A Study to Investigate Treatment of HU and VPA, or 6-MP and VPA in Unfit AML/HR-MDS Patients

NCT06199557 | Recruiting Phase 1 DMC

• 1 other identifier: HUVPA_6MPVPA
• Study Type: interventional
• Target: 48
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Acute Myeloid Leukemia, Adult; Myelodysplastic Syndromes, Adult

Outcome Measures

Primary Outcomes (3)

• 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

  Evaluation every 4th week, i.e. after each treatment cycle.

• 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.

  Evaluation every 4th week, i.e. after each treatment cycle.

• 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).

  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 (8)

• Clinical benefit.

  After 3 and 6 cycles (i.e. after 3 and 6 months from the treatment onset).

• Duration of clinical benefit.

  During the treatment period of 6 months, and during follow-up, up to 6 months after end treatment.

• Time to progression.

  From the treatment onset, during the treatment period of 6 months, and during follow-up, up to 6 months after end treatment.

• Changes in reported Quality of Life (QoL) compared to baseline.

  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).

• Survival analyses, ORR.

  After 3 and 6 cycles (i.e. after 3 and 6 months from the treatment onset).

Other Outcomes (2)

• Biomarkers (exploratory).

  Through study completion, an average of 5 years, or prolonged if necessary.

• Relation of serum concentrations of VPA to treatment response (exploratory).

  Exploratory outcome, during the study period, an average of 5 years.

Study Arms (2)

Hydroxyurea (HU) + Valproic Acid (VPA) part 1

ACTIVE COMPARATOR

Combination treatment 1 (T1): hydroxyurea + valproic acid, combination treatment 2 (T2): 6-mercaptopurine + valproic acid. Each patient enrolled will receive at least one cycle with T1: hydroxyurea and valproic acid. The 1st cycle in the study always constitutes of hydroxyurea (1000 mg twice a day) plus valproic acid (300 mg + 600 mg) for 14 days; then 14 days with no medication. Each cycle duration is 28 days. Patients who do not experience clinical benefit after 1st cycle, or experience unacceptable and unmanageable toxicity after 1st cycle, will not be eligible to continue on this regimen and they will be allocated to treatment combination 2. T2 constitutes of 6-mercaptopurine ( 50 mg once a day) plus valproic acid 300 mg + 600 mg ) for 14 days; followed by 14 days with no medication. Each cycle duration is 28 days.

Drug: Hydroxyurea, Hydroxycarbamide; Drug: Valproic acid; Drug: 6-Mercaptopurine (6-MP)

Hydroxyurea (HU) + Valproic Acid (VPA) part 2

ACTIVE COMPARATOR

Part B consists of two cohort expansions where the setup is identical to part A: one for HU + VPA and one for 6-MP + VPA, 16 patients in each, in total 32 new patients. In part B the same principles will apply for response, withdrawal and allocation from HU+ VPA to 6-MP + VPA. The treatment duration in all arms can last to up 6 cycles in total. Each cycle duration is 28 days.

Drug: Hydroxyurea, Hydroxycarbamide; Drug: Valproic acid; Drug: 6-Mercaptopurine (6-MP)

Interventions

Hydroxyurea, Hydroxycarbamide DRUG

Hydroxyurea (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.

Also known as: Hydroxyurea Medac

Hydroxyurea (HU) + Valproic Acid (VPA) part 1; Hydroxyurea (HU) + Valproic Acid (VPA) part 2

Valproic acid DRUG

Valproic 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.

Also known as: Orfiril Long depot, Belvo, Depakote, Dyzantil, Convulex, Syonell, Epilim

Hydroxyurea (HU) + Valproic Acid (VPA) part 1; Hydroxyurea (HU) + Valproic Acid (VPA) part 2

6-Mercaptopurine (6-MP) DRUG

In 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.

Also known as: Puri-Nethol

Hydroxyurea (HU) + Valproic Acid (VPA) part 1; Hydroxyurea (HU) + Valproic Acid (VPA) part 2

Eligibility Criteria

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

You may qualify if:

• Participants are eligible for the study only if all of the following criteria apply:
• o Female or male, age 18 years or older
• 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
• Newly diagnosed HR-MDS, or relapsed/refractory HR-MDS 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
• has declined standard therapy
• Secondary AML (MDS-related/ therapy- induced), or
• Acute promyelocytic leukemia not eligible for standard therapy and/or specific therapy.
• Adequate renal and hepatic functions unless clearly disease related as indicated by the following laboratory values:
• Serum creatinine ≤1.5 x ULN;
• Estimated creatinine clearance ≥ 40 mL/min (Cockcroft-Gault equation);
• Hepatic function;

You may not qualify if:

• Participants are excluded from the study if any of the following criteria apply:
• 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
• Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, infection, hypertension, pulmonary disease et cetera) at the investigators discretion.
• Breastfeeding women
• Cardiac dysfunction as defined by:
• myocardial infarction within the last 3 months of study entry, or
• congestive heart failure NYHA class IV or
• unstable angina, or
• unstable cardiac arrhythmias
• SARS-CoV-2 infection \< 7 days or Covid-19-vaccine \< 7 days from study onset
• Patients with a history of non-compliance to medical regimens or who are considered unreliable with respect to compliance.
• Patients with any serious concomitant medical condition that could, in the opinion of the investigator, compromise participation in the study.
• Patients with senile dementia, mental impairment or any other psychiatric disorder that prohibits the patient from understanding and giving informed consent.

Sponsors & Collaborators

• Haukeland University Hospital: lead

Study Sites (1)

Haukeland University Hospital

Bergen, Bergen, 5021, Norway

RECRUITING

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Related Links

• The Nobel Prize in Physiology or Medicine 1988 was awarded jointly to Sir James W. Black, Gertrude B. Elion and George H. Hitchings for their discoveries of important principles for drug treatment.
• Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia
• Sarcoma 180 screening data

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Myelodysplastic Syndromes

Interventions

Hydroxyurea; Valproic Acid; Epilim; Mercaptopurine

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Diseases

Intervention Hierarchy (Ancestors)

Urea; Amides; Organic Chemicals; Pentanoic Acids; Valerates; Acids, Acyclic; Carboxylic Acids; Fatty Acids, Volatile; Fatty Acids; Lipids; Sulfhydryl Compounds; Sulfur Compounds; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Bjørn Tore Gjertsen, MD, PhD

  Helse-Bergen HF

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Bjørn Tore Gjertsen, MD, PhD

CONTACT

004741566248; bjorn.tore.gjertsen@helse-bergen.no

Irini Ktoridou-Valen, MD

CONTACT

004746664928; irini.ktoridou-valen@helse-bergen.no

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This a two-part, open-label phase 1/2 study that will include clinical sites in Norway and other Nordic countries. The study consists of part A and part B.

Study Record Dates

• First Submitted: December 12, 2023
• First Posted: January 10, 2024
• Study Start: May 23, 2024
• Primary Completion: November 30, 2025
• Study Completion (Estimated): September 30, 2029
• Last Updated: June 29, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: During the study period.
• Access Criteria: Collaboration.

Locations

NO (1)