NP39761 IDASANUTLIN In HYDROXYUREA-RESISTANT/INTOLERANT PV
Research type
Research Study
Full title
A PHASE II, single-Arm, open-Label Study To Evaluate the Efficacy, safety, Pharmacokinetics and Pharmacodynamics of IDASANUTLIN MONOTHERAPY In participants with HYDROXYUREA-RESISTANT/INTOLERANT POLYCYTHAEMIA VERA
IRAS ID
270628
Contact name
Bethan Psaila
Contact email
Sponsor organisation
F Hoffmann-La Roche Ltd
Eudract number
2017-000861-58
Duration of Study in the UK
3 years, 0 months, 3 days
Research summary
Patients with Polycythaemia vera (PV) have a median survival of approximately 18 months from diagnosis if untreated and approximately 18 years if treated. Progression to other haematologic malignancies and heightened potential for thrombosis (cardiovascular events) comprise the two most common causes of mortality. Therefore, prevention of thrombotic events is an important treatment goal, accomplished by maintaining haematocrit (Hct) ≤45% which correlates to decreased cardiovascular risk and risk of death.
Predominant first line treatment for PV is hydroxyurea (HU), which serves as a cytoreductive agent to manage elevated blood counts and to decrease frequency of phlebotomy.However, HU doesn’t appear to affect the underlying disease biology, and many patients have inadequate response or intolerable side effects. Resistance or intolerance to HU was found to occur in 11% and 13% of patients, respectively, and is associated with higher risk of death.
For PV patients resistant or intolerant to HU, ruxolitinib, a JAK2 kinase inhibitor, was approved as Jakafi in December 2014 in US and as Jakavi in March 2015 in EU. In a pivotal Phase III trial (RESPONSE), ruxolitinib met its primary endpoint of improved composite response, however as a second line agent in PV, it requires continuous daily treatment and following interruption/discontinuation, symptoms and blood counts return to pretreatment and overall, 34% of patients discontinued ruxolitinib over a 5-year follow-up period.
The tumor suppressor p53 is a powerful growth suppressive and pro apoptