Clinical trial NCT03999723: Combining Active and Passive DNA Hypomethylation
Official title: Combining Active and Passive DNA Hypomethylation: A Randomized, Placebo-Controlled Phase II Study of the Efficacy and Safety of Oral Vitamin C in Combination With Azacitidine in Patients With Higher-Risk MDS, CMML-2 or Low-Blast Count AML
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Myelodysplastic Syndromes
Acute Myeloid Leukemia
Chronic Myelomonocytic Leukemia
Keywords: Vitamin C
Ascorbic acid
Azacitidine
Hypomethylating agents
Randomized, Placebo-Controlled Trial
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
Collaborators: name: Van Andel Institute - Stand Up To Cancer Epigenetics Dream Team
name: Karolinska University Hospital
name: Skane University Hospital
name: Sahlgrenska University Hospital
name: University of Southern California
name: Imperial College London
name: University of Copenhagen
name: Zealand University Hospital
name: Aalborg University Hospital
name: Odense University Hospital
name: Technical University of Denmark
name: Aarhus University Hospital
name: Uppsala University Hospital
First posted: 2019-06-27
Enrollment: 196
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A multicentre, randomized, parallel-group, placebo-controlled, double-blind phase 2 study
Primary purpose: TREATMENT

Brief summary: This is a multicentre, randomized, parallel-group, placebo-controlled, double-blind phase 2 study of the efficacy and safety of oral vitamin C supplement in combination with azacitidine in patients with higher-risk MDS, CMML-2 or low-blast count AML. The primary purpose is to investigate if oral vitamin C supplementation to azacitidine, compared with azacitidine + placebo, can increase the effectiveness of epigenetic therapy in patients with higher-risk myeloid malignancies, who are not candidates for allogeneic hematopoietic stem cell transplantation.

Detailed description: EVI-3 is a phase 2 international, multicentre, randomized, parallel-group, placebo-controlled, double-blind study of the efficacy and safety of oral vitamin C supplement in combination with azacitidine (AZA) in patients with higher-risk myeloid malignancies with or without mutations in genes recurrently affected in myeloid malignancies. Treatment allocation is in 1:1 ratio (vitamin C vs. placebo) by block randomization stratified by clinical site. Study entry is staggered. Patients are randomized to either oral vitamin C 1000 mg daily or placebo from start of AZA treatment until end of study (EOS) or until AZA treatment is discontinued at the discretion of the treating physician, whichever occurs earlier. The accrual time is estimated to 48 months and 6 months follow-up, thus, maximum treatment duration will be approximately 54 months. A total of 196 patients is planned for enrollment.

Study visits are scheduled at baseline, after 1st AZA treatment cycle, after 6 AZA treatment cycles, and, if AZA treatment is continued, at EOS or end of AZA treatment. Evaluations at study visits include bone marrow investigation, peripheral blood tests, patient-reported outcome measures, adverse events and compliance. Bone marrow aspirate and peripheral blood will be collected for biobank at each study visit.

All patients will undergo follow-up once yearly from EOS. Follow-up will include information on duration of AZA therapy, survival and disease progression from myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML) to acute myeloid leukemia (AML), if diagnosed following a clinical indication for a bone marrow test.

Eligibility criteria: Inclusion Criteria:

• Patients eligible for treatment with azacitidine with one of the following diagnoses according to World Health Organization 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:

* Patient eligible for allogeneic stem cell transplantation
* Prior therapy with hypomethylating agents
* Any matter constituting an exclusion criterion for treatment with azacitidine
* Patient receiving other active cancer treatment, including investigational agents, with the exception of hydroxyurea for white blood cell (WBC) control, G-CSF, and low permanent doses of steroid (≤ 25 mg oral prednisolone per day) for inflammatory disorders
* Therapeutic radiation or chemotherapy within the past 6 months
* 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 azacitidine treatment after allogeneic stem cell transplantation
* Eastern Cooperative Oncology Group (ECOG) performance status ≥3
* Uncontrolled comorbidity including impaired hepatic function (total serum bilirubin \>1.5 × upper limit of the normal range (ULN), serum alanine transaminase \>3 × ULN, chronic hepatitis with decompensated cirrhosis), disabling psychiatric disease, severe neurologic disease, severe metabolic disease, or severe cardiac disease (NYHA class 3-4)

Primary outcomes:
measure: Event-free survival
timeFrame: 0-54 months
Secondary outcomes:
measure: Adverse events and serious adverse events
timeFrame: 0-54 months
measure: Overall survival
timeFrame: 0-54 months
measure: Overall response rate
timeFrame: 0-54 months
measure: Patient-reported outcome (PRO) measures
timeFrame: 0-54 months
measure: Variant allele frequency (VAF) of mutated clones
timeFrame: 0-54 months
measure: Global 5-hydroxymethylcytosine (5-hmC)/5-methylcytosine (5-mC)
timeFrame: 0-54 months
measure: Site specific 5-hmC/5-mC
timeFrame: 0-54 months
measure: Gene expression
timeFrame: 0-54 months
measure: mRNA expression of HERV and HERV specific T-cell responses
timeFrame: 0-54 months
measure: Duration of azacitidine (AZA) therapy
timeFrame: 0-54 months
Other outcomes:
Locations:
city: Aalborg
country: Denmark
facility: Aalborg University Hospital
city: Aarhus
country: Denmark
facility: Aarhus University Hospital
city: Copenhagen
country: Denmark
facility: Rigshospitalet
city: Copenhagen
country: Denmark
facility: Herlev University Hospital
city: Odense
country: Denmark
facility: Odense University Hospital
city: Roskilde
country: Denmark
facility: Zealand University Hospital
city: Gothenburg
country: Sweden
facility: Sahlgrenska University Hospital
city: Lund
country: Sweden
facility: Skåne University Hospital
city: Stockholm
country: Sweden
facility: Karolinska University Hospital
city: Uppsala
country: Sweden
facility: Uppsala University Hospital
Study officials:
affiliation: Rigshospitalet, Denmark
name: Kirsten Grønbæk, Prof., MD
role: STUDY_DIRECTOR
affiliation: Rigshospitalet, Denmark
name: Stine Ulrik Mikkelsen, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Rigshospitalet, Denmark
name: Ali Al-Mousawi, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, Filiberti A, Flechtner H, Fleishman SB, de Haes JC, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993 Mar 3;85(5):365-76. doi: 10.1093/jnci/85.5.365.
citation: Goswami P, Oliva EN, Ionova T, Else R, Kell J, Fielding AK, Jennings DM, Karakantza M, Al-Ismail S, Lyness J, Collins GP, McConnell S, Langton C, Al-Obaidi MJ, Oblak M, Salek S. Paper and electronic versions of HM-PRO, a novel patient-reported outcome measure for hematology: an equivalence study. J Comp Eff Res. 2019 May;8(7):523-533. doi: 10.2217/cer-2018-0108. Epub 2019 Apr 30.