The Bispecific PSMAxCD3 Antibody CC-1 in Patients with Castration Resistant Prostate Carcinoma
Trial statusRecruiting
Trial phasePhase 1
Trial typeInterventional
Biological sexMale
Age18+
SponsorUniversity Hospital Tuebingen
About this trial
This trial is a first in human (FIH) study in patients with castration resistant metastatic prostate cancer (CRPC) after failure of third-line therapy aiming to evaluate safety and efficacy of CC-1, a bispecific antibody (bsAb) with PSMAxCD3 specificity developed within DKTK. CC-1 binds to human prostate-specific membrane antigen (PSMA) on prostate cancer cells as well as to tumor vessels of CRPC, thereby allowing for a dual mode of anti-cancer action. CC-1 was developed in a novel format which not only prolongs serum half-life but most importantly reduces off-target T cell activation with expected fewer side effects. Together with preemptive IL-6 receptor (IL-6R) blockade using tocilizumab, this allows for application of effective bsAb doses with expected high anticancer activity. The study comprises two phases. The first phase is a doseescalation phase with concomitant prophylactic application of tocilizumab to evaluate the maximally tolerated dose (MTD) of CC-1. This is followed by a dose-expansion phase (also with prophylactic IL-6R blockade using tocilizumab), as this approach has been shown to be efficient and beneficial for patients. A translational research program comprising, among others, analysis of CC-1 half-life and the induced immune response as well as molecular profiling in liquid biopsies will serve to better define the mode of action of CC-1 and to identify biomarkers for further clinical development.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
Existence of a written informed consent
Patient is able to understand and comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations
CRPC after third line therapy
Life expectance of > 3 months
Disqualifiers
Other malignancy within the last 5 years except: adequately treated non-melanoma skin cancer
Concurrent or previous treatment within 30 days in another interventional clinical trial with an investigational anticancer therapy
Persistent toxicity (≥Grade 2 according to Common Terminology Criteria for Adverse Events [CTCAE] version 5.0) caused by previous cancer therapy, excluding alopecia and neurotoxicity (≤ 2 grade)
Clinical signs of active infection (>Grade 2 according to CTCAE version 5.0)
Trial design
Design model
Single group
Treatments tested in this trial
CC-1, PSMAxCD3
DrugInfusion of CC-1 over 24 hours for 7 days with possible intra-patient dose-escalation
Treatment groups
86 Participants
are divided into 1 treatment groupGroup A: CC-1 therapyExperimental treatment 1 intervention
Trial outcomes
Primary outcomes
1
Incidence and severity of adverse events (AEs) (CTCAE V5.0) over 21 days (i.e. until end of first treatment cycle (day 28))
Grade 1 No interruption- No dose adjustment Grade 2 Interrupt until Grade 0/1- No dose adjustment Any Grade ≥ 3 Interrupt until Grade 0/1 Permanently stop, except that no DLT is caused; if the latter and if AE is resolved to Grade 0/1, resume with dose reduction by two dose levels
Time frame
Each cycle is 28 days; Safety Assessment on day 1-9,15,22,28Secondary outcomes
1
Immunogenicity:
Number and percentage of subjects who develop HAHA at day 21 of every cycle and EOSf as compared to baseline.
Time frame
at day 90 of the last cycle of a given patient2
Cytokine induction
Cytokines levels in serum as assessed at baseline and at day 1-9, day 15 and day 21 in first cycle. The panel of the assay contains rather T cell specific cytokines, such as IL-2, as well as cytokines produced by a broader range of cells (e.g. IFN-ɣ, TNF, etc.) and in particular IL-6 and IL-1β, the effects of former to be blocked by tocilizumab during the study, the latter associated in recent reports with the induction of central nervous system complications during cytokine release. Cytokine levels in samples are measured centrally at the Tübingen site. Serum samples from the other sites are shipped to Universitätsklinikum Tübingen. A commercially available, flow cytometry-based assay will be used (LEGENDplexTM, Biolegend) that allows parallel determination of different cytokines in one serum sample.
Time frame
baseline and at day 1-9, day 15 and day 21 in the first cycle.3
Measurment of the CC-1 blood serum concentration
Determination of the CC-1 blood serum concentrations assessed at day 1-7, 15 in the first cycle; Samples for pharmacokinetics (5ml serum) should be collected immediately prior to each single CC- 1 application and 2h, 4h, 8h and 24h after completion of the last dose as well as on day 15 and 21. An established potency assay for CC-1 that takes advantage of genetically engineered Jurkat T cells that express a luciferase reporter driven by an NFAT-response element (Promega assay). Using 22RV1 prostate carcinoma cells as PSMAexpressing target cells, the biological activity of the antibody is determined by analysis of CD3-induced luciferase activity in the effectorcell which can be quantified by luminescence assays. Serum levels can then be determined by comparison with luminescence levels induced by a reference standard.
Time frame
At Day1-7, 15 and 21 in the first cycle4
Anti-tumor activity
Absolute changes from baseline in the tumor-marker PSA Measurement
Time frame
day 8, 15 and d21 of each cycle, and at day 90 after last cycle of given patientSponsors and contacts
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University Hospital Tuebingen
Lead sponsor
German Cancer Research Center
Collaborator
Source ClinicalTrials.gov