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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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