A phase 1/2 multicenter open-label study to investigate treatment of hydroxyurea (HU) in combination with valproic acid (VPA) or 6- mercaptopurine (6-MP) in combination with VPA in patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (HR-MDS) considered unfit for standard chemotherapy- HUVAMER

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Helse Bergen HF

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

21 May 2024 → ongoing

Decision date (initial)

2023-05-08

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2022-501992-15-00

ClinicalTrials.gov

NCT06199557

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety, Efficacy

1. To determine the safety and tolerability of the treatment combination of hydroxyurea and valproic acid administered at established clinical doses
2. To establish the preliminary efficacy (clinical benefit as defined by this protocol) of the treatment combination of hydroxyurea and valproic acid administered at established clinical doses
3. To establish the preliminary efficacy (clinical benefit as defined by this protocol) of the treatment combination of 6-mercaptopurine and valproic acid administered at established clinical doses
4. To evaluate changes in patients performance status for baseline and during the study period

Secondary objectives 5

1. Survival analyses (see endpoints)
2. To evaluate changes in reported Quality of Life (QoL) compared to baseline
3. Exploratory: To examine baseline and longitudinal potential biomarker expression that may predict pharmacologic activity and outcome
4. Exploratory: To analyze longitudinal biomarker expression in relation to treatment response
5. Exploratory: Serum concentrations of VPA will be related to treatment response, if feasible

Conditions and MedDRA coding

Acute Myeloid Leukemia (AML)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Female or male, age 18 years or older
2. Written informed consent
3. Patients NOT eligible for standard therapy (ELN 2022 ), defined as HCT-CI ≥ 3
4. Patients NOT eligible for standard therapy for other reasons, including patient’s choice of therapy
5. Patients with a diagnosis of AML according to ELN 2022 classification, or relapsed / refractory AML, or sAML (MDS-related/ therapy- induced), or high-risk MDS, or acute promyelocytic leukemia not eligible for standard therapy and/or specific therapy
6. Adequate renal and hepatic functions unless clearly disease related as indicated by the following laboratory values: (a) Serum creatinine ≤1.5 x ULN; (b) Estimated creatinine clearance ≥40 mL/min (Cockcroft-Gault equation); (c) 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) 1. ≤2.5 × ULN 2. ≤5 × ULN for patients with liver metastases iv. Alkaline phosphatase (ALP) 1. ≤2.5 × ULN
7. European Cooperative Oncology Group (ECOG) performance status 0, 1 or 2
8. Breastfeeding women
9. 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: (a) Natural menopause with last menses >1 year ago (b) Radiation induced oophorectomy with last menses >1 year ago (c) Chemotherapy induced menopause with last menses >1 year ago

Exclusion criteria 11

1. Patients on treatment for AML (any anti-leukemic therapy including investigational agents) or treated less than 2 weeks before inclusion
2. Concurrent history of active malignancy in the past six months prior to diagnosis except for: (a) basal and squamous cell carcinoma of the skin (b) in situ carcinoma of the cervix
3. Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, infection, hypertension, pulmonary disease et cetera) at the investigators discretion.
4. Cardiac dysfunction as defined by: (a) myocardial infarction within the last 3 months of study entry, or (b) medical history recorded reduced left ventricular function with an ejection fraction < 40% as measured by MUGA scan or echocardiogram, or (c) congestive heart failure NYHA class IV or (d) unstable angina, or (e) unstable cardiac arrhythmias
5. SARS-CoV-2 infection < 7 days or Covid-19-vaccine < 7 days from study onset
6. Patients with a history of non-compliance to medical regimens or who are considered unreliable with respect to compliance
7. Patients with any serious concomitant medical condition that could, in the opinion of the investigator, compromise participation in the study.
8. Patients with senile dementia, mental impairment or any other psychiatric disorder that prohibits the patient from understanding and giving informed consent.
9. Current concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol.
10. Known hypersensitivity to study medications or its excipients
11. Any psychological, familial, sociological, and geographical condition potentially hampering compliance with the study protocol and follow-up schedule.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 4

1. Safety and tolerability assessed by monitoring the incidence, frequency and severity of AEs, including evaluation of the following: i. DLTs ii. Physical examinations iii. Clinical laboratory blood and urine samples
2. Determine clinical benefit (as defined by this protocol) in patients receiving hydroxyurea in combination with valproic acid
3. Determine clinical benefit* in patients receiving 6-mercaptopurine in combination with valproic acid
4. Baseline and longitudinal ECOG status of the patient (Eastern Cooperative Oncology Group)

Secondary endpoints 2

1. (a) The percentage of patients with clinical benefit after 3 and 6 cycles in each arm ( A1, A2, B1, B2) (b) Overall response rate (ORR; defined as the percentage of patients with a response of CR, CRh, CRi, MLFS, PR or no response as assessed by ELN response criteria 2022) (c) Duration of clinical benefit (d) Time to progression (e) Overall Survival (OS)
2. Usage of health-related quality of life questionnaires: i. EQ -5D-5L ii. SF-36, QLQ-C30 iii. NCI- PRO-CTCAE (b) Lower number of hospital admissions and blood-/platelet transfusions during and after study investigation compared to baseline.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Helse Bergen HF

Sponsor organisation

Helse Bergen HF

Address

Jonas Lies Vei 65

City

Bergen

Postcode

5021

Country

Norway

Scientific contact point

Organisation

Helse Bergen HF

Contact name

Bjørn Tore Gjertsen

Public contact point

Organisation

Helse Bergen HF

Contact name

Bjørn Tore Gjertsen

Locations

1 EU/EEA country · 2 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Urgent safety measures 1 · Art. 54 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 29 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications