Clinical trial NCT03130790: Varlitinib in Combination With mFOLFOX6 for Advanced or Metastatic Gastric Cancer (First Line)
Official title: A Two-Part Phase 2/ 3 Multicentre, Double-Blind, Randomized, Placebo Controlled Study of Varlitinib Plus mFOLFOX6 Verses Placebo Plus mFOLFOX6 In Subjects With HER1/ HER2 Co Expressing Advanced or Metastatic Gastric Cancer Without Prior Exposure to Systemic Therapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Gastric Cancer
Lead sponsor: ASLAN Pharmaceuticals
Sponsor class: OTHER
First posted: 2017-04-26
Enrollment: 52
Sex: ALL
Minimum age (years): 21
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This protocol for Varlitinib is developed for the treatment of Gastric Cancer. Varlitinib (also known as ASLAN001) is a small-molecule, adenosine triphosphate competitive inhibitor of the tyrosine kinases - epidermal growth factor receptor (EGFR), human epidermal growth factor receptor (HER)2, and HER4. Varlitinib may be beneficial to subjects with cancer by simultaneous inhibition of these receptors. The purpose of this study is to determine the safety and efficacy of Varlitinib in combination with mFOLFOX6 for the treatment of Gastric Cancer. Treatment groups are Varlitinib+mFOLFOX6 and Placebo+mFOLFOX6.

Detailed description: Phase 2 is planned to recruit approximately 50 or more eligible subjects in order to obtain data from 40 evaluable patients. Anticipated completion date in Dec 2018. Recruitment completed.

Phase 3 is planned to recruit 350 patients. Anticipated completion date in Dec 2022. Not yet recruiting.

Eligibility criteria: Inclusion Criteria - Phase 2 Part

1. Subjects of respective country's legal age or older at the time of written informed consent.
2. Subjects with histologically confirmed inoperable locally advanced, recurrent, or metastatic adenocarcinoma of the stomach or GEJ cancers may include Siewert Class I, II, or III types.
3. Mandatory provision of an unstained, archived tumor tissue sample in a quantity sufficient to allow for local lab analysis of HER1 and HER2 expression status. If archived tumor tissue is not available, subject must agree to undergo fresh core biopsy to obtain adequate tumor tissue
4. Subjects with tumors with IHC evidence of expression of HER1 (at level of + or ++ or +++) and HER-2 (at level of +, or ++) using standard criteria in the local lab. Subjects with HER-2 over expression at level of +++ determined by IHC and subject confirmed HER2 2+ by IHC with HER2 gene amplification confirmed by FISH but has contradiction to trastuzumab\*.

   \*For details of contraindication related to trastuzumab, refer to package insert or US treatment guideline.
5. Have radiographically measurable disease as defined by RECIST v1.1
6. Subjects with Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
7. Estimated life expectancy of more than 4 months
8. Able to swallow and retain oral medication
9. Subject with adequate organ and hematological function:

   d) Hematological function, as follows: i. Absolute neutrophil count (ANC) ≥1.5 x 109/L ii. Platelet count ≥ 100 x 109/L iii. HgB≥9 g/dL (packed red cell blood transfusions are not allowed within one week prior to baseline hematology profile).

   e) Renal functions, as follows: i. Serum creatinine ≤1.5x upper limit of normal (ULN) or estimated glomerular filtration rate (eGFR)\> 60 mL/min/1.73m2 f) Hepatic function, as follows: i. Total bilirubin ≤1.5 x ULN ii. AST and ALT ≤2.5 x ULN (or ≤5 x ULN in subjects with liver metastasis) iii. Albumin ≥25 g/L
10. Negative serum human chorionic gonadotropin (HCG)/ or urine pregnancy test within 7 days prior to randomization for premenopausal women of reproductive capacity and for women 12 months after menopause
11. Willingness to use highly effective birth control method (failure rate \<1%) while on study.

