Hydroxyurea plus valproic acid or 6‑mercaptopurine plus valproic acid for unfit adults with AML or high‑risk MDS

A Phase 1/2 Multicenter Open-label Study to Investigate Treatment of Hydroxyurea in Combination With Valproic Acid (VPA), or 6- Mercaptopurine in Combination With VPA in Patients With AML or HR-MDS Unfit for Standard Therapy

This study will try two low‑toxicity oral drug combinations—hydroxyurea plus valproic acid, or 6‑mercaptopurine plus valproic acid—in adults with acute myeloid leukemia or high‑risk myelodysplastic syndrome who are not fit for standard chemotherapy.

Quick facts

• Phase: Phase1; Phase2
• Study type: Interventional
• Enrollment: 48 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Haukeland University Hospital (Academic / other)
• Drugs / interventions: Chemotherapy, immunotherapy, Radiation
• Locations: 1 site (Bergen, Bergen)
• Trial ID: NCT06199557 on ClinicalTrials.gov

What this trial studies

This is an open‑label phase 1/2, two‑part trial (part A in Norway, part B expanding to other Nordic sites) testing two oral combinations in adults with newly diagnosed or relapsed/refractory AML or high‑risk MDS who are considered unfit for standard therapy. All participants begin with combination 1 (hydroxyurea + valproic acid) given on a 28‑day cycle (14 days on treatment, 14 days off); patients without clinical benefit after the first cycle may be switched to combination 2 (6‑mercaptopurine + valproic acid). Part A is a dose‑finding/safety phase and Part B is a cohort expansion if results are positive. The trial focuses on safety, tolerability, and preliminary signs of disease control using commonly used low‑toxicity agents.

Who should consider this trial

Good fit: Adults aged 18 or older with newly diagnosed or relapsed/refractory AML or high‑risk MDS who are judged unfit for standard treatment (for example HCT‑CI ≥ 3), deemed unlikely to tolerate or benefit from standard therapy, or who have declined standard therapy are eligible.

Not a fit: Patients who are fit for standard intensive induction, who are candidates for effective targeted therapies, or whose disease requires urgent intensive treatment are unlikely to benefit from this low‑intensity approach.

Why it matters

Potential benefit: If successful, these oral, low‑toxicity combinations could offer a better‑tolerated treatment option to control disease and improve quality of life for older or comorbid patients who cannot undergo intensive therapy.

How similar studies have performed: Hydroxyurea, valproic acid and 6‑mercaptopurine are well‑known low‑toxicity drugs and small prior studies of valproic acid combinations have shown mixed and generally preliminary signals, so this specific combination strategy remains relatively unexplored in large trials.

Eligibility criteria

Inclusion Criteria:

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;

    i. Serum bilirubin ≤ 1.5 x upper limit of normal (ULN); ii. Aspartate aminotransferase (AST)
    1. ≤2.5 × ULN
    2. ≤5 × ULN for patients with liver metastases

       iii. Alanine aminotransferase (ALT)

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    1. ≤2.5 × ULN
    2. ≤5 × ULN for patients with liver metastases

       iv. Alkaline phosphatase (ALP)

    1\. ≤2.5 × ULN
* European Cooperative Oncology Group (ECOG) performance status 0, 1, 2 or 3
* Female patients of childbearing potential must have a negative serum pregnancy test within 3 days prior to taking their first dose of study medication. Male patients and female patients of reproductive potential must agree to practice highly effective methods of contraception (such as hormonal implants, combined oral contraceptives, injectable contraceptives, intrauterine device with hormone spirals, total sexual abstinence, vasectomy) throughout the study and for \>3 months after the last dose of study medication. Female patients are considered NOT of childbearing potential if they have a history of surgical sterility or evidence of post-menopausal status defined as any of the following:

  1. Natural menopause with last menses \>1 year ago
  2. Radiation induced oophorectomy with last menses \>1 year ago
  3. Chemotherapy induced menopause with last menses \>1 year ago

Exclusion Criteria:

Participants are excluded from the study if any of the following criteria apply:

* 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
* 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.
* Current concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol.
* Known hypersensitivity to study medications or its excipients.
* Any psychological, familial, sociological, and geographical condition potentially hampering compliance with the study protocol and follow-up schedule.

Where this trial is running

Bergen, Bergen

• Haukeland University Hospital — Bergen, Bergen, Norway (Recruiting)

Study contacts

• Principal investigator: Bjørn Tore Gjertsen, MD, PhD — Helse-Bergen HF
• Study coordinator: Bjørn Tore Gjertsen, MD, PhD

Conditions Acute Myeloid Leukemia, Adult; Myelodysplastic Syndromes, Adult