Combining Active and Passive DNA Hypomethylation

NCT03999723 | Recruiting Phase 2 DMC

• 1 other identifier: H-18040929
• Study Type: interventional
• Target: 196
• Locations: 2 countries
• Sites: 10

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.

Conditions

Myelodysplastic Syndromes; Acute Myeloid Leukemia; Chronic Myelomonocytic Leukemia

Keywords

Vitamin C; Ascorbic acid; Azacitidine; Hypomethylating agents; Randomized, Placebo-Controlled Trial

Outcome Measures

Primary Outcomes (1)

• Event-free survival

  Event-free survival in months in the group of patients receiving oral vitamin C + AZA (arm A) vs. the group of patients receiving placebo + AZA (arm B) calculated from the time of randomization to EOS. Event is defined as death, relapse, progression or lack of a response at 6 AZA cycles as defined by IWG 2006 (MDS and CMML) and ELN 2017 (AML) response criteria

  0-54 months

Secondary Outcomes (10)

• Adverse events and serious adverse events

  0-54 months

• Overall survival

  0-54 months

• Overall response rate

  0-54 months

• Patient-reported outcome (PRO) measures

  0-54 months

• Variant allele frequency (VAF) of mutated clones

  0-54 months

Study Arms (2)

Vitamin C

EXPERIMENTAL

Oral vitamin C (ascorbic acid) will be given in a dose of 1000 mg daily (two capsules of 500 mg once daily) starting day 1 in the 1st azacitidine (AZA) cycle (D1/C1) and continuing until discontinuation of AZA or end of study, whichever occurs earlier.

Dietary Supplement: Vitamin C

Placebo

PLACEBO COMPARATOR

Placebo will be administered orally as two capsules once daily that look and taste identical to the capsules containing vitamin C. Treatment will start day 1 in the 1st azacitidine (AZA) cycle (D1/C1) and continuing until discontinuation of AZA or end of study, whichever occurs earlier. The content of the placebo capsules is glucose monohydrate, potato starch, gelatin, magnesium stearate and talc.

Dietary Supplement: Placebo

Interventions

Vitamin C DIETARY_SUPPLEMENT

Oral vitamin C (ascorbic acid) 1000 mg daily will be administered from day 1 in the 1st AZA cycle (D1/C1) and continued until discontinuation of AZA or EOS as combination treatment.

Also known as: Ascorbic acid

Vitamin C

Placebo DIETARY_SUPPLEMENT

Placebo capsules (two capsules once daily) will be administered from day 1 in the 1st AZA cycle (D1/C1) and continued until discontinuation of AZA or EOS.

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• Patient eligible for allogeneic stem cell transplantation
• Prior therapy with hypomethylating agents
• 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
• 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)

Sponsors & Collaborators

• Kirsten Grønbæk: lead
• Van Andel Institute - Stand Up To Cancer Epigenetics Dream Team: collaborator
• Karolinska University Hospital: collaborator
• Skane University Hospital: collaborator
• Sahlgrenska University Hospital: collaborator
• University of Southern California: collaborator
• Imperial College London: collaborator
• University of Copenhagen: collaborator
• Zealand University Hospital: collaborator
• Aalborg University Hospital: collaborator
• Odense University Hospital: collaborator
• Technical University of Denmark: collaborator
• Aarhus University Hospital: collaborator
• Uppsala University Hospital: collaborator

Study Sites (10)

Aalborg University Hospital

Aalborg, 9100, Denmark

RECRUITING

Aarhus University Hospital

Aarhus, Denmark

RECRUITING

Rigshospitalet

Copenhagen, 2100, Denmark

RECRUITING

Herlev University Hospital

Copenhagen, 2730, Denmark

RECRUITING

Odense University Hospital

Odense, 5000, Denmark

ACTIVE NOT RECRUITING

Zealand University Hospital

Roskilde, Denmark

TERMINATED

Sahlgrenska University Hospital

Gothenburg, Sweden

RECRUITING

Skåne University Hospital

Lund, Sweden

RECRUITING

Karolinska University Hospital

Stockholm, Sweden

RECRUITING

Uppsala University Hospital

Uppsala, Sweden

RECRUITING

Related Publications (2)

• 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.

  PMID: 8433390 BACKGROUND

• 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.

  PMID: 31037971 BACKGROUND

MeSH Terms

Conditions

Myelodysplastic Syndromes; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Chronic

Interventions

Ascorbic Acid

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Myelodysplastic-Myeloproliferative Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Sugar Acids; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Hydroxy Acids; Carbohydrates

Study Officials

• Kirsten Grønbæk, Prof., MD

  Rigshospitalet, Denmark

  STUDY DIRECTOR

• Stine Ulrik Mikkelsen, MD, PhD

  Rigshospitalet, Denmark

  PRINCIPAL INVESTIGATOR

• Ali Al-Mousawi, MD

  Rigshospitalet, Denmark

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Kirsten Grønbæk, Prof., MD

CONTACT

+45 35 45 60 86; kirsten.groenbaek@regionh.dk

Krista Smidt Bech, BSc, Nurse

CONTACT

+45 35 45 60 80; krista.smidt.bech.01@regionh.dk

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Double-blind masking (Participant, Care Provider, Investigator, (some) Outcomes Assessors)
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor, MD, DMSc

Model Details: A multicentre, randomized, parallel-group, placebo-controlled, double-blind phase 2 study

Study Record Dates

• First Submitted: June 25, 2019
• First Posted: June 27, 2019
• Study Start: September 11, 2019
• Primary Completion: December 1, 2025
• Study Completion (Estimated): December 1, 2027
• Last Updated: April 17, 2024

Record last verified: 2024-04

Data Sharing

• IPD Sharing: Will not share

Locations

SE (4); DK (6)