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
Brief Title
Combining Active and Passive DNA Hypomethylation
Protocol ID
NCT03999723
Lead Sponsor
Kirsten Grønbæk
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.
Study Period
Enrollment Count
196 participants
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)
Filters
Myelodysplastic Syndromes
Acute Myeloid Leukemia
Chronic Myelomonocytic Leukemia
PHASE2
RECRUITING
ADULT
OLDER_ADULT