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Mapatumumab, a Fully Human Agonistic Monoclonal Antibody That Targets TRAIL-R1, in Combination with Gemcitabine and Cisplatin: a Phase I Study Constantijne H

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Mapatumumab, a Fully Human Agonistic Monoclonal Antibody That Targets TRAIL-R1, in Combination with Gemcitabine and Cisplatin: a Phase I Study Constantijne H Published OnlineFirst August 18, 2009; DOI: 10.1158/1078-0432.CCR-09-0996 Cancer Therapy: Clinical Mapatumumab, a Fully Human Agonistic Monoclonal Antibody That Targets TRAIL-R1, in Combination with Gemcitabine and Cisplatin: a Phase I Study Constantijne H. Mom,1 Jaap Verweij,2 Corina N.A.M. Oldenhuis,1 Jourik A. Gietema,1 Norma Lynn Fox,3 Renée Miceli,3 FerryA.L.M. Eskens, 2 Walter J. Loos,2 Elisabeth G.E. de Vries,1 and Stefan Sleijfer2 Abstract Purpose: To evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of mapatumumab, a fullyhuman monoclonal antibodytargeting tumor necrosis factor – related apoptosis–inducing ligand receptor 1 (TRAIL-R1), in combination with gemcita- bine and cisplatin. Experimental Design: Patients with advanced solid tumors received gemcitabine 1,250 mg/m2 i.v. on days 1 and 8 and cisplatin 80 mg/m2 i.v. on day1 of each 21-day cycle. Escalating mapatumumab doses were administered i.v. every 21 days. Toxicity was evaluated and pharmacokinetic analysis of plasma mapatumumab, gemcitabine, 2-difluoro-2-deoxyuridine, and unbound and total platinum was done. TRAIL-R1 tumor expression was determined immunohistochemically. Results: Forty-nine patients received mapatumumab (1 mg/kg, n = 4; 3 mg/kg, n =7; 10 mg/kg, n = 12; 20 mg/kg, n = 13; or 30 mg/kg, n = 13). A median of six cycles (range, 1-48) was administered. The adverse events most commonlyobserved reflect the tox- icityprofile of gemcitabine and cisplatin. Dose-limiting toxicities were seen in 3 of 12 patients at 10 mg/kg, consisting of grade 3 transaminitis, neutropenic fever, and grade 4 thrombocytopenia. At 20 mg/kg, 2 of 12 patients had dose-limiting toxicities, including grade 4 thrombocytopenia and grade 4 fatigue. The maximum tolerated dose was not reached. Pharmacokinetic interactions have not been observed. Twelve patients had a partial response, and 25 patients showed stable disease with a median duration of 6 months. Conclusions: Mapatumumab in combination with gemcitabine and cisplatin is safe and well tolerated at doses up to 30 mg/kg. Further studies on this combination are warranted. (Clin Cancer Res 2009;15(17):5584–90) The tumor necrosis factor–related apoptosis–inducing ligand Authors' Affiliations: 1Department of Medical Oncology, University Medical (TRAIL) pathway is an attractive target for antitumor therapy 2 Center Groningen, Groningen, The Netherlands; Department of Medical because the activation of death receptors (DR) on the cell Oncology, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands; and 3Human Genome Sciences, Inc., Rockville, Maryland surface results in stimulation of the intracellular signaling Received 4/19/09; revised 5/29/09; accepted 6/2/09; published OnlineFirst routes leading to apoptosis. The naturally occurring ligand 8/18/09. TRAIL is a member of the tumor necrosis factor superfamily Grant support: Human Genome Sciences, Inc. that can bind to five different receptors, including TRAIL re- The costs of publication of this article were defrayed in part by the payment ceptors 1 (TRAIL-R1; DR4) and 2 (TRAIL-R2; DR5), through of page charges. This article must therefore be herebymarked advertisement in accordance with 18 U.S.C. Section 1734 solelyto indicate this fact. which TRAIL transmits its apoptotic signal (1, 2). For yet un- Note: Supplementarydata for this article are available at Clinical Cancer known reasons, TRAIL, in preclinical models, selectively in- Research Online (http://clincancerres.aacrjournals.org/). duces apoptosis in tumor cells without toxic effects on Presented in part at the AACR-NCI-EORTC International Conference on normal cells. Molecular Targets and Cancer Therapeutics, November 14-18, 2005, Philadelphia, PA; EORTC-NCI-AACR International Conference on Molecular Mapatumumab (TRM-1, ETR1) is a fully human immuno- Targets and Cancer Therapeutics, November 7-10, 2006, Prague, Czech globulin G1 λ agonistic monoclonal antibody to TRAIL-R1 Republic; and the 44th Annual Meeting of the American Societyof Clinical competing with TRAIL for binding to TRAIL-R1. Single agent Oncology, May 30-June 3, 2008, Chicago, IL. mapatumumab induces apoptosis in a range of cancer cell Request for reprints: Elisabeth G.E. de Vries, Department of Medical Oncol- lines and inhibits tumor growth in various human tumor ogy, University Medical Center Groningen, P.O. Box 30.001, 9700 RB, Gro- mouse xenograft models (3). Expression of TRAIL-R1 is fre- ningen, The Netherlands. Phone: 31-50-3612821/1847; Fax: 31-50-3614862; E-mail: [email protected]. quently observed in human tumors, including pancreatic, F 2009 American Association for Cancer Research. ovarian, colorectal, gastric, uterine, lung, and breast carcino- doi:10.1158/1078-0432.CCR-09-0996 mas (4). Clin Cancer Res 2009;15(17) September 1, 20095584 www.aacrjournals.org Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2009 American Association for Cancer Research. Published OnlineFirst August 18, 2009; DOI: 10.1158/1078-0432.CCR-09-0996 Mapatumumab, Gemcitabine, and Cisplatin: Phase I Study upper limit of normal; no previous chemotherapy, immunotherapy, ra- Translational Relevance diotherapy, or hormonal therapy within 3 wk; no treatment with monoclonal antibodies within previous 3 wk (murine or chimeric) or The tumor necrosis factor–related apoptosis– 8 wk (human or humanized); and no investigational agents within inducing ligand (TRAIL) pathwayis an attractive 4 wk. Specific exclusion criteria included known positive HIV status; target for antitumor therapy. Mapatumumab, a known chronic or acute viral hepatitis; clinical signs of brain metasta- ≥ monoclonal antibodytargeting TRAIL receptor 1, ses; hearing loss requiring the use of a hearing aid; neuropathy grade 2; and myocardial infarction, cerebrovascular accident, or ≥ New York was safe in previous phase I and II studies, although Heart Association class III congestive heart failure within 6 mo before no objective responses were observed. Combination study entry. of mapatumumab with gemcitabine and cisplatin re- The study was approved by the local ethics committees and the com- sulted in synergistic antitumor activity in preclinical petent regulatory authorities. All patients provided written informed models. This phase I studyshows that mapatumu- consent. mab at 30 mg/kg once every3 weeks can be safely Study design. A cycle was defined as 21 d. Mapatumumab was ad- combined with gemcitabine and cisplatin, without ministered at escalating dose levels (1, 3, 10, 20, and 30 mg/kg). At pharmacokinetic interactions. Anticancer activity each dose level, three to four patients were enrolled initially. Patients was encouraging. This combination therapyshould were considered to be evaluable for toxicity if they had completed be further explored in a randomized setting. one full cycle. Dose escalation decisions were made based on the safety assessments of all patients in the dose cohort using the National Cancer Institute Common Toxicity Criteria for Adverse Events version 3.0. Dose escalation was considered if <33% of the patients experienced dose- In two phase I studies in patients with solid tumors, single- limiting toxicity (DLT). If one of three to four patients experienced a agent mapatumumab was well tolerated, and adverse events DLT, the dose level was expanded to a total of six evaluable patients. were generally mild to moderate in severity (5, 6). The maxi- If a DLT was observed in two or more of six patients in a cohort, the mum tolerated dose in these studies was not reached with maximum tolerated dose was exceeded. To further characterize safety 10 mg/kg every 14 days (6) and 20 mg/kg every 28 days (5). at a certain dose level, up to 12 additional patients could be included. Pharmacokinetic results showed a mean terminal elimination By the initial DLT criteria, electrolyte disturbances secondary to inad- equate antiemetic therapy and chemotherapy-induced transient liver half-life of 18 to 21 days. In addition, in phase II studies with – enzyme elevations were considered dose limiting. The protocol was mapatumumab in patients with non small cell lung carcino- amended after inclusion of the fifth patient in the 10-mg/kg cohort ma, colorectal cancer, and non-Hodgkin's lymphoma, a similar to consider only those events as DLTs that were at least possibly related – – toxicity profile was observed (7 9). In the non small cell lung to mapatumumab or to its interaction with gemcitabine and/or cisplat- carcinoma and colorectal cancer studies, stable disease was the in. DLTs were thereafter defined as grade 4 neutropenia lasting >7 d, best observed response in 30% of the patients. Three patients febrile neutropenia, grade 4 thrombocytopenia; and grade 3 or 4 non- with follicular lymphoma experienced a tumor response. hematologic adverse events, with the following qualifications: grade ≥3 Combination therapy may synergistically enhance antitumor transaminase elevations that did not resolve to grade ≤1 before cycle 2, activity because mapatumumab induces apoptosis through the grade ≥3 nausea and vomiting despite optimal antiemetic treatment, extrinsic pathway, whereas chemotherapy results in cell death persistent grade ≥2 neuropathy, serum creatinine twice or more than by activating the intrinsic pathway. Accordingly, the addition the upper limit of normal, and grade 4 fatigue. Electrolyte disturbances of mapatumumab to gemcitabine or cisplatin resulted in in- due to inadequately treated vomiting were not considered dose-limiting if
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