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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.
 
ClinicalTrials.gov Identifier: NCT01522768
Recruitment Status : Active, not recruiting
First Posted : February 1, 2012
Last Update Posted : March 18, 2020
Sponsor:
Collaborators:
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

Tracking Information
First Submitted Date  ICMJE January 25, 2012
First Posted Date  ICMJE February 1, 2012
Last Update Posted Date March 18, 2020
Actual Study Start Date  ICMJE March 2012
Estimated Primary Completion Date February 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 30, 2012)
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
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 6, 2016)
  • 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.
  • determine predictive biomarker for afatinib response [ Time Frame: 2 years ]
    To perform exploratory analysis on available archival, pre-, and post-treatment tumor specimens
Original Secondary Outcome Measures  ICMJE
 (submitted: January 30, 2012)
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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Afatinib and Paclitaxel in Patients With Advanced HER2-Positive Trastuzumab-Refractory Advanced Esophagogastric Cancer
Official Title  ICMJE A Phase II Study of Afatinib and Paclitaxel in Patients With Advanced HER2-Positive Trastuzumab Refractory Advanced Esophagogastric Cancer
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Esophageal Cancer
  • Gastric Cancer
Intervention  ICMJE 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.
Study Arms  ICMJE 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.
Intervention: Drug: Afatinib and Paclitaxel
Publications * Sanchez-Vega F, Hechtman JF, Castel P, Ku GY, Tuvy Y, Won H, Fong CJ, Bouvier N, Nanjangud GJ, Soong J, Vakiani E, Schattner M, Kelsen DP, Lefkowitz RA, Brown K, Lacouture ME, Capanu M, Mattar M, Qeriqi B, Cecchi F, Tian Y, Hembrough T, Nagy RJ, Lanman RB, Larson SM, Pandit-Taskar N, Schöder H, Iacobuzio-Donahue CA, Ilson DH, Weber WA, Berger MF, de Stanchina E, Taylor BS, Lewis JS, Solit DB, Carrasquillo JA, Scaltriti M, Schultz N, Janjigian YY. EGFR and MET Amplifications Determine Response to HER2 Inhibition in ERBB2-Amplified Esophagogastric Cancer. Cancer Discov. 2019 Feb;9(2):199-209. doi: 10.1158/2159-8290.CD-18-0598. Epub 2018 Nov 21.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: October 9, 2019)
42
Original Estimated Enrollment  ICMJE
 (submitted: January 30, 2012)
27
Estimated Study Completion Date  ICMJE February 2021
Estimated Primary Completion Date February 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01522768
Other Study ID Numbers  ICMJE 11-166
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Memorial Sloan Kettering Cancer Center
Study Sponsor  ICMJE Memorial Sloan Kettering Cancer Center
Collaborators  ICMJE
  • Boehringer Ingelheim
  • University of Southern California
  • Dana-Farber Cancer Institute
  • United States Department of Defense
Investigators  ICMJE
Principal Investigator: Yelena Janjigian, MD Memorial Sloan Kettering Cancer Center
PRS Account Memorial Sloan Kettering Cancer Center
Verification Date March 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP