As no promising agents are available in treating recurrent/metastatic gastric cancer, development of novel agents, especially biological targeting agents, is essential for improving the survival of gastric cancer. 
This is a study to determine the maximum tolerated dose (MTD) and the recommended dose schedule of varlitinib in combination with paclitaxel and to further assess the safety and clinical efficacy of this combined treatment in EGFR(Epidermal growth factor receptor)/HER2(Human epidermal growth factor receptor 2) co-expressing advanced or metastatic gastric cancer after first line treatment.

Treatment

Phase 1b>
We will be started with oral varlitinib 300mg, bid, continuous dose. Initially, 3 patients per cohort are planned to be included in this part of the study, until the occurrence of first DLT(dose limited toxicity) within 4 weeks of treatment and observation. If it is well tolerated i.e. no DLT(dose limited toxicity) is observed from initial 3 patients, the RP2D(Recommended phase 2 dose) for varlitinib will be 300mg, bid, continuous schedule. If one DLT(dose limited toxicity)  is observed from initial 3 patients, 3 more patients will be added to this cohort. If 1 DLT(dose limited toxicity)  is observed from these 6 patients, the RP2D(Recommended phase 2 dose) for varlitinib will be 300mg, bid, continuous dosing schedule. If 2 or more patients (in 6 patients cohort) experience DLT(dose limited toxicity), the RP2D(Recommended phase 2 dose) for varlitinib will be 300mg, bid, intermittent dosing (day 3-6/week schedule). Paclitaxel will be administered to each patient as an intravenous infusion of 80mg/m2 every weekly (i.e. on days 1,8 and 15) for 4 weeks (i.e. 3 weeks of study treatment administration and 1 week of rest period).

Phase 2>
We will be started with oral Varlitinib will be administered based on RP2D and Paclitaxel will be administered as intravenous infusion of 80mg/m2 every weekly for 3 weeks with 1 week of rest period until the time of disease progression, development of intolerable toxicities, patient’s refusal or consent withdrawal or death.

Arm Label

Target Number of Participant

Arm Type

Arm Description

Phase 1b : Oral varlitinib will be 300mg BID, continues dose 
Paclitaxel will be administered an intraveous infusion of 80mg/m2 
every weekly ( on days 1,8 and 15) 

Phase 2 : Oral varlitinib will be administered based on RP2D.
Paclitaxel will be administered as intravenous infusion of 80mg/m2 every weekly for 3 weeks and a rest period of 1 week until the time of disease progression.

Gender

Age

Description

1. Capable of understanding and complying with the requirements of the study and have signed the Informed Consent Form (ICF).
2. Able to communicate well with the Investigator and understand and comply with the requirements of the study.
3. Has a histologically or cytologically confirmed diagnosis of advanced or metastatic gastric adenocarcinoma (systemic metastasis or locally advanced unresectable gastric cancer). A subject must have previously received 1st line chemotherapy including fluoropyrimidine and/or platinum and have showed progression.
4. Not received paclitaxel-based chemotherapy previously.
5. Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or1
6. Has a measurable or evaluable disease as determined by RECIST 1.1 criteria.
7. Able to swallow orally administered medication.
8. Life expectancy of at least 3 months
9. Has an adequate baseline organ function defined as:
- White blood cells ≥3000/mm3 and neutrophils ≥1500/mm3
- Platelets ≥100000/mm3
- Hemoglobin ≥9.0 g/dL
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3.0 × upper limit of normal (ULN) of the study site (or ≤5.0 × ULN in patients with liver metastases)
- Total bilirubin ≤2.0 × ULN
- Creatinine≤1.5 × ULN or creatinine clearance (either measured value or estimated value using the Cockcroft-Gault equation) >60ml/min.
10. Provision of an unstained, archived tumor tissue sample in a quantity sufficient to allow for central analysis of EGFR and HER2 expression status.
11. Tumours with immunohistochemistry (IHC) evidence of expression of HER1 (at level of +, or ++, or +++) and HER-2 (at level of +, or ++, or +++) using standard criteria. Also, Subjects with HER-2 IHC (at level of +, or ++, or +++) and EGFR gene amplification/ mutation by NGS are included.

1. Has multiple cancers 
2. Has a current or past history of interstitial lung disease or pulmonary fibrosis diagnosed on imaging (preferably CT) or clinical findings
3. Has brain or leptomeningeal metastases. Patients may be randomized for the study if they are asymptomatic and require no treatment.
4. History of uncontrollable or significant cardiovascular disease meeting any of the following;
- myocardial infarction within 180 days before study enrolment
- uncontrolled angina pectoris within 180 days before study enrolment
- New York Heart Association (NYHA) Class III or IV congestive heart failure
- uncontrolled hypertension despite appropriate treatment (e.g., systolic blood pressure ≥150mmHg or diastolic blood pressure ≥90 mmHg lasting 24 hours or more)
- arrhythmia requiring treatment
- baseline corrected QT interval (Fridericia’s formula) (QTcF) > 450 ms or patients with known long QT syndrome; torsade de pointes
5. Has an active systemic infection requiring treatment.
6. Has a contraindication to paclitaxel.
7. Has undergone surgery (any surgery involving general anesthesia) within 28 days before study treatment.
8. Subjects with malabsorption syndrome, diseases significantly affecting gastrointestinal function, has total gastrectomy, or difficulty in swallowing and retaining oral medications.
9. Has received radiotherapy for gastric cancer within 28 days before treatment or radiotherapy for bone metastases within 14 days before treatment
10. Positive test result for human immunodeficiency virus-1 (HIV-1) antibody, Hepatitis B surface protein (HBs) antigen and HBV titer>2000 IU/ml (10,000 copy/ml), or hepatitis C virus (HCV) antibody positive result
11. Any unresolved  Grade 2 (per CTCAE v4.0) toxicity from previous anti-cancer therapy at the time of enrollment such as neuropathy, except alopecia or anemia
12. Previously treated with varlitinib
13. Unable to comply to the study protocol
14. Have participated in a study involving another investigational drug within 21 days prior to the first dose of study drug
15. Has a history of drug hypersensitivity reactions or hypersensitivity to drugs chemically related to the study drug.

To determine the maximal tolerated dose (MTD) schedule

within 4weeks from the start of the first treatment.

To determine the recommended Phase 2 dose (RP2D) schedule of varlitinib and paclitaxel combination.

within 4weeks from the start of the first treatment.

Progression free survival

According to RECIST 1.1, It is performed up to 24weeks every 6weeks.

Adverse event

Every visit.