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      Phase II single arm open label multicentre clinical trial to evaluate the efficacy and side effects of a combination of gefitinib and methotrexate to treat tubal ectopic pregnancies (GEM II): study protocol

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          Abstract

          Introduction

          Tubal ectopic pregnancy (tEP) is the most common life-threatening condition in gynaecology. tEPs with pretreatment serum human chorionic gonadotrophin (hCG) levels <1000 IU/L respond well to outpatient medical treatment with intramuscular methotrexate (MTX). TEPs with hCG >1000 IU/L take a significant time to resolve with MTX and require multiple outpatient monitoring visits. Gefitinib is an orally active epidermal growth factor receptor (EGFR) antagonist. In preclinical studies, we found that EP implantation sites express high levels of EGFR and that gefitinib augments MTX-induced regression of pregnancy-like tissue. We performed a phase I toxicity study administering oral gefitinib and intramuscular MTX to 12 women with tEPs. The combination therapy did not cause significant toxicities and was well tolerated. We noted that combination therapy resolved the tEPs faster than MTX alone. We now describe the protocol of a larger single arm trial to estimate the efficacy and side effects of combination gefitinib and MTX to treat stable tEPs with hCG 1000–10 000 IU/L

          Methods and analysis

          We propose to undertake a single-arm multicentre open label trial (in Edinburgh and Melbourne) and recruit 28 women with tEPs (pretreatment serum hCG 1000–10 000 IU/L). We intend to give a single dose of intramuscular MTX (50 mg/m 2) and oral gefitinib (250 mg) daily for 7 days. Our primary outcome is the resolution of EP to non-pregnant hCG levels <15 IU/L without requirement of surgery. Our secondary outcomes are comparison of time to resolution against historical controls given MTX only, and safety and tolerability as determined by clinical/biochemical assessment.

          Ethics and dissemination

          Ethical approval has been obtained from Scotland A Research Ethics Committee (MREC 11/AL/0350), Southern Health Human Research Ethics Committee B (HREC 11180B) and the Mercy Health Human Research Ethics Committee (R12/25). Data will be presented at international conferences and published in peer-reviewed journals.

          Trial registration number

          ACTRN12611001056987.

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          Sample size tables for exact single-stage phase II designs.

          R A'Hern (2001)
          Tables for single-phase II trials based on the exact binomial distribution are presented. These are preferable to those generated using Fleming's design, which are based on the normal approximation and can give rise to anomalous results. For example, if the upper success rate is accepted, the lower success rate, which the trial is designed to reject, may be included in the final confidence interval for the proportion being estimated. Copyright 2001 John Wiley & Sons, Ltd.
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            United States Food and Drug Administration Drug Approval summary: Gefitinib (ZD1839; Iressa) tablets.

