Combining Active and Passive DNA Hypomethylation

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.

Eligibility

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)

Conditions4

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