Product description and target market
Elacytarabine is a novel cancer drug candidate under development for the treatment of blood-related cancers (haematological
malignancies). A pivotal phase III study in late stage Acute Myeloid Leukaemia (AML) opened for patient enrolment in June
2010.
Elacytarabine - an improved cytarabine - independent of hENT1
Elacytarabine is a lipid-conjugated derivative of cytarabine, the current standard treatment for AML. It is designed to improve
the efficacy of cytarabine by enabling the drug to enter cancer cells without requiring membrane expression of transporter
proteins. The entry of cytarabine into tumour cells is dependent upon the expression of specific membrane transporter proteins,
particularly hENT1 (human equilibrative nucleoside transporter 1). A substantial portion of AML patients have a deficient uptake of cytarabine
in their leukaemic cells due to deficient expression of hENT1. Cellular uptake of elacytarabine, in contrast to cytarabine, is independent of hENT1, which offers a potential clinical advantage to elacytarabine in the treatment of AML.
The CLAVELA study in late-stage AML
The pivotal phase III study, the CLAVELA study, is an open-label, randomised controlled trial comparing elacytarabine with the investigator's choice of treatment in patients
with late-stage AML (i.e. those who have failed two or three previous treatment regimes). The study will recruit 380 patients
at 75 hospitals in the USA, Canada, Europe and Australia. For more information see clinicaltrials.gov.
The Chairman of the CLAVELA study's steering committee is Professor Francis J. Giles, Galway/DublinUniversity, Ireland. Other members of the steering committee are Professor Martin Tallman, Memorial Sloan-Kettering Cancer Center, New York, USA, Professor Hartmut Doehner, University of Ulm, Ulm, Germany and Professor Alan Burnett, Cardiff University, School of Medicine, Cardiff, UK.
The primary objective of the study is to compare overall survival (OS) between patients treated with elacytarabine and those treated with the investigator's choice. The secondary objectives are to compare the response rates, duration of response, and safety profile of elacytarabine with the investigator's choice treatments.
Patients randomised to the investigators' choice group can receive a range of treatments including:
- High-dose cytarabine for up to six days
- MEC - mitoxantrone, etoposide and cytarabine
- FLAG or FLAG-IDA - fludarabine, cytarabine, G-CSF and idarubicin
- Low-dose cytarabine for up to two weeks
- Hypomethylating agents - azacytidine or decitabine
- Hydroxyurea with the intent to control the white blood cell count (WBC)
- Palliative care
The results from this study, if positive, will be used by Clavis Pharma to support regulatory filings in the USA, Canada, Australia and Europe.
There is currently no standard therapy available for these patients and life expectancy is very short. The key results from the Phase II study were:
- Median survival three times longer (5.3 months vs. 1.5 months)
- Remission rate significantly increased (18% vs 4.1%, p<0.0001)
- Short-term mortality of 13%, substantially lower than the reported 25% for historical controls.
Phase II study in early stage AML
A phase II study in early-stage AML patients is open for recruitment in Europe and the USA. For more information see clinicaltrials.gov database.
A Phase II study of elacytarabine in combination with idarubicin in AML patients who have failed their first course of treatment is ongoing. The objective of the study is to determine response rates to the combination treatment and the relationship to the patient's nucleoside transporter (hENT1) status. The goal is to demonstrate that the efficacy of elacytarabine is independent of the patient's hENT1 status. Professor David Rizzieri from Duke University Medical Center, Durham, USA, is the Coordinating Investigator of the study.
Orphan Drug and Fast Track Designation
The US Food & Drug Administration (FDA) and the European Commission have granted an Orphan Drug designation to elacytarabine for the treatment of AML. These designations entitle Clavis Pharma
to exclusive marketing rights for seven and ten years in the US and the EU, respectively, from the date of marketing approval.
The clinical development program of elacytarabine has also been granted Fast Track designation by the FDA. Fast Track is a
process designed to facilitate the development and expedite the review of drugs to treat serious diseases and fill an unmet
medical need. The purpose of Fast Track is to get important new drugs to the patient earlier. A Fast Track priority review
is expected to take six months from New Drug Application (NDA) submission, rather than ten months for a standard review.
