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Phase I/II Randomised Trial of 5-azacitidine Versus 5-azacitidine in Combination With Vorinostat in Patients With Relapsed Acute Myeloid Leukaemia Ineligible for Intensive Chemotherapy

Phase 1/Phase 2
18 Years
Not Enrolling
Leukemia, Myeloid, Acute

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Trial Information

Phase I/II Randomised Trial of 5-azacitidine Versus 5-azacitidine in Combination With Vorinostat in Patients With Relapsed Acute Myeloid Leukaemia Ineligible for Intensive Chemotherapy

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. Therefore there is an urgent
need to develop more effective treatment options for the treatment of AML in older patients,
particularly patients with relapsed disease.

Given the clinical activity of azacitidine monotherapy in de novo AML and its activity in
relapsed disease post-transplant, it is reasonable to propose that this agent may be a
valuable treatment option in older patients with relapsed disease. Phase II trials in AML
also demonstrate increased clinical activity of azacitidine when combined with a histone
deacetylase inhibitor (HDACi), no randomised trials have yet examined this question of
azacitidine monotherapy compared to azacitidine combined with a HDACi.

This will represent the first randomised trial, addressing whether there is a clinical
benefit to be gained from combining treatment of azacitidine with a HDACi in patients with
relapsed AML for whom no effective treatment currently exists.

Inclusion Criteria:

- Adults with Acute Myeloid Leukaemia in first relapse (except Acute Promyelocytic
Leukaemia (APL) who are deemed ineligible for intensive chemotherapy on the grounds
of age or co-morbidities

- Patients must have achieved a previous morphological CR as defined by Cheson criteria
after treatment with myelosuppressive chemotherapy

- 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 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

- 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

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Phase I - Maximum tolerated dose (MTD) of combination therapy arm

Outcome Description:

MTD of vorinostat defined as the dose at which only 0 or 1 out of 6 patients experience a dose limiting toxicity (DLT) in either cohort 1 or cohort 2 of Phase I. Patients are expected to have a total of 6 cycles of treatment which is expected to be completed over 6 months. This will be measured for all patients receiving treatment and recruitment is expected to be over a period of 12-18 months.

Outcome Time Frame:

Upto 6 months

Safety Issue:


Principal Investigator

Charles F Craddock, Professor

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Birmingham


United Kingdom: Medicines and Healthcare Products Regulatory Agency

Study ID:




Start Date:

September 2012

Completion Date:

September 2016

Related Keywords:

  • Leukemia, Myeloid, Acute
  • Leukemia
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid