Abstract LB-185: Preliminary results of PROCLAIM-CX-2009, a first-in-human, dose-finding study of the Probody drug conjugate CX-2009 in patients with advanced solid tumors
Authors: Meric-Bernstam Funda , Boni Valentina , Spira Alexander I. , Sanborn Rachel E. , Arkenau H-Tobias , Sweis Randy , Burris Howard , Li Rachel , Yalamanchili Sreeni , Will Matthias , Liu Joyce F. , Harding James J. , Gautam Pratigya 
Published: August 2019

Abstract
Background: CX-2009 is a Probody™ drug conjugate (PDC) directed against CD166 (ubiquitously expressed in normal epithelium and overexpressed in carcinomas) that incorporates DM4, a potent but toxic microtubulin inhibitor (MTI). PDCs are preferentially activated by tumor microenvironment proteases with minimal binding in the inactive/masked state in nonmalignant tissue. Preclinically, CX-2009 led to significant tumor growth inhibition or regression in multiple solid tumor types. CX-2009 (masked) had extended exposure compared with the corresponding CD166-targeting ADC (unmasked), consistent with significantly reduced target-mediated drug disposition. These results indicate CX-2009 is efficiently activated in the tumor with low nonmalignant tissue engagement. Preliminary safety and antitumor activity from a first-in-human investigational dose escalation study are reported.
Methods: In the dose escalation of this ongoing phase 1/2 study (NCT03149549), 37 patients (pts) with advanced solid tumors received CX-2009 0.25-10 mg/kg IV every 21 days. 7 tumor types were enrolled in this study because of their high CD166 expression and MTI sensitivity: breast carcinoma (BC), castration-resistant prostate carcinoma, non-small cell lung carcinoma (NSCLC), epithelial ovarian carcinoma (EOC), endometrial carcinoma, head and neck squamous cell carcinoma, and cholangiocarcinoma. The study was initiated with accelerated dose titration in 1 single-subject cohort (0.25 mg/kg), followed by a standard 3+3 design up to 10 mg/kg to determine MTD.
Results: As of 30 Nov 2018, 37 pts were enrolled with advanced solid tumors (27% BC 27% EOC, 46% other) and a median of 6 (range 1-15) prior therapies. High CD166 by IHC was found in 14/24 tumors; median number of doses was 2 (range, 1-11), 19% of pts remain on treatment. One dose-limiting toxicity (grade 3 vomiting, 8 mg/kg) was observed. MTD was not reached at 10 mg/kg. Grade 1-2 treatment-related adverse events (TRAEs) occurred in 57% of pts and the most common (&gt;10%) were fatigue, anorexia (16% each), infusion-related reaction, diarrhea, and nausea (14% each). Grade 3-4 TRAEs were seen in 22% of pts (most frequently keratitis: 4 pts; 8, 9, and 10 mg/kg groups) and were managed and reversed with topical steroids. Of 25 pts evaluable for radiographic response, 3 had unconfirmed partial responses (BC, 8 and 9 mg/kg; EOC, 9 mg/kg; 2 CD166 high, 1 unknown; greatest tumoral shrinkage 85%) and 1 had durable stable disease for 24 weeks (NSCLC, 6 mg/kg, CD166 low).
Conclusions: CX-2009 was tolerable at dose levels up to 10 mg/kg. Preliminary antitumor activity is observed at dose levels starting at 6 mg/kg and above, warranting further investigation. The study is ongoing, enrolling translational cohorts. PK data and data on Probody integrity in the periphery will be presented. Probody is a trademark of CytomX Therapeutics, Inc.
Source of Funding: CytomX Therapeutics, Inc.
Citation Format: Funda Meric-Bernstam, Valentina Boni, Alexander I. Spira, Rachel E. Sanborn, H-Tobias Arkenau, Randy Sweis, Howard Burris, Rachel Li, Sreeni Yalamanchili, Matthias Will, Joyce F. Liu, James J. Harding, Pratigya Gautam. Preliminary results of PROCLAIM-CX-2009, a first-in-human, dose-finding study of the Probody drug conjugate CX-2009 in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-185.