Inclusion Criteria - Phase 3 Part

1. Subjects of respective country's legal age or older at the time of written informed consent.
2. Subjects with histologically confirmed inoperable locally advanced, recurrent, or metastatic adenocarcinoma of the stomach or GEJ cancers may include Siewert Class I, II, or III types.
3. Mandatory provision of an unstained, archived tumor tissue sample in a quantity sufficient to allow for local lab analysis of HER1 and HER2 expression status. If archived tumor tissue is not available, subject must agree to undergo fresh core biopsy to obtain adequate tumor tissue.
4. Subjects with tumors with IHC evidence of expression of HER1 (at level of + or ++ or +++) and HER-2 (at level of +, or ++) using standard criteria in the local lab. Subjects with HER-2 over expression at level of +++ determined by IHC and subject confirmed HER2 2+ by IHC with HER2 gene amplification confirmed by FISH but has contradiction to trastuzumab\*.
5. Note: \*For details of contraindication related to trastuzumab, refer to package insert or US treatment guideline
6. Subjects with ECOG performance status of 0 to 1
7. Able to swallow and retain oral medication
8. Subject with adequate organ and hematological function:

   a) Hematological function, as follows: i. Absolute neutrophil count (ANC) ≥1.5 x 109/L ii. Platelet count ≥100 x 109/L iii. HgB≥9 g/dL (packed red cell blood transfusions are not allowed within one week prior to baseline hematology profile).

   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 ≤2.5 x ULN (or ≤5 x ULN in subjects with liver metastasis) iii. Albumin ≥25 g/L
9. Negative serum human chorionic gonadotropin (HCG)/ or urine pregnancy test within 7 days prior to randomization for premenopausal women of reproductive capacity and for women 12 months after menopause
10. Willingness to use highly effective birth control method (failure rate \<1%) while on study.

Exclusion Criteria:

1. Subject with HER-2 over expression at level of +++ determined by IHC or subject confirmed HER2 2+ by IHC with HER2 gene amplification confirmed by Fluorescence in situ hybridization (FISH) in the central lab.
2. Prior systemic anti-cancer treatment for inoperable locally advanced, recurrent, or metastatic adenocarcinoma of the stomach or GEJ. However, previous neo adjuvant chemotherapy is allowed if subject has progression of disease more than 6 months after neoadjuvant treatment.
3. Subjects have undergone major surgery within 28 days prior to randomization
4. Subject with brain lesion, known brain metastases (unless previously treated and well controlled for a period of at least 4weeks).
5. Subject with malabsorption syndrome, diseases significantly affecting gastrointestinal function, extensive resection of the stomach or small bowel, or difficulty in swallowing and retaining oral medications.
6. Subjects with an uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, New York heart Association class III or IV congestive heart failure, unstable angina pectoris, clinically significant cardiac arrhythmia, diabetes, hypertension, or psychiatric illness/social situations that would limit compliance with study requirements.
7. Subjects 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).
8. Female subjects who are pregnant or breast feeding.
9. Subjects who were previously treated with varlitinib.
10. Subjects who took other investigational drugs and/or used investigational medical devices or have undergone major surgery within 28 days before initiating varlitinib therapy.
11. Are currently on or have received anti-cancer therapy, radiation or local treatment within the past 28 days
12. Subject with unresolved or unstable serious toxicity (≥ CTCAE 4.03 Grade 2) from prior administration of another investigational drug and/or prior cancer treatment(excluding hair loss)
13. Subjects with a known history of human immunodeficiency virus (HIV), decompensated cirrhosis, hepatitis B infection with hepatitis B virus DNA exceeding 2000 IU/mL or hepatitis C (treatment naïve or after treatment without sustained virologic response).
14. Known history of drug addiction within the past 1 year.
15. Subjects who need continuous treatment with proton pump inhibitors during the study period.
16. 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 subject or the validity of the study results.

