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

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.

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. Part A will run in Norway only. Part B will run in Norway and the Nordic countries.

Both part A and part B have two different treatment combinations (T), combination 1 and combination 2. Part B is a cohort expansion of part A (if part A proves to be positive).

Treatment combination 1 (T1): hydroxyurea + valproic acid. Treatment combination 2 (T2): 6-mercaptopurine + valproic acid.

Each patient enrolled in the trial will start and will receive at least one cycle with T1:

hydroxyurea and valproic acid. The first cycle in the study always constitutes of hydroxyurea (1000 mg twice a day) plus valproic acid (300 mg + 600 mg) for 14 days; this will be followed by a 14-day period with no medication. Each cycle duration is 28 days.

Patients who do not experience clinical benefit after the first cycle will not be eligible to continue on this regimen and they will be allocated to treatment combination 2. On the other hand, patients who do experience clinical benefit after cycle 1 with combination 1 (HU + VPA) will be further eligible to continue on this regimen/combination. However, patients on T1 will be withdrawn after consequent cycles, as soon as they do not meet the criteria for clinical benefit as defined by this protocol. Each patient who does not meet the criteria of clinical benefit after the first cycle with treatment combination 1 will switch to treatment combination 2 (T2). T2 constitutes of 6-mercaptopurine (50 mg once a day) plus valproic acid (300 mg + 600 mg) for 14 days; this will be followed by a 14-day period with no medication. Each cycle duration is 28 days. Patients will be further eligible to continue this regimen/combination for as long as they experience clinical benefit, otherwise they will be withdrawn from the study as soon as they do not meet the criteria for clinical benefit as defined by this protocol.

There will be 8 patients allocated for the treatment combination 1 with HU + VPA and up to 8 patients allocated for the treatment combination 2 with 6MP + VPA. For each of the two treatment combinations, if one or more patients, of 8, experience clinical benefit\* the group will be expanded with 16 more patients in Part B. Part B consists of two cohort expansions where the setup is identical to part A, one for HU + VPA and one for 6MP + VPA, 16 patients in each, in total up to 32 new patients.

In part B, the same principles will apply for response, withdrawal and allocation from HU+ VPA to 6MP + VPA. Patients treated with combination 1, who do not experience clinical benefit or experience unacceptable, unmanageable toxicity after cycle 1, will not be eligible to continue on this regimen, and they will be allocated to combination 2. It is expected that cohort expansion of combination 2 will proceed slower than cohort expansion for combination 1.

If 5 or more patients of the total of 24 (part A (n=8) + part B (n=16)) experience clinical benefit, there will be considered a phase II/III expansion cohort for further effect assessment.

The treatment duration in all groups can last to up 6 cycles in total, each cycle lasts for 28 days. The rationale for the flow in the study aims to ensure that the patients do not undergo prolonged periods with excessive and ineffective treatment. Assessment of treatment response consecutively after each cycle will guide the treating physician to swiftly change the treatment combination or withdraw the patient from the study accordingly.

The switch to a second treatment combination as a part of the study ensures that more therapy options are available for, potentially, all patients who enroll in the trial.

The enrollment is stopped when 8+16 patients with HU +VPA are treated, or if 8+16 patients are treated with 6MP + VPA. Patients will switch over to 6MP +VPA, if lack of clinical benefit. Some dose modifications are allowed when indicated according to the protocol. At screening and during the study treatment, tumor debulking with HU + 6MP is required for 5 to 7 days to reduce WBC to less than 25×10\*9/L (\<20% blasts in the peripheral blood), before each cycle, HU + VPA, or 6MP + VPA. Tumor debulking with HU + 6MP may be repeated ahead of every cycle (for both treatment combinations), and in the treating physician's discretion, if the patient tolerates this.

The objectives of this study include:

* To determine the safety and tolerability of the treatment combinations of hydroxyurea + valproic acid, and 6-mercaptopurine + valproic acid administered at established clinical doses
* To establish the preliminary efficacy of the treatment combination of hydroxyurea and valproic acid administered at established clinical doses
* To establish the preliminary efficacy of the treatment combination of 6-mercaptopurine and valproic acid administered at established clinical doses
* To evaluate changes in patients performance status for baseline and during the study period

The adaptive study design is based on a Simon two-stage model of expanding cohorts. This model, tested in the TAPUR, DRUP and Impress-Norway studies, has been designed to effectively test a set of drugs using a minimum of number of patients (see also Chapter 9 on Statistics).

Each arm (A1, A2, B1 and B2) will be monitored using a Simon-like two-stage 'admissible' monitoring plan to identify patients with evidence of clinical benefit. Both arms in part A will enroll 8 participants, and will be considered positive if ≥1 patient show clinical benefit after at least 28 days on treatment (for each arm). In case of a positive part A (arm A1 and A2, separately), part B (arm B1 and B2, separately) will be initiated enrolling 16 additional participants in each arm into the cohort.

If there are 0 patients with "clinical benefit" (as defined by this protocol) among the first 8 participants in an arm, then the respective arm will not proceed to expansion. Otherwise, an additional 16 participants will be included in each cohort expansion (B1 and B2, respectively). Four or fewer responses out of 24 will suggest a lack of activity, while 5 or more responses will suggest that further investigation of the drug in a phase 3 clinical trial is warranted.

* Study duration: 5 years
* Treatment duration: up to 6 months for each treatment combination
* Visit frequency: every 7 days (if applicable, during the first cycle), thereafter every 28 days

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.