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CTRI Number  CTRI/2019/11/021955 [Registered on: 11/11/2019] Trial Registered Prospectively
Last Modified On: 07/11/2019
Post Graduate Thesis  No 
Type of Trial  Interventional 
Type of Study   Drug 
Study Design  Other 
Public Title of Study   Trastuzumab in advanced biliary tract cancers 
Scientific Title of Study   Trastuzumab in HER2 positive Advanced Biliary tract cancers - single arm prospective phase II clinical trial  
Trial Acronym  (TAB trial) 
Secondary IDs if Any  
Secondary ID  Identifier 
NIL  NIL 
 
Details of Principal Investigator or overall Trial Coordinator (multi-center study)  
Name  Vikas Ostwal  
Designation  Associate professor and Medical Oncologist  
Affiliation  Tata Memorial Hospital  
Address  Department of Medical Oncology Tata Memorial Hospital 11th Floor Room no 1102 Dr Ernest Borges Marg parel Mumbai

Mumbai
MAHARASHTRA
400012
India 
Phone  9702288801  
Fax    
Email  dr.vikas.ostwal@gmail.com  
 
Details of Contact Person
Scientific Query
 
Name  Vikas Ostwal  
Designation  Associate professor and Medical Oncologist  
Affiliation  Tata Memorial Hospital  
Address  Department of Medical Oncology Tata Memorial Hospital 11th Floor Room no 1102 Dr Ernest Borges Marg parel Mumbai

Mumbai
MAHARASHTRA
400012
India 
Phone  9702288801  
Fax    
Email  dr.vikas.ostwal@gmail.com  
 
Details of Contact Person
Public Query
 
Name  Vikas Ostwal  
Designation  Associate professor and Medical Oncologist  
Affiliation  Tata Memorial Hospital  
Address  Department of Medical Oncology Tata Memorial Hospital 11th Floor Room no 1102 Dr Ernest Borges Marg parel Mumbai

Mumbai
MAHARASHTRA
400012
India 
Phone  9702288801  
Fax    
Email  dr.vikas.ostwal@gmail.com  
 
Source of Monetary or Material Support  
Intramural and extramural grant ( educational grant from Dr reddy s limited 302 Sameer Arcade, 3rd Floor, Thane West, Thane - 400601, Jambli Naka  
 
Primary Sponsor  
Name  Tata Memorial Hospital  
Address  Dr Ernest Borges Marg Parel Mumbai 400012 
Type of Sponsor  Research institution and hospital 
 
Details of Secondary Sponsor  
Name  Address 
NIL  NIL 
 
Countries of Recruitment     India  
Sites of Study  
No of Sites = 1  
Name of Principal Investigator  Name of Site  Site Address  Phone/Fax/Email 
vikas ostwal   Tata Memorial Hospital   Department of Medical Oncology 11th Floor Room number 1102 Homibhaba building Dr Ernest Borges Marg Parel Mumbai 400012
Mumbai
MAHARASHTRA 
9702288801

dr.vikas.ostwal@gmail.com 
 
Details of Ethics Committee  
No of Ethics Committees= 1  
Name of Committee  Approval Status 
Institutional Ethics Commitee   Approved 
 
Regulatory Clearance Status from DCGI  
Status 
Not Applicable 
 
Health Condition / Problems Studied  
Health Type  Condition 
Patients  (1) ICD-10 Condition: C249||Malignant neoplasm of biliary tract, unspecified,  
 
Intervention / Comparator Agent  
Type  Name  Details 
Intervention  gemcitabin plus cisplatin plus Trastuzumab  -3 weekly gemcitabine (1000 mg/m2 IV on day 1 and day 8 q 3 weekly) plus cisplatin (25 mg/m2 IV on day 1 and day 8 q 3 weekly) plus -3 weekly Trastuzumab Initial dose of 8 mg/kg as a 90-minute intravenous infusion followed by subsequent doses of 6 mg/kg as an intravenous infusion over 30–90 minutes every three weeks  
Comparator Agent  None  None open label  
 
Inclusion Criteria  
Age From  18.00 Year(s)
Age To  75.00 Year(s)
Gender  Both 
Details  histologically confirmed adenocarcinoma of the biliary tract, with the following specifications

Biliary tract cancers including gallbladder cancer, intrahepatic cholangiocarcinoma, perihilar cholangiocarcinoma HER2-positive by IHC or FISH (detailed later)

ECOG performance status 0 - 1

Patient who can give informed consent for the study.
Patient does not have any contraindications to receive chemotherapy, or trastuzumab
Adequate hematological, hepatic and renal function parameters
Normal cardiac ejection fraction and cardiac function, as assessed by echocardiography, ejection fraction ejection fraction equal or more than 50% or above lower limit of normal.
ECG with no clinical relevant abnormalities

Women of childbearing age should have a negative pregnancy test at the time of randomization and should be willing to use adequate contraception during the treatment phase of the trial.

No major surgery within last 4 weeks

written patient consent form
 
 
ExclusionCriteria 
Details  distal cholangiocarcinoma which would be considered as ampullary carcinomas

Known hypersensitivity or contraindications against gemcitabine, cisplatin or trastuzumab

clinically significant active coronary heart disease, cardiomyopathy or congestive heart failure, NYHA III-IV,

Clinically significant valvular defect

Past or current history of other malignancies not curatively treated and without evidence of disease for more than 5 years, except for curatively treated basal cell carcinoma of the skin and in situ carcinoma of the cervix

Severe dyspnea at rest due to complications of advanced malignancy or requiring supplementary oxygen therapy

Other severe internal disease or acute infection
Baseline neuropathy more NCI Grade I
Chronic inflammatory bowel disease
Unhealed surgical wounds
On-treatment participation in another clinical study in the period 30 days prior to inclusion and during the study

Subject pregnant or breastfeeding, or planning to become pregnant within 6 months after the end of treatment

Received any prior chemotherapy / radiotherapy or cancer directed therapy

Any active ILD or history of lung illness requiring bronchodilator drugs.


 
 
Method of Generating Random Sequence   Not Applicable 
Method of Concealment   Not Applicable 
Blinding/Masking   Open Label 
Primary Outcome  
Outcome  TimePoints 
The primary endpoint of the study is to estimate the median PFS % at 6 months with gemcitabine-cisplatin-trastuzumab  60 months 
 
Secondary Outcome  
Outcome  TimePoints 
estimate the median -OS % at 6 months with gemcitabine-cisplatin-trastuzumab
-comparing the tolerance of gemcitabine-cisplatin - trastuzumab
-estimating the quality of life while on treatment 
60 months 
 
Target Sample Size   Total Sample Size="90"
Sample Size from India="90" 
Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials"
Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials" 
Phase of Trial   Phase 2 
Date of First Enrollment (India)   28/11/2019 
Date of Study Completion (India) Applicable only for Completed/Terminated trials 
Date of First Enrollment (Global)  Date Missing 
Date of Study Completion (Global) Applicable only for Completed/Terminated trials 
Estimated Duration of Trial   Years="5"
Months="0"
Days="0" 
Recruitment Status of Trial (Global)   Not Applicable 
Recruitment Status of Trial (India)  Not Yet Recruiting 
Publication Details   Nil  
Individual Participant Data (IPD) Sharing Statement

Will individual participant data (IPD) be shared publicly (including data dictionaries)?  

Brief Summary   Study design :Patients with unresectable or metastatic gallbladder cancer/intrahepatic cholangiocarcinoma/extrahepatic cholangiocarcinoma, who are fit to receive palliative first line gemcitabine cisplatin chemotherapy will be evaluated for study. Once they satisfy inclusion and exclusion criteria, patients will be consented and accrued to trial with the following regimen -

1.      3 weekly gemcitabine (1000 mg/m2 IV on day 1 and day 8 q 3 weekly) plus cisplatin (25 mg/m2 IV on day 1 and day 8 q 3 weekly) plus

2.      3 weekly Trastuzumab ( Initial dose of 8 mg/kg as a 90-minute intravenous infusion followed by subsequent doses of 6 mg/kg as an intravenous infusion over 30–90 minutes every three weeks )

Cycle repeated and continued till progression, unacceptable toxicity, consent withdrawal, death or lost to follow up.

Rationale : Current standard of care in advanced BTC

The current standard of care for advanced unresectable BTC is a gemcitabine-platinum combination, based on the seminal ABC-02 study. This study showed an overall survival benefit of a median of 3.6 months for gemcitabine cisplatin combination over single agent gemcitabine alone. The other commonly used 1st line regimen is gemcitabine - oxaliplatin, which has shown superiority to 5 fluorouracil based regimens in various studies.

HER2-positivity in BTC

HER2 is a receptor tyrosine encoded by proto-oncogenes.  Growth  factors  such  as epidermal growth factor (EGF) or transforming growth factor  (TGF)  bind  to  these  receptors  at  their  extracellular  ligand-binding  domain  and  initiate  intracellular signaling  cascades,  leading  to  tumor  cell  proliferation, migration,  invasion,  resistance  to  apoptosis  and  angiogenesis.  In  an  experimental  tumor  model  a  high proportion of  ErbB-2 (HER2) transgenic mice develop BTC,  suggesting  a  role  of   ErbB-2  signaling  in  biliary carcinogenesis. Overall,  overexpression  of   EGFR  and  HER2  in  tumor cells has been associated with a poor prognosis, but also  offers  the  therapeutic  option  of   pharmacologically  targeting  these  receptors. To  date,  EGFR  and  HER2  overexpression  has  been  reported  in  up  to  about  80%  of   BTC,  mostly  in  small  patient  cohorts. HER2/NEU (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma-derived oncogene homolog [avian]) receptor tyrosine kinases, has been implicated in BTC pathogenesis. Harder et al, studied the HER2 expression in biopsy samples from 124 patients with advanced BTC. HER2 gene amplification was present in 6/124, resulting in an overall amplification rate of 5%.

A large study of 187 patients from Chile evaluated the over-expression of the HER2 neu gene in advanced Gallbladder cancer (GBC) and observed an expression rate of 12.8%. Overexpression was more frequent in the advanced cancers and in the better-differentiated tumors (13.8% and 17.4%, respectively), but the difference was non-significant. The patients with overexpression of HER2/neu had a worse overall survival, when compared with those who had no expression at 5 years (34% vs. 41%).

A systematic review and metanalysis of 40 studies including 3839 patients evaluating the HER2/HER3 pathway in BTC reported a mean HER2 positivity rate of 26.5%, though high quality studies reported a rate of 20.3%. In the studies, which were considered to be high quality by the authors of the metanalysis, mean HER2 overexpression rate was statistically significantly higher in extrahepatic cholangiocarcinomas (EHCCs) compared to intrahepatic cholangiocarcinomas (IHCCs) and in GBCs compared to IHCCs.

The above discussion suggests that approximately 20% of BTC on the whole will have an over-expressed HER2 gene and this is a potentially worthwhile therapeutic target

Safety of gemcitabine-cisplatin-trastuzumab combination

The combination of gemcitabine-cisplatin and trastuzumab has been evaluated in multiple solid tumors, specifically breast cancers and lung cancers. The combination has been found to have reasonable efficacy as well as safety, with grade 3/4 adverse events rates for Hematological toxicities being 5%-55%, and non - Hematological toxicities being  <5%. Rates of drop in left ventricular ejection fraction and cardiac dysfunction were along expected lines as is already commonly known in breast and gastric cancer patients. 