Primary outcomes:
measure: Percentage change from baseline in tumor size at Week 12 - Phase 2 part
timeFrame: At baseline and every 6 weeks for 24 weeks, after which reduced to once every 12 weeks until progression (up to approximately 3 months)
measure: Overall Survival (OS) - Phase 3 part
timeFrame: When 247 OS events have occured. 247 OS is estimated to occur after approximately 45 months
Secondary outcomes:
measure: Objective Response Rate (ORR) - Phase 2 part
timeFrame: At baseline and every 6 weeks for 24 weeks, after which reduced to once every 12 weeks until progression (up to approximately 12 months)
measure: Progression-free survival (PFS) - Phase 2 part
timeFrame: At baseline and every 6 weeks for 24 weeks, after which reduced to once every 12 weeks until progression (up to approximately 12 months)
measure: Time to response (TTR) - Phase 2 part
timeFrame: At baseline and every 6 weeks for 24 weeks, after which reduced to once every 12 weeks until progression (up to approximately 12 months)
measure: Duration of Response (DoR) - Phase 2 part
timeFrame: At baseline and every 6 weeks for 24 weeks, after which reduced to once every 12 weeks until progression (up to approximately 12 months)
measure: Disease Control Rate (DCR) - Phase 2 part
timeFrame: At baseline and every 6 weeks for 24 weeks, after which reduced to once every 12 weeks until progression (up to approximately 12 months)
measure: Overall Survival (OS) - Phase 2 part
timeFrame: From randomization to end of study (Last subject last visit (LSLV)) (up to approximately 24 months)
measure: Pharmacokinetic: area under the plasma concentration time curve (AUC) from 0 to 6 hours (AUC0-6) - Phase 2 part
timeFrame: Pharmacokinetic measurements will be taken on pre-dose, 1, 3, and 6 hours post dose on Day 1 and on Day 15
measure: Pharmacokinetic: maximum observed plasma concentration (Cmax) - Phase 2 part
timeFrame: Pharmacokinetic measurements will be taken on pre-dose, 1, 3, and 6 hours post dose on Day 1 and on Day 15
measure: Pharmacokinetic: time to Cmax (tmax) - Phase 2 part
timeFrame: Pharmacokinetic measurements will be taken on pre-dose, 1, 3, and 6 hours post dose on Day 1 and on Day 15
measure: Pharmacokinetic: accumulation ratio for AUC (Rac AUC0-6) - Phase 2 part
timeFrame: Pharmacokinetic measurements will be taken on pre-dose, 1, 3, and 6 hours post dose on Day 1 and on Day 15
measure: Pharmacokinetic: accumulation ratio for Cmax (Rac Cmax) - Phase 2 part
timeFrame: Pharmacokinetic measurements will be taken on pre-dose, 1, 3, and 6 hours post dose on Day 1 and on Day 15
measure: Objective Response Rate (ORR) - Phase 3 part
timeFrame: When 247 Overall Survival (OS) events have occured (up to approximately 45 months)
measure: Progression-free survival (PFS) - Phase 3 part
timeFrame: When 247 Overall Survival (OS) events have occured (up to approximately 45 months)
measure: Time to response (TTR) - Phase 3 part
timeFrame: When 247 Overall Survival (OS) events have occured (up to approximately 45 months)
measure: Duration of Response (DoR) - Phase 3 part
timeFrame: When 247 Overall Survival (OS) events have occured (up to approximately 45 months)
measure: Disease Control Rate (DCR) - Phase 3 part
timeFrame: When 247 Overall Survival (OS) events have occured (up to approximately 45 months)
measure: Incidence of Adverse Events (AEs) - Phase 3 part
timeFrame: When 247 Overall Survival (OS) events have occured (up to approximately 45 months)
measure: Health-related quality of life (QoL) - Phase 3 part
timeFrame: When 247 OS events have occured. 247 OS is estimated to occur after approximately 45 months
measure: European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Core 30 items (EORTC QLQ-C30) measuring patients general cancer symptoms and functioning - Phase 3 part
timeFrame: When 247 OS events have occured. 247 OS is estimated to occur after approximately 45 months
measure: European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Gastric Cancer 22 items (EORTC QLQ STO22) measuring patients general cancer symptoms and functioning - Phase 3 part
timeFrame: When 247 OS events have occured. 247 OS is estimated to occur after approximately 45 months
Other outcomes:
Locations:
city: Tallinn
country: Estonia
facility: 2 Sites
city: Hong Kong
country: Hong Kong
facility: 1 Site
city: Daegu
country: Korea, Republic of
facility: 2 Sites
city: Incheon
country: Korea, Republic of
facility: 1 Site
city: Jeongnam
country: Korea, Republic of
facility: 1 Site
city: Seoul
country: Korea, Republic of
facility: 11 Sites
city: Suwon
country: Korea, Republic of
facility: 2 Sites
city: Kaunas
country: Lithuania
facility: 2 Sites
city: Vilnius
country: Lithuania
facility: 1 Site
city: Kuala Lumpur
country: Malaysia
facility: 2 Sites
city: Singapore
country: Singapore
facility: 1 Site
city: Kaohsiung
country: Taiwan
facility: 1 Site
city: Taichung
country: Taiwan
facility: 1 Site
city: Taipei
country: Taiwan
facility: 1 Site
city: Khon Kaen
country: Thailand
facility: 1 Site
city: Pathum Thani
country: Thailand
facility: 1 Site
Study officials:
References: