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