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A phase Ib trial of docetaxel, carboplatin and erlotinib in ovarian, fallopian tube and primary peritoneal cancers

Identifieur interne : 000022 ( Pmc/Curation ); précédent : 000021; suivant : 000023

A phase Ib trial of docetaxel, carboplatin and erlotinib in ovarian, fallopian tube and primary peritoneal cancers

Auteurs : P A Vasey [Royaume-Uni, Australie] ; M. Gore [Royaume-Uni] ; R. Wilson [Royaume-Uni] ; G. Rustin [Royaume-Uni] ; H. Gabra [Royaume-Uni] ; J-P Guastalla [France] ; E P Lauraine [France] ; J. Paul [Royaume-Uni] ; K. Carty [Royaume-Uni] ; S. Kaye [Royaume-Uni]

Source :

RBID : PMC:2410113

Abstract

The safety and maximum tolerated dose (MTD) of erlotinib with docetaxel/carboplatin were assessed in patients with ovarian cancer. Chemonaive patients received intravenous docetaxel (75 mg m−2) and carboplatin (area under the curve 5) on day 1 of a 3-week cycle, and oral erlotinib at 50 (cohort 1), 100 (cohort 2a) or 75 mg day−1 (cohort 2b) for up to six cycles. Dose-limiting toxicities were determined in cycle 1. Forty-five patients (median age 59 years) received treatment. Dose-limiting toxicities occurred in 1/5/5 patients (cohorts 1/2a/2b). The MTD of erlotinib in this regimen was determined to be 75 mg day−1 (cohort 2b; the erlotinib dose was escalated to 100 mg day−1 in 11 out of 19 patients from cycle 2 onwards). Neutropaenia was the predominant grade 3/4 haematological toxicity (85/100/95% respectively). Common non-haematological toxicities were diarrhoea, fatigue, nausea and rash. There were five complete and seven partial responses in 23 evaluable patients (52% response rate). Docetaxel/carboplatin had no measurable effect on erlotinib pharmacokinetics. In subsequent single-agent maintenance, erlotinib was given at 100–150 mg day−1, with manageable toxicity, until tumour progression. Further investigation of erlotinib in epithelial ovarian carcinoma may be warranted, particularly as maintenance therapy.


Url:
DOI: 10.1038/sj.bjc.6604371
PubMed: 18506181
PubMed Central: 2410113

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PMC:2410113

Le document en format XML

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Crewe Road South, Edinburgh, Scotland EH4 2XU,
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<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<name sortKey="Guastalla, J P" sort="Guastalla, J P" uniqKey="Guastalla J" first="J-P" last="Guastalla">J-P Guastalla</name>
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<institution>Centre Léon-Bérard</institution>
rue Laennec, 69373, Lyon, Cedex 08,
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<name sortKey="Lauraine, E P" sort="Lauraine, E P" uniqKey="Lauraine E" first="E P" last="Lauraine">E P Lauraine</name>
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<name sortKey="Carty, K" sort="Carty, K" uniqKey="Carty K" first="K" last="Carty">K. Carty</name>
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<institution>CR-UK Clinical Trials Unit, Beatson Oncology Centre, Western Infirmary</institution>
Dumbarton Road, Glasgow, Scotland G11 6NT,
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Downs Road, Sutton, Surrey SM2 5PT,
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<p>The safety and maximum tolerated dose (MTD) of erlotinib with docetaxel/carboplatin were assessed in patients with ovarian cancer. Chemonaive patients received intravenous docetaxel (75 mg m
<sup>−2</sup>
) and carboplatin (area under the curve 5) on day 1 of a 3-week cycle, and oral erlotinib at 50 (cohort 1), 100 (cohort 2a) or 75 mg day
<sup>−1</sup>
(cohort 2b) for up to six cycles. Dose-limiting toxicities were determined in cycle 1. Forty-five patients (median age 59 years) received treatment. Dose-limiting toxicities occurred in 1/5/5 patients (cohorts 1/2a/2b). The MTD of erlotinib in this regimen was determined to be 75 mg day
