Abstract B47: CBP501, a novel cell cycle dysregulator, in combination with cisplatin (CDDP) and pemetrexed (PM) - results of two phase I/II studies
Authors: Sharma Sunil , Tibes Raoul , Bastos Bruno , Borad Mitesh , Wong Bryan , Wasserman Ernesto , Fernandez Cristian , Kawabe Takumi , Von Hoff Daniel , Shapiro Geoffrey I. 
Published: June 2012

Abstract
Background: CBP501 is a synthetic peptide that appears to increase intracellular CDDP and enhance DNA damage caused by bleomycin and CDDP in cancer cells, which may lead to cell death. Activity has been identified in various tumor models. Previously it was determined that the MTD of single agent CBP501 was 25 mg/m2, with histamine release syndrome (HRS) as the dose limiting toxicity (DLT). Two clinical trials have evaluated CBP501 combinations, determining maximum tolerated dose (MTD), DLT, safety, activity and PK: Study A, phase I, CBP501 with CDDP; Study B, phase I/II, CBP501 with CDDP and PM. Both phase I studies were performed in patients (pts) with solid tumors. The phase II part of Study B is ongoing and will not be presented here.
Materials and Methods: Eligibility criteria were standard. CBP501 was given i.v. over 1 hr via central or peripheral catheter, with prophylactic anti-allergics for HRS. MTD was the level below that in which 2 of 3–6 pts had DLT during C1 and C2 for Study A, and C1 for Study B. Study A: q3w, initial CBP501/CDDP doses 3.6/50 mg/m2. Study B: q3w, initial CBP501/CDDP/PM doses 16/75/500 mg/m2. PK is reported separately.
Results: The studies were conducted in 3 US centers from Nov-06 to Aug-09. 54 pts were included and treated.
Study A) 48 pts in 7 dose levels: M/F 18/30; median age 61 (31–81); PS 0/1: 15/33; median number of prior lines 4 (0–14); primary site: ovarian (14 pts), mesothelioma (MST; 8), NSCLC (5), endometrial (4), prostate (4), other (13); total cycles (cy) administered 182 (median 4, range 1–13). Two DLTs (G3 HRS) occurred at CBP501/CDDP 36.4/75 mg/m2; the MTD was thus defined as 25/75 mg/m2. G3–4 toxicities included fatigue (4 pts), nausea (3), anemia (3), neutropenia (2), HRS (2), vomiting, QTc prolongation and renal failure (1 pt each). HRS was the most common AE, observed in 34 pts (70 %), but did not cause respiratory or hemodynamic problems. Efficacy: 3 confirmed partial responses (PR) were observed (2 platinum-resistant ovarian pts, 1 pleural MST pt); 3 ovarian pts had CA-125 responses. Sustained stable disease (SD) was observed in 5 ovarian pts (10, 9, 7, 5 and 4 cy), 2 pleural MST (13 and 5 cy), 1 neuroendocrine tumor pt (6 cy) and 1 salivary gland adenocarcinoma pt (9 cy).
Study B) 6 pts to date, in 2 dose levels (16 and 25 mg/m2 CBP501) with fixed doses of CDDP/PM (75/500 mg/m2/): M/F: 5/1; median age 63 (37–74); PS 0/1: 1/5; primary site: mesothelioma (4 pts), ACUP (1), bladder (1); total cy administered 30 (median 5, range 1–9). No DLTs have been observed; the highest dose studied was defined as the RD for phase II studies. G3–4 related AEs were: DVT (2 pts), anemia (1 pt), syncope (1 pt) and fatigue and anorexia (1 pt). Anemia, fatigue and HRS were the most common AEs, in 6, 5 and 5 pts, respectively. Efficacy: PR was observed in 1 MST pt (9 cy), and SD in 3 MST pts (9, 5 and 4 cy).
Conclusion: CBP501 appears to be well tolerated in combination with CDDP and CDDP/PM. The most frequent CBP501 toxicity was HRS, which is manageable. CBP501 did not enhance the expected toxicity of CDDP/PM. PR was seen in platinum-resistant ovarian pts and MST pts. Two randomized phase II studies of CBP501/CDDP/PM are ongoing in pleural MST and NSCLC.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B47.