Abstract CT228: Phase Ib clinical study of CBP501, cisplatin and nivolumab administered every 3 weeks in patients with advanced refractory tumors. Dose escalation cohort
Authors: Matrana Marc , Tsai Frank , Satti Suma , Cleary James , Estes Jacob , Do Khanh , Kolmakov Valentin , Kawabe Takumi , Shapiro Geoffrey I. 
Published: August 2019

Abstract
Background:
CBP501 is a 12 amino acid calmodulin-modulating peptide that increases platinum influx into tumor cells and induces tumor immunogenic cell death. CBP501 also suppresses platinum-induced release of cytokines, such as IL-6, IL-10 and VEGF, lowers cancer stem cell populations and reduces the migration, invasion and epithelial-mesenchymal transition of tumor cells. Preclinical studies show synergistic anti-tumor activity when combined with platinum agents and immune checkpoint inhibitors (anti-PD1, PD-L1 and CTLA-4 antibodies) in the CT26 syngeneic mouse model. Here, we report dose-finding results from a Phase Ib study of CBP501 combined with cisplatin and nivolumab in a triple drug combination.
Methods:
An open-label phase I trial was conducted using a 3+3 design: CBP501 and cisplatin were dosed simultaneously by 1h infusion Q3W at 4 different combined dose levels (CBP501: 16 or 25 mg/m2; cisplatin: 60 or 75 mg/m2). Nivolumab (240 mg) was dosed on the same day, as a 1h infusion following CBP501/cisplatin. The DLT observation period was during the first 21-day cycle. Immuno-histochemistry for PD-L1 and CD8-positivity were performed in archival tumor samples.
Results:
As of 28 Dec. 2018 for AEs, 19 patients were dosed and no DLTs were reported. Treatment-related adverse events as assessed by the investigator occurred in 19 patients (100%). Fifteen patients experienced infusion reactions related to CBP501, manifesting as erythema or hives. These were managed with interruption of the infusion, administration of antihistamines, and resumption of the infusion if reactions resolved within 30 minutes (17/19 treated patients). These reactions occurred at both CBP501 dose levels evaluated. Other events occurring in &gt;/= 2 patients included anemia (10), fatigue/asthenia (8), leukopenia/neutropenia/granulocytopenia (7), thrombocytopenia (5), anorexia/weight loss (4), nausea (3), vomiting (2), hypersensitivity (2) lymphopenia (2), and acute kidney injury/renal failure (2). Eleven treatment-related Grade 3 or 4 AEs occurred in six patients, anemia (4), acute renal failure (1), diarrhea (1), fatigue (1), acute encephalopathy (1), hypocalcemia (1), neutropenia/leukopenia (1), and thrombocytopenia (1). The recommended phase 2 dose (RP2D) is 60 mg/m2 cisplatin with 25 mg/m2 CBP501 and 240 mg nivolumab. Partial responses were seen for 2 heavily pretreated patients, 1 with pancreatic cancer (PD-L1 (+) tumor cells 70%, CD8 (+) cells 18%) and 1 with microsatellite stable (MSS) colorectal cancer. Disease control rate (DCR), defined
as CR, PR and &gt;3M SD was 35% (6 /17 evaluable patients). Notably, DCR was 50% in heavily pretreated pancreatic cancer (2/4) and cholangiocarcinoma (1/2) patients.
Conclusions:
The triple-drug combination is tolerable and an RP2D has been determined. Pancreatic and MSS colorectal cancers were selected for expansion cohorts. Pre- and on-treatment biopsies will be obtained to assess modulation of the immune microenvironment by combination treatment. (NCT03113188).
Citation Format: Marc Matrana, Frank Tsai, Suma Satti, James Cleary, Jacob Estes, Khanh Do, Valentin Kolmakov, Takumi Kawabe, Geoffrey I. Shapiro. Phase Ib clinical study of CBP501, cisplatin and nivolumab administered every 3 weeks in patients with advanced refractory tumors. Dose escalation cohort [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 CT228.