<sup>−1</sup>
(cohort 2b; the erlotinib dose was escalated to 100 mg day
<sup>−1</sup>
in 11 out of 19 patients from cycle 2 onwards). Neutropaenia was the predominant grade 3/4 haematological toxicity (85/100/95% respectively). Common non-haematological toxicities were diarrhoea, fatigue, nausea and rash. There were five complete and seven partial responses in 23 evaluable patients (52% response rate). Docetaxel/carboplatin had no measurable effect on erlotinib pharmacokinetics. In subsequent single-agent maintenance, erlotinib was given at 100–150 mg day
<sup>−1</sup>
, with manageable toxicity, until tumour progression. Further investigation of erlotinib in epithelial ovarian carcinoma may be warranted, particularly as maintenance therapy.</p>
</div>
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<journal-title>British Journal of Cancer</journal-title>
<issn pub-type="ppub">0007-0920</issn>
<issn pub-type="epub">1532-1827</issn>
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<publisher-name>Nature Publishing Group</publisher-name>
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<article-id pub-id-type="pmid">18506181</article-id>
<article-id pub-id-type="pmc">2410113</article-id>
<article-id pub-id-type="pii">6604371</article-id>
<article-id pub-id-type="doi">10.1038/sj.bjc.6604371</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Clinical Studies</subject>
</subj-group>
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<title-group>
<article-title>A phase Ib trial of docetaxel, carboplatin and erlotinib in ovarian, fallopian tube and primary peritoneal cancers</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name>
<surname>Vasey</surname>
<given-names>P A</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="aff" rid="aff9">9</xref>
<xref ref-type="corresp" rid="caf1">*</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Gore</surname>
<given-names>M</given-names>
</name>
<xref ref-type="aff" rid="aff2">2</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Wilson</surname>
<given-names>R</given-names>
</name>
<xref ref-type="aff" rid="aff3">3</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Rustin</surname>
<given-names>G</given-names>
</name>
<xref ref-type="aff" rid="aff4">4</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Gabra</surname>
<given-names>H</given-names>
</name>
<xref ref-type="aff" rid="aff5">5</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Guastalla</surname>
<given-names>J-P</given-names>
</name>
<xref ref-type="aff" rid="aff6">6</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Lauraine</surname>
<given-names>E P</given-names>
</name>
<xref ref-type="aff" rid="aff7">7</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Paul</surname>
<given-names>J</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Carty</surname>
<given-names>K</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Kaye</surname>
<given-names>S</given-names>
</name>
<xref ref-type="aff" rid="aff8">8</xref>
</contrib>
</contrib-group>
<aff id="aff1">
<label>1</label>
<institution>CR-UK Clinical Trials Unit, Beatson Oncology Centre, Western Infirmary</institution>
Dumbarton Road, Glasgow, Scotland G11 6NT,
<country>UK</country>
</aff>
<aff id="aff2">
<label>2</label>
<institution>Royal Marsden Hospital</institution>
Fulham Road, London SW15 3SW,
<country>UK</country>
</aff>
<aff id="aff3">
<label>3</label>
<institution>Belfast City Hospital</institution>
Lisburn Road, Belfast, Ireland BT9 7AB,
<country>UK</country>
</aff>
<aff id="aff4">
<label>4</label>
<institution>Mount Vernon Hospital</institution>
Rickmansworth Road, Northwood, Hertfordshire HA6 2RN,
<country>UK</country>
</aff>
<aff id="aff5">
<label>5</label>
<institution>Western General Hospital</institution>
Crewe Road South, Edinburgh, Scotland EH4 2XU,
<country>UK</country>
</aff>
<aff id="aff6">
<label>6</label>
<institution>Centre Léon-Bérard</institution>
rue Laennec, 69373, Lyon, Cedex 08,
<country>France</country>
</aff>
<aff id="aff7">
<label>7</label>
<institution>Hopital de L'Hotel-Dieu, place du Parvis Notre-Dame</institution>
75181 Paris Cedex 4,
<country>France</country>
</aff>
<aff id="aff8">
<label>8</label>
<institution>Royal Marsden Hospital</institution>
Downs Road, Sutton, Surrey SM2 5PT,
<country>UK</country>
</aff>
<aff id="aff9">
<label>9</label>
<institution>Division of Medicine, University of Queensland</institution>
Brisbane Q4029,
<country>Australia</country>
</aff>
<author-notes>
<corresp id="caf1">
<label>*</label>
Author for correspondence:
<email xlink:href="mailto:pvasey@hoca.com.au">pvasey@hoca.com.au</email>
</corresp>
</author-notes>
<pub-date pub-type="epub">
<day>27</day>
<month>05</month>
<year>2008</year>
</pub-date>
<pub-date pub-type="collection">
<day>27</day>
<month>05</month>
<year>2008</year>
</pub-date>
<pub-date pub-type="ppub">
<day>03</day>
<month>06</month>
<year>2008</year>
</pub-date>
<volume>98</volume>
<issue>11</issue>
<fpage>1774</fpage>
<lpage>1780</lpage>
<history>
<date date-type="received">
<day>26</day>
<month>11</month>
<year>2007</year>
</date>
<date date-type="rev-recd">
<day>25</day>
<month>03</month>
<year>2008</year>
</date>
<date date-type="accepted">
<day>28</day>
<month>03</month>
<year>2008</year>
</date>
</history>
<copyright-statement>Copyright 2008, Cancer Research UK</copyright-statement>
<copyright-year>2008</copyright-year>
<permissions>
<copyright-holder>Cancer Research UK</copyright-holder>
</permissions>
<abstract>
<p>The safety and maximum tolerated dose (MTD) of erlotinib with docetaxel/carboplatin were assessed in patients with ovarian cancer. Chemonaive patients received intravenous docetaxel (75 mg m
<sup>−2</sup>
) and carboplatin (area under the curve 5) on day 1 of a 3-week cycle, and oral erlotinib at 50 (cohort 1), 100 (cohort 2a) or 75 mg day
<sup>−1</sup>
(cohort 2b) for up to six cycles. Dose-limiting toxicities were determined in cycle 1. Forty-five patients (median age 59 years) received treatment. Dose-limiting toxicities occurred in 1/5/5 patients (cohorts 1/2a/2b). The MTD of erlotinib in this regimen was determined to be 75 mg day
<sup>−1</sup>
(cohort 2b; the erlotinib dose was escalated to 100 mg day
<sup>−1</sup>
in 11 out of 19 patients from cycle 2 onwards). Neutropaenia was the predominant grade 3/4 haematological toxicity (85/100/95% respectively). Common non-haematological toxicities were diarrhoea, fatigue, nausea and rash. There were five complete and seven partial responses in 23 evaluable patients (52% response rate). Docetaxel/carboplatin had no measurable effect on erlotinib pharmacokinetics. In subsequent single-agent maintenance, erlotinib was given at 100–150 mg day
<sup>−1</sup>
, with manageable toxicity, until tumour progression. Further investigation of erlotinib in epithelial ovarian carcinoma may be warranted, particularly as maintenance therapy.</p>
</abstract>
<kwd-group>
<kwd>docetaxel</kwd>
<kwd>carboplatin</kwd>
<kwd>erlotinib</kwd>
<kwd>HER1/EGFR</kwd>
<kwd>gynaecological</kwd>
<kwd>cancer</kwd>
</kwd-group>
</article-meta>
</front>
<floats-wrap>
<fig id="fig1">
<label>Figure 1</label>
<caption>
<p>Mean plasma concentration–time curves for erlotinib alone and in combination with docetaxel and carboplatin for cohort 1.</p>
</caption>
<graphic mime-subtype="eps" xlink:href="6604371f1"></graphic>
</fig>
<table-wrap id="tbl1" position="float">
<label>Table 1</label>
<caption>
<p content-type="table-title">Baseline patient and disease characteristics</p>
</caption>
<table frame="hsides" rules="groups" border="1" width="85%">
<colgroup>
<col align="left"></col>
<col align="char" char="."></col>
<col align="char" char="."></col>
<col align="char" char="."></col>
</colgroup>
<thead valign="bottom">
<tr>
<th align="left" valign="top" charoff="50">
<bold>Characteristics</bold>
</th>
<th align="char" valign="top" char="." charoff="50">
<bold>Cohort 1</bold>
</th>
<th align="char" valign="top" char="." charoff="50">
<bold>Cohort 2a</bold>
</th>
<th align="char" valign="top" char="." charoff="50">
<bold>Cohort 2b</bold>
</th>
</tr>
</thead>
<tbody valign="top">
<tr>
<td align="left" valign="top" charoff="50">Patients (
<italic>n</italic>
)</td>
<td align="char" valign="top" char="." charoff="50">13</td>
<td align="char" valign="top" char="." charoff="50">13</td>
<td align="char" valign="top" char="." charoff="50">19</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">Median age (range) (years)</td>
<td align="char" valign="top" char="." charoff="50">59.5 (47.9–68.3)</td>
<td align="char" valign="top" char="." charoff="50">56.0 (32.4–65.7)</td>
<td align="char" valign="top" char="." charoff="50">61.9 (49.1–68.7)</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">
<italic>ECOG PS (n)</italic>
</td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> 0</td>
<td align="char" valign="top" char="." charoff="50">6</td>
<td align="char" valign="top" char="." charoff="50">5</td>
<td align="char" valign="top" char="." charoff="50">4</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> 1</td>
<td align="char" valign="top" char="." charoff="50">7</td>
<td align="char" valign="top" char="." charoff="50">8</td>
<td align="char" valign="top" char="." charoff="50">15</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
</tr>
<tr>
<td colspan="4" align="left" valign="top" charoff="50">
<italic>FIGO stage (n)</italic>
</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> III</td>
<td align="char" valign="top" char="." charoff="50">1</td>
<td align="char" valign="top" char="." charoff="50">0</td>
<td align="char" valign="top" char="." charoff="50">0</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> IIIa</td>
<td align="char" valign="top" char="." charoff="50">0</td>
<td align="char" valign="top" char="." charoff="50">1</td>
<td align="char" valign="top" char="." charoff="50">0</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> IIIb</td>
<td align="char" valign="top" char="." charoff="50">3</td>
<td align="char" valign="top" char="." charoff="50">2</td>
<td align="char" valign="top" char="." charoff="50">1</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> IIIc</td>
<td align="char" valign="top" char="." charoff="50">6</td>
<td align="char" valign="top" char="." charoff="50">7</td>
<td align="char" valign="top" char="." charoff="50">15</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> IV</td>
<td align="char" valign="top" char="." charoff="50">3</td>
<td align="char" valign="top" char="." charoff="50">3</td>
<td align="char" valign="top" char="." charoff="50">3</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
</tr>
<tr>
<td colspan="4" align="left" valign="top" charoff="50">
<italic>Histology (n)</italic>
</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> Serous adenocarcinoma</td>
<td align="char" valign="top" char="." charoff="50">11</td>
<td align="char" valign="top" char="." charoff="50">10</td>
<td align="char" valign="top" char="." charoff="50">17</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> Endometroid carcinoma</td>
<td align="char" valign="top" char="." charoff="50">1</td>
<td align="char" valign="top" char="." charoff="50">0</td>
<td align="char" valign="top" char="." charoff="50">0</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> Adenocarcinoma</td>
<td align="char" valign="top" char="." charoff="50">1</td>
<td align="char" valign="top" char="." charoff="50">2</td>
<td align="char" valign="top" char="." charoff="50">2</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> Other
<sup>a</sup>
</td>
<td align="char" valign="top" char="." charoff="50">0</td>
<td align="char" valign="top" char="." charoff="50">1</td>
<td align="char" valign="top" char="." charoff="50">0</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
</tr>
<tr>
<td colspan="4" align="left" valign="top" charoff="50">
<italic>Disease bulk (n)</italic>
</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> None or microscopic</td>
<td align="char" valign="top" char="." charoff="50">3</td>
<td align="char" valign="top" char="." charoff="50">2</td>
<td align="char" valign="top" char="." charoff="50">7</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> <2 cm</td>
<td align="char" valign="top" char="." charoff="50">6</td>
<td align="char" valign="top" char="." charoff="50">4</td>
<td align="char" valign="top" char="." charoff="50">2</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> ⩾2 cm</td>
<td align="char" valign="top" char="." charoff="50">4</td>
<td align="char" valign="top" char="." charoff="50">5</td>
<td align="char" valign="top" char="." charoff="50">6</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> Not available</td>
<td align="char" valign="top" char="." charoff="50">0</td>
<td align="char" valign="top" char="." charoff="50">2</td>
<td align="char" valign="top" char="." charoff="50">4</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> RECIST evaluable disease at baseline</td>
<td align="char" valign="top" char="." charoff="50">6</td>
<td align="char" valign="top" char="." charoff="50">6</td>
<td align="char" valign="top" char="." charoff="50">11</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn id="t1-fn1">
<label>a</label>
<p>Primary epithelial carcinoma of the ovary with hepatoid differentiation.</p>
</fn>
</table-wrap-foot>
</table-wrap>
<table-wrap id="tbl2" position="float">
<label>Table 2</label>
<caption>
<p content-type="table-title">Most common non-haematologic AEs (grades 3 and 4) occurring in more than one patient in any cohort, during treatment with chemotherapy</p>
</caption>
<table frame="hsides" rules="groups" border="1" width="85%">
<colgroup>
<col align="left"></col>
<col align="char" char="."></col>
<col align="char" char="."></col>
<col align="char" char="("></col>
<col align="char" char="."></col>
<col align="char" char="("></col>
<col align="char" char="."></col>
</colgroup>
<thead valign="bottom">
<tr>
<th align="left" valign="top" charoff="50"> </th>
<th colspan="2" align="center" valign="top" char="." charoff="50">
<bold>Cohort 1 (
<italic>n</italic>
=13)</bold>
<hr></hr>
</th>
<th colspan="2" align="center" valign="top" char="(" charoff="50">
<bold>Cohort 2a (
<italic>n</italic>
=13)</bold>
<hr></hr>
</th>
<th colspan="2" align="center" valign="top" char="(" charoff="50">
<bold>Cohort 2b (
<italic>n</italic>
=19)</bold>
<hr></hr>
</th>
</tr>
<tr>
<th align="left" valign="top" charoff="50">
<bold>AE</bold>
</th>
<th align="char" valign="top" char="." charoff="50">
<bold>Grade 3
<italic>n</italic>
(%)</bold>
</th>
<th align="char" valign="top" char="." charoff="50">
<bold>Grade 4
<italic>n</italic>
(%)</bold>
</th>
<th align="char" valign="top" char="(" charoff="50">
<bold>Grade 3
<italic>n</italic>
(%)</bold>
</th>
<th align="char" valign="top" char="." charoff="50">
<bold>Grade 4
<italic>n</italic>
(%)</bold>
</th>
<th align="char" valign="top" char="(" charoff="50">
<bold>Grade 3
<italic>n</italic>
(%)</bold>
</th>
<th align="char" valign="top" char="." charoff="50">
<bold>Grade 4
<italic>n</italic>
(%)</bold>
</th>
</tr>
</thead>
<tbody valign="top">
<tr>
<td align="left" valign="top" charoff="50">Diarrhoea</td>
<td align="char" valign="top" char="." charoff="50">0</td>
<td align="char" valign="top" char="." charoff="50">0</td>
<td align="char" valign="top" char="(" charoff="50">4 (31)</td>
<td align="char" valign="top" char="." charoff="50">0</td>
<td align="char" valign="top" char="(" charoff="50">3 (16)</td>
<td align="char" valign="top" char="." charoff="50">0</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">Fatigue</td>
<td align="char" valign="top" char="." charoff="50">0</td>
<td align="char" valign="top" char="." charoff="50">0</td>
<td align="char" valign="top" char="(" charoff="50">4 (31)</td>
<td align="char" valign="top" char="." charoff="50">0</td>
<td align="char" valign="top" char="(" charoff="50">3 (16)</td>
<td align="char" valign="top" char="." charoff="50">0</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">Rash/desquamation</td>
<td align="char" valign="top" char="." charoff="50">0</td>
<td align="char" valign="top" char="." charoff="50">0</td>
<td align="char" valign="top" char="(" charoff="50">3 (23)</td>
<td align="char" valign="top" char="." charoff="50">0</td>
<td align="char" valign="top" char="(" charoff="50">2 (10)</td>
<td align="char" valign="top" char="." charoff="50">0</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">Dehydration</td>
<td align="char" valign="top" char="." charoff="50">0</td>
<td align="char" valign="top" char="." charoff="50">0</td>
<td align="char" valign="top" char="(" charoff="50">1 (8)</td>
<td align="char" valign="top" char="." charoff="50">0</td>
<td align="char" valign="top" char="(" charoff="50">3 (16)</td>
<td align="char" valign="top" char="." charoff="50">0</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">Dysphagia</td>
<td align="char" valign="top" char="." charoff="50">0</td>
<td align="char" valign="top" char="." charoff="50">0</td>
<td align="char" valign="top" char="(" charoff="50">0</td>
<td align="char" valign="top" char="." charoff="50">1 (8)</td>
<td align="char" valign="top" char="(" charoff="50">2 (10)</td>
<td align="char" valign="top" char="." charoff="50">0</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">Nausea</td>
<td align="char" valign="top" char="." charoff="50">0</td>
<td align="char" valign="top" char="." charoff="50">0</td>
<td align="char" valign="top" char="(" charoff="50">3 (23)</td>
<td align="char" valign="top" char="." charoff="50">0</td>
<td align="char" valign="top" char="(" charoff="50">0</td>
<td align="char" valign="top" char="." charoff="50">0</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">Abdominal pain</td>
<td align="char" valign="top" char="." charoff="50">0</td>
<td align="char" valign="top" char="." charoff="50">0</td>
<td align="char" valign="top" char="(" charoff="50">1 (8)</td>
<td align="char" valign="top" char="." charoff="50">0</td>
<td align="char" valign="top" char="(" charoff="50">1 (5)</td>
<td align="char" valign="top" char="." charoff="50">0</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">Dermatology/skin other</td>
<td align="char" valign="top" char="." charoff="50">1 (8)</td>
<td align="char" valign="top" char="." charoff="50">0</td>
<td align="char" valign="top" char="(" charoff="50">0</td>
<td align="char" valign="top" char="." charoff="50">0</td>
<td align="char" valign="top" char="(" charoff="50">1 (5)</td>
<td align="char" valign="top" char="." charoff="50">0</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">Dizziness</td>
<td align="char" valign="top" char="." charoff="50">0</td>
<td align="char" valign="top" char="." charoff="50">0</td>
<td align="char" valign="top" char="(" charoff="50">1 (8)</td>
<td align="char" valign="top" char="." charoff="50">0</td>
<td align="char" valign="top" char="(" charoff="50">1 (5)</td>
<td align="char" valign="top" char="." charoff="50">0</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">Stomatitis/pharyngitis</td>
<td align="char" valign="top" char="." charoff="50">0</td>
<td align="char" valign="top" char="." charoff="50">0</td>
<td align="char" valign="top" char="(" charoff="50">0</td>
<td align="char" valign="top" char="." charoff="50">0</td>
<td align="char" valign="top" char="(" charoff="50">2 (10)</td>
<td align="char" valign="top" char="." charoff="50">0</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">Fainting</td>
<td align="char" valign="top" char="." charoff="50">0</td>
<td align="char" valign="top" char="." charoff="50">0</td>
<td align="char" valign="top" char="(" charoff="50">1 (8)</td>
<td align="char" valign="top" char="." charoff="50">0</td>
<td align="char" valign="top" char="(" charoff="50">1 (5)</td>
<td align="char" valign="top" char="." charoff="50">0</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">Vomiting</td>
<td align="char" valign="top" char="." charoff="50">0</td>
<td align="char" valign="top" char="." charoff="50">0</td>
<td align="char" valign="top" char="(" charoff="50">2 (15)</td>
<td align="char" valign="top" char="." charoff="50">0</td>
<td align="char" valign="top" char="(" charoff="50">0</td>
<td align="char" valign="top" char="." charoff="50">0</td>
</tr>
</tbody>
</table>
</table-wrap>
<table-wrap id="tbl3" position="float">
<label>Table 3</label>
<caption>
<p content-type="table-title">Summary of grade 3 and 4 haematologic toxicities, during treatment with chemotherapy</p>
</caption>
<table frame="hsides" rules="groups" border="1" width="85%">
<colgroup>
<col align="left"></col>
<col align="char" char="("></col>
<col align="center"></col>
<col align="char" char="("></col>
<col align="char" char="("></col>
<col align="char" char="("></col>
<col align="char" char="("></col>
</colgroup>
<thead valign="bottom">
<tr>
<th align="left" valign="top" charoff="50"> </th>
<th colspan="2" align="center" valign="top" char="(" charoff="50">
<bold>Cohort 1 (
<italic>n</italic>
=13)</bold>
<hr></hr>
</th>
<th colspan="2" align="center" valign="top" char="(" charoff="50">
<bold>Cohort 2a (
<italic>n</italic>
=13)</bold>
<hr></hr>
</th>
<th colspan="2" align="center" valign="top" char="(" charoff="50">
<bold>Cohort 2b (
<italic>n</italic>
=19)</bold>
<hr></hr>
</th>
</tr>
<tr>
<th align="left" valign="top" charoff="50">
<bold>Parameter</bold>
</th>
<th align="char" valign="top" char="(" charoff="50">
<bold>Grade 3
<italic>n</italic>
(%)</bold>
</th>
<th align="center" valign="top" charoff="50">
<bold>Grade 4
<italic>n</italic>
(%)</bold>
</th>
<th align="char" valign="top" char="(" charoff="50">
<bold>Grade 3
<italic>n</italic>
(%)</bold>
</th>
<th align="char" valign="top" char="(" charoff="50">
<bold>Grade 4
<italic>n</italic>
(%)</bold>
</th>
<th align="char" valign="top" char="(" charoff="50">
<bold>Grade 3
<italic>n</italic>
(%)</bold>
</th>
<th align="char" valign="top" char="(" charoff="50">
<bold>Grade 4
<italic>n</italic>
(%)</bold>
</th>
</tr>
</thead>
<tbody valign="top">
<tr>
<td align="left" valign="top" charoff="50">Leucopaenia</td>
<td align="char" valign="top" char="(" charoff="50">9 (69)</td>
<td align="center" valign="top" charoff="50">0</td>
<td align="char" valign="top" char="(" charoff="50">4 (31)</td>
<td align="char" valign="top" char="(" charoff="50">6 (46)</td>
<td align="char" valign="top" char="(" charoff="50">13 (68)</td>
<td align="char" valign="top" char="(" charoff="50">3 (16)</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">Thrombocytopaenia</td>
<td align="char" valign="top" char="(" charoff="50">1 (8)</td>
<td align="center" valign="top" charoff="50">0</td>
<td align="char" valign="top" char="(" charoff="50">2 (15)</td>
<td align="char" valign="top" char="(" charoff="50">3 (23)</td>
<td align="char" valign="top" char="(" charoff="50">0</td>
<td align="char" valign="top" char="(" charoff="50">0</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">Anaemia</td>
<td align="char" valign="top" char="(" charoff="50">0</td>
<td align="center" valign="top" charoff="50">0</td>
<td align="char" valign="top" char="(" charoff="50">1 (8)</td>
<td align="char" valign="top" char="(" charoff="50">0</td>
<td align="char" valign="top" char="(" charoff="50">0</td>
<td align="char" valign="top" char="(" charoff="50">0</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">RBC transfusions</td>
<td align="char" valign="top" char="(" charoff="50">3</td>
<td align="center" valign="top" charoff="50">6</td>
<td align="char" valign="top" char="(" charoff="50">6</td>
<td align="char" valign="top" char="(" charoff="50"> </td>
