The Bispecific PSMAxCD3 Antibody CC-1 in Patients with Castration Resistant Prostate Carcinoma

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.

Eligibility

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)

Conditions2

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