The AML18 Pilot Trial will evaluate the feasibility of three interventions that are planned to be included in the forthcoming NCRI AML18 Trial. One intervention will be to evaluate combining the Tyrosine Kinase Inhibitor AC220 with three courses of standard DAE (Daunorubicin, Ara-C, Etoposide). AC220 will be given following each treatment course, daily by mouth for 7, 14 or 21 days. AC220 will be evaluated at 3 dose levels of 60, 90 and 135 mg flat dose. A 4th dose level of 40 mg will be introduced should patients not respond well to 60 mg. The second intervention to be tested is the combination of the CXCR4 inhibitor Plerixafor with up to three courses of the chemotherapy combination of DClo (Daunorubicin, Clofarabine). Patients/investigators will be able to choose which intervention to enter. Depending on recruitment requirements, only one intervention might be available at any one time. The third intervention Patients will receive 3 treatments of 100 mg of ganetespib on days 1, 8 and 15 of each course where day 1 is the first day of the chemotherapy. The chemotherapy will be DAE/DAE/DA. Three courses of chemotherapy will be given each of which will be associated with 3 administrations of ganetespib.
Full Title of Study: “An NCRI Acute Myeloid Leukaemia Working Group Pilot Trial Under the Auspices of the Cardiff Experimental Cancer Medicine Centre to Establish the Feasibility of Combining Either the Tyrosine Kinase Inhibitor AC220,CXCR4 Inhibitor Plerixafor or HSP90 Inhibitor Ganetespib With Chemotherapy in Older Patients With Acute Myeloid Leukaemia and High Risk Myelodysplastic Syndrome.”
- Study Type: Interventional
- Study Design
- Allocation: Randomized
- Intervention Model: Single Group Assignment
- Primary Purpose: Treatment
- Masking: None (Open Label)
- Study Primary Completion Date: December 2013
The AML18 Pilot Trial is available to any patient who has primary or secondary AML as defined by the WHO Classification (Appendix A) (excluding Acute Promyelocytic Leukaemia), or high risk Myelodysplastic Syndrome (i.e. > 10% marrow blasts) who is not considered suitable for the current NCRI trial for younger patients (MRC AML 17). This trial has the primary aim of assessing the feasibility of three treatments that are planned for the forthcoming NCRI AML18 Trial. The first is the feasibility of adding AC220, given sequentially initially for 7 days, to three courses of standard chemotherapy. AC220 will be assessed at up to three daily dose levels: – 60mg/day, 90mg/day, 135 mg/day and also, if required, at 40mg/day. The protocol will also assess in a separate study cohort the feasibility of combining the CXCR4 inhibitor, Plerixafor, at a fixed dose in combination with up to three courses of chemotherapy. The third intervention patients will receive 3 treatments of ganetespib on days 1, 8 and 15 of each course where day 1 is the first day of the chemotherapy. The chemotherapy will be DAE/DAE/DA. Three courses of chemotherapy will be given each of which will be associated with 3 administrations of ganetespib. THERAPEUTIC INTERVENTIONS Therapeutic Interventions for AC220 Assessment: Patients will enter one of 3 dose level cohorts either 60mg/day, 90mg/day or 135mg/day with the provision to assess 40mg/day if required. Each cohort will receive three courses of chemotherapy approximately 4 to 5 weeks apart, which will comprise DAE ( Daunorubicin, Ara-C, Etoposide) over 10 days (Course 1) , DAE over 8 days (Course 2) and DA (Daunorubicin, Ara-C) over 5 days (Course 3). Two days after the last day of chemotherapy patients will receive the AC220 orally, daily for 7 consecutive days. Formal safety and pharmaco-kinetic assessments will be undertaken on day 1, 7 and 14 of each course of AC220, and interim toxicities will also be required to be reported. Sufficient patients must enter each AC220 dose level cohort to ensure that at least 3 patients are evaluable for all three courses. Cohort 2 (i.e.60mg/day for 14 days) can open to recruitment after a minimum of 3 evaluable patients have completed course 1. Cohort 3 (40mg/day dose level for either 7/14 days) will be undertaken if cohort 1 or 2 are unsuccessful i.e. fail to satisfy the safety criteria. It is anticipated that the 'study dose' will be established from the experience of cohorts 1 to 5. Cohort 6 ('study dose') will receive AC220 for 21 days after each chemotherapy course. In this cohort there must be a minimum of a 10 days break between the end of the AC220 course and the start of the subsequent chemotherapy course. Therapeutic Interventions for Plerixafor Assessment: The aim is to assess the feasibility of combining a fixed dose (240mcg/kg) of Plerixafor given on each day of chemotherapy for up to 3 courses, and if so to combine this with G-CSF in courses 2 and 3. The three chemotherapy courses will be Daunorubicin/Clofarabine (DClo) for courses 1 & 2 and Daunorubicin/Ara-C (DA) for course 3. Each course will last 5 days and Plerixafor will be given for 5 days. Cohort 1 will receive three courses of chemotherapy with Plerixafor in course 1 only. Cohort 2 will receive three courses with Plerixafor in course 1 and 2. Cohort 3 will receive chemotherapy with Plerixafor in all three courses. Cohort 4 will be the same as cohort 3 but they will also receive G-CSF in course 2 and 3. Therapeutic Interventions for Ganetespib Assessment: There will be one feasibility cohort of 10 evaluable patients who require to be evaluable after 30 days after the first course, where day 1 is the first day of chemotherapy. Patients will receive 3 treatments of ganetespib on days 1, 8 and 15 of each course where day 1 is the first day of the chemotherapy. The chemotherapy will be DAE/DAE/DA. Three courses of chemotherapy will be given each of which will be associated with 3 administrations of ganetespib.
- Drug: Plerixafor
- Fixed dose of Plerixafor (240mcg/kg) given by subcutaneous injection on each day of chemotherapy for up to 3 courses (depending on cohort). The three chemotherapy courses will be Daunorubicin/Clofarabine for courses 1&2 and Daunorubicin/Ara-C for course 3. Each course will last 5 days, and Plerixafor will be given for 5 days.
- Drug: AC220
- Each cohort of patients will receive three courses of chemotherapy approximately 4 to 5 weeks apart which will comprise of Daunorubicin/Ara-C/Etoposide in Courses 1&2 and Daunorubicin/Ara-C in Course 3. Two days after the last day of each chemotherapy course, patients will receive AC220 orally for 7, 14 or 21 (depending on cohort) consecutive days. Depending on which cohort the patient enters, they will receive either 60mg, 90mg or 135mg of AC220 daily, with a provision to assess 40mg if necessary.
- Drug: Ganetespib
- Patients will receive 3 treatments of ganetespib on days 1, 8 and 15 of each course where day 1 is the first day of the chemotherapy. The chemotherapy will be DAE/DAE/DA. Three courses of chemotherapy will be given each of which will be associated with 3 administrations of ganetespib.
Arms, Groups and Cohorts
- Experimental: AC220 Intervention
- Experimental: Plerixafor Intervention
- Experimental: Ganetespib
Clinical Trial Outcome Measures
- Response (CR, CRi, PR) achievement, and reasons for failure
- Time Frame: Duration of treatment
- Time Frame: At 30 days and 8 weeks
- Toxicity (haematological and non-haematological)
- Time Frame: Duration of trial treatment
- Time Frame: At 6 and 12 months
Participating in This Clinical Trial
Gender Eligibility: All
Minimum Age: 60 Years
Maximum Age: N/A
Are Healthy Volunteers Accepted: No
- Lead Sponsor
- Cardiff University
- Leukaemia & Lymphoma Research Group
- Provider of Information About this Clinical Study
- Principal Investigator: Alan K Burnett, Chief Investigator – Cardiff University
- Overall Official(s)
- Alan K Burnett, Study Chair, Cardiff University
- Nigel H Russell, Study Chair, Nottingham University
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