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.
60 Years
N/A
Both
Acute Myeloid Leukaemia, High Risk Myelodysplastic Syndrome
Trial Information
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.
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.
Inclusion Criteria:
- They have one of the forms of acute myeloid leukaemia, except Acute Promyelocytic
Leukaemia or CML in blast crisis as defined by the WHO Classification (Appendix A) —
this can be any type of de novo or secondary AML - or high risk Myelodysplastic
Syndrome, defined as greater than 10% marrow blasts (RAEB-2).
- Serum creatinine ≤ 1.5 × ULN (upper limit of normal)
- White cell count of <30 x 109/L at diagnosis (for Plerixafor option only). If WCC is
>30 x 109/l patients in the Plerixafor pilot should have the WCC reduced to <30 x
109/L using Hydroxycarbamide to avoid the risk of hyperleucocytosis
- Serum potassium, magnesium, and calcium levels should be at least within
institutional normal limits, and every effort should be made to keep potassium at
institutional normal limits, and every effort should be made to keep potassium
concentrations above 4.0 mEq/dL, and serum calcium at normal concentration.
- Total serum bilirubin ≤ 1.5 × ULN (upper limit of normal) and serum aspartate
transaminase (AST) and/or alanine transaminase (ALT) ≤ 2.5 × ULN
- Sexually mature males must agree to use an adequate and medically accepted method of
contraception throughout the study if their sexual partners are women of child
bearing potential (WOCBP).
- Over 60 years of age
- Provided written informed consent
Exclusion Criteria:
- They have previously received cytotoxic chemotherapy for AML. [Hydroxycarbamide, or
similar low-dose therapy, to control the white count prior to initiation of intensive
therapy is not an exclusion].
- They are in blast transformation of chronic myeloid leukaemia (CML).
- They have a concurrent active malignancy excluding basal cell carcinoma.
- They are pregnant or lactating.
- They have Acute Promyelocytic Leukaemia
- Known infection with human immunodeficiency virus (HIV)
Patients are not eligible for the AC220 option if they have:
- Uncontrolled or significant cardiovascular disease, including :
- A myocardial infarction within 12 months
- Uncontrolled angina within 6 months
- Current or history of congestive heart failure New York Heart Association (NYHA)
class 3 or 4, unless an echocardiogram (ECHO) or Multiple Gated Acquisition Scan
(MUGA) performed either within 1 month prior to study screening or during screening
results in a left ventricular ejection fraction (LVEF) that is ≥ 45% (or
institutional lower limit of normal value).
- Diagnosed or suspected congenital long QT syndrome. Any history of clinically
significant ventricular arrhythmias (such as ventricular tachycardia, ventricular
fibrillation, or torsades de pointes [TdP]); any history of arrhythmia will be
discussed with the Sponsor's Medical Monitor prior to patient's entry into the study.
- Prolonged QTcF interval on pre-entry ECG (≥450 ms) - this will be the average of 3
readings within a 2 hour period.
- Any history of second or third degree heart block (may be eligible if the patient
currently has a pacemaker).
- Heart rate < 50/minute on pre-entry ECG
- Uncontrolled hypertension
- Obligate need for a cardiac pacemaker
- Complete left bundle branch block
- Atrial fibrillation
Type of Study:
Interventional
Study Design:
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
Response (CR, CRi, PR) achievement, and reasons for failure
Outcome Time Frame:
Duration of treatment
Safety Issue:
No
Principal Investigator
Alan K Burnett
Investigator Role:
Study Chair
Investigator Affiliation:
Cardiff University
Authority:
United Kingdom: Medicines and Healthcare Products Regulatory Agency
Study ID:
SPON 845-10
NCT ID:
NCT01236144
Start Date:
April 2011
Completion Date:
August 2014
Related Keywords:
- Acute Myeloid Leukaemia
- High Risk Myelodysplastic Syndrome
- Myeloid
- Leukaemia
- Acute
- Myelodysplastic
- Pilot
- Cardiff
- Haematology
- Burnett
- AC220
- Plerixafor
- Ganetespib
- Leukemia
- Leukemia, Myeloid, Acute
- Leukemia, Myeloid
- Myelodysplastic Syndromes
- Preleukemia
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