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Afatinib and Paclitaxel in Patients With Advanced HER2-Positive Trastuzumab-Refractory Advanced Esophagogastric Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01522768
Recruitment Status : Active, not recruiting
First Posted : February 1, 2012
Last Update Posted : March 21, 2022
Boehringer Ingelheim
University of Southern California
Dana-Farber Cancer Institute
United States Department of Defense
Information provided by (Responsible Party):
Memorial Sloan Kettering Cancer Center

Brief Summary:
The purpose of this study is to find out what effects, good or bad, the combination of standard chemotherapy agent paclitaxel with the investigational (experimental) drug afatinib 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 and paclitaxel has on the tumor.

Condition or disease Intervention/treatment Phase
Esophageal Cancer Gastric Cancer Drug: Afatinib and Paclitaxel Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 42 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of Afatinib and Paclitaxel in Patients With Advanced HER2-Positive Trastuzumab Refractory Advanced Esophagogastric Cancer
Actual Study Start Date : March 2012
Estimated Primary Completion Date : February 2023
Estimated Study Completion Date : February 2023

Arm Intervention/treatment
Experimental: Afatinib and Paclitaxel
This is a multi-institution, open-label, non-randomized, Phase II evaluation of oral afatinib daily and intravenous paclitaxel (weekly, 3 weeks on, 1 week off) in patients with trastuzumab refractory HER2-positive metastatic or recurrent esophagogastric adenocarcinoma. An initial biopsy prior to the start of therapy is required for the correlative studies evaluating the biologic effects of afatinib. It will be obtained for all patients whose tumors are feasible to biopsy. At the site investigator's discretion, a second biopsy will also be obtained. At the discretion of the MSK Principal Investigator, select participants who show response on this study and then progress may be asked to have an optional third biopsy.
Drug: Afatinib and Paclitaxel
All patients receiving therapy on trial with afatinib and trastuzumab will continue on afatinib and trastuzumab until disease progression or intolerable toxicity. All additional patients will be enrolled on afatinib and paclitaxel. Patients will be treated with afatinib and paclitaxel combination. Patients will receive oral afatinib 40 mg daily plus paclitaxel 80 mg/m^2 intravenously on day 1, 8, and 15 of a 28-day cycle.

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

  2. determine predictive biomarker for afatinib response [ Time Frame: 2 years ]
    To perform exploratory analysis on available archival, pre-, and post-treatment tumor specimens

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Pathologically or cytologically 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. 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 MSK Principal Investigator discretion 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.
  • 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 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 CTCAEGrade >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. 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01522768

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United States, California
University of Southern California
Los Angeles, California, United States, 90033
United States, Massachusetts
Massachusetts General Hospital Cancer Center
Boston, Massachusetts, United States, 02114
United States, New Jersey
Memoral Sloan Kettering Basking Ridge
Basking Ridge, New Jersey, United States
Memoral Sloan Kettering Monmouth
Middletown, New Jersey, United States, 07748
Memorial Sloan Kettering Bergen
Montvale, New Jersey, United States, 07645
United States, New York
Memorial Sloan Kettering Commack
Commack, New York, United States, 11725
Memorial Sloan Kettering Westchester
Harrison, New York, United States, 10604
Memorial Sloan Kettering Cancer Center
New York, New York, United States, 10065
Memorial Sloan Kettering Rockville Centre
Rockville Centre, New York, United States
Sponsors and Collaborators
Memorial Sloan Kettering Cancer Center
Boehringer Ingelheim
University of Southern California
Dana-Farber Cancer Institute
United States Department of Defense
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Principal Investigator: Yelena Janjigian, MD Memorial Sloan Kettering Cancer Center
Additional Information:
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: Memorial Sloan Kettering Cancer Center Identifier: NCT01522768    
Other Study ID Numbers: 11-166
First Posted: February 1, 2012    Key Record Dates
Last Update Posted: March 21, 2022
Last Verified: March 2022
Keywords provided by Memorial Sloan Kettering Cancer Center:
Additional relevant MeSH terms:
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Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Protein Kinase Inhibitors
Enzyme Inhibitors