Cancer Therapy: Clinical Phase I Studies of CBP501, a G 2 Checkpoint Abrogator, as Monotherapy and in Combination with Cisplatin in Patients with Advanced Solid Tumors Geoffrey I. Shapiro 1 , Raoul Tibes 3 , Michael S. Gordon 4 , Bryan Y. Wong 5 , Joseph Paul Eder 1 , Mitesh J. Borad 3 , David S. Mendelson 4 , Nicholas J. Vogelzang 5 , Bruno R. Bastos 1 , Glen J. Weiss 3 , Cristian Fernandez 6 , William Sutherland 7 , Hitoshi Sato 8 , William E. Pierceall 9 , David Weaver 9 , Scott Slough 7 , Ernesto Wasserman 6 , Donald W. Kufe 1 , Daniel Von Hoff 3 , Takumi Kawabe 8 , and Sunil Sharma 5 Abstract Purpose: Two phase I dose-escalation studies were conducted to determine the maximum tolerated dose (MTD) and safety profile of the G 2 checkpoint abrogator CBP501, as a single agent and in combination with cisplatin. Experimental Design: Patients with advanced solid tumors were treated with CBP501 alone (D1/D8/ D15, q4w, from 0.9 mg/m 2 ), or with cisplatin (both on D1, q3w, from 3.6 mg/m 2 CBP501, 50 mg/m 2 cisplatin). Dose escalation proceeded if dose-limiting toxicity (DLT) was observed in 1 or less of 3 to 6 patients; CBP501 dose increments were implemented according to the incidence of toxicity. MTD was determined from DLTs occurring during the first two cycles. Results: In the combination study, the DLT was a histamine-release syndrome (HRS) occurring 10 to 60 minutes after initiating infusion that was attenuated by prophylaxis comprising dexamethasone, diphen- hydramine, ranitidine, and loratadine. The MTD was 25 mg/m 2 CBP501 and 75 mg/m 2 cisplatin, with two patients at the highest dose (36.4 mg/m 2 CBP501, 75 mg/m 2 cisplatin) experiencing grade 3 HRS. The only DLT with monotherapy was transient G 3 rise of troponin in one patient. Grade 3 to 4 treatment–related events were rare. Promising activity was observed with CBP501/cisplatin, mainly in ovarian and mesothe- lioma patients who had previously progressed on platinum-containing regimens. Among ovarian cancer patients, low expression of DNA repair proteins was associated with partial response or stable disease. Conclusions: CBP501 is well tolerated in patients as monotherapy and with cisplatin. At the recommended phase II dose (RP2D), the combination is feasible and HRS manageable with pro- phylaxis. Evidence of antitumor activity was observed in platinum-resistant patients. Clin Cancer Res; 17(10); 3431–42. Ó2011 AACR. Introduction Most cancer cells exhibit genomic instability, often with mutations in genes encoding p53 and Rb pathway mem- bers, or oncoproteins such as KRAS and c-MYC, that compromise the G 1 checkpoint (1, 2). These cells are therefore dependent on the G 2 checkpoint for survival following DNA damage (3). G 2 checkpoint abrogation is a therapeutic strategy designed to prevent cell cycle arrest in response to DNA damage, resulting in impaired DNA repair and increased tumor cell death (4). Because non- transformed cells retain both the G 1 checkpoint and backup p53-dependent pathways at the G 2 checkpoint, G 2 checkpoint abrogation in combination with DNA Authors' Affiliations: 1 Dana-Farber Cancer Institute, Brigham and Women's Hospital and Harvard Medical School, Boston, 2 On-Q-ity, Waltham, Massachusetts; 3 TGen & Virginia G. Piper Cancer Center, 4 Pinnacle Oncology Hematology, Scottsdale, Arizona; 5 Nevada Cancer Institute, Las Vegas, Nevada; 6 Pharm-Olam International, Houston, Texas; 7 Nuvisan Oncology, Le Kremlin-Bicetre, France; and 8 CanBas Co., Ltd., Shizuoka, Japan Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Presented in part at EORTC-NCI-AACR 2006 and AACR-NCI-EORTC 2009 Symposia on Molecular Targets and Cancer Therapeutics, ASCO 2008 and the International Symposium on Malignant Mesothelioma 2010. Current address for B.Y. Wong and M.J. Borad: Mayo Clinic, Scottsdale, Arizona. Current address for N.J. Vogelzang: Comprehensive Cancer Centers of Nevada & US Oncology Research, Las Vegas, Nevada. Current address for B.R. Bastos: Cleveland Clinic, Weston, Florida. Current address for S. Sharma: Huntsman Cancer Institute, Salt Lake City, Utah. Corresponding Author: Geoffrey I. Shapiro, Early Drug Development Center, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215. Phone: 617-632-4942; Fax: 617-632-1977; E-mail: geoffrey_shapiro@dfci.harvard.edu doi: 10.1158/1078-0432.CCR-10-2345 Ó2011 American Association for Cancer Research. Clinical Cancer Research www.aacrjournals.org 3431 Downloaded from http://aacrjournals.org/clincancerres/article-pdf/17/10/3431/1998295/3431.pdf by guest on 12 June 2022