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

Multicenter, Phase II Study of Chemotherapy in Combination With Trastuzumab in Patients of Pretreated, HER2 Positive, Relapse or Metastatic Carcinoma of Digestive System

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.

Study Overview

• Status: Unknown
• Conditions: Colorectal Cancer; Esophageal Squamous Cell Carcinoma; Biliary Tract Cancer; Targeted Therapy; HER2
• Intervention / Treatment: Drug: chemotherapy in combination with trastuzumab for arm1; Drug: chemotherapy in combination with trastuzumab for arm2; Drug: chemotherapy in combination with trastuzumab for arm3; Drug: chemotherapy in combination with trastuzumab for arm4

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.

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100142
      • Recruiting
      • Beijing Cancer Hospital
      • Contact: xicheng wang, Doctor; Phone Number: 88196561; Email: xicheng_wang@hotmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Signed informed consent.
• Male and female patients aged from 18 to 75 years

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

  • genetic testing conformed KRAS/NRAS/BRAF all wild type for colorectal cancer
  • 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: GI tumor beyond CRC, ESCC, BTC,GC&GEJA; HER2 positive GI tumor beyond CRC, ESCC, BTC,GC&GEJA	Drug: chemotherapy in combination with trastuzumab for arm1; Arm1: GI tumor beyond CRC, ESCC, BTC and GC&GEJA Trastuzumab (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 chemotherapy (by investigator's choice)
EXPERIMENTAL: Esophageal squamous cell carcinoma; HER2 positive Esophageal squamous cell carcinoma	Drug: chemotherapy in combination with trastuzumab for arm2; Arm2: esophageal squamous cell carcinoma (ESCC) Trastuzumab (Herceptin ®): the same as above Combined with Irinotecan: 120 mg/m2 IV, day 1 and day 8, every 3 weeks.
EXPERIMENTAL: Biliary tract cancer; HER2 positive Biliary tract cancer	Drug: chemotherapy in combination with trastuzumab for arm3; Arm 3: biliary tract cancer (BTC) Trastuzumab (Herceptin®): the same as above Combined chemotherapy (by investigator's choice) The combined chemotherapy of cohort 1 and 3 is Irinotecan: 120 mg/m2 IV, day 1and day 8, every 3 weeks. OR 5-Fu: 720 mg/m2/day, continuous IV. Infusion over 5 days, every 3 weeks. OR Capecitabine(Xeloda®):1000 mg/m2 bid, d1-d14, every 3 weeks. The chemotherapy regimen is chosen at the Investigator's discretion and can be determined on an individual patient basis. Special cases should be discussed with the principal investigator.
EXPERIMENTAL: Colorectal cancer; HER2 positive and RAS/BRAF wild type colorectal cancer	Drug: chemotherapy in combination with trastuzumab for arm4; Trastuzumab (Herceptin ®): same as above Combined with Irinotecan: 120 mg/m2 iv, day 1and day 8, every 3 weeks. OR Capecitabine(Xeloda®)1000 mg/m2 bid, d1-d14, every 3 weeks. OR Irinotecan: 120 mg/m2 iv, day 1and day 8 and Capecitabine(Xeloda®)1000 mg/m2 bid, d1-d14, every 3 weeks (by investigator's choice)

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease control rate	The percentage of patients who achieve complete remission(CR) or partial remission (PR) or stable disease(SD) determined by the RECIST v1.1 criteria.	baseline up to death or disease progression,which ever occurs first(up to approximately 8.5 years)
best overall response	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.	10-30 weeks
Progression free survival	Defined as the initiation of treatment to the day of first documentation of PD or date of death, whichever occurs first.	baseline up to death or disease progression,which ever occurs first(up to approximately 8.5 years)
Overall survival	Is the time from the initiation of treatment to the date of death from any cause.	baseline up to death or disease progression,which ever occurs first(up to approximately 8.5 years)
time to response	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.	6-30 weeks
duration of response	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.	6-30 weeks
time to progression(TTP)	Defined as the initiation of treatment to the day of first documentation of PD.	6-30 weeks
Quality of Life by Eastern Cooperative Oncology Group(ECOG)performance status( PS) scoring criteria		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)
Number of participants with treatment-related adverse events as assessed by CTCAE v4.03		baseline up to approximately 8.5 years

Collaborators and Investigators

• Sponsor: Shen Lin
• Investigators: Principal Investigator: Lin Shen, Master, Director

Study record dates

Study Major Dates

• Study Start (ACTUAL): July 1, 2017
• Primary Completion (ANTICIPATED): July 1, 2021
• Study Completion (ANTICIPATED): September 1, 2021

Study Registration Dates

• First Submitted: May 16, 2017
• First Submitted That Met QC Criteria: June 12, 2017
• First Posted (ACTUAL): June 14, 2017

Study Record Updates

• Last Update Posted (ACTUAL): July 19, 2019
• Last Update Submitted That Met QC Criteria: July 17, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: colorectal cancer; Targeted therapy; Esophageal squamous cell carcinoma; Biliary tract cancer; Human epidermal growth factor receptor 2
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Head and Neck Neoplasms; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Esophageal Diseases; Biliary Tract Diseases; Neoplasms, Squamous Cell; Esophageal Neoplasms; Carcinoma; Colorectal Neoplasms; Carcinoma, Squamous Cell; Esophageal Squamous Cell Carcinoma; Biliary Tract Neoplasms; Antineoplastic Agents; Antineoplastic Agents, Immunological; Trastuzumab
• Other Study ID Numbers: CGOG2006

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No