Randomised Study of Azacitidine Versus Azacitidine With Vorinostat in Patients With AML or High Risk MDS

Study Overview
=================
Brief Summary
-----------------
This is a multicentre, open-label, randomised phase II trial comparing azacitidine monotherapy with combined azacitidine and vorinostat in patients with newly diagnosed, relapsed or refractory acute myeloid leukaemia or high risk myelodysplastic syndromes ineligible for intensive chemotherapy.

Detailed Description
-----------------
Acute Myeloid Leukaemia (AML) is a common haematological malignancy. As a result of improvements in myelosuppressive chemotherapy and stem cell transplantation, the outcome of children and young adults with AML has improved substantially in the past three decades. By contrast there has only been limited progress in the development of new treatments for older adults in whom long term survival is less than 20% at present. There is an urgent need to develop more effective treatment options for the treatment of AML and high risk MDS in older adults. Accumulating evidence suggests that Azacitidine is a potentially important treatment modality in newly diagnosed, relapsed/refractory AML and high risk MDS. Phase II trials in AML and MDS demonstrate increased clinical activity of azacitidine when combined with a HDACi. However no randomised trials have yet examined the important question of whether concurrent HDACi administration increases the clinical activity of Azacitidine. Vorinostat is a new HDACi which shows significant clinical activity in combination with Azacitidine in patients with AML and MDS. We therefore propose a randomised trial of azacitidine compared with azacitidine and vorinostat combination therapy in older adults with newly diagnosed, relapsed, refractory AML or high risk MDS ineligible for intensive chemotherapy. This will represent the first randomised trial, addressing whether there is a clinical benefit to be gained from combining treatment with azacitidine with a HDACi in patients with newly diagnosed, relapsed, refractory AML or high risk MDS for whom limited therapeutic options currently exist.

Official Title
-----------------
Phase II Randomised Trial of 5-azacitidine Versus 5-azacitidine in Combination With Vorinostat in Patients With Acute Myeloid Leukaemia or High Risk Myelodysplastic Syndromes Ineligible for Intensive Chemotherapy

Conditions
-----------------
Leukemia, Myeloid, Acute

Intervention / Treatment
-----------------
* Drug: Azacitidine
* Drug: Vorinostat


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: - Adults with AML (except Acute Promyelocytic Leukaemia (APL)) as defined by the World Health Organisation (WHO) Classification or patients with high risk MDS categorised as INT-2 or high risk according to the International Prognostic Scoring System (IPSS) who are deemed ineligible for intensive chemotherapy on the grounds of age or co-morbidities with ONE of the following disease status:- i) Newly diagnosed OR ii) Relapsed Disease: patients must have achieved a previous morphological CR and show evidence of recurrent disease OR iii) Refractory Disease: patients who have failed to achieve a morphological CR with previous therapy Patients are able to receive treatment as out-patient Adequate renal and hepatic function as defined in the Protocol Patients have given written informed consent ECOG performance status less than or equal to 2 Exclusion Criteria: Patients with greater than class III NYHA cardiac impairment Blastic transformation of Chronic Myeloid Leukaemia Prior allogeneic/autologous haematopoietic stem cell transplant Pregnant or lactating women Adults of reproductive potential not willing to use appropriate, effective, contraception during the trial and for specified amount of time afterwards Patients who have received prior histone deacetylase inhibitor (HDACi) treatment as anti-tumour therapy. (Patients who have received HDACi treatment for other indications e.g valproic acid for epilepsy may enrol after a 30-day washout period) Previous anti-tumour therapies, including prior experimental agents or approved anti-tumour small molecules and biologics, within 30 days before the start of protocol treatment. (Patients receiving anti-tumour therapies to control blood counts may enrol into the trial) Patients who have received prior treatment with demethylating agents such as 5-azacitidine or decitabine Patients with contraindications to receiving azacitidine or vorinostat such as hypersensitivity, patients unable to have a subcutaneous injection or swallow oral capsules Active symptomatic fungal, bacterial, and/or viral infection including known active HIV or known viral (A, B, or C) hepatitis Any co-morbidity that could limit compliance with the trial

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: azacitidine<br>azacitidine (75mg/m2) by SC injection on 7 consecutive days (excluding weekends), starting day 1 of 28-day cycles for up to 6 cycles. This should be delivered in a 5-2-2 schedule | Drug: Azacitidine<br>* Azacitidine both arms; 75mg/m^2 by subcutaneous injection for 7 days of a 28-day cycle for up to 6 cycles.<br>* Other names: vidaza, ATC code L01BC07, cas number 320-67-2;|
| Active Comparator: azacitidine and vorinostat<br>Patients will receive (75mg/m2) azacitidine by SC injection on 7 consecutive days (excluding weekends), starting day 1 of 28-day cycles for up to 6 cycles. Azacitidine should be delivered in a 5-2-2 schedule. Vorinostat (300mg bid) will be taken orally for 7 consecutive days starting on day 3 of each cycle in 28-day cycles for up to 6 cycles. (Day 3 is defined as the 3rd day of azacitidine administration). | Drug: Azacitidine<br>* Azacitidine both arms; 75mg/m^2 by subcutaneous injection for 7 days of a 28-day cycle for up to 6 cycles.<br>* Other names: vidaza, ATC code L01BC07, cas number 320-67-2;Drug: Vorinostat<br>* Vorinostat (with azacitidine) combined therapy arm; 300mg twice daily for 7 days starting on day 3 of each cycle in 28-day cycles for up to 6 cycles.<br>* Other names: MK-0683, ATC code L01XX38, cas number 149647-78-9;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase II - Overall Response Rate | Patients are expected to receive 6 cycles of treatment which is expected to be completed over a period of 6 months. Each cycle lasts for 28 days. Overall response rate (CR, CRi, PR) as defined by Cheson criteria will be assessed during this time. This will be measured for all patients receiving treatment recruited over a 24 month period. | Upto 6 months | 
| Phase II - Overall Survival | Overall survival is defined as the time from date of randomisation to the date of death from any cause. Patients discontinuing study, lost to follow up or still alive at the end of the study (up to 24 months) will be censored at the date of last follow-up. | Up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase II - Toxicities measured by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) | Toxicities will be measured and graded according to the NCI CTCAE v4 from the date of randomisation until 28 days following treatment discontinuation over the duration of the follow up period which is 24 months. | Up to 28 days | 
| Phase II - Complete Remission (CR) within 6 cycles of treatment | Complete remission within 6 cycles of treatment as defined by Cheson criteria will be assessed. It is expected patients will receive 6 cycles of treatment, which is expected to be completed over a period of 6 months, as each cycle is 28 days. This will be measured for all patients receiving treatment recruited over a 24 month period. | Up to 6 months | 
| Phase II - Duration of response | This will be measured from date of documented response until date of documented progression, assessed for up to 24 months. | Up to 24 months | 
| Phase II - Dose intensity | Dose intensity defined as the total dose prescribed to each patient as a proportion of the protocol dose. This will measured for each patient receiving treatment, assessed up to 24 months. | Up to 24 months | 
| Phase II - Quality of Life measured by questionnaires | Quality of Life will be measured using the EORTC QLQ-C30 and EuroQol EQ-5D-5L questionnaires. This will be measured for each patient receiving treatment until end of treatment, assessed for up to 24 months. | Up to 24 months | 
| Phase II - Medical Resource Use | Medical resource use is defined in terms of days in hospital, blood product usage and days on anti-biotics and will be measured from date of randomisation until 24 months. | Up to 24 months |