Clinical First-in-human Dose Escalation Study Evaluating the Safety and Tolerability of Intranodal Administration of an RNA-based Cancer Vaccine Targeting Two Tumor-associated Antigens in Patients With Advanced Melanoma
Overview
- Phase
- Phase 1
- Intervention
- Not specified
- Conditions
- Melanoma
- Sponsor
- BioNTech RNA Pharmaceuticals GmbH
- Enrollment
- 29
- Locations
- 4
- Primary Endpoint
- Number of adverse events
- Status
- Completed
- Last Updated
- 6 years ago
Overview
Brief Summary
Clinical first-in-human dose escalation study evaluating the safety and tolerability of intranodal administration of an RNA-based cancer vaccine targeting two tumor-associated antigens in patients with advanced melanoma
Detailed Description
RBL001/RBL002 are naked ribonucleic acid (RNA) based recombinant vaccines that were optimized to induce antigen specific CD8+ and CD4+ T cell responses against malignant melanoma target antigens. The Targeted antigens are well characterized antigens in melanoma that have been previously utilized with excellent safety and proven immunogenicity as vaccine targets in a number of independent clinical trials. The overall rationale of the study is to determine safety of the novel RNA based vaccine approach and determine vaccine target antigen directed immune responses as early biomarkers for clinical mode of action. The RBL001/RBL002 vaccine is expected to lead to several effects contributing to its immunological (therapeutic) effect. First, ultrasound guided administration of naked RNA drug product into lymph nodes is expected to result in rapid uptake of naked RNA by lymph node resident professional antigen-presenting cells (APCs). Incorporated RNA is known to translocate to the cytoplasm leading to its translation by the host ribosome complex into the respective protein antigens. The recombinant vaccine is optimized for immunogenicity and enables presentation of diverse antigenic epitopes 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, RNA administration will also lead to transient activation (change of surface marker expression and cytokine secretion) of APCs in the targeted lymph nodes particularly via signaling of TLR 7 and 8 leading to an adjuvant effect, supporting the induction of target-specific T cell responses with systemic anti-tumor activity.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Stage IIC, IIIA-C or unresectable stage IV of cutaneous melanoma (AJCC 2009 melanoma classification)
- •First line therapy for subjects not eligible or declining other first line therapies after all available treatment options have been transparently disclosed (to be documented!)
- •Antigen expression confirmed by RT-PCR analysis from FFPE
- •≥ 18 years of age
- •Written informed consent (part I and part II)
- •ECOG performance status (PS) 0-1 or Karnofsky Index 70-100 %
- •Life expectancy \> 3 months
- •WBC ≥ 3x109/L
- •Hemoglobin ≥ 10 g/dl
- •Platelet count ≥ 100,000/mm³
Exclusion Criteria
- •Pregnancy or breastfeeding
- •Primary ocular melanoma
- •Presence of history (\< 5 years) of a second malignancy other than squamous or basal cell carcinoma, non-active prostate cancer or cervical carcinoma in situ
- •Brain metastases
- •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
- •Acute or chronic active hepatitis B or C infection, EBV or CMV
- •Receipt of allogenic stem cell transplantation
- •Clinically relevant autoimmune disease
Outcomes
Primary Outcomes
Number of adverse events
Time Frame: 90 days
Number of Patients with adverse events, total number of adverse events, dose-limiting toxicities
Secondary Outcomes
- Clinical Monitoring of Tumor Lesions(90 days)
- Determination of antitumoral immune responses(90 days)