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Bispecific PSMAxCD3 Antibody CC-1 in Patients With Squamous Cell Carcinoma of the Lung

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ClinicalTrials.gov Identifier: NCT04496674
Recruitment Status : Recruiting
First Posted : August 3, 2020
Last Update Posted : February 17, 2022
University Hospital Tuebingen
Information provided by (Responsible Party):
German Cancer Research Center

Brief Summary:
This trial is a phase I study in patients with metastatic non-small-cell lung cancer (NSCLC) after failure of second 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 tumor cells of squamous cell carcinoma of the lung (SCC) as well as to tumor vessels of SCC, 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 dose-escalation 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). 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
Lung Cancer Squamous Cell Drug: CC-1 and Toczilizumab Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 86 participants
Allocation: N/A
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 SCC of the lung
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: PPhase-I Study to Evaluate the Safety, Tolerability and Preliminary Efficacy of the Bispecific PSMAxCD3 Antibody CC-1 as Single Agent and Combined With Checkpoint Blockade in Patients With Squamous Cell Carcinoma of the Lung
Actual Study Start Date : February 2, 2022
Estimated Primary Completion Date : March 31, 2025
Estimated Study Completion Date : September 30, 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lung Cancer

Arm Intervention/treatment
Experimental: Treatment with bispecific Ab CC-1
administration of bispecific PSAMxCD3 Ab CC-1.
Drug: CC-1 and Toczilizumab
Adminsitration of CC-1 and Toczilizumab

Primary Outcome Measures :
  1. Incidence and severity of adverse events (AEs) (CTCAE V5.0) over 22 days [ Time Frame: 10-72 patients. at least 1 cycle (for 22 day cycles) plus 21 days follow-up, but may vary depending on treatment-induced clinical benefit and optional additional cycles ]

    Incidence and severity of adverse events (AEs) (CTCAE V5.0) over 22 days (i.e. until end of first treatment cycle)

    Full hematology assessments for safety hemoglobin, red blood cells, platelets, mean cell volume, mean cell hemoglobin concentration, mean cell hemoglobin, white blood cells, absolute differential white cell count and absolute neutrophil count or segmented neutrophil count and Band forms should be performed at each visit and when clinically indicated.

    Biochemistry assessments for safety:

    sodium, potassium, calcium, magnesium, glucose, creatinine, total bilirubin, gamma glutamyltransferase, alkaline phosphatase,aspartate transaminase, alanine transaminase, urea or blood urea nitrogen, total protein, albumin and lactic dehydrogenase are performed.

  2. Dose expansion part [ Time Frame: 14 patients.at least 1 cycle (for 22 day cycles) plus 21 days follow-up, but may vary depending on treatment-induced clinical benefit and optional additional cycles ]

    To define the recommended phase-II dose of CC-1 under preemptive IL-6R blockade


Secondary Outcome Measures :
  1. Immunogenicity [ Time Frame: day 15, day 43 ]

    Number and percentage of subjects who develop HAHA at day 15 of every cycle and End Of Safety follw-up (day 43 of last cycle of a given patient) as compared to baseline.

    n case of CC-1 in this study, AESIs include cytokine-release syndrome (CRS) as the major "class toxicity" for bsAbs, anaphylactic reactions and immunogenicity of the drug substance

    With regard to trial schedule and AESI occurrence, AESIs constitute:

    • CRS (i.e. within treatment period)
    • Anaphylactic reactions upon study drug administration (i.e., within 24h)
    • Development of anti-CC-1 antibodies (HAHA) (day 15, day 43)

    AESIs are always be addressed as part of the patient safety report to the DSMB, also non-occurrence will be mentioned . Depending on severity of the AESI, dose reduction or discontinuation of treatment (DLT) may be necessary. Of note, allergic /anaphylactic reactions are not defined as DLT.

  2. Anti-tumor activity [ Time Frame: End of safety follow up,day 22 of cycle 3 and 4 ]

    Objective tumor response assessed by RECIST on routine imaging at End of safety follow-up and thereafter for 12 months every 3 months.

    • For patients receiving more than one cycle objective tumor response will be assessed by RECIST on additional routine imaging every 6 weeks, i.e. prior to the application of cycle 3 (day 22 +/- 5 days of cycle 2) and cycle 5 (day 22 +/-5 days of cycle 4).

    Tumor response rate (TRR) The TRR is defined as the percentage of patients with complete remissions (CR) and partial remissions (PR) according to RECIST version 1.1. The TRR will be assessed at 3 and 6 months, as well as every 3 months during the extended treatment period (compare Trial Schedule). For patients receiving additional treatment cycles TRR will be assessed before the application of cycle 3 (day 22 +/- 5 days of cycle 2) and cycle 5 (day 22 +/-5 days of cycle 4).

  3. Survival [ Time Frame: 12 month after end of safety follow up ]
    OS is defined as the time from screening to time of death from any cause. Patients without event are censored at the last date of follow-up.

Other Outcome Measures:
  1. PSMA PET CT [ Time Frame: baseline, End Of safety follow up and at any timepoint dury study treatment if progressive disease is assumed in routine imaging ]

    Correlation with immunhistochemical proven PSMA expression on tumor at baseline

    • Value of PSMA-PET-CT in the context of treatment with CC-1 and progressive disease will be performed in terms of a translational research program to correlate PSMA expression as assessed by cryobiopsy with PSMA imaging. PSMA-PET CT will be performed at baseline, EOSf and at any time point during study treatment (cycle 1-6) if progressive disease is assumed in routine imaging, next imaging will be amended by PSMA-PET. Thus, a minimum of 2 and maximum of 3 PSMA-PET-CTs will be performed per patient.

  2. Cytokine induction: [ Time Frame: at baseline and at day 1-9, day 15 and day 22 in first cycle. ]
    Cytokines levels in serum as assessed

  3. Pharmacokonteic [ Time Frame: at day 1-9, day 15 and day 22 in the first cycle. ]
    CC-1 serum concentrations assessed

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:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • • 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
    • SCC of the lung with detectable PSMA expression by tumor cells after second line treatment. PSMA expression is to be determined by central immunohistochemical assessment of fresh or cryopreserved tumor samples. Only patients with proven PSMA expression by tumor cells as defined by ≥10% positivity of tumor cells can be included.
    • 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 (ECOG) Performance Status ≤ 2
    • Patient aged ≥ 18, no upper age limit
    • Female patients of child bearing potential and male patients with partners of child bearing potential, who are sexually active, must agree to the use of two effective forms (at least one highly effective method) of contraception. This should be started from the signing of the informed consent and continue throughout period of taking study treatment and for 1 month (female patients) / 3 months (male patients) after last dose of study drug. Postmenopausal or evidence of non-childbearing status. For women of childbearing potential: negative urine or serum pregnancy test within 21 days prior to study treatment and confirmed prior to treatment on day 1. Postmenopausal or evidence of non-childbearing status is defined as:
  • Amenorrhoeic for 1 year or more following cessation of exogenous hormonal treatments
  • Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the post menopausal range for women under 50
  • Radiation-induced oophorectomy with last menses >1 year ago
  • Chemotherapy-induced menopause with >1 year interval since last menses
  • Surgical sterilisation (bilateral oophorectomy or hysterectomy)

    • Adequate bone marrow, renal, and hepatic function defined by laboratory tests within 14 days prior to study treatment:

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 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:

  • • Other malignancy within the last 5 years except: adequately treated non-melanoma skin cancer, carcinoma in situ of the cervix, carcinoma in situ of the breast, histological finding of prostate cancer of TNM stage T1

    • PSMA expression <10% by tumor cells
    • 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)
    • Cerebral/Meningeal manifestation of the SCC of the lung
    • History of HIV infection
    • Immunocompromised patients
    • Viral active or chronic 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
    • 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): NCT04496674

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

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Robert Bosch Centrum für Tumorerkrankungen Not yet recruiting
Stuttgart, BW, Germany, 70376
Contact: Hans-Georg Kopp, Prof. Dr.    +49 (0)711 8101-2001    hans-georg.kopp@rbk.de   
University Hospital Tuebingen, CCU Translational Immunology Recruiting
Tuebingen, Bw, Germany, 72076
Contact: Juliane Walz, Prof. Dr.       juliane.walz@med.uni-tuebingen.de   
Contact: Jonas Heitmann, Dr.       jonas.heitmann@med.uni-tuebingen.de   
Sponsors and Collaborators
German Cancer Research Center
University Hospital Tuebingen
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Responsible Party: German Cancer Research Center
ClinicalTrials.gov Identifier: NCT04496674    
Other Study ID Numbers: PSMAxCD3_SCC_01
First Posted: August 3, 2020    Key Record Dates
Last Update Posted: February 17, 2022
Last Verified: February 2022

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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 German Cancer Research Center:
third line therapy
Metastatic squamous cell cancer
Additional relevant MeSH terms:
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Carcinoma, Squamous Cell
Lung Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms, Squamous Cell
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases