A programme of development for older patients with acute myeloid leukaemia and high risk myelodysplastic syndrome

Patients will be randomised to standard treatment, Low Dose Ara-C, versus one of four alternative novel treatment approaches. The available treatment arms are thus: Arm1: Low dose Ara-C and AC220 (quizartinib) Arm 2: Low dose Ara-C combined with ganetespib: closed no longer active Arm 3: Low dose Ara-C combined with tosedostat: closed no longer active Arm 4: Low dose Ara-C + Selinexor Arm 5: Low dose Ara-C combined with Lenalidomide During the course of the Programme other novel therapies (Drug X) are expected to become available, and will be considered for inclusion in this comparison. The current treatment arm available in Australia is Arm 3: Low Dose Ara-C combined with Tosedostat. Arm 1: Low Dose Ara-C and AC220 (Quizartinib) Ara-C 20 mg twice daily by subcutaneous injection daily on days 1-10 (20 doses) to be repeated at 28 to 42 day intervals. In some patients it may be necessary to extend the intervals to up to 42 days. A minimum of 4 courses should be administered. If it is considered appropriate, further courses can be administered (with no limit to the number given). AC220 will be taken in a dose of 90mg (three 30mg tablets or oral solution) orally, daily for 21 consecutive days commencing on day 1 of each Low dose Ara-C treatment. Arm 2: Low dose Ara-C combined with Ganetespib Ara-C 20 mg twice daily by subcutaneous injection daily on days 1-10 (20 doses) to be repeated at 28 to 42 day intervals. In some patients it may be necessary to extend the intervals to up to 42 days. A minimum of 4 courses should be administered. If it is considered appropriate, further courses can be administered (with no limit to the number given). The dose of ganetespib (120mg/m2) will be given as a 1 hour intravenous infusion commencing on day 1 of each Low dose Ara-C treatment, irrespective of when each course of the Low dose Ara-C is started. This will be repeated on days 8, 15, 22 and 29 of each Low dose Ara-C course. Four courses will be given at 4 to 6 week intervals. Arm 3: Low Dose Ara-C combined with Tosedostat Ara-C 20 mg twice daily by subcutaneous injection daily on days 1-10 (20 doses) to be repeated at 28 to 42 day intervals. In some patients it may be necessary to extend the intervals to up to 42 days. A minimum of 4 courses should be administered. If it is considered appropriate, further courses can be administered (with no limit to the number given). Tosedostat will be taken in a dose of 120mg (2 capsules) orally once a day with a glass of water after food, preferably in the morning at about the same time every day to ensure an even dose interval. Treatment should commence on day 1 of the first course of Low dose Ara-C and continue daily for 6 months. Patients may stay on treatment if they are deriving benefit. Arm 4: Low Dose Ara-C and Selinexor Ara-C 20 mg twice daily by subcutaneous injection daily on days 1-10 (20 doses) to be repeated at 28 to 42 day intervals. In some patients it may be necessary to extend the intervals to up to 42 days. A minimum of 4 courses should be administered. If it is considered appropriate, further courses can be administered (with no limit to the number given). For each course of Low Dose Ara-C, selinexor dosing will take place on days 1 & 3 of each week between Low Dose Ara-C courses. The dose of Selinexor will be 30mg/m2, starting at day 12, where day 1 is the first day of Low Dose Ara-C. Four courses of Low Dose Ara-C + Selinexor are intended. The interval between the courses can vary, but it is intended that Selinexor will be given on 2 days per week for each week between Low Dose Ara-C. On completion of the Low Dose Ara-C courses Selinexor will continue once weekly at 40 mg/m2 to be given on the same day each week. The aim is to give 6 months of maintenance treatment but patients will be permitted to continue if it is thought that they are deriving benefit. Arm 5: Low dose Ara-C combined with Lenalidomide Ara-C 20 mg twice daily by subcutaneous injection daily on days 1-10 (20 doses) to be repeated at 28 to 42 day intervals. In some patients it may be necessary to extend the intervals to up to 42 days. A minimum of 4 courses should be administered. If it is considered appropriate, further courses can be administered (with no limit to the number given). Lenalidomide is administered orally once daily in a flat 10mg dose for 21 days, where day 1 is day 1 of LD Ara-C. This course will be repeated after a 2 week rest period and continue for four courses. Patients who are considered to be benefiting after having received the planned four courses i.e. continue in remission or have stable disease, should continue to receive treatment until disease progression in the following schedule: - Low dose Ara-C + lenalidomide at 4-6 weekly intervals, or - Lenalidomide only, at 4 weekly intervals, if patient has experienced significant Low dose Ara-C toxicity (equivalent to ongoing grade 3 haematological toxicity)