Patient case: 70-year-old male with melanoma; genetic feature: NF1 truncation

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

Summary: 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.

Eligibility: 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

Relevance to patient case: not relevant