Protocol of a prospective, multicentre phase I study to evaluate the safety, tolerability and preliminary efficacy of the bispecific PSMAxCD3 antibody CC-1 in patients with castration-resistant prostate carcinoma

Abstract

IntroductionProstate cancer is the second most common cancer in men worldwide. When the disease becomes resistant to androgen-deprivation therapy, treatment options are sparse. To address the high medical need in castration-resistant prostate cancer (CRPC), we generated a novel PSMAxCD3 bispecific antibody termed CC-1. CC-1 binds to prostate-specific membrane antigen that is expressed on prostate cancer cells and tumour vessels, thereby allowing a dual anticancer effect.Methods and analysisThis first in human clinical study is a prospective and multicentre trial which enrols patients with metastatic CRPC after failure of established third-line therapy. CC-1 is applied after prophylactic interleukin-6 receptor blockade with tocilizumab (once 8 mg/kg body weight). Each patient receives at least one cycle of CC-1 over a time course of 7 days in an inpatient setting. If clinical benefit is observed, up to five additional cycles of CC-1 can be applied. The study is divided in two parts: (1) a dose escalation phase with intraindividual dose increase from 28 µg to the target dose of 1156 µg based on a modified fast titration design by Simon et al to determine safety, tolerability and the maximum tolerated dose (MTD) as primary endpoints and (2) a dose expansion phase with additional 14 patients on the MTD level of part (1) to identify first signs of efficacy. Secondary endpoints compromise overall safety, tumour response, survival and a translational research programme with, among others, the analysis of CC-1 half-life, the induced immune response, as well as the molecular profiling in liquid biopsies.Ethics and disseminationThe PSMAxCD3 study was approved by the Ethics Committee of The University Hospital Tübingen (100/2019AMG1) and the Paul-Ehrlich-Institut (3684/02). Clinical trial results will be published in peer-reviewed journals.Trial registration numbersClinicalTrials.gov Registry (NCT04104607) and ClinicalTrials.eu Registry (EudraCT2019-000238-20).

Mass spectrometry for quality control of bispecific antibodies after SDS‐PAGE in‐gel digestion

“…In summary, our findings encourage the implementation of MS technology to analyze impurities and the integrity of recombinant antibodies. This allowed in our case to meet GMP regulations and to initiate a clinical trial with CC-1 (Heitmann et al, 2020).…”

“…In summary, our findings encourage the implementation of MS technology to analyze impurities and the integrity of recombinant antibodies. This allowed in our case to meet GMP regulations and to initiate a clinical trial with CC-1(Heitmann et al, 2020).ACKNOWLEDGMENTSWork of the authors is supported by funds of the Bundesministerium für Bildung und Forschung (BMBF) and the Ministry of Economy of Baden-Württemberg in the framework of the Excellence Strategy of the University of Tübingen. In addition, this study was supported by the German Cancer Consortium and the Helmholtz validation fund (OPTIMAB).…”

“…Based on this protocol, we report on the development and GMP‐compliant production of the PSMAxCD3 bsAb CC‐1, and its surrogate molecule for syngeneic mouse models, in a novel IgG‐based bsAb format termed IgGsc (Coloma & Morrison, 1997; Zekri et al, 2020). After optimization, including our MS‐based protocol, we were able to finish preclinical evaluation and GMP‐compliant production of CC‐1, which has recently entered a first‐in‐human clinical trial for the treatment of castration‐resistant prostate carcinoma (NCT04104607) (Heitmann et al, 2020).…”

Bispecific Antibodies in Prostate Cancer Therapy: Current Status and Perspectives

“…Accordingly, in the last decade, several studies reported on this and other PSMA targeting radiolabeled agents that showed clinical activity in CRPC [ 57 , 58 , 59 , 60 ]. In line, a plethora of preclinically characterized therapeutic constructs and almost all bsAbs that underwent clinical evaluation in PC are directed to PSMA [ 61 , 62 , 63 , 64 ].…”

“…In line with the first notion, pharmacokinetic studies in mice showed the expected long serum half-life as compared to smaller formats missing an Fc part. An open-label, multicenter dose escalation and dose expansion phase I trial is effectively recruiting since 2019 (patients with CRPC) [ 62 ], with highly promising clinical results regarding lacking immunogenicity (development of ADAs), safety, and also efficacy.…”