A Study to Investigate Treatment of HU and VPA, or 6-MP and VPA in Unfit AML/HR-MDS Patients
Trial statusRecruiting
Trial phasePhase 1, Phase 2
Trial typeInterventional
Biological sexAll
Age18+
SponsorHaukeland University Hospital
About this trial
The purpose of this study is to investigate the safety, tolerability, and preliminary efficacy of the combination treatment of hydroxyurea capsules and valproic acid capsules, or the combination treatment of 6-mercaptopurine tablets and valproic acid capsules in male and female patients aged 18 years or older with acute myeloid leukemia or high- risk myelodysplastic syndrome.
The population to be studied is newly diagnosed AML patients who are considered unfit for standard induction chemotherapy, HR-MDS unfit/ineligible for standard treatment, and relapsed/refractory AML/HR-MDS patients who are considered unfit for standard therapy ,or are, for some reason, ineligible for another type of therapy. Clinically, hydroxyurea, valproic acid and 6-mercaptopurine are historically very well-known therapeutic agents with low toxicity profiles. The rationale for this study is that the combination of these drugs with low toxicity will be well tolerated in elderly AML patients with comorbidities, or lower performance status. This combination could have a beneficial therapeutic effect on overall survival and contribute to a better quality of life.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
Written informed consent
Patients with Newly diagnosed AML, as defined by ELN 2022 criteria, or relapsed/refractory AML who: - are unfit, defined as HCT-CI ≥ 3, or - in the opinion of the investigator are not candidates for standard therapy or unlikely to tolerate or derive significant clinical benefit from standard therapy, or
the patient has declined standard therapy
are unfit, defined as HCT-CI ≥ 3, or
Disqualifiers
Patients on treatment for AML (any anti-leukemic therapy including investigational agents) or treated less than 2 weeks before inclusion.
Concurrent history of active malignancy in the past six months prior to diagnosis except for
basal and squamous cell carcinoma of the skin
in situ carcinoma of the cervix
Trial design
Design model
Sequential
Treatments tested in this trial
Hydroxyurea, Hydroxycarbamide
DrugHydroxyurea (HU/hydroxycarbamide) is a hydroxylated analogue of urea which prevents DNA synthesis by inhibiting the activity of ribonucleotide reductase (RNR). HU has been used to treat a variety of diseases. As an antineoplastic drug, HU has some advantages. It may be used by ambulatory patients and has relatively few side effects, which are relieved almost immediately after withdrawal of the drug. The drug is readily absorbed from the gastrointestinal tract following oral administration. At present, HU has an important role as standard of care for treating hyperleukocytosis in chronic and acute myeloid leukemia.
Valproic acid
DrugValproic acid (VPA) has been used clinically as an anticonvulsant and mood-stabilizing drug. During the last two decades, VPA has been described as a histone deacetylase (HDAC) inhibitor and gained increased interest for use in cancer therapy. VPA is administered orally with available routine measurements of serum levels and has a low toxicity profile.
6-Mercaptopurine (6-MP)
DrugIn 1953, 6-MP was an approved antileukemic agent resulting in remissions in children with acute lymphocytic leukemia (ALL). After adding 6-MP to methotrexate and prednisolone in the treatment regimen, the one-year mean survival of children with ALL was increased from 29% to 50%. 6-MP, even about 70 years after its discovery, remains the standard maintenance therapy once the children are in complete remission.
Treatment groups
48 Participants
are divided into 2 treatment groupsGroup A: Hydroxyurea (HU) + Valproic Acid (VPA) part 1Active comparator 3 interventions
Group B: Hydroxyurea (HU) + Valproic Acid (VPA) part 2Active comparator 3 interventions
Trial outcomes
Primary outcomes
1
Safety and tolerability of the treatment combinations of hydroxyurea + valproic acid, and 6-mercaptopurine + valproic acid administered at established clinical doses.
Safety and tolerability assessed by monitoring the incidence, frequency, and severity of AEs by using CTCAE v5.0, including evaluation of the following: * DLTs * Physical examinations * Clinical laboratory blood samples
Time frame
Evaluation every 4th week, i.e. after each treatment cycle.2
Preliminary efficacy of the treatment combination of hydroxyurea and valproic acid administered at established clinical doses.
Clinical benefit in patients receiving hydroxyurea in combination with valproic acid. Clinical benefit in patients receiving 6-mercaptopurine in combination with valproic acid. Clinical benefit, in this protocol, is defined as stable disease, partial response (decrease of bone marrow blast percentage to between 5% to 25% and decrease of pre-treatment bone marrow blast percentage by at least 50%), or better response \[European Leukemia Net (ELN) 2022 response criteria in AML\], and/or stable or improved ECOG performance status.
Time frame
Evaluation every 4th week, i.e. after each treatment cycle.3
Changes in patients performance status from baseline and during the study period.
Baseline and longitudinal ECOG performance status of the patient (Eastern Cooperative Oncology Group). The ECOG performance status scale is best at 0 (fully active, able to carry on all pre-disease performance without restriction), and worst at 5 (dead).
Time frame
Evaluation at baseline, i.e. before onset treatment, after 4 weeks on treatment (i.e.after first cycle), and every 4th week to a total of 24 weeks. (i.e. after each treatment cycle, up to a total of 6 cycles).Secondary outcomes
1
Clinical benefit.
The percentage of patients with clinical benefit (as described over) in each group (A1, A2, B1, B2).
Time frame
After 3 and 6 cycles (i.e. after 3 and 6 months from the treatment onset).2
Duration of clinical benefit.
The duration of clinical benefit (in days), in each group (A1, A2, B1, B2).
Time frame
During the treatment period of 6 months, and during follow-up, up to 6 months after end treatment.3
Time to progression.
The time to progression (days), in each group (A1, A2, B1, B2).
Time frame
From the treatment onset, during the treatment period of 6 months, and during follow-up, up to 6 months after end treatment.4
Changes in reported Quality of Life (QoL) compared to baseline.
Use of health-related quality of life questionnaires: * EQ -5D-5L * QLQ-C30 * NCI- PRO-CTCAE
Time frame
At baseline, i.e. before onset treatment, after 4 weeks on treatment (i.e.after first cycle), and after each treatment cycle (every 4th week).Other outcomes
1
Biomarkers (exploratory).
Detecting changes in the expression level of intracellular or extracellular signaling markers, may predict positive pharmacological activity of the investigational combinations, and therefore treatment response. These parameters are exploratory and will be measured by mass cytometry on baseline patient samples before treatment onset, and longitudinally with the treatment, sampled every 4th week.
Time frame
Through study completion, an average of 5 years, or prolonged if necessary.2
Relation of serum concentrations of VPA to treatment response (exploratory).
Measure of VPA concentrations in serum (normal reference values: 300 - 700 µmol/L).
Time frame
Exploratory outcome, during the study period, an average of 5 years.Sponsors and contacts
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Source ClinicalTrials.gov