Combining Active and Passive DNA Hypomethylation

Официальное название

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

Обзор

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.

Подробное описание

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.

Вмешательства

• Пищевая добавка Vitamin C
  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.
• Пищевая добавка Placebo
  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.

Первичные конечные точки

• Event-free survival [Срок оценки: 0-54 months]

Вторичные конечные точки (10)

• Adverse events and serious adverse events [Срок оценки: 0-54 months]
• Overall survival [Срок оценки: 0-54 months]
• Overall response rate [Срок оценки: 0-54 months]
• Patient-reported outcome (PRO) measures [Срок оценки: 0-54 months]
• Variant allele frequency (VAF) of mutated clones [Срок оценки: 0-54 months]
• Global 5-hydroxymethylcytosine (5-hmC)/5-methylcytosine (5-mC) [Срок оценки: 0-54 months]
• Site specific 5-hmC/5-mC [Срок оценки: 0-54 months]
• Gene expression [Срок оценки: 0-54 months]
• mRNA expression of HERV and HERV specific T-cell responses [Срок оценки: 0-54 months]
• Duration of azacitidine (AZA) therapy [Срок оценки: 0-54 months]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• 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)

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Четверное слепое

Основная цель

Лечение

Центры проведения

Дания · 6 центров

• Aalborg University Hospital — Aalborg
• Aarhus University Hospital — Aarhus
• Rigshospitalet — Copenhagen
• Herlev University Hospital — Copenhagen
• Odense University Hospital — Odense
• Zealand University Hospital — Roskilde

Швеция · 4 центра

• Sahlgrenska University Hospital — Gothenburg
• Skåne University Hospital — Lund
• Karolinska University Hospital — Stockholm
• Uppsala University Hospital — Uppsala

Публикации

• 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
• 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

Идентификаторы

NCT: NCT03999723 · H-18040929

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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