<td align="char" valign="top" char="(" charoff="50"> </td>
<td align="char" valign="top" char="(" charoff="50"> </td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">Neutropaenia</td>
<td align="char" valign="top" char="(" charoff="50">2 (15)</td>
<td align="char" valign="top" char="(" charoff="50">9 (69)</td>
<td align="char" valign="top" char="(" charoff="50">1 (8)</td>
<td align="char" valign="top" char="(" charoff="50">12 (92)</td>
<td align="char" valign="top" char="(" charoff="50">2 (11)</td>
<td align="char" valign="top" char="(" charoff="50">16 (84)</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">Febrile neutropaenia</td>
<td align="char" valign="top" char="(" charoff="50">0</td>
<td align="char" valign="top" char="(" charoff="50">1 (8)</td>
<td align="char" valign="top" char="(" charoff="50">2 (15)</td>
<td align="char" valign="top" char="(" charoff="50">2 (15)</td>
<td align="char" valign="top" char="(" charoff="50">3 (16)</td>
<td align="char" valign="top" char="(" charoff="50">2 (11)</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">Infection/febrile neutropaenia</td>
<td align="char" valign="top" char="(" charoff="50">0</td>
<td align="char" valign="top" char="(" charoff="50">1 (8)</td>
<td align="char" valign="top" char="(" charoff="50">0</td>
<td align="char" valign="top" char="(" charoff="50">1 (8)</td>
<td align="char" valign="top" char="(" charoff="50">0</td>
<td align="char" valign="top" char="(" charoff="50">1 (5)</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn id="t3-fn1">
<label></label>
<p>RBC transfusion threshold not mandated in protocol.</p>
</fn>
</table-wrap-foot>
</table-wrap>
<table-wrap id="tbl4" position="float">
<label>Table 4</label>
<caption>
<p content-type="table-title">PK parameters of erlotinib given alone or in combination with docetaxel and carboplatin (cohort 1)</p>
</caption>
<table frame="hsides" rules="groups" border="1" width="85%">
<colgroup>
<col align="left"></col>
<col align="char" char="("></col>
<col align="char" char="("></col>
<col align="char" char="("></col>
</colgroup>
<thead valign="bottom">
<tr>
<th align="left" valign="top" charoff="50">
<bold>Parameter</bold>
</th>
<th align="char" valign="top" char="(" charoff="50">
<bold>Erlotinib alone (day −1)</bold>
</th>
<th align="char" valign="top" char="(" charoff="50">
<bold>Erlotinib in combination with docetaxel/carboplatin (day 1)</bold>
</th>
<th align="char" valign="top" char="(" charoff="50">
<bold>Erlotinib alone (day 7)</bold>
</th>
</tr>
</thead>
<tbody valign="top">
<tr>
<td align="left" valign="top" charoff="50">
<italic>C</italic>
<sub>max</sub>
(ng ml
<sup>–1</sup>
)</td>
<td align="char" valign="top" char="(" charoff="50">922 (760–1119)</td>
<td align="char" valign="top" char="(" charoff="50">752 (624–906)</td>
<td align="char" valign="top" char="(" charoff="50">953 (738–1230)</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">
<italic>T</italic>
<sub>max</sub>
(h)</td>
<td align="char" valign="top" char="(" charoff="50">2.4 (1.5–3.9)</td>
<td align="char" valign="top" char="(" charoff="50">3.8 (1.9–7.6)</td>
<td align="char" valign="top" char="(" charoff="50">2.9 (2.0–3.6)</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">AUC
<sub>(0–24 h)</sub>
(ng h ml
<sup>−1</sup>
)</td>
<td align="char" valign="top" char="(" charoff="50">10 520 (7482–14 791)</td>
<td align="char" valign="top" char="(" charoff="50">11 041 (8241–14 825)</td>
<td align="char" valign="top" char="(" charoff="50">11 246 (7762–16 293)</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn id="t4-fn1">
<label></label>
<p>Data shown are geometric means (95% CIs) derived from the repeated measures analysis of variance, based on
<italic>n</italic>
=10 patients with full profiles on each day (other three patients did not have full profiles on each day).</p>
</fn>
</table-wrap-foot>
</table-wrap>
</floats-wrap>
</pmc>
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