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EVI-3: Combining Active and Passive DNA Hypomethylation (NMDSG19A)

 

Sponsor: Kirsten Grønbæk

Project group:

Principal Investigator: Dr. Kirsten Grønbæk (Rigshospitalet, Copenhagen)

Coordinator Denmark: Dr. Kirsten Grønbæk (Rigshospitalet, Copenhagen)

Coordinator Sweden: Dr. Hege Gravdahl Garelius (Sahlgrenska University Hospital, Gothenburg)

Coordinator Norway: Dr. Synne Torkildsen (Oslo University Hospital, Oslo)

Coordinator Finland: Dr. Freja Ebeling (Helsinki University Hospital Comprehensive Cancer Center, Helsinki)

Coordinator United Kingdom: Dr. Timothy Chevassut (Royal Sussex County Hospital, Brighton)

Van Andel Research Institute (VARI) - Stand Up To Cancer Epigenetics Dream Team

Co-investigators: Dr. Eva Hellström-Lindberg (Karolinska University Hospital, Huddinge), Dr. Lars Nilsson (Skåne University Hospital, Lund), Dr. David Bowen (Leeds Teaching Hospitals NHS Trust, Leeds), Dr. Bo Kok Mortensen (Herlev University Hospital, Copenhagen), Dr. Jack Maibom (Zealand University Hospital, Roskilde), Dr. Klas Raaschou-Jensen (Odense University Hospital, Odense), Dr. Marianne Tang Severinsen (Aalborg University Hospital, Aalborg), Dr. Stine Ulrik Mikkelsen (Rigshospitalet, Copenhagen), Dr. Amalie Bach Nielsen (Rigshospitalet, Copenhagen)

Genetic analyses: VARI

Experimental substudies: VARI, Dr. Petra Hajkova (Imperial College Faculty of Medicine, London), Dr. Mette Klarskov Andersen (Rigshospitalet, Copenhagen), Prof. Jens Lykkesfeldt (University of Copenhagen, Copenhagen), Prof. Sine Reker Hadrup (Technical University of Denmark, Copenhagen)

Study objectives:

Primary objectives:

The primary objective of this trial is to investigate if oral vitamin C supplementation increases the efficacy of azacitidine (AZA) treatment in AZA-naïve patients with higher-risk MDS, CMML-2 or low-blast count AML (20-30% blasts). The efficacy of oral vitamin C in combination with AZA will be assessed by duration of AZA therapy in patients randomized to AZA + oral vitamin C compared to patients randomized to AZA + placebo. AZA treatment duration represents a composite measure of rate of response to AZA therapy and duration of response.

Secondary objectives:

  1. Number and rate of adverse events and serious adverse events
  2. Overall survival in months
  3. Rate of overall response and rates of individual responses (as according to international consensus criteria)
  4. Change in patient-reported outcome (PRO) measures including health-related quality of life scores (EORTC QLQ-C30 and Hematological Malignancy (HM)-PRO)
  5. Change in variant allele frequency of mutated clones in bone marrow mononuclear cells
  6. Change in global 5-hydroxymethylcytosine (hmC)/5-methylcytosine (mC) in bone marrow CD34+ cells
  7. Change in 5-hmC/5-mC at specific loci at promoters/enhancers/long terminal repeats or at other regulatory genomic regions of tumor suppressors, oncogenes, genes involved in hematopoietic development or human endogenous retrovirus (HERV) in bone marrow CD34+ cells
  8. Change in expression of genes involved in viral defense pathways, cell differentiation and tumor suppression in bone marrow CD34+ cells
  1. Change in levels of mRNA expression of HERV in bone marrow CD34+ cells and HERV specific T-cell responses

Status: Study ready for inclusion of patients in Denmark; other sites awaiting regional/national ethics committee approval and contracts

Start: September 1st, 2019 (Copenhagen)

Expected accrual time: 36 months

First patient inclusion: Q3 2019

Last patient inclusion: Q3 2022

Eligibility criteria:

Inclusion criteria:

  • Patients eligible for treatment with AZA with one of the following diagnoses according to WHO 2016:
    • MDS; Higher-risk MDS according to the IPSS-R, i.e., intermediate- to very high-risk (IPSS-R score >3)
    • CMML; CMML with 10-29 percent marrow blasts without myeloproliferative disorder
    • AML; AML with 20-30 percent blasts (low-blast count AML)

Note: Patients with therapy-related MDS are eligible if they have not received radiation or chemotherapy for six months.

Exclusion criteria:

  • Patients eligible for allogeneic stem cell transplantation
  • Prior therapy with hypomethylating agents
  • Any matter constituting an exclusion criterion for treatment with AZA
  • Patients receiving other active cancer treatment, including investigational agents, with exception of hydroxyurea for white blood cell control and granulocyte colony-stimulating factor
  • History of allergic reactions to ascorbic acid
  • History of kidney or urinary tract stones requiring intervention within the past year
  • Lack of ability to understand the information given, or lack of willingness to sign a written informed consent document
  • Unwillingness to comply with the protocol
  • Unwillingness to discontinue any and all use of vitamin C medication/supplementation including multivitamin at least 3 days (but preferably longer) prior to inclusion and baseline sampling
  • Planned AZA treatment after allogeneic stem cell transplantation

Contact person(s):  Dr. Kirsten Grønbæk / Research coordinating nurse Astrid Østergaard Mortensen:

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Instruction video:

 

 

 

Sponsor: Nordic MDS group

Project group:

Principal investigator: Dr Lars Möllgård (Sahlgrenska, Gothenburg)

Study committee: Lars Möllgård (Sahlgrenska, Gothenburg), Olle Werlenius (Sahlgrenska, Gothenburg), Johan Aurelius (Sahlgrenska Cancer Center, Gothenburg), Kristoffer Hellstrand (Sahlgrenska Cancer Center, Gothenburg), Eva Hellström Lindberg (Karolinska, Huddinge), Lars Nilsson (Skåne University Hospital, Lund), Mats Brune (Sahlgrenska, Gothenburg), Anna Martner (Sahlgrenska Cancer Center, Gothenburg) and Fredrik Bergh Thorén (Sahlgrenska Cancer Center, Gothenburg).

Immunological substudies: Johan Aurelius, Sahlgrenska Cancer Center, Gothenburg

Primary objective

  • To evaluate the safety and feasibility of treatment with HDC/IL-2 in CMML.

Secondary objectives

  • To evaluate the clinical efficacy of HDC/IL-2 treatment in CMML.
  • To investigate the immunological effects of HDC/IL-2 in CMML.

Status: Recruiting

Start: Q1 2017

Treatment: Enrolled subjects will receive histamine dihydrochloride (HDC; Ceplene®) and/or IL-2 (Proleukin®) subcutaneously (s.c.) twice daily (BID) in 3-week periods followed by 3- or 6 week rest periods.

Study population:

  • >=18 years of age at the time of signing the informed consent form.
  • CMML-1 with indication for treatment according to NMDSG guidelines.
  • Life expectancy of more than three months and ability to undergo routine outpatient evaluations for efficacy, safety, and compliance.
  • Informed consent obtained and signed.

Contact person: Lars Möllgård

E-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.

Sponsor: Nordic MDS group

Project group:

Principal investigator: Dr Eva Hellström Lindberg (Karolinska, Huddinge)

Coordinator Sweden: Dr Magnus Tobiasson (Karolinska, Huddinge)

Coordinator Denmark: Dr Kirsten Grønbæk (Rigshospitalet, Copenhagen)

Co-investigators: Dr Martin Jädersten (Karolinska, Huddinge), Dr Elisabeth Ejerblad (Uppsala), Dr Fryderyk Lorenz (Umeå), Dr Hege Garelius (Göteborg), Dr Lars Nilsson (Lund), Dr Petar Antunovic (Linköping), Dr Ingunn Dybedahl (Rikshospitalet, Oslo, PI Norway), Dr Astrid Olsnes Kittang (Bergen), Dr Kirsten Grønbæk (Rigshospitaltet, Copenhagen, PI Denmark), Dr Lone Smidstrup Friis (Rigshospitalet, Copenhagen), Dr Gitte Olesen (Århus)

Genetic analyses: Professor Richard Rosenquist and Associate professor Lucia Cavalier (Uppsala)

Study design: Per Ljungman (Karolinska, Huddinge), Richard Rosenquist and Lucia Cavalier (Uppsala)

Experimental substudies: Sten-Eirik Jacobsen (Karolinska, Huddinge)

Study objectives:

  • Phase I, year 1-2

Primary objectives:

1. To determine the predictive value, sensitivity and specificity of patient-specific molecular MRD markers for resistant disease and relapse in patients with MDS undergoing SCT.

Secondary objectives:

  1. To define cut-off values signalling impending relapse for the different mutations (e.g. different cut-offs for TP53 and TET2).
  2. To evaluate the sensitivity of MRD from peripheral blood samples compared to bone marrow samples.
  3. To determine the prognostic value of pre-treatment mutational profile for outcome after SCT.
  4. To, during this clinical trial, collect a biobank of consecutive blood and bone marrow samples from each patient allowing for studies of stem / progenitor cells, microenvironment and immune system before and after transplantation with regard to genetic, epigenetic and immunological features.
  • Phase II, year 3-4

Primary objectives: 

  1. After having the digital PCR method established as an accredited method allowing for results of the MRD analyses to be delivered to treating clinicians, we aim to evaluate the efficacy of pre-emptive treatment on the MDS-clone and the potential of avoiding relapse. Most likely, approaches will differ between different MDS subsets / molecular profiles. We will take the results from the first phase into account before outlining the next phase in detail and will after send in a new ethical application. The transition from phase I to phase II will be evaluated by a safety committee headed by an independent researcher.

Status: Study ready for inclusion

Start: Expected accrual time, FPI and LPI. Q3 2016 and Q3 2019

Inclusion criteria:

  • Patients with MDS, MDS/MPN or AML with dysplastic features and 20-29% marrow blasts undergoing allogeneic stem cell transplantation.
  • One or more mutations identified in the mutational screening.
  • Written informed consent.

Contact person:  Magnus Tobiasson

E-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.

Sponsor: University Medical Center Nijmegen St Radboud for the European LeukemiaNet MDS Working Party.

Principle investigator: Dr David Bowen, Leeds Teaching Hospitals.