Clinical Trials /

Anti-HER2 Therapy in Patients of HER2 Positive Metastatic Carcinoma of Digestive System

NCT03185988

Description:

To seek the efficacy signals of trastuzumab in combination with chemotherapy in pretreated patients of HER2 positive, relapse or metastatic carcinoma of digestive system as response rate (RR) determined by the Investigator using RECIST 1.1, and provide evidence for phase III clinical trial.

Related Conditions:
  • Ampulla of Vater Carcinoma
  • Bile Duct Carcinoma
  • Colorectal Carcinoma
  • Digestive System Carcinoma
  • Esophageal Squamous Cell Carcinoma
  • Gallbladder Carcinoma
  • Hepatocellular Carcinoma
  • Pancreatic Carcinoma
  • Small Intestinal Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Anti-HER2 Therapy in Patients of HER2 Positive Metastatic Carcinoma of Digestive System
  • Official Title: Multicenter, Phase II Study of Chemotherapy in Combination With Trastuzumab in Patients of Pretreated, HER2 Positive, Relapse or Metastatic Carcinoma of Digestive System

Clinical Trial IDs

  • ORG STUDY ID: CGOG2006
  • NCT ID: NCT03185988

Conditions

  • Targeted Therapy
  • HER2
  • Biliary Tract Cancer
  • Esophageal Squamous Cell Carcinoma

Interventions

DrugSynonymsArms
chemotherapy in combination with trastuzumabGI tumor beyond CRC, ESCC, BTC,GC&GEJA
chemotherapy in combination with trastuzumabGI tumor beyond CRC, ESCC, BTC,GC&GEJA
chemotherapy in combination with trastuzumabGI tumor beyond CRC, ESCC, BTC,GC&GEJA

Purpose

To seek the efficacy signals of trastuzumab in combination with chemotherapy in pretreated patients of HER2 positive, relapse or metastatic carcinoma of digestive system as response rate (RR) determined by the Investigator using RECIST 1.1, and provide evidence for phase III clinical trial.

Detailed Description

      Human epidermal growth factor receptor 2, (HER2) is overexpressed /amplified in multiple
      carcinomas, for example, gastric cancer(GC), gastroesophageal junction
      adenocarcinoma(GEJA),and breast cancer.And HER2 is closely related to tumor proliferation
      &metastases.About 90% Chinese esophagus cancer are squamous cell origin. The reported HER2
      overexpression ranged from 5-30%, Beijing cancer hospital reported an 11% positive rate. The
      variety of HER2 positive rate may because of the absence of standard HER2 testing criteria.
      The current treatment for metastatic Esophageal squamous Cell Carcinoma (ESCC) is not
      satisfactory. Fluorouracil and platinum are considered as first line standard of care (SOC)
      with a 20-30% RR and 7-9 months overall survival (OS). In second line setting, there is no
      SOC in china. And the efficacy is not satisfactory. Esophageal adenocarcinoma has a higher
      HER2 positive rate of 14%, but no data reported of using trastuzumab in these patients in
      China. Biliary tract cancer (BTC), including intrahepatic/extrahepatic cholangiocarcinoma and
      Gallbladder cancer (GBC) is very aggressive, total 5y survival is less than 5% for
      unresectable patients. GBC is account for approximately 2/3 of BTC, and it's estimated the
      incidence in china is 52800 and the mortality is 40700 in 2015. Most patients are diagnosed
      in advanced stage and lose the opportunity of surgery. However, there is no SOC for
      unresectable BTC, gemcitabine plus platinum provided a 30% RR and 10 month OS. In second line
      treatment, no differences were seen between various experimental agents. The reported HER2
      positive rate range from 5.1% to 57% in biliary duct cancer and 4.7% to 64% in GBC.
      Researchers reported her2 amplification is related to tumor stage and lymph nodes metastasis
      in 221 BTC patients. Another study reported a 16.6% positive rate and worse prognosis with a
      sample size of 230 GBC patients. Meanwhile, HER2 pathway mutation rate reached 37%. All imply
      that BTC may be the potential anti HER therapy population. Besides, other digestive system
      tumor has low HER2 positive rate (Small intestinal cancer 0.9-3%; hepatocellular carcinoma
      2.4%; Pancreatic cancer 3%; etc.). However, the patient pool is large and has no SOC in
      second Line. Whether these HER2 + patients can gain benefit form anti- her treatment is worth
      investigating. In 2016 American Society of Clinical Oncology (ASCO), a study reported that
      using trastuzumab and pertuzumab combination, 35% metastatic colorectal cancer (CRC) and 50%
      BTC patients who heavily pretreated had objective response. However, china doesn't have
      studies for these patients. .

