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

Sponsor

Memorial Sloan Kettering Cancer Center (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT01522768

Collaborator

Boehringer Ingelheim (Industry), University of Southern California (Other), Dana-Farber Cancer Institute (Other), United States Department of Defense (U.S. Fed)

Enrollment

Locations

Arm

131.1

Anticipated Duration (Months)

4.7

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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

Study Design

Study Type:

Interventional

Anticipated 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 :

Mar 1, 2012

Anticipated Primary Completion Date :

Feb 1, 2023

Anticipated Study Completion Date :

Feb 1, 2023

Arms and Interventions

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.

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.

Outcome Measures

Primary Outcome Measures

efficacy [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

toxicity, safety and tolerability [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 [2 years]
To perform exploratory analysis on available archival, pre-, and post-treatment tumor specimens

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Southern California	Los Angeles	California	United States	90033
2	Massachusetts General Hospital Cancer Center	Boston	Massachusetts	United States	02114
3	Memoral Sloan Kettering Basking Ridge	Basking Ridge	New Jersey	United States
4	Memoral Sloan Kettering Monmouth	Middletown	New Jersey	United States	07748
5	Memorial Sloan Kettering Bergen	Montvale	New Jersey	United States	07645
6	Memorial Sloan Kettering Commack	Commack	New York	United States	11725
7	Memorial Sloan Kettering Westchester	Harrison	New York	United States	10604
8	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
9	Memorial Sloan Kettering Rockville Centre	Rockville Centre	New York	United States