Clinical Trials /

Evaluation of the Safety and Tolerability of i.v. Administration of a Cancer Vaccine in Patients With Advanced Melanoma

NCT02410733

Description:

The purpose of this study is to determine the safety and tolerability of intravenous administration of a tetravalent RNA-lipoplex cancer vaccine targeting four tumor-associated antigens in patients with advanced melanoma.

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Evaluation of the Safety and Tolerability of i.v. Administration of a Cancer Vaccine in Patients With Advanced Melanoma
  • Official Title: Clinical First-in-human Dose Escalation Study Evaluating the Safety and Tolerability of Intravenous Administration of a Tetravalent RNA-lipoplex Cancer Vaccine Targeting Four Tumour-associated Antigens in Patients With Advanced Melanoma

Clinical Trial IDs

  • ORG STUDY ID: RB_0003-01
  • NCT ID: NCT02410733

Conditions

  • Melanoma

Interventions

DrugSynonymsArms
Lipo-MERITLipo-MERIT

Purpose

The purpose of this study is to determine the safety and tolerability of intravenous administration of a tetravalent RNA-lipoplex cancer vaccine targeting four tumor-associated antigens in patients with advanced melanoma.

Detailed Description

      -  The Lipo-MERIT vaccine consists of the four naked ribonucleic acid (RNA)-drug products
           (DPs) RBL001.1, RBL002.2, RBL003.1, and RBL004.1 that are optimised to induce
           antigen-specific CD8+ and CD4+ T cell responses against four selected malignant
           melanoma-associated antigens respectively.

        -  In this study, naked RNA DPs will be formulated with liposomes to form RNA-lipoplexes
           (RNA(LIP)) that (i) protect RNA from degradation in the serum, (ii) enable in vivo
           targeting of systemic antigen-presenting cells (APC), and therefore (iii) constitute a
           novel vaccine formulation that supports intravenous administration.

        -  The Lipo-MERIT vaccine is expected to lead to several effects contributing to its
           immunological (therapeutic) effect. First, the RNA-lipoplexes home to APCs in lymphoid
           organs after intravenous injection, where they are rapidly taken up by professional
           APCs. Incorporated RNA is translocated to the cytoplasm leading to its translation by
           the host ribosome complex into four Antigen encoding proteins which are processed and
           presented on both HLA-class I as well as HLA-class II molecules. Consecutively,
           antigen-specific CD8+ and CD4+ T cell responses will be triggered by HLA-peptide
           complexes on the surface of antigen-presenting cells.

        -  In addition, the Lipo-MERIT vaccine is expected to transiently activate APCs (change of
           surface marker expression and cytokine secretion) via signalling of TLRs, subsequently
           leading to the transient induction of inflammatory cytokines (such as IFN-α and IP-10)
           supporting the induction of tumour-antigen specific T cell responses.
    

Trial Arms

NameTypeDescriptionInterventions
Lipo-MERITExperimental• 5 dose escalation cohorts (3 patients each cohort) One expanded cohort: 24 patients will be treated with the MTD or a target dose defined by the sponsor

    Eligibility Criteria

            Inclusion Criteria:
    
              -  Cohort I: stage IV malignant melanoma (AJCC 2009 melanoma classification)
    
              -  Cohorts II-V: stage IIIB-C, or stage IV of malignant melanoma (AJCC 2009 melanoma
                 classification)
    
              -  Therapy only for subjects not eligible or declining any other available approved
                 therapy after all available treatment options have been transparently disclosed (to be
                 documented!)
    
              -  Expression of either one of four TAA confirmed by RT-qPCR analysis from FFPE
    
              -  ≥ 18 years of age
    
              -  Written informed consent
    
              -  ECOG performance status (PS) 0-1
    
              -  Life expectancy > 6 months
    
              -  WBC ≥ 3x10E9/L
    
              -  Hemoglobin ≥ 10 g/dL
    
              -  Platelet count ≥ 100,000/mm³
    
              -  LDH level < 2.0 x ULN
    
              -  ALT/AST < 3 x ULN (except patients with liver metastasis)
    
              -  Negative pregnancy test (measured by β-HCG) for females with childbearing age
    
            Exclusion Criteria:
    
              -  Pregnancy or breastfeeding
    
              -  Primary ocular melanoma
    
              -  Concurrence of a second malignancy other than squamous or basal cell carcinoma,
                 non-active prostate cancer or cervical carcinoma in situ or non-active treated
                 urothelial carcinoma
    
              -  Brain metastases
    
              -  Post-splenectomy patients
    
              -  Known or symptomatic pleural effusions and/or ascites
    
              -  Known hypersensitivity to the active substance or to any of the excipients
    
              -  A serious local infection (e. g. cellulitis, abscess) or systemic infection (e. g.
                 pneumonia, septicemia) which requires systemic antibiotic treatment within 2 weeks
                 prior to the first dose of study medication
    
              -  Positive test for acute or chronic active hepatitis B or C infection
    
              -  Clinically relevant autoimmune disease
    
              -  Systemic immune suppression:
    
                   -  HIV disease
    
                   -  Use of chronic oral or systemic steroid medication (topical or inhalational
                      steroids are permitted)
    
                   -  Other clinical relevant systemic immune suppression
    
              -  Symptomatic congestive heart failure (NYHA 3 or 4)
    
              -  Unstable angina pectoris
    
              -  Radiotherapy and minor surgery within 14 days prior to the first administration of
                 study treatment
    
              -  Myelosuppressive chemotherapy within 14 days and after reconstitution of blood values
                 prior to the first administration of study treatment
    
              -  Ipilimumab within 28 days prior to the first administration of study treatment
    
              -  Interferon, major surgery,vaccination, and other investigational agents within 28 days
                 or 5 half-lifes depending on what gives the longer range before the first treatment
    
              -  Approved BRAF inhibitors Vemurafenib or Dabrafenib, approved anti-PD-1 antibodies
                 Opdivo or Keytruda as well as the approved MEK inhibitor Trametinib in patients of the
                 dose escalation cohorts. Concomitant treatment with approved BRAF Inhibitors, approved
                 anti-PD-1 antibodies or MEK inhibitor as well as the approved combination of BRAF-MEK
                 inhibitors is allowed for patients included in the expanded cohort, after analysis of
                 safety data collected for the dose escalation cohorts and DSMB approval. Local
                 radiation will be allowed as concurrent treatment.
    
              -  Fertile males and females who are unwilling to use a highly effective method of birth
                 control (less than 1% per year, e.g. condom with spermicide, diaphragm with
                 spermicide, birth control pills, injections, patches or intrauterine device) during
                 study treatment and 28 days after the last dose of study treatment
    
              -  Presence of a serious concurrent illness or other condition (e. g. psychological,
                 family, sociological, or geographical circumstances) that does not permit adequate
                 follow-up and compliance with the protocol
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Number of Adverse Events as a Measure of safety and tolerability
    Time Frame:120 days
    Safety Issue:
    Description:Number of patients with adverse events, total number of adverse events, dose limiting toxicities

    Secondary Outcome Measures

    Measure:Change of induced T-cell responses for Lipo-MERIT vaccine from visit 2 (day 1) to day 71 (assessed by immunoassays)
    Time Frame:71 days
    Safety Issue:
    Description:Vaccine induced T-cell responses assessed by immunoassays in peripheral blood and skin
    Measure:Clinical Monitoring of tumour lesions (determined by CT or MRI results evaluated by irRECIST)
    Time Frame:90 days
    Safety Issue:
    Description:Tumour lesion status as determined by CT or MRI results evaluated by irRECIST

    Details

    Phase:Phase 1
    Primary Purpose:Interventional
    Overall Status:Unknown status
    Lead Sponsor:Biontech RNA Pharmaceuticals GmbH

    Trial Keywords

    • melanoma
    • Lipo-MERIT
    • cancer vaccine
    • RB_0003-01
    • BioNTech
    • BioNTech RNA Pharmaceuticals
    • BioNTech RNA
    • RNA

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