Current standard of care in advanced BTC

The current standard of care for advanced unresectable BTC is a gemcitabine-platinum combination, based on the seminal ABC-02 study. This study showed an overall survival benefit of a median of 3.6 months for gemcitabine cisplatin combination over single agent gemcitabine alone. The other commonly used 1st line regimen is gemcitabine - oxaliplatin, which has shown superiority to 5 fluorouracil based regimens in various studies.

HER2-positivity in BTC

HER2 is a receptor tyrosine encoded by proto-oncogenes.  Growth  factors  such  as epidermal growth factor (EGF) or transforming growth factor  (TGF)  bind  to  these  receptors  at  their  extracellular  ligand-binding  domain  and  initiate  intracellular signaling  cascades,  leading  to  tumor  cell  proliferation, migration,  invasion,  resistance  to  apoptosis  and  angiogenesis.  In  an  experimental  tumor  model  a  high proportion of  ErbB-2 (HER2) transgenic mice develop BTC,  suggesting  a  role  of   ErbB-2  signaling  in  biliary carcinogenesis. Overall,  overexpression  of   EGFR  and  HER2  in  tumor cells has been associated with a poor prognosis, but also  offers  the  therapeutic  option  of   pharmacologically  targeting  these  receptors. To  date,  EGFR  and  HER2  overexpression  has  been  reported  in  up  to  about  80%  of   BTC,  mostly  in  small  patient  cohorts. HER2/NEU (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma-derived oncogene homolog [avian]) receptor tyrosine kinases, has been implicated in BTC pathogenesis. Harder et al, studied the HER2 expression in biopsy samples from 124 patients with advanced BTC. HER2 gene amplification was present in 6/124, resulting in an overall amplification rate of 5%.

A large study of 187 patients from Chile evaluated the over-expression of the HER2 neu gene in advanced Gallbladder cancer (GBC) and observed an expression rate of 12.8%. Overexpression was more frequent in the advanced cancers and in the better-differentiated tumors (13.8% and 17.4%, respectively), but the difference was non-significant. The patients with overexpression of HER2/neu had a worse overall survival, when compared with those who had no expression at 5 years (34% vs. 41%).

A systematic review and metanalysis of 40 studies including 3839 patients evaluating the HER2/HER3 pathway in BTC reported a mean HER2 positivity rate of 26.5%, though high quality studies reported a rate of 20.3%. In the studies, which were considered to be high quality by the authors of the metanalysis, mean HER2 overexpression rate was statistically significantly higher in extrahepatic cholangiocarcinomas (EHCCs) compared to intrahepatic cholangiocarcinomas (IHCCs) and in GBCs compared to IHCCs.

The above discussion suggests that approximately 20% of BTC on the whole will have an over-expressed HER2 gene and this is a potentially worthwhile therapeutic target

Safety of gemcitabine-cisplatin-trastuzumab combination

The combination of gemcitabine-cisplatin and trastuzumab has been evaluated in multiple solid tumors, specifically breast cancers and lung cancers. The combination has been found to have reasonable efficacy as well as safety, with grade 3/4 adverse events rates for Hematological toxicities being 5%-55%, and non - Hematological toxicities being  <5%. Rates of drop in left ventricular ejection fraction and cardiac dysfunction were along expected lines as is already commonly known in breast and gastric cancer patients.

Summary :

Study possibility of benefit will be more than risk and it may benefit future patients as data extrapoliated from previous approved indication of Transtuzumab in breast and gastric cancer her2 positive cancer showed benefit

Primary endpoint The primary endpoint of the study is to estimate the median PFS % at 6 months with gemcitabine-cisplatintrastuzumab Secondary endpoints and objectives The secondary endpoints and objectives include ● estimate the median OS % at 6 months with gemcitabine-cisplatin-trastuzumab ● comparing the tolerance of gemcitabine-cisplatin - trastuzumab ● estimating the quality of life while on treatment Translational objectives Blood samples will be collected prior and during treatment for future genomic analysis

 
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