RBL001/RBL002 Phase I Clinical Trial

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Melanoma

Intervention / Treatment
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* Biological: RBL001/RBL002


Participation Criteria
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Eligibility Criteria
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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 LDH level < 2.0 x ULN Negative pregnancy test (measured by β-HCG) for females of childbearing age Suitable lymph nodes for injection using ultrasound guidance 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 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, chemotherapy, major surgery, immunotherapy, vaccination, any other concurrent anticancer therapy or any investigational drug within 28 days before the first treatment of this study Minor surgery within 14 days before the first treatment of this study Treatment with Ipilimumab within 84 days before the first treatment of this study Fertile males and females who are unwilling to employ adequate means of contraception (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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RBL001/RBL002 intranodal administration<br>All participants will be treated with RBL001/RBL002 after allocation to one of the four escalating dose cohorts: Cohort-1 50 µg RBL001 and 50 µg RBL002 Cohort-2 100 µg RBL001 and 100 µg RBL002 Cohort-3 300 µg RBL001 and 300 µg RBL002 Cohort-4 600 µg RBL001 and 600 µg RBL002 | Biological: RBL001/RBL002<br>* Each participant will receive 8 repeated intranodal administrations of RBL001 and RBL002 during a time frame of 43 to 51 days.<br>* Other names: cancer vaccine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of adverse events | Number of Patients with adverse events, total number of adverse events, dose-limiting toxicities | 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determination of antitumoral immune responses | Cellular immune responses, cytokines, AB responses, serum biomarkers, and further immunological parameters will be determined once or repeatedly in the course of treatment. In the latter case changes from baseline will be tabulated. | 90 days | 
| Clinical Monitoring of Tumor Lesions | Tumor lesion status as determined by CT or MRI results evaluated by irRC and RECIST. | 90 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Biontech, Biontech RNA Pharmaceuticals GmbH, Biontech RNA, MERIT, RNA, Immuno Therapy, RB_0001-01, Ribological, Melanoma, RBL001, RBL002, cancer vaccine