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Immunotherapy of Peritoneal Carcinomatosis with the Antibody Catumaxomab in Colon, Gastric, Or Pancreatic Cancer: an Open-Label, Multicenter, Phase I/II Trial

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Immunotherapy of Peritoneal Carcinomatosis with the Antibody Catumaxomab in Colon, Gastric, Or Pancreatic Cancer: an Open-Label, Multicenter, Phase I/II Trial Original Article · Originalarbeit Onkologie 2011;34:101–108 Published online: February 18, 2011 DOI: 10.1159/000324667 Immunotherapy of Peritoneal Carcinomatosis with the Antibody Catumaxomab in Colon, Gastric, or Pancreatic Cancer: An Open-Label, Multicenter, Phase I/II Trial Michael A. Ströhleina Florian Lordickb Dominik Rüttingerc Klaus-Uwe Grütznera Oliver C. Schemanskia Michael Jägerd Horst Lindhofere Michael Hennigf Karl-Walter Jauchc Christian Peschelg Markus M. Heissa aDepartment of Abdominal, Vascular and Transplant Surgery, Cologne Merheim Medical Center, University of Witten-Herdecke, Cologne, bDepartment of Medical Oncology, National Center for Tumor Disease, University of Heidelberg, cDepartment of Surgery, Klinikum Großhadern, Ludwig Maximilians University Munich, dTRION Research GmbH, Martinsried, eTRION Pharma GmbH, fFresenius Biotech GmbH, Munich, gDepartment of Hematology and Medical Oncology, Klinikum rechts der Isar, Technical University Munich, Germany Keywords Schlüsselwörter Epithelial cell adhesion molecule (EpCAM) · Epitheliales Zell-Adhäsionsmolekül (EpCAM) · Catumaxomab · Antibody, trifunctional · Immunotherapy · Catumaxomab · Antikörper, trifunktionaler · Peritoneal carcinomatosis Immuntherapie · Peritonealkarzinose Summary Zusammenfassung Background: Peritoneal carcinomatosis (PC) is common in Hintergrund: Die Peritoealkarzinose (PC) ist eine häufige, gastrointestinal (GI) cancer and there is no effective stan- schwerwiegende Folge von gastrointestinalen (GI) Tumo- dard treatment. We investigated the tolerability and maxi- ren, für die derzeit keine wirkungsvolle Standardtherapie mum tolerated dose (MTD) of the trifunctional antibody existiert. Dieser Beitrag beschreibt die Verträglichkeit und catumaxomab in patients with PC. Methods: In this open- Maximaldosis (MTD) des trifunktionalen Antikörpers Catu- label, phase I/II clinical trial, patients with epithelial cell maxomab bei Patienten mit PC. Methoden: In dieser offe- adhesion molecule (EpCAM)-positive PC from GI cancer re- nen Phase-I/II-Studie erhielten Patienten mit EpCAM (epithe- ceived 4 sequential intraperitoneal catumaxomab infusions: liales Zell-Adhäsionsmolekül)-positiver PC aufgrund eines day 0: 10 mg; day 3: 10 or 20 mg; day 7: 30, 50, or 100 mg; and GI-Tumors 4 sequenzielle Infusionen Catumaxomab intra- day 10: 50, 100, or 200 mg. Dose escalation was guided by peritoneal: Tag 0: 10 mg; Tag 3: 10 oder 20 mg; Tag 7: 30, 50 dose-limiting toxicities. Results: The MTD was 10, 20, 50, oder 100 mg; Tag 10: 50, 100 oder 200 mg. Die Dosissteige- and 200 mg on days 0, 3, 7, and 10, respectively. Catumax- rung richtete sich nach den dosislimitierenden Toxizitäten. omab had an acceptable safety profile: Most common treat- Ergebnisse: Die MTD wurde bei 10, 20, 50 und 200 mg ent- ment-related adverse events (at the MTD) were fever, vom- sprechend an den Tagen 0, 3, 7 und 10 bestimmt. Catuma- iting, and abdominal pain. At final examination, 11/17 evalu- xomab zeigte ein akzeptables Sicherheitsprofil: Die meisten able patients (65%) were progression free: 1 patient had a behandlungsbedingten Nebenwirkungen (bei Erreichen der complete and 3 a partial response. Median overall survival MTD) waren Fieber, Übelkeit und abdominale Schmerzen. from the time of diagnosis of PC was 502 days. Conclusions: 11 von 17 auswertbaren Patienten waren zum Zeitpunkt der Intraperitoneal catumaxomab is a promising option for the finalen Auswertung progressionsfrei: 1 Patient hatte eine treatment of PC from GI cancer. komplette, 3 eine partielle Remission. Das mediane Gesamt- überleben seit PC-Diagnosestellung lag bei 502 Tagen bei Patienten mit Catumaxomab-Therapie. Schlussfolgerungen: Die intraperitoneale Catumaxomab-Therapie ist eine viel- versprechende Therapieoption bei PC aufgrund von GI- Tumoren. ©2011S.KargerGmbH,Freiburg Prof.Dr.med.MarkusM.Heiss 0378-584X/11/0343-0101$38.00/0 DepartmentofAbdominalVascularandTransplantSurgery Fax+497614520714 CologneMerheimMedicalCenter,UniversityofWitten-Herdecke [email protected] Accessibleonlineat: OstmerheimerStraße200,51109Cologne,Germany www.karger.com www.karger.com/onk Tel.+492218907-3770,Fax-8561 [email protected] Introduction EpCAM-positivePC,atumorsamplewascollectedduringlaparoscopy or laparotomy 7 days before treatment and analyzed histochemically. Aportsystemwasimplantedtoensuresafeinfusionsintotheperitoneal Peritonealcarcinomatosis(PC)isacommoneventinpatients cavity.Homogenousdistributionwascontrolledbycomputedtomogra- withgastrointestinal(GI)cancerandisassociatedwithpoor phy (CT) scans after intraperitoneal administration of 2000 ml of survival and deteriorating quality of life [1–3]. Systemic balancedelectrolytesolutionwithcontrastmedium. chemotherapy has shown minimal efficacy [4, 5]. Only Catumaxomab was manufactured by TRION Pharma, Munich, selected patients with small-volume PC benefit from peri- Germany/FreseniusBiotech,Munich,Germany.Inpart1ofthestudy, patients received 4 6-h intraperitoneal infusions of catumaxomab to- tonectomyplusintraoperativeintraperitonealchemotherapy getherwith1000mlelectrolytesolution,toensurehomogeneousdistribu- [6,7].Currently,thereisnoeffectivetreatmentforthemajor- tion.Adelayofupto4daysforeachinfusionwasallowed.Premedica- ityofpatientswithadvancedPC. tionconsistedoforalacetaminophen(1000mg).Thedoselevelsforthe Catumaxomab (anti-EpCAM × anti-CD3) (Removab®, infusions were composed according to a dynamic escalation schedule Fresenius Biotech GmbH, Munich, Germany) is a trifunc- asfollows–day0:10mg;day3:10or20mg;day7:30,50,or100mg;and day10:50,100,or200mg,whichwasbasedonformerstudies[12,17]. tionalantibodythatbindstheepithelialcelladhesionmole- Doseescalationwasguidedbytheoccurrenceofdose-limitingtoxicities cule (EpCAM) on tumor cells and CD3 on T lymphocytes. (DLTs):TheMTDwasdeterminedseparatelyforthefirst,second,third, ItsintactFcregion,whichiscomposedof2potentimmuno- and fourth infusion. If none of 3 patients experienced DLTs, the next globulin(Ig)isotypes(mouseIgG2aandratIgG2b),bindsto dose level for the first, second, third, and fourth infusion was imple- type I and III Fcg receptors on accessory cells, including mented.Ifoneof3patientsexperiencedDLTs,afurther3patientswere investigatedatthatdoselevel.Ifnoneoftheadditional3patientsexperi- monocytes, macrophages, and dendritic cells [8, 9]. These encedDLTs,subsequentpatientsreceivedthenexthighestdosesched- specificitiesinduceeffectivetumorcellkilling[10,11],which ule. If 2 or more of 2–6 patients experienced DLTs, the dose-steering wasrecentlydemonstratedinpatientswithmalignantascites board(DSB)definedtheMTD.Inpart2ofthestudy,theprotocolwas [12–14]. amendedinordertoinvestigateashorteradministrationperiodof3hat EpCAMisoverexpressedintumorcellsofmorethan90% theMTDinanother6patients.Inpart3,patientsreceived3-hintraperi- tonealinfusionsofcatumaxomabatdoseshigherthantheMTDtogether of patients with GI cancer [15]. Although EpCAM is ex- withdexamethasone10mg. pressed on normal epithelial tissues, it is specific for tumor cellsintheperitonealcavitybecauseperitonealcellsareof Assessments mesothelialoriginandthereforedonotexpressEpCAM.In Toxicityandvitalsignswereassesseddaily.Humananti-mouseantibody addition,Tlymphocytesandaccessorycellsarepresentinthe (HAMA) titers were measured to investigate the immunogenicity of catumaxomab.Otherimmunologicmarkersincludedinterleukin-6(IL-6) peritonealcavity[16].Thus,intraperitonealadministrationof andtumornecrosisfactor-alpha(TNF-a).PCburdenwasstagedusing catumaxomab provides the advantage of targeted immuno- theclassificationofGillyetal.(stages0–IV;stageI:malignantgranula- therapyforperitonealtumorcells.Basedonthisrationaleand tions<5mmingreatestdimension,localizedinonepartoftheabdomen; theconvincingresultsinpatientswithmalignantascites[12, stageII:malignantgranulations<5mm,diffusetothewholeabdomen; 13],thisstudyinvestigatedtheeffectsofintraperitonealcatu- stageIII:malignantgranulations5–2cm;stageIV:largemalignantcakes (> 2 cm) [18]. Peritoneal lavages were examined for EpCAM-positive maxomabtherapyinpatientswithnon-ascites-accumulating tumor cells using immunohistochemistry at the start and end of treat- and non-resectable PC from colon, gastric, or pancreatic ment.ToxicitywasgradedusingtheNationalCancerInstituteCommon cancer. Toxicity Criteria (NCI-CTC, version 2.0, 1999). Adverse events were codedusingtheMedicalDictionaryforRegulatoryActivities(MedDRA) andtabulatedbydosegroupandtimeoffirstappearance,todetermine theincidenceofadverseevents,treatment-relatedadverseeventswitha Patients and Methods definite,probable,possible,ornon-assessablerelationshiptothestudy drug,andadverseeventsofNCI-CTCgrade≥3orthoseleadingtotreat- Patients mentdiscontinuation.ADLTwasdefinedasanyadverseeventgrade≥3 Patients aged ≥ 18 years with an immunohistochemical diagnosis of thatcausedinterruptionofcatumaxomabinfusionandcouldnotbere- EpCAM-positive PC from gastric, colorectal, or pancreatic cancer and lievedbystandardtherapeuticmeasures,oranylaboratoryabnormality withaKarnofskyperformancestatus(KPS)≥60%wereeligible.Exclu- grade ≥ 3 that failed to show a significant trend toward normal within sion criteria were: prior exposure to mouse monoclonal antibodies or 96 h, or any other condition considered critical to the patient’shealth. treatmentwithanyinvestigationaldrugwithintheprevious30days;inad- Tumorassessmentsinpatientswithmeasurablediseaseweremadeac- equateorgan,immunologic,orendocrinefunction;uncontrolledacuteor cordingtotheResponseEvaluationCriteriainSolidTumors(RECIST) chronicinfection;chronicsteroidtherapy;historyofsevereallergicreac-
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