PittsburghV1, France, Analysis, bibRecord, 000608

A Phase I Study of Veliparib in Combination with Metronomic Cyclophosphamide in Adults with Refractory Solid Tumors and Lymphomas

Identifieur interne : 000608 ( France/Analysis ); précédent : 000607; suivant : 000609

A Phase I Study of Veliparib in Combination with Metronomic Cyclophosphamide in Adults with Refractory Solid Tumors and Lymphomas

Auteurs : Shivaani Kummar [France] ; JIUPINGJI [États-Unis] ; Robert Morgan [Brésil] ; Heinz-Josef Lenz [États-Unis] ; Shannon L. Puhalla [États-Unis] ; Chandra P. Belani [États-Unis] ; David R. Gandara [États-Unis] ; Deborah Allen [France] ; Brian Kiesel [États-Unis] ; Jan H. Beumer [États-Unis] ; Edward M. Newman [Brésil] ; Larry Rubinstein [France] ; Alice Chen [France] ; YIPING ZHANG [États-Unis] ; LIHUA WANG [États-Unis] ; Robert J. Kinders [États-Unis] ; Ralph E. Parchment [États-Unis] ; Joseph E. Tomaszewski [France] ; James H. Doroshow [France]

Source :

Clinical cancer research [ 1078-0432 ] ; 2012.

RBID : Pascal:12-0183515

Descripteurs français

Pascal (Inist)
- Homme, Essai clinique phase I, Traitement, Association médicamenteuse, Cyclophosphamide, Adulte, Résistance traitement, Tumeur solide, Lymphome, Anticancéreux, Véliparib, Hémopathie maligne lymphoïde.
Wicri :
- topic : Homme, Adulte.

English descriptors

KwdEn :
- Adult, Antineoplastic agent, Cyclophosphamide, Drug combination, Human, Lymphoid neoplasm, Lymphoma, Phase I trial, Solid tumor, Treatment, Treatment resistance, Veliparib.

Abstract

Purpose: Oral administration of the alkylating agent cyclophosphamide at low doses, metronomic dosing, is well tolerated, with efficacy in multiple tumor types. PARP inhibition potentiates effects of cyclophosphamide in preclinical models. We conducted a phase I trial of the PARP inhibitor veliparib and metronomic cyclophosphamide in patients with refractory solid tumors and lymphoid malignancies. Experimental Design: Objectives were to establish the safety and maximum tolerated dose (MTD) of the combination; characterize veliparib pharmacokinetics (PK); measure poly(ADP-ribose) (PAR), a product of PARP, in tumor biopsies and peripheral blood mononuclear cells (PBMC); and measure the DNA-damage marker γH2AX in PBMCs and circulating tumor cells (CTC). Cyclophosphamide was administered once daily in 21-day cycles in combination with veliparib administered once daily for 7, 14, or 21 days. Results: Thirty-five patients were enrolled. The study treatment was well tolerated, and the MTD was established as veliparib 60 mg with cyclophosphamide 50 mg given once daily. Seven patients had partial responses; an additional six patients had disease stabilization for at least six cycles. PAR was significantly decreased in PBMCs (by at least 50%) and tumor biopsies (by at least 80%) across dose levels (DL); γH2AX levels were increased in CTCs from seven of nine patients evaluated after drug administration. Conclusions: The combination of veliparib with metronomic cyclophosphamide is well tolerated and shows promising activity in a subset of patients with BRCA mutations. A phase II trial of the combination compared with single-agent cyclophosphamide is ongoing in BRCA-positive ovarian cancer, triple-negative breast cancer, and low-grade lymphoma.

Affiliations:

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Pascal:12-0183515

Le document en format XML

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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">A Phase I Study of Veliparib in Combination with Metronomic Cyclophosphamide in Adults with Refractory Solid Tumors and Lymphomas</title>
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<region type="state">Californie</region>
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<author><name sortKey="Puhalla, Shannon L" sort="Puhalla, Shannon L" uniqKey="Puhalla S" first="Shannon L." last="Puhalla">Shannon L. Puhalla</name>
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<sZ>10 aut.</sZ>
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</affiliation>
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<author><name sortKey="Belani, Chandra P" sort="Belani, Chandra P" uniqKey="Belani C" first="Chandra P." last="Belani">Chandra P. Belani</name>
<affiliation wicri:level="2"><inist:fA14 i1="09"><s1>Penn State College of Medicine</s1>
<s2>Hershey, Pennsylvania</s2>
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<sZ>6 aut.</sZ>
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<placeName><region type="state">Pennsylvanie</region>
</placeName>
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<author><name sortKey="Gandara, David R" sort="Gandara, David R" uniqKey="Gandara D" first="David R." last="Gandara">David R. Gandara</name>
<affiliation wicri:level="2"><inist:fA14 i1="06"><s1>University of California, Davis Cancer Center</s1>
<s2>Sacramento, California</s2>
<s3>USA</s3>
<sZ>7 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<placeName><region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Allen, Deborah" sort="Allen, Deborah" uniqKey="Allen D" first="Deborah" last="Allen">Deborah Allen</name>
<affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Center for Cancer Research and, National Cancer Institute</s1>
<s2>Bethesda</s2>
<s3>FRA</s3>
<sZ>1 aut.</sZ>
<sZ>8 aut.</sZ>
<sZ>19 aut.</sZ>
</inist:fA14>
<country>France</country>
<wicri:noRegion>Bethesda</wicri:noRegion>
<wicri:noRegion>National Cancer Institute</wicri:noRegion>
<wicri:noRegion>Bethesda</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Kiesel, Brian" sort="Kiesel, Brian" uniqKey="Kiesel B" first="Brian" last="Kiesel">Brian Kiesel</name>
<affiliation wicri:level="1"><inist:fA14 i1="07"><s1>Molecular Therapeutics/Drug Discovery Program, University of Pittsburgh Cancer Institute</s1>
<s3>USA</s3>
<sZ>5 aut.</sZ>
<sZ>9 aut.</sZ>
<sZ>10 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<wicri:noRegion>Molecular Therapeutics/Drug Discovery Program, University of Pittsburgh Cancer Institute</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Beumer, Jan H" sort="Beumer, Jan H" uniqKey="Beumer J" first="Jan H." last="Beumer">Jan H. Beumer</name>
<affiliation wicri:level="1"><inist:fA14 i1="07"><s1>Molecular Therapeutics/Drug Discovery Program, University of Pittsburgh Cancer Institute</s1>
<s3>USA</s3>
<sZ>5 aut.</sZ>
<sZ>9 aut.</sZ>
<sZ>10 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<wicri:noRegion>Molecular Therapeutics/Drug Discovery Program, University of Pittsburgh Cancer Institute</wicri:noRegion>
</affiliation>
<affiliation wicri:level="3"><inist:fA14 i1="08"><s1>University of Pittsburgh School of Pharmacy</s1>
<s2>Pittsburgh</s2>
<s3>USA</s3>
<sZ>10 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<placeName><settlement type="city">Pittsburgh</settlement>
<region type="state">Pennsylvanie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Newman, Edward M" sort="Newman, Edward M" uniqKey="Newman E" first="Edward M." last="Newman">Edward M. Newman</name>
<affiliation wicri:level="1"><inist:fA14 i1="04"><s1>City of Hope Comprehensive Cancer Center</s1>
<s2>Duarte</s2>
<s3>BRA</s3>
<sZ>3 aut.</sZ>
<sZ>11 aut.</sZ>
</inist:fA14>
<country>Brésil</country>
<wicri:noRegion>City of Hope Comprehensive Cancer Center</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Rubinstein, Larry" sort="Rubinstein, Larry" uniqKey="Rubinstein L" first="Larry" last="Rubinstein">Larry Rubinstein</name>
<affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Division of Cancer Treatment and Diagnosis, National Cancer Institute</s1>
<s2>Bethesda</s2>
<s3>FRA</s3>
<sZ>1 aut.</sZ>
<sZ>12 aut.</sZ>
<sZ>13 aut.</sZ>
<sZ>18 aut.</sZ>
<sZ>19 aut.</sZ>
</inist:fA14>
<country>France</country>
<wicri:noRegion>Bethesda</wicri:noRegion>
<wicri:noRegion>National Cancer Institute</wicri:noRegion>
<wicri:noRegion>Bethesda</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Chen, Alice" sort="Chen, Alice" uniqKey="Chen A" first="Alice" last="Chen">Alice Chen</name>
<affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Division of Cancer Treatment and Diagnosis, National Cancer Institute</s1>
<s2>Bethesda</s2>
<s3>FRA</s3>
<sZ>1 aut.</sZ>
<sZ>12 aut.</sZ>
<sZ>13 aut.</sZ>
<sZ>18 aut.</sZ>
<sZ>19 aut.</sZ>
</inist:fA14>
<country>France</country>
<wicri:noRegion>Bethesda</wicri:noRegion>
<wicri:noRegion>National Cancer Institute</wicri:noRegion>
<wicri:noRegion>Bethesda</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Yiping Zhang" sort="Yiping Zhang" uniqKey="Yiping Zhang" last="Yiping Zhang">YIPING ZHANG</name>
<affiliation wicri:level="2"><inist:fA14 i1="03"><s1>Applied/ Developmental Research Support Directorate, Science Applications International Corporation-Frederick, Inc., National Cancer Institute at Frederick</s1>
<s2>Frederick, Maryland</s2>
<s3>USA</s3>
<sZ>2 aut.</sZ>
<sZ>14 aut.</sZ>
<sZ>15 aut.</sZ>
<sZ>16 aut.</sZ>
<sZ>17 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<placeName><region type="state">Maryland</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Lihua Wang" sort="Lihua Wang" uniqKey="Lihua Wang" last="Lihua Wang">LIHUA WANG</name>
<affiliation wicri:level="2"><inist:fA14 i1="03"><s1>Applied/ Developmental Research Support Directorate, Science Applications International Corporation-Frederick, Inc., National Cancer Institute at Frederick</s1>
<s2>Frederick, Maryland</s2>
<s3>USA</s3>
<sZ>2 aut.</sZ>
<sZ>14 aut.</sZ>
<sZ>15 aut.</sZ>
<sZ>16 aut.</sZ>
<sZ>17 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<placeName><region type="state">Maryland</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Kinders, Robert J" sort="Kinders, Robert J" uniqKey="Kinders R" first="Robert J." last="Kinders">Robert J. Kinders</name>
<affiliation wicri:level="2"><inist:fA14 i1="03"><s1>Applied/ Developmental Research Support Directorate, Science Applications International Corporation-Frederick, Inc., National Cancer Institute at Frederick</s1>
<s2>Frederick, Maryland</s2>
<s3>USA</s3>
<sZ>2 aut.</sZ>
<sZ>14 aut.</sZ>
<sZ>15 aut.</sZ>
<sZ>16 aut.</sZ>
<sZ>17 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<placeName><region type="state">Maryland</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Parchment, Ralph E" sort="Parchment, Ralph E" uniqKey="Parchment R" first="Ralph E." last="Parchment">Ralph E. Parchment</name>
<affiliation wicri:level="2"><inist:fA14 i1="03"><s1>Applied/ Developmental Research Support Directorate, Science Applications International Corporation-Frederick, Inc., National Cancer Institute at Frederick</s1>
<s2>Frederick, Maryland</s2>
<s3>USA</s3>
<sZ>2 aut.</sZ>
<sZ>14 aut.</sZ>
<sZ>15 aut.</sZ>
<sZ>16 aut.</sZ>
<sZ>17 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<placeName><region type="state">Maryland</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Tomaszewski, Joseph E" sort="Tomaszewski, Joseph E" uniqKey="Tomaszewski J" first="Joseph E." last="Tomaszewski">Joseph E. Tomaszewski</name>
<affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Division of Cancer Treatment and Diagnosis, National Cancer Institute</s1>
<s2>Bethesda</s2>
<s3>FRA</s3>
<sZ>1 aut.</sZ>
<sZ>12 aut.</sZ>
<sZ>13 aut.</sZ>
<sZ>18 aut.</sZ>
<sZ>19 aut.</sZ>
</inist:fA14>
<country>France</country>
<wicri:noRegion>Bethesda</wicri:noRegion>
<wicri:noRegion>National Cancer Institute</wicri:noRegion>
<wicri:noRegion>Bethesda</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Doroshow, James H" sort="Doroshow, James H" uniqKey="Doroshow J" first="James H." last="Doroshow">James H. Doroshow</name>
<affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Center for Cancer Research and, National Cancer Institute</s1>
<s2>Bethesda</s2>
<s3>FRA</s3>
<sZ>1 aut.</sZ>
<sZ>8 aut.</sZ>
<sZ>19 aut.</sZ>
</inist:fA14>
<country>France</country>
<wicri:noRegion>Bethesda</wicri:noRegion>
<wicri:noRegion>National Cancer Institute</wicri:noRegion>
<wicri:noRegion>Bethesda</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Division of Cancer Treatment and Diagnosis, National Cancer Institute</s1>
<s2>Bethesda</s2>
<s3>FRA</s3>
<sZ>1 aut.</sZ>
<sZ>12 aut.</sZ>
<sZ>13 aut.</sZ>
<sZ>18 aut.</sZ>
<sZ>19 aut.</sZ>
</inist:fA14>
<country>France</country>
<wicri:noRegion>Bethesda</wicri:noRegion>
<wicri:noRegion>National Cancer Institute</wicri:noRegion>
<wicri:noRegion>Bethesda</wicri:noRegion>
</affiliation>
</author>
</analytic>
<series><title level="j" type="main">Clinical cancer research</title>
<title level="j" type="abbreviated">Clin. cancer res.</title>
<idno type="ISSN">1078-0432</idno>
<imprint><date when="2012">2012</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
<seriesStmt><title level="j" type="main">Clinical cancer research</title>
<title level="j" type="abbreviated">Clin. cancer res.</title>
<idno type="ISSN">1078-0432</idno>
</seriesStmt>
</fileDesc>
<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adult</term>
<term>Antineoplastic agent</term>
<term>Cyclophosphamide</term>
<term>Drug combination</term>
<term>Human</term>
<term>Lymphoid neoplasm</term>
<term>Lymphoma</term>
<term>Phase I trial</term>
<term>Solid tumor</term>
<term>Treatment</term>
<term>Treatment resistance</term>
<term>Veliparib</term>
</keywords>
<keywords scheme="Pascal" xml:lang="fr"><term>Homme</term>
<term>Essai clinique phase I</term>
<term>Traitement</term>
<term>Association médicamenteuse</term>
<term>Cyclophosphamide</term>
<term>Adulte</term>
<term>Résistance traitement</term>
<term>Tumeur solide</term>
<term>Lymphome</term>
<term>Anticancéreux</term>
<term>Véliparib</term>
<term>Hémopathie maligne lymphoïde</term>
</keywords>
<keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Homme</term>
<term>Adulte</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en">Purpose: Oral administration of the alkylating agent cyclophosphamide at low doses, metronomic dosing, is well tolerated, with efficacy in multiple tumor types. PARP inhibition potentiates effects of cyclophosphamide in preclinical models. We conducted a phase I trial of the PARP inhibitor veliparib and metronomic cyclophosphamide in patients with refractory solid tumors and lymphoid malignancies. Experimental Design: Objectives were to establish the safety and maximum tolerated dose (MTD) of the combination; characterize veliparib pharmacokinetics (PK); measure poly(ADP-ribose) (PAR), a product of PARP, in tumor biopsies and peripheral blood mononuclear cells (PBMC); and measure the DNA-damage marker γH2AX in PBMCs and circulating tumor cells (CTC). Cyclophosphamide was administered once daily in 21-day cycles in combination with veliparib administered once daily for 7, 14, or 21 days. Results: Thirty-five patients were enrolled. The study treatment was well tolerated, and the MTD was established as veliparib 60 mg with cyclophosphamide 50 mg given once daily. Seven patients had partial responses; an additional six patients had disease stabilization for at least six cycles. PAR was significantly decreased in PBMCs (by at least 50%) and tumor biopsies (by at least 80%) across dose levels (DL); γH2AX levels were increased in CTCs from seven of nine patients evaluated after drug administration. Conclusions: The combination of veliparib with metronomic cyclophosphamide is well tolerated and shows promising activity in a subset of patients with BRCA mutations. A phase II trial of the combination compared with single-agent cyclophosphamide is ongoing in BRCA-positive ovarian cancer, triple-negative breast cancer, and low-grade lymphoma.</div>
</front>
</TEI>
<affiliations><list><country><li>Brésil</li>
<li>France</li>
<li>États-Unis</li>
</country>
<region><li>Californie</li>
<li>Maryland</li>
<li>Pennsylvanie</li>
</region>
<settlement><li>Los Angeles</li>
<li>Pittsburgh</li>
</settlement>
</list>
<tree><country name="France"><noRegion><name sortKey="Kummar, Shivaani" sort="Kummar, Shivaani" uniqKey="Kummar S" first="Shivaani" last="Kummar">Shivaani Kummar</name>
</noRegion>
<name sortKey="Allen, Deborah" sort="Allen, Deborah" uniqKey="Allen D" first="Deborah" last="Allen">Deborah Allen</name>
<name sortKey="Chen, Alice" sort="Chen, Alice" uniqKey="Chen A" first="Alice" last="Chen">Alice Chen</name>
<name sortKey="Doroshow, James H" sort="Doroshow, James H" uniqKey="Doroshow J" first="James H." last="Doroshow">James H. Doroshow</name>
<name sortKey="Doroshow, James H" sort="Doroshow, James H" uniqKey="Doroshow J" first="James H." last="Doroshow">James H. Doroshow</name>
<name sortKey="Kummar, Shivaani" sort="Kummar, Shivaani" uniqKey="Kummar S" first="Shivaani" last="Kummar">Shivaani Kummar</name>
<name sortKey="Rubinstein, Larry" sort="Rubinstein, Larry" uniqKey="Rubinstein L" first="Larry" last="Rubinstein">Larry Rubinstein</name>
<name sortKey="Tomaszewski, Joseph E" sort="Tomaszewski, Joseph E" uniqKey="Tomaszewski J" first="Joseph E." last="Tomaszewski">Joseph E. Tomaszewski</name>
</country>
<country name="États-Unis"><region name="Maryland"><name sortKey="Jiupingji" sort="Jiupingji" uniqKey="Jiupingji" last="Jiupingji">JIUPINGJI</name>
</region>
<name sortKey="Belani, Chandra P" sort="Belani, Chandra P" uniqKey="Belani C" first="Chandra P." last="Belani">Chandra P. Belani</name>
<name sortKey="Beumer, Jan H" sort="Beumer, Jan H" uniqKey="Beumer J" first="Jan H." last="Beumer">Jan H. Beumer</name>
<name sortKey="Beumer, Jan H" sort="Beumer, Jan H" uniqKey="Beumer J" first="Jan H." last="Beumer">Jan H. Beumer</name>
<name sortKey="Gandara, David R" sort="Gandara, David R" uniqKey="Gandara D" first="David R." last="Gandara">David R. Gandara</name>
<name sortKey="Kiesel, Brian" sort="Kiesel, Brian" uniqKey="Kiesel B" first="Brian" last="Kiesel">Brian Kiesel</name>
<name sortKey="Kinders, Robert J" sort="Kinders, Robert J" uniqKey="Kinders R" first="Robert J." last="Kinders">Robert J. Kinders</name>
<name sortKey="Lenz, Heinz Josef" sort="Lenz, Heinz Josef" uniqKey="Lenz H" first="Heinz-Josef" last="Lenz">Heinz-Josef Lenz</name>
<name sortKey="Lihua Wang" sort="Lihua Wang" uniqKey="Lihua Wang" last="Lihua Wang">LIHUA WANG</name>
<name sortKey="Parchment, Ralph E" sort="Parchment, Ralph E" uniqKey="Parchment R" first="Ralph E." last="Parchment">Ralph E. Parchment</name>
<name sortKey="Puhalla, Shannon L" sort="Puhalla, Shannon L" uniqKey="Puhalla S" first="Shannon L." last="Puhalla">Shannon L. Puhalla</name>
<name sortKey="Yiping Zhang" sort="Yiping Zhang" uniqKey="Yiping Zhang" last="Yiping Zhang">YIPING ZHANG</name>
</country>
<country name="Brésil"><noRegion><name sortKey="Morgan, Robert" sort="Morgan, Robert" uniqKey="Morgan R" first="Robert" last="Morgan">Robert Morgan</name>
</noRegion>
<name sortKey="Newman, Edward M" sort="Newman, Edward M" uniqKey="Newman E" first="Edward M." last="Newman">Edward M. Newman</name>
</country>
</tree>
</affiliations>
</record>

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A Phase I Study of Veliparib in Combination with Metronomic Cyclophosphamide in Adults with Refractory Solid Tumors and Lymphomas

A Phase I Study of Veliparib in Combination with Metronomic Cyclophosphamide in Adults with Refractory Solid Tumors and Lymphomas

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