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.
- 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.
Inclusion Criteria:
- Cohort I: stage IV malignant melanoma (AJCC 2009 melanoma classification)
- Cohorts II-VII end expanded cohorts: stage IIIB-C, or stage IV of malignant melanoma
(AJCC 2009 melanoma classification) Expanded cohorts C only patients with stage IV
melanoma (AJCC 2009 melanoma classification) with measurable disease (at least one
target lesion according irRECIST 1.1) [applicable for all patients after approval of
protocol version 10.0]
- 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 ≥ 9 g/dL
- Platelet count ≥ 100,000/mm³
- 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
- Patients with history of treated or inactive brain metastasis are eligible for
treatment in expanded cohort C, provided they meet all of the following criteria:
- measurable disease outside of the brain (in addition to inactive brain
metastasis);
- no ongoing requirement of corticosteroids as therapy for brain metastases,
- with corticosteroids discontinued ≥1 week prior to visit 2 (day 1) with no
ongoing symptoms attributable to brain metastasis;
- the screening brain radiographic imaging is ≥ 4 weeks since completion of
radiotherapy
- Post-splenectomy Patients
- 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 active 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 study treatment
administration
- Myelosuppressive chemotherapy within 14 days and after reconstitution of blood values
prior to the first study treatment administration
- Ipilimumab within 28 days prior to the first study treatment administration
- Treatments with BRAF inhibitors, MEK inhibitors, or the combination of both, and
anti-PD-1 antibodies within 14 days prior to the first administration of study
treatment (not applicable for patients with parallel treatment in expanded cohorts A,
B, or C at the discretion of the investigator)
- Interferon, major surgery, vaccination, and other investigational agents within 28
days or 5 half-lives depending on what gives the longer range before the first
treatment
- Approved BRAF inhibitors vemurafenib or dabrafenib, approved anti-PD-1 inhibitors
nivolumab or pembrolizumab as well as approved MEK inhibitor trametinib, or the
approved combination of BRAF-MEK inhibitors in patients in 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 cohorts, after analysis of safety data collected
for the dose escalation cohorts and DSMB approval. Local radiation will be allowed as
concurrent treatment for patients in expanded cohort as well.
- After approval of protocol version 10.0 only anti-PD-1 antibodies are allowed for
treatment of patients in expanded cohort C.
- 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 for at least 28 days (male patients) and 90 days (female patients
of childbearing potential)after the last dose of study treatment
- Presence of a severe 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
