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

Introduction: Prostate 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 analysis: This 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 dissemination: The 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 numbers: ClinicalTrials.gov Registry (NCT04104607) and ClinicalTrials.eu Registry (EudraCT2019-000238-20).

Keywords: adult oncology; immunology; urological tumours.

Conflict of interest statement

Competing interests: GJ and HRS are listed as inventors on the patent application ‘Novel PSMA binding antibody and uses thereof’, EP16151281 and others, with the German Cancer Research Center (DKFZ), Heidelberg, Germany, as applicant. The other authors declare no competing interests.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Study overview. CC-1, bispecific PSMAxCD3 antibody; CRPC, castration-resistant prostate carcinoma; MTD, maximum tolerated dose.

Figure 2

Dosing in different parts of CC-1 study. Part I: intraindividual dose escalation: tocilizumab (8 mg/kg body weight) is applied once as pretreatment >1 hour prior to the start of CC-1 infusion on day 1 of each cycle. CC-1 is administered as a 24-hour continuous intravenous infusion with escalated doses of CC-1. We perform a daily, intraindividual dose escalation to the next higher dose level. Dose escalations are depicted in the first patient (A), second (B), third (C). (D) Fourth to tenth patient of part I and part II: dose expansion at maximum tolerated dose (MTD): after pre-emptive interleukin-6 receptor blockade CC-1 is administered as a 24-hour continuous intravenous infusion started at the MTD dose level. The dose levels applied on day 1 and day 2 must not exceed 110 µg (maximum day 1 level) and 300 µg (maximum day 2 level), respectively. CC-1, bispecific PSMAxCD3 antibody.

Figure 3

Flow chart of phase I design. In part of the phase I this is a dose escalation. Rather than the classical 3+3 design our escalation is intraindividual based in case no dose-limiting toxicity (DLT) occurs until maximum tolerated dose (MTD) is reached. If a DLT is reported, we will switch back to 3+3 design. D, dose level; pt, patient.

Figure 4

Study schedule. Screening: ≤14 days. Assessment of baseline values for imaging and quality of life; infusion period: days 1–7 (hospitalised as inpatient); on day 1 baseline assessment for prostate-specific antigen, cytokines and liquid biopsy, vital signs, concomitant medication, signs and symptoms of disease; infusion free period: days 8–9 no infusion, but still hospitalised as inpatient (discharge on day 9); day 9/10–21 (±2) outpatient; visit at day 15 (±2) and 21 (±2) (end of treatment/EOT); follow-up period: outpatient, visit at day 90 (±7) (end of safety follow-up, EOSf); after EOSf follow-up every 90 days (up to one 1 year, ongoing adverse events have to be followed to resolution).