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the Bispecific PSMAxCD3 Antibody CC-1 in Patients With Castration Resistant Prostate Carcinoma (PSMAxCD3)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04104607
Recruitment Status : Recruiting
First Posted : September 26, 2019
Last Update Posted : November 19, 2019
Sponsor:
Collaborator:
German Cancer Research Center
Information provided by (Responsible Party):
University Hospital Tuebingen

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Castration-Resistant Prostatic Cancer Drug: CC-1, PSMAxCD3 Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 86 participants
Intervention Model: Single Group Assignment
Intervention Model Description: Open-label, multicenter dose escalation and dose expansion phase I trial, designed to gain evidence of maximally tolerated and recommended phase-II dose of CC-1 in adult patients with CRPC.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: First in Human Study to Evaluate the Safety, Tolerability and Preliminary Efficacy of the Bispecific PSMAxCD3 Antibody CC-1 in Patients With Castration Resistant Prostate Carcinoma
Actual Study Start Date : November 15, 2019
Estimated Primary Completion Date : March 1, 2020
Estimated Study Completion Date : September 1, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Prostate Cancer

Arm Intervention/treatment
Experimental: CC-1 therapy
Infusion of CC-1 over 24 hours for 7 days with possible intra-patient dose-escalation. In case of clinical benefit, additional cycles with a total of up to six are possible.
Drug: CC-1, PSMAxCD3
Infusion of CC-1 over 24 hours for 7 days with possible intra-patient dose-escalation




Primary Outcome Measures :
  1. Incidence and severity of adverse events (AEs) (CTCAE V5.0) over 21 days (i.e. until end of first treatment cycle (day 28)) [ Time Frame: Each cycle is 28 days; Safety Assessment on day 1-9,15,22,28 ]
    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


Secondary Outcome Measures :
  1. Immunogenicity: [ Time Frame: at day 90 of the last cycle of a given patient ]
    Number and percentage of subjects who develop HAHA at day 21 of every cycle and EOSf as compared to baseline.

  2. Cytokine induction [ Time Frame: baseline and at day 1-9, day 15 and day 21 in the first cycle. ]
    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.

  3. Measurment of the CC-1 blood serum concentration [ Time Frame: At Day1-7, 15 and 21 in the first cycle ]

    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.


  4. Anti-tumor activity [ Time Frame: day 8, 15 and d21 of each cycle, and at day 90 after last cycle of given patient ]
    Absolute changes from baseline in the tumor-marker PSA Measurement

  5. Anti-tumor activity [ Time Frame: at day 90 and thereafter for 6 months every 3 months after last cycle of given patient ]
    Objective tumor response assessed by RECIST on routine imaging

  6. Survival [ Time Frame: one year after day 90 ]
    overall and progression free survival status as percentage of patients alive

  7. Quality of life Assessment according to EORTC QLQ C-30 form [ Time Frame: baseline, day 8, 21, 90 (EOSf) and 6 months after start of CC-1 treatment. ]

    QoL is defined as overall quality of life scores (EORTC QLQ C-30) at baseline, day 8, day 21, EOSf and 6 months after start of CC-1 treatmentOverall quality of life scores (EORTC QLQ C-30) The QoL analyses will be performed as previously described. The QoL scales will be scored and analysed according to the EORTC recommendations as described in the EORTC QLQ-C30 scoring manual. The Quality of Life subscales and single item sub-scores will be summarized by the mean and median and plotted by time. The change from baseline for all domains will be examined. Overall quality of life scores will be assessed with the EORTC QLQ C-30 questionnaire (https://www.onkopedia.com/de/wissensdatenbank/wissensdatenbank/allgemeinzustand/EORT CQLQC30.pdf).

    Scale is 1 to 4 corresponding with (1) not at all, (2) a little, (3) quite a bit, (4) verymuch




Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Patients with CRPC will be included in this clinical trial. Patients must meet all of the following inclusion criteria to be eligible for enrolment into the study:

  • 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
  • At least one measurable lesion that can be accurately assessed at baseline by CT or MRI and is suitable for repeated assessment
  • Eastern Cooperative Oncology Group Performance (ECOG) Status ≤ 2
  • Patient aged ≥ 18, no upper age limit
  • Male patients with partners of child-bearing potential, who are sexually active, must agree to the use of two highly effective forms of contraception. This should be started from the signing of the informed consent and continue throughout period of taking study treatment for 3 months after last dose of study drug.
  • Adequate bone marrow, renal, and hepatic function defined by laboratory tests within 14 days prior to study treatment:

    • Hemoglobin ≥ 10 g/dl
    • Neutrophil count ≥ 1,500/mm3
    • Platelet count ≥ 100,000/μl
    • Bilirubin ≤ 1.5 x upper limit of normal (ULN)
    • ALT and AST ≤ 2.5 x ULN
    • Alkaline phosphatase ≤ 2.5 x ULN
    • PT-INR/PTT ≤ 1.5 x ULN
    • Creatine kinase ≤ 2.5 x ULN
    • Serum creatinine ≤ 1.5 mg/dl or creatinine clearance ≥ 60 ml/min

Exclusion Criteria:

Patients fulfilling any of the following criteria cannot be enrolled in the trial:

  • 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)
  • History of HIV infection
  • Immunocompromised patients
  • Active or chronic viral hepatitis (HBV or HCV)
  • History of autoimmune disease
  • History of relevant CNS pathology or current relevant CNS pathology (e.g. seizure, paresis, aphasia, cerebrovascular ischemia/hemorrhage, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, psychosis, coordination or movement disorder) Epilepsy requiring pharmacologic treatment
  • Therapeutic anticoagulation therapy
  • Major surgery within 4 weeks of starting study treatment. Patients must have recovered from any effects of major surgery.
  • Patients receiving any systemic chemotherapy or radiotherapy within 2 weeks prior to study treatment or a longer period depending on the defined characteristics of the agents used
  • Heart failure NYHA III/IV
  • Severe obstructive or restrictive ventilation disorder
  • Known history of GI-perforation
  • Pre-existing HAHA
  • Known intolerance to CC-1, tocilizumab or other immunoglobulin drug products as well as hypersensitivity to any of the excipients present in the respective drug products (CC-1, tocilizumab)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04104607


Contacts
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Contact: Helmut R Salih, Prof. +49 (0)7071 29-83275 helmut.salih@med.uni-tuebingen.de
Contact: Juliane Walz, PD Dr. med. +49 (0)7071 29-83275 juliane.walz@med.uni-tuebingen.de

Locations
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Germany
University Hospital Tuebingen Recruiting
Tuebingen, Baden-Wuerttemberg, Germany, 72076
Contact: Helmut R Salih, Prof.    +49(0)707129 ext 83275    helmut.salih@med.uni-tueningen.de   
Contact: Juliane walz, PD Dr.    +49(0)707129 ext 87305    juliane.walz@med.uni-tuebingen.de   
University hospital Heidelberg Not yet recruiting
Heidelberg, BadenWuerttemberg, Germany, 69120
Contact: Richard Schlenk, Prof.    +49 (0)6221 56-6228    richard.schlenk@nct-heidelberg.de   
Sponsors and Collaborators
University Hospital Tuebingen
German Cancer Research Center
Investigators
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Principal Investigator: Helmut R Salih, Prof. KKE Translational Immunology, University Hospital Tübingen

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Responsible Party: University Hospital Tuebingen
ClinicalTrials.gov Identifier: NCT04104607    
Other Study ID Numbers: DKTK_PMO_1605
2019-000238-20 ( EudraCT Number )
First Posted: September 26, 2019    Key Record Dates
Last Update Posted: November 19, 2019
Last Verified: September 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University Hospital Tuebingen:
PSMA
Resistant Prostate Cancer
PSMAxCD3
CC-1
Additional relevant MeSH terms:
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Prostatic Neoplasms
Prostatic Neoplasms, Castration-Resistant
Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Genital Diseases, Male
Prostatic Diseases
Antibodies
Immunologic Factors
Physiological Effects of Drugs