      The concurrent basket trial will explore the efficacy and safety of trastuzumab with
      chemotherapy in Chinese patients of pretreated, HER2 positive, relapse or metastatic
      carcinoma of digestive system.
    

Trial Arms

NameTypeDescriptionInterventions
GI tumor beyond CRC, ESCC, BTC,GC&GEJAExperimentalTrastuzumab (Herceptin ®): 6 mg/kg every 3 weeks (8 mg/kg as loading dose at 1st administration), iv, d1. The first infusion is to be given over 90 minutes, and subsequent infusions are to be given over 30 minutes if the first infusion is well tolerated. Combined with Irinotecan: 120 mg/m2 iv, day 1and day 8, every 3 weeks. OR 5-Fu: 720 mg/m2/day continuous iv. Infusion, d1-d5, every 3 weeks. OR Capecitabine(Xeloda®): 1000 mg/m2 bid, d1-d14, every 3 weeks. (by investigator's choice)
  • chemotherapy in combination with trastuzumab
  • chemotherapy in combination with trastuzumab
  • chemotherapy in combination with trastuzumab
Esophageal squamous cell carcinomaExperimentalTrastuzumab (Herceptin ®): same as above Combined with Irinotecan: 120 mg/m2 iv, day 1and day 8, every 3 weeks.
  • chemotherapy in combination with trastuzumab
  • chemotherapy in combination with trastuzumab
  • chemotherapy in combination with trastuzumab
Biliary tract cancerExperimentalTrastuzumab (Herceptin ®): same as above Combined with Irinotecan: 120 mg/m2 iv, day 1and day 8, every 3 weeks. OR 5-Fu: 720 mg/m2/day continuous iv. Infusion, d1-d5, every 3 weeks. OR Capecitabine(Xeloda®): 1000 mg/m2 bid, d1-d14, every 3 weeks. (by investigator's choice)
  • chemotherapy in combination with trastuzumab
  • chemotherapy in combination with trastuzumab
  • chemotherapy in combination with trastuzumab

Eligibility Criteria

        Inclusion Criteria:

          -  Signed informed consent.

          -  Male and female patients aged from 18 to 75 years

          -  Histologically confirmed Esophagus squamous cell carcinoma, biliary tract cancer, and
             digestive system tumor beyond CRC and GC&GEJA with the following specifications:

               -  Detection of a carcinoma with HER2 3+ (IHC) or HER2 2+ (IHC) with amplification
                  proven by fluorescence in situ hybridization(FISH), silver in situ
                  hybridization(SISH) or chromogenic in situ hybridization(CISH) using gastric
                  cancer criteria by an accredited local pathologist.

          -  Relapse or metastatic diseases, at least one measurable lesion according to RECIST
             1.1, anticipated survival ≥ 12 weeks.

          -  ECOG Performance status 0-1.

          -  Patients who failed at least first line systemic therapy.

          -  Adequate organ function as determined by the following laboratory results:

               -  Absolute neutrophil count ≥1500 cells/mm3,

               -  Platelet count ≥ 90,000 cells/mm3,

               -  Hemoglobin ≥9.0 g/dL

               -  Total bilirubin ≤ 1.5 upper limit of normal (ULN).

               -  serum glutamate oxaloacetate transaminase(SGOT,AST), serum glutamate pyruvate
                  transaminase(SGPT,ALT) < 2.5 ULN without liver metastases; < 5 ULN with liver
                  metastases.

               -  serum creatinine < 1.5

               -  ULN OR creatinine clearance ≥ 40 mL/ min.

          -  If able to reproduce, patients must be willing to use highly effective methods of
             contraception during treatment and for 7 months after the end of treatment.

        Exclusion Criteria:

          -  Known hypersensitivity against treatment regimen.

          -  Baseline left ventricular ejection fraction(LVEF) < 50% (measured by echocardiography
             or MUGA).

          -  Previous anti-her treatment.

          -  Immune therapy, biological therapy or any participation in clinical trial in previous
             two weeks.

          -  Surgery and not recovered in previous three weeks

          -  Clinical evidence of brain metastases, or uncontrolled epilepsy.

          -  Serious uncontrolled systemic intercurrent illness, e.g. infections or poorly
             controlled diabetes.

          -  Other malignancy within the last 5 years, except for carcinoma in situ of the cervix,
             or basal cell carcinoma.

          -  Clinically significant active coronary heart disease, cardiomyopathy or congestive
             heart failure, New York Heart Association(NYHA) III-IV; poorly controlled hypertension
             (systolic BP > 180 mmHg or diastolic BP > 100 mmHg); clinically significant valvular
             heart disease; unstable angina pectoris, myocardial infarction or high risk
             uncontrollable arrhythmias.

          -  Long term or high dose corticosteroids administration ( inhalation or short term oral
             administration for antiemesis and orexigenic is allowed)

          -  Patients of legally incapacity or of medical and ethical reasons not fit for study.

          -  Pregnant or lactating, or intending to become pregnant during the study.

          -  Jaundice, ascites, and / or alkaline phosphatase ≥3 × ULN; and / or ≥3 grade (CTC-AE)
             of persistent proteinuria, urinary protein / creatinine ratio> 3.5g / 24 hours or
             renal failure need blood or peritoneal dialysis.

          -  Presence of > grade 2(CTC-AE) persistent infection; unhealed wounds, ulcer or
             fracture, or patients with a history of organ transplant.

          -  Evidence of coagulation disorders. Like presence ≥grade 3 (CTC-AE) bleeding events.

          -  Known HIV or hepatitis B virus(HBV), hepatitis C virus(HCV) infection.

          -  Any > grade 1 unresolved toxicity due to previous treatment (CTC-AE), except for
             alopecia, anemia and hypothyroidism).

          -  Not suitable for the study evaluated by investigators

          -  Known dihydropyrimidine dehydrogenase (DPD) deficiency.

          -  History of exposure to the following cumulative doses of anthracyclines:

               -  Doxorubicin > 500 mg/m2 OR Epirubicin > 720 mg/m2.

                    -  If another anthracycline or more than one anthracycline has been used, then
                       the cumulative dose must not exceed the equivalent of 500 mg/m2 doxorubicin.
      
Maximum Eligible Age:75 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Response Rate(RR) for each cohort in intent to treat (ITT) population
Time Frame:baseline up to death or disease progression,which ever occurs first(up to approximately 8.5 years)
Safety Issue:
Description:The percentage of patients, whose tumor volume in first time shrink to pre-defined criteria, including CR and PR

Secondary Outcome Measures

Measure:Disease control rate
Time Frame:baseline up to death or disease progression,which ever occurs first(up to approximately 8.5 years)
Safety Issue:
Description:The percentage of patients who achieve complete remission(CR) or partial remission (PR) or stable disease(SD) determined by the RECIST v1.1 criteria.
Measure:best overall response
Time Frame:10-30 weeks
Safety Issue:
Description:The percentage of patients who achieve either a CR or PR as determined by the RECIST v1.1 criteria based on investigator's assessment that is confirmed by a repeat assessment performed no less than 4 weeks after the criteria for response are first met.
Measure:Progression free survival
Time Frame:baseline up to death or disease progression,which ever occurs first(up to approximately 8.5 years)
Safety Issue:
Description:Defined as the initiation of treatment to the day of first documentation of PD or date of death, whichever occurs first.
Measure:Overall survival
Time Frame:baseline up to death or disease progression,which ever occurs first(up to approximately 8.5 years)
Safety Issue:
Description:Is the time from the initiation of treatment to the date of death from any cause.
Measure:time to response
Time Frame:6-30 weeks
Safety Issue:
Description:Defined as the initiation of treatment to the day of first documentation of response. Only patients who achieve an objective response will be included in the analysis.
Measure:duration of response
Time Frame:6-30 weeks
Safety Issue:
Description:Defined as the time from the date of the first documented objective response to the date of first documented PD or death, whichever occurs first. Only patients who achieve an objective response will be included in the analysis.
Measure:time to progression(TTP)
Time Frame:6-30 weeks
Safety Issue:
Description:Defined as the initiation of treatment to the day of first documentation of PD.
Measure:Quality of Life by Eastern Cooperative Oncology Group(ECOG)performance status( PS) scoring criteria
Time Frame:Day 1 of each 21-day treatment cycle up to 28 days and 60-90 days after Day 1 of last treatment cycle(up to approximately 8.5 years)
Safety Issue:
Description:
Measure:Number of participants with treatment-related adverse events as assessed by CTCAE v4.03
Time Frame:baseline up to approximately 8.5 years
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Shen Lin

Trial Keywords

  • Human epidermal growth factor receptor 2
  • Biliary tract cancer
  • Esophageal squamous cell carcinoma
  • Targeted therapy

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