Afatinib (BIBW 2992) and Trastuzumab in Patients With Advanced HER2-Positive Trastuzumab-Refractory Advanced Esophagogastric Cancer

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by Memorial Sloan-Kettering Cancer Center
Sponsor:
Collaborator:
Boehringer Ingelheim
Information provided by (Responsible Party):
Memorial Sloan-Kettering Cancer Center
ClinicalTrials.gov Identifier:
NCT01522768
First received: January 25, 2012
Last updated: July 16, 2014
Last verified: July 2014
  Purpose

The purpose of this study is to find out what effects, good or bad, the combination of trastuzumab with the investigational (experimental) drug afatinib (BIBW 2992) that targets HER2, has on HER2-positive esophagogastric cancer that started to get bigger despite previous treatment with trastuzumab. The doctors will also study the tumor to understand why it grew while on trastuzumab treatment and to see the effects afatinib has on the tumor.


Condition Intervention Phase
Esophageal Cancer
Gastric Cancer
Drug: Afatinib (BIBW 2992) and trastuzumab
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Study of Afatinib (BIBW 2992) and Trastuzumab in Patients With Advanced HER2-Positive Trastuzumab-Refractory Advanced Esophagogastric Cancer

Resource links provided by NLM:


Further study details as provided by Memorial Sloan-Kettering Cancer Center:

Primary Outcome Measures:
  • efficacy [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    of afatinib in patients with metastatic HER2-positive esophagogastric cancer as measured by overall clinical benefit defined as response rate (ORR) = stable disease (SD) complete response (CR) or partial response (PR) at 4 months by RECIST 1.1 criteria


Secondary Outcome Measures:
  • toxicity, safety and tolerability [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
    The type, frequency, severity, timing, and relationship of each adverse event will be determined as per the NCI Common Toxicity Criteria, version 4.0.

  • the expression level [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    To determine the expression level of HER2 and p95-HER2 in pre and post-treatment tissue samples and correlate this with response to afatinib in HER2-positive tumors.

  • determine predictive biomarker for afatinib response [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    To perform exploratory analysis on available archival, pre-, and post-treatment tumor specimens


Estimated Enrollment: 40
Study Start Date: March 2012
Estimated Study Completion Date: February 2015
Estimated Primary Completion Date: February 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Afatinib (BIBW 2992) and trastuzumab
This is a single institution, open-label, non-randomized, phase II evaluation of oral afatinib daily with trastuzumab in patients with trastuzumab refractory HER2-positive metastatic or recurrent esophagogastric adenocarcinoma.
Drug: Afatinib (BIBW 2992) and trastuzumab
Patients will be treated with afatinib and trastuzumab combination. Patients will receive intravenous trastuzumab 4 mg/kg every 2 weeks (after the initial 6 mg/kg loading dose if at least 4 weeks elapsed since the last dose of trastuzumab) in combination with afatinib 30 mg daily continuously until disease progression, unacceptable toxicity or serious intercurrent illness develops or if patient consent is withdrawn.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Pathologically or cytologically MSKCC confirmed esophagogastric cancer.
  • HER2 overexpression and/or amplification as determined by immunohistochemistry (3+) or FISH (≥2.0)
  • Previously received trastuzumab as part of a regimen in the perioperative or metastatic setting with evidence of progression 9Zr-trastuzumab use as imaging agent for 89Zr-trastuzumab PET permitted..
  • May have previously received lapatinib as part of a regimen in the perioperative or metastatic setting with evidence of progression of disease. Washout period for lapatinib of 14 days.
  • Completion of previous chemotherapy regimen ≥2 weeks prior to the start of study treatment.

Other chemotherapy regimens may have been administered between the time of progression on prior trastuzumab containing regimen and protocol therapy. No restriction on prior chemotherapy regimens for advanced stage disease.

  • At least one measurable metastatic lesion according to RECIST 1.1 criteria. Ascites, pleural effusions, and bone metastases are not considered measurable. Minimum indicator lesion size = 10 mm by helical CT or = 20 mm by conventional techniques. Pathological nodes must be = 15 mm by the short axis to be considered measurable.
  • Patients aged 18 years or older, as no dosing or adverse event data are currently available on the use of afatinib in patients <18 years of age, children are excluded from this study.
  • Life expectancy of at least three (3) months.
  • Karnofsky performance status ≥60%
  • All patients with disease technically amenable to biopsy will be asked to undergo a biopsy. Patient must agree to allow 2 biopsies of any malignant lesion that can be accessed by endoscopy or with the aid or radiology (i.e. CT guided).
  • Patients who have previously provided samples at any time after trastuzumab resistance will be exempt from biopsy at the start of therapy.
  • Consent to preservation of frozen and fixed samples of tumor cores for evaluation
  • Able to swallow and retain oral medication.
  • Negative serum HCG pregnancy test for premenopausal women of reproductive capacity and for women less than 12 months after menopause.
  • Willingness to use birth control while on study.
  • Asymptomatic, central nervous system metastases are permitted.

Exclusion Criteria:

  • Patients receiving any concurrent anticancer therapy or investigational agents with the intention of treating esophagogastric cancer Concurrent trastuzumab permitted. 89Zr-trastuzumab use as imaging agent for 89Zr-trastuzumab PET permitted..
  • Patients who are unwilling to consent to tumor biopsy Women who are pregnant or breast feeding.
  • Concurrent radiotherapy is not permitted for disease progression on treatment on protocol (except in the context specified in section 9.0), but might be allowed for pre-existing non-target lesions with approval from the principal investigator of the trial.
  • Concurrent medical conditions which may increase the risk of toxicity, including ongoing or active infection, history of significant bleeding disorder unrelated to cancer (congenital bleeding disorders, acquired bleeding disorders within one year), HIV-positive or active hepatitis.

History or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure NYHA classification of 3, unstable angina or poorly controlled arrhythmia. Myocardial infarction within 6 months prior to study entry.

  • Baseline (< 1 month before treatment) cardiac left ventricular function with resting ejection fraction of less than 50% measured by echocardiogram.
  • Known pre-existing interstitial lung disease.
  • Significant or recent acute gastrointestinal disorders with diarrhea as a major symptom e.g., Crohn's disease, malabsorption, or CTCAE grade >2 diarrhea of any etiology.
  • Unwillingness to give written informed consent, unwillingness to participate, or inability to comply with the protocol for the duration of the study.
  • Active hepatitis B infection, active hepatitis C infection or known HIV carrier
  • Known or suspected active drug or alcohol abuse. Restricted Therapies
  • Additional experimental anti-cancer treatment and/or standard chemo-, immunotherapy, hormone treatment (with the exception of megestrol acetate), or concurrent radiotherapy is not allowed concomitantly with the administration of study treatment (with the exception listed in section 9.0) 89Zr-trastuzumab use as imaging agent for 89Zr-trastuzumab PET permitted.. Afatinib is a substrate of P-gp and its plasma concentrations can be affected by the use of P-gp inhibitors (data on file) and it is also likely that P-gp inducers could also influence afatinib plasma concentrations.
  • The use of potent P-gp inhibitors (including cyclosporine, erythromycin, ketoconazole, itraconazole, quinidine, Phenobarbital salt with quinidine, ritonavir, valspodar, verapamil) and potent P-gp inducers (including St John's wort, rifampicin) has to be avoided during treatment with afatinib. Any exemptions to this have to be discussed with the principal investigator.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01522768

Contacts
Contact: Yelena Janjigian, MD 646-888-4186
Contact: David Ilson, MD 646-888-4183

Locations
United States, New York
Memorial Sloan-Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Yelena Janjigian, MD    646-888-4186      
Contact: David Ilson, MD    646-888-4183      
Principal Investigator: Yelena Janjigian, MD         
Sponsors and Collaborators
Memorial Sloan-Kettering Cancer Center
Boehringer Ingelheim
Investigators
Principal Investigator: Yelena Janjigian, MD Memorial Sloan-Kettering Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: Memorial Sloan-Kettering Cancer Center
ClinicalTrials.gov Identifier: NCT01522768     History of Changes
Other Study ID Numbers: 11-166
Study First Received: January 25, 2012
Last Updated: July 16, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Memorial Sloan-Kettering Cancer Center:
ESOPHAGUS
STOMACH
Afatinib (BIBW 2992)
Trastuzumab
11-166

Additional relevant MeSH terms:
Stomach Neoplasms
Esophageal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Stomach Diseases
Head and Neck Neoplasms
Esophageal Diseases
Trastuzumab
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on October 01, 2014