13. 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.
14. Patients who have received immunotherapy for cancer, including but not limited to
immune checkpoint inhibitors, monoclonal antibody, cancer vaccine, and cell therapy.
15. Patient with unresolved or unstable serious toxicity (≥ CTCAE 4.03 Grade 2) from prior
administration of another investigational drug and/or prior cancer treatment.
16. Have a history of (non-infectious) pneumonitis that required steroids or current
pneumonitis, or have a history of interstitial lung disease or current interstitial
lung disease.
Gender
All
Ages
N/A - N/A
Accepts Healthy Volunteers
No
Contacts
ASLAN Pharmaceuticals ASLAN Pharmaceuticals, ,
Location Countries
Korea, Republic of
Location Countries
Korea, Republic of
Administrative Informations
NCT ID
NCT02992340
Organization ID
ASLAN001-007
Responsible Party
Sponsor
Study Sponsor
Aslan Pharmaceuticals
Study Sponsor
ASLAN Pharmaceuticals ASLAN Pharmaceuticals, Study Director, [email protected]
Verification Date
January 2020