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Afatinib Dimaleate and Paclitaxel in Treating Patients with Trastuzumab-Refractory Metastatic Esophagus or Stomach Cancer

Trial Status: Closed to Accrual

This phase II trial studies how well afatinib dimaleate and paclitaxel work in treating patients with esophagus or stomach cancer that has come back after being treated with trastuzumab or spread to other places in the body. Afatinib dimaleate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving afatinib dimaleate with paclitaxel may work better in treating patients with esophagus or stomach cancer.

Inclusion Criteria

  • Pathologically or cytologically confirmed esophagogastric cancer
  • HER2 overexpression and/or amplification as determined by immunohistochemistry (3+) or fluorescence in situ hybridization (FISH) (>= 2.0)
  • Previously received trastuzumab as part of a regimen in the perioperative or metastatic setting with evidence of progression; 89Zr-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 Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) criteria; ascites, pleural effusions, and bone metastases are not considered measurable; minimum indicator lesion size = 10 mm by helical computed tomography (CT) or = 20 mm by conventional techniques; pathological nodes must be = 15 mm by the short axis to be considered measurable
  • 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 human chorionic gonadotrophin (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; 89Zr-trastuzumab uses as imaging agent for 89Zr-trastuzumab PET permitted
  • Prior disease progression on docetaxel or paclitaxel in metastatic setting
  • Patients who are unwilling to consent to mandatory tumor biopsy; patients with archival tissue permitted to enroll on study per Memorial Sloan-Kettering (MSK) principal investigator discretion
  • Women who are pregnant or breast feeding
  • Concurrent radiotherapy is not permitted for disease progression on treatment on protocol, 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), human immunodeficiency virus (HIV)-positive
  • Subjects with acute hepatitis B are not eligible; subjects with chronic hepatitis are eligible if their condition is stable and, in the opinion of the investigator, if consulted, would not pose a risk to subject safety
  • History or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure New York Heart Association (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 Common Terminology Criteria for Adverse Events (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
  • Known HIV carrier
  • Known or suspected active drug or alcohol abuse
  • 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; 89Zr-trastuzumab use as imaging agent for 89Zr-trastuzumab PET permitted
  • The use of potent permeability glycoprotein (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


Los Angeles
USC / Norris Comprehensive Cancer Center
Contact: Syma Iqbal
Phone: 323-865-0451

New Jersey

Basking Ridge
Memorial Sloan Kettering Basking Ridge
Contact: Yelena Y. Janjigian
Phone: 212-639-8608
Memorial Sloan Kettering Monmouth
Contact: Yelena Y. Janjigian
Phone: 212-639-8608
Memorial Sloan Kettering Bergen
Contact: Yelena Y. Janjigian
Phone: 212-639-8608

New York

Memorial Sloan Kettering Commack
Contact: Yelena Y. Janjigian
Phone: 212-639-8608
New York
Memorial Sloan Kettering Cancer Center
Contact: Yelena Y. Janjigian
Phone: 212-639-8608
Memorial Sloan Kettering Nassau
Contact: Yelena Y. Janjigian
Phone: 212-639-8608
West Harrison
Memorial Sloan Kettering Westchester
Contact: Yelena Y. Janjigian
Phone: 212-639-8608


I. To determine toxicity, safety and tolerability of afatinib (afatinib dimaleate) with paclitaxel in patients with metastatic human epidermal growth receptor 2 (HER2)-positive esophagogastric cancer.


I. To estimate secondary efficacy endpoints of afatinib and paclitaxel, including overall clinical benefit defined as response rate (ORR) = stable disease (SD), complete response (CR) or partial response (PR), median overall survival and progression free survival (PFS).


I. To perform exploratory analysis on available archival, pre- and post-treatment tumor specimens to determine predictive biomarkers for afatinib response.

II. To utilize cell-free tumor deoxyribonucleic acid (cfDNA) from blood specimens collected during the course of treatment to explore the mechanism of primary and acquired resistance to afatinib therapy.

III. To explore changes in 89Zr-trastuzumab positron emission tomography (PET) with afatinib treatment.


Patients receive afatinib dimaleate orally (PO) once daily (QD) on days 1-28 and paclitaxel intravenously (IV) on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up within 14 days.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Memorial Sloan Kettering Cancer Center

Principal Investigator
Yelena Y. Janjigian

  • Primary ID 11-166
  • Secondary IDs NCI-2012-00414
  • ID NCT01522768