A Strategy of High-Dose Lenalidomide in Combination with Epigenetic Therapies for Relapsed or Refractory Acute Myeloid Leukaemia (AML)- Phase I (AMLM17)

Funding

Other Collaborative groups,Australasian Leukaemia and Lymphoma Group

Scientific enquiries

Dr Andrew Wei

Brief Summary

The outcome in patients with Acute Myeloid Leukaemia (AML) who fail to respond to treatment or relapse after treatment is extremely poor. There is no standard treatment for these patients. This study aims to investigate the appropriate dose of the drug romidepsin (a type of chemotherapy) delivered with high dose lenalidomide (a type of chemotherapy) in the treatment of advanced AML. The study plans to treat up to 18 patients in a number of sites throughout Australia. The primary aim of this init .... The outcome in patients with Acute Myeloid Leukaemia (AML) who fail to respond to treatment or relapse after treatment is extremely poor. There is no standard treatment for these patients. This study aims to investigate the appropriate dose of the drug romidepsin (a type of chemotherapy) delivered with high dose lenalidomide (a type of chemotherapy) in the treatment of advanced AML. The study plans to treat up to 18 patients in a number of sites throughout Australia. The primary aim of this initial study is to find a safe dose of romidepsin when delivered with high dose lenalidomide. This initial stage of the study will flow into a larger study comparing 3 different treatments in advanced AML, however if you participate in this Phase I study, you will not then be eligible for the following Phase II study. Trial details: In this study you will receive the drug romidespin delivered intravenously (i.v) on days 1,8 and 15 of a 6-week treatment cycle at a dose of either 8, 10, 12 or 14mg/m^2, or on days 1 and 15 at 8mg/m^2. The actual dose will depend on what stage of the trial is currently open. At the same time as the romidespin treatment, you will also receive 50mg oral lenalidomide on a daily basis on days 8-28. The strength of the drug and your tolerance of it will be assessed after 2 cycles, and overall, your treatment should continue for at least 6-12 cycles. Beyond this time, the decision as to whether or not your treatment continues will be at the discretion of the study's Principal Investigator (PI). Who is it for? This study is open to male or female patients aged 18-80 with either a diagnosis of Acute Myeloid Leukaemia (AML) and failing previous therapy, either primary refractory or relapsed after no more than 3 previous lines of chemotherapy OR a diagnosis of Myelodysplasia transformed to AML after previous treatment. The full details of this study’s inclusion and exclusion criteria can be found in the relevant sections within this record.
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Key Inclusion Criteria

1.Male or female patients with one of the following diagnoses: a. AML failing previous therapy, either primary refractory (failure to achieve greater than or equal to 50% blast reduction to 10-25% marrow blasts) or relapsed (greater than or equal to 50% increase in blasts to greater than or equal to 10% bone marrow blasts) after no more than 3 previous lines of chemotherapy, which may include hypomethylating agents OR b.Myelodysplasia transformed to AML with greater than or equal to 20% bone mar .... 1.Male or female patients with one of the following diagnoses: a. AML failing previous therapy, either primary refractory (failure to achieve greater than or equal to 50% blast reduction to 10-25% marrow blasts) or relapsed (greater than or equal to 50% increase in blasts to greater than or equal to 10% bone marrow blasts) after no more than 3 previous lines of chemotherapy, which may include hypomethylating agents OR b.Myelodysplasia transformed to AML with greater than or equal to 20% bone marrow blasts after previous treatment, which may include previous treatment with hypomethylating agents 2.Age 18-80 inclusive 3.ECOG Performance Status 0-2 4.White Cell Count <15 x 10^9/L 5.Adequate hepatic function as defined by bilirubin less than or equal to 2 x the upper limit of normal (ULN) and Aspartate transaminase & Alanine transaminase less than or equal to 3 x ULN 6.Adequate renal function as defined by serum creatinine less than or equal to 1.3 ULN 7.Serum potassium greater than or equal to 3.8 mmol/L and magnesium greater than or equal to 0.85 mmol/L 8.Females of childbearing potential must use effective methods of contraception or practice absolute abstinence for 4 weeks prior to lenalidomide therapy, during treatment and 4 weeks after treatment discontinuation 9.Male patients must use contraception during lenalidomide treatment and for 4 weeks after discontinuation of treatment 10.Subjects must agree not to donate blood, semen or sperm while on lenalidomide and for 4 weeks after treatment discontinuation 11.Provision of written informed consent
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Key Exclusion Criteria

1.History of major non-compliance to medication 2.Post allogeneic-stem cell transplant patients on immunosuppression therapy greater than or equal to 5mg prednisolone/day or equivalent 3.Evidence of central nervous system (CNS) leukaemia 4.Impaired cardiac function or clinically significant cardiac disease as follows: a. Left Ventricle Ejection Fraction (LVEF) <45% as determined by Multi-gated Acquisition (MUGA) scan or echocardiogram (ECHO) b. Complete left bundle branch block or right bundle b .... 1.History of major non-compliance to medication 2.Post allogeneic-stem cell transplant patients on immunosuppression therapy greater than or equal to 5mg prednisolone/day or equivalent 3.Evidence of central nervous system (CNS) leukaemia 4.Impaired cardiac function or clinically significant cardiac disease as follows: a. Left Ventricle Ejection Fraction (LVEF) <45% as determined by Multi-gated Acquisition (MUGA) scan or echocardiogram (ECHO) b. Complete left bundle branch block or right bundle branch block + left anterior hemiblock (bifascicular block) c. Obligate use of a cardiac pacemaker d. Congenital long QT syndrome or QTc > 480 msec on the screening electrocardiogram (ECG) e. Clinically significant resting bradycardia (< 50 bpm) f. Angina pectoris or acute myocardial infarction (AMI) greater than or equal to 3 months prior to starting study drug g. Unstable angina, congestive cardiac failure (CCF) or AMI within the last 6 months 5. Patients taking any concurrent medications which have a known risk of prolonging the QTc interval or inducing Torsades de Pointes tachycardia 6. Clinically significant respiratory disease 7. Uncontrolled active infection with known HIV or Hepatitis type B or C infection 8. Currently active gastrointestinal disease or other disease, that prevents the patient from absorbing or taking oral medication 9. Any other concurrent severe and/or uncontrolled medical conditions that in the opinion of the investigator could potentiate unacceptable safety risks or jeopardise compliance with the protocol 10. Previous adverse reaction to the trial drug/s 11. Other clinically important abnormalities as determined by the investigator that may interfere with his or her participation in or compliance with the study 12. Female patients who are pregnant or breastfeeding and the lack of adequate contraception 13. Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
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