            Bertrand C. Liang, Gang Chen, Gary Cohen … (2004)
            On May 5, 2003, gefitinib (Iressa; ZD1839) 250-mg tablets (AstraZeneca Inc.) received accelerated approval by the United States Food and Drug Administration as monotherapy for patients with locally advanced or metastatic non-small cell lung cancer after failure of both platinum-based and docetaxel chemotherapies. Information provided in this summary includes chemistry manufacturing and controls, clinical pharmacology, and clinical trial efficacy and safety results. Gefitinib is an anilinoquinazoline compound with the chemical name 4-quinazolinamine,N-(3-chloro-4-flurophenyl)-7-methoxy-6-[3-(4-morpholinyl)propoxy]. It has the molecular formula C(22)H(24)ClFN(4)O(3). Gefitinib is often referred to as a "specific" or "selective" inhibitor of epidermal growth factor receptor. Studies demonstrate, however, that gefitinib inhibits the activity of other intracellular transmembrane tyrosine-specific protein kinases at concentrations similar to those at which it inhibits the epidermal growth factor signal. Maximum plasma concentrations resulting from clinically relevant doses are 0.5-1 microM or more, well within the IC(50) values of several tyrosine kinases. No clinical studies have been performed that demonstrate a correlation between epidermal growth factor receptor expression and response to gefitinib. Gefitinib is 60% available after oral administration and is widely distributed throughout the body. Gefitinib is extensively metabolized in the liver by cytochrome P450 3A4 enzyme. Over a 10-day period, approximately 86% of an orally administered radioactive dose is recovered in the feces, with <4% of the dose in the urine. After daily oral administration, steady-state plasma levels are reached in 10 days and are 2-fold higher than those achieved after single doses. Gefitinib effectiveness was demonstrated in a randomized, double-blind, Phase II, multicenter trial comparing two oral doses of gefitinib (250 versus 500 mg/day). A total of 216 patients were enrolled. The 142 patients who were refractory to or intolerant of a platinum and docetaxel comprised the evaluable population for the efficacy analysis. A partial tumor response occurred in 14% (9 of 66) of patients receiving 250 mg/day gefitinib and in 8% (6 of 76) of patients receiving 500 mg/day gefitinib. The overall objective response rate (RR) for both doses combined was 10.6% (15 of 142 patients; 95% confidence interval, 6.0-16.8%). Responses were more frequent in females and in nonsmokers. The median duration of response was 7.0 months (range, 4.6-18.6+ months). Other submitted data included the results of two large trials conducted in chemotherapy-naive, stage III and IV non-small cell lung cancer patients. Patients were randomized to receive gefitinib (250 or 500 mg daily) or placebo, in combination with either gemcitabine plus cisplatin (n = 1093) or carboplatin plus paclitaxel (n = 1037). Results from this study showed no benefit (RR, time to progression, or survival) from adding gefitinib to chemotherapy. Consequently, gefinitib is only recommended for use as monotherapy. Common adverse events associated with gefitinib treatment included diarrhea, rash, acne, dry skin, nausea, and vomiting. Interstitial lung disease has been observed in patients receiving gefitinib. Worldwide, the incidence of interstitial lung disease was about 1% (2% in the Japanese post-marketing experience and about 0.3% in a United States expanded access program). Approximately one-third of the cases have been fatal. Gefitinib was approved under accelerated approval regulations on the basis of a surrogate end point, RR. No controlled gefitinib trials, to date, demonstrate a clinical benefit, such as improvement in disease-related symptoms or increased survival. Accelerated approval regulations require the sponsor to conduct additional studies to verify that gefitinib therapy produces such benefit.
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              Gefitinib--a novel targeted approach to treating cancer.

              Roy S. Herbst, Masahiro Fukuoka, José Baselga (2004)
              Twenty years after the epidermal growth factor receptor (EGFR) was identified as a potential anticancer target, the EGFR inhibitor gefitinib (Iressa; AstraZeneca) has been approved for the treatment of patients with advanced non-small-cell lung cancer in many countries. Studies have indicated its potential for treating patients with other types of solid tumours. Investigation of gefitinib has not only increased our knowledge about the biology of EGFR signalling, but is contributing to our evolving understanding of which tumours are EGFR dependent.
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                Author and article information

                Journal
                Journal ID (nlm-ta): BMJ Open
                Journal ID (iso-abbrev): BMJ Open
                Journal ID (hwp): bmjopen
                Journal ID (publisher-id): bmjopen
                Title: BMJ Open
                Publisher: BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                ISSN (Electronic): 2044-6055
                Publication date Collection: 2013
                Publication date (Electronic): 18 July 2013
                Volume: 3
                Issue: 7
                Electronic Location Identifier: e002902
                Affiliations
                [1 ]MRC Centre for Reproductive Health, University of Edinburgh , Edinburgh, UK
                [2 ]Translational Obstetrics Group, University of Melbourne, Mercy Hospital for Women , Melbourne, Australia
                [3 ]Monash Institute of Medical Research , Clayton, Australia
                [4 ]Obstetrics and Gynaecology, Division of Applied Clinical Sciences, University of Aberdeen , Aberdeen Maternity Hospital , Aberdeen, UK
                [5 ]Mercy Hospital for Women , Melbourne, Australia
                Author notes
                [Correspondence to ] Dr Andrew Horne; andrew.horne@ 123456ed.ac.uk
                Article
                Publisher ID: bmjopen-2013-002902
                DOI: 10.1136/bmjopen-2013-002902
                PMC ID: 3717468
                PubMed ID: 23872290
                SO-VID: 8c046717-71a7-4da8-a0b7-73b665df08d6
                Copyright © Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions
                License:

                This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 3.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/3.0/

                History
                Date received : 18 March 2013
                Date revision received : 9 May 2013
                Date accepted : 16 June 2013
                Categories
                Subject: Obstetrics and Gynaecology
                Subject: Protocol
                Subject: 1506
                Subject: 1845
                Subject: 1694
                Subject: 1723

                ScienceOpen disciplines: Medicine
                Keywords: reproductive medicine,gynaecology
                Data availability:
                ScienceOpen disciplines: Medicine
                Keywords: reproductive medicine, gynaecology

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