London: Clinical Trial of 'omacetaxine' (ChemGenex Pharmaceuticals) for CML with the T3151 gene mutation

Omacetaxine mepesuccinate (formerly known as Ceflatonin®, homoharringtonine or HHT) is a first-in-class small molecule with established clinical activity as a single agent in a range of hematological malignancies. Omacetaxine has a novel mechanism of action, and induces apoptosis by inhibition of protein synthesis, particularly Mcl-1. As omacetaxine acts independently of tyrosine kinase inhibitors, it has therapeutic advantages for patients who have developed resistance to tyrosine kinase inhibitor therapy. Omacetaxine is administered subcutaneously.

We are currently conducting registration-directed clinical trials in CML patients who have failed imatinib therapy and who have the T315I point mutation. These patients, who are increasing in number, do not respond to TKI therapy. Interim data presented at ASH in 2008 reported major cytogenetic responses in 20% of chronic phase patients, and complete hematologic responses in 80% of chronic phase patients. ChemGenex received Fast Track Status for omacetaxine this sub-set of CML patients form the U.S. FDA in November 2006.

In addition to this registration-directed clinical trial, we have a phase 2 trial in CML patients who have failed multiple TKI therapies, and a phase 2 trial in AML patients.

ChemGenex’s development strategy is to seek initial approval for omacetaxine in T315I+ CML as a single agent. We also plan to develop omacetaxine as a single agent in multi-TKI resistant CML patients and as a combination therapy with TKIs in some CML patients. Opportunities for development and possible approval in MDS, acute myelogenous leukemia (AML) and solid tumors will also be pursued.

ChemGenex has one issued patent and has filed nine patent applications covering omacetaxine compositions, formulations, synthesis and uses.

A trial of omacetaxine for chronic myeloid leukaemia with the T3151 gene mutation
This trial is looking at a drug called omacetaxine (OM) for chronic myeloid leukaemia in people who have a change to the T3151 gene.

Doctors often treat chronic myeloid leukaemia (CML) with a drug called imatinib (also called Glivec). This works well for many people. But sometimes CML doesn't respond to imatinib or becomes resistant to it after a time.

We know from research that if you have a particular gene change (a gene mutation), you are more likely to be resistant to imatinib. People taking part in this trial have this mutation to the T3151 gene.

OM is a new type of chemotherapy. In this trial, researchers want to find out if it helps people with CML who have already had imatinib. The aims of the trial are to

* See if OM helps people with CML who have the T3151 gene mutation
* Learn more about the side effects

Recruitment

Starts 01/09/2006
Ends 31/12/2009

Phase

Phase 2

Who can enter this trial

You can enter this trial if you

* Have CML that has the Philadelphia chromosome and is not responding to treatment
* Have the T3151 gene mutation
* Have already had treatment with imatinib
* Finished any other treatment for CML (apart from hydroxyurea) at least 2 weeks ago and have recovered from any side effects
* Have satisfactory blood test results
* Are well enough to take part in the trial
* Are willing to use reliable contraception during this trial and for 6 months after if there is any chance that you or your partner could become pregnant
* Are at least 18 years old

You cannot enter this trial if you

* Are due to have a bone marrow or stem cell transplant
* Are in blast crisis with immature white blood cells that stem from lymphoid stem cells in your blood or bone marrow
* Have any other cancer, apart from non melanoma skin cancer or carcinoma in situ of the cervix
* Have had another experimental drug as part of a clinical trial in the last month
* Have had a heart attack in the last 3 months or have another serious heart problem - the trial doctor will advise you about this
* Have an infection that is not responding to treatment
* Have any other serious medical condition
* Are HIV or HTLV positive
* Are pregnant or breast feeding

Trial design

This is an international trial that will recruit more than 80 people in different countries. There are 2 parts to the trial. These are called the induction phase and the maintenance phase.

During the induction phase you have OM injections under the skin (subcutaneous) twice each day for 2 weeks. You then have 2 weeks without any treatment. This 4 week period is called a cycle of treatment. You have up to 6 cycles of treatment, so the induction phase could last up to 6 months.

If you have a large number of white blood cells or platelets before you start treatment, you may also have a drug called hydroxyurea during the first 2 cycles of treatment.

If the treatment helps you, the doctors will ask you to take part in the maintenance phase of the trial. You have subcutaneous OM injections twice a day for one week, followed by 3 weeks without treatment. If the injections continue to help you and you don't have bad side effects, you may carry on having treatment in this way for up to 2 and a half years.

The trial team will teach you (or somebody you live with) how to give the injections at home. If this is not possible, a nurse can come to your home twice a day to give you the injections.

Hospital visits

You will see the doctors and have some tests before you start treatment. The tests include

* Physical examination
* A trace of your heart (ECG)
* Chest X-ray
* Blood tests
* Urine test

You will also have a bone marrow test if you have not had one in the last month.

During the induction phase of the trial, you go to hospital once a month to see the doctors. You have a blood test each week, but you may be able to have this at your GP surgery. In the first cycle only, you have another ECG after 2 weeks of treatment.

During the maintenance phase, you continue to go to hospital once a month. In the first 3 cycles of maintenance treatment, you have blood tests every 2 weeks. After that, you have them once a month.

You will have a number of bone marrow tests during treatment and an ECG at least once every 3 months.

Side effects

The most common side effects of OM are

* A drop in the number of white blood cells and platelets, leading to an increased risk of infection and bleeding or bruising problems
* Low blood pressure
* Fast or irregular heart beat

Other possible side effects include

* Diarrhoea
* Sickness
* Fever or chills
* Depression
* Tiredness

As OM is a new drug, there may be other side effects that doctors don't know about yet.

Location of trial

London

Contact details

The Information Nurses
Cancer Research UK
P.O. Box 123
61, Lincoln's Inn Fields
London
WC2A 3PX
Tel:
Email: cancer.info@cancer.org.uk

Chief Investigator

Dr D Marin

Supported by

ChemGenex Pharmaceuticals