A Trial 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.

NCT01236144 | Completed Phase 1 DMC

• 3 other identifiers: SPON 845-102010-021444-1810/MRE09/27
• Study Type: interventional
• Target: 113
• Locations: 1 country
• Sites: 13

Brief Summary

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.

Conditions

Acute Myeloid Leukaemia; High Risk Myelodysplastic Syndrome

Keywords

Myeloid; Leukaemia; Acute; Myelodysplastic; Pilot; Cardiff; Haematology; Burnett; AC220; Plerixafor; Ganetespib

Outcome Measures

Primary Outcomes (4)

• Response (CR, CRi, PR) achievement, and reasons for failure

  Duration of treatment

• Mortality

  At 30 days and 8 weeks

• Toxicity (haematological and non-haematological)

  Duration of trial treatment

• Survival

  At 6 and 12 months

Study Arms (3)

AC220 Intervention

EXPERIMENTAL

Drug: AC220

Plerixafor Intervention

EXPERIMENTAL

Drug: Plerixafor

Ganetespib

EXPERIMENTAL

Drug: Ganetespib

Interventions

Plerixafor DRUG

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.

Also known as: Mozobil

Plerixafor Intervention

AC220 DRUG

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.

AC220 Intervention

Ganetespib DRUG

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.

Ganetespib

Eligibility Criteria

• Age: 60 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Cardiff University: lead
• Leukaemia & Lymphoma Research Group: collaborator
• Experimental Cancer Medicine Centres: collaborator

Study Sites (13)

Aberdeen Royal Infirmary

Aberdeen, United Kingdom

Location

Belfast City Hospital

Belfast, United Kingdom

Location

Birmingham Heartlands Hospital

Birmingham, United Kingdom

Location

Addenbrooke's Hospital

Cambridge, United Kingdom

Location

University Hospital of Wales

Cardiff, United Kingdom

Location

Castle Hill Hospital

Hull, United Kingdom

Location

St James's University Hospital

Leeds, United Kingdom

Location

Royal Liverpool University Hospital

Liverpool, United Kingdom

Location

St Bartholomew's Hospital

London, United Kingdom

Location

Christie Hospital

Manchester, United Kingdom

Location

Manchester Royal Infirmary

Manchester, United Kingdom

Location

Freeman Hospital

Newcastle, United Kingdom

Location

Nottingham University Hospital

Nottingham, United Kingdom

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Leukemia

Interventions

plerixafor; STA 9090

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Study Officials

• Alan K Burnett

  Cardiff University

  STUDY CHAIR

• Nigel H Russell

  Nottingham University

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Chief Investigator

Study Record Dates

• First Submitted: November 5, 2010
• First Posted: November 8, 2010
• Study Start: April 1, 2011
• Primary Completion: December 1, 2013
• Study Completion: January 1, 2014
• Last Updated: June 11, 2014

Record last verified: 2014-06

Locations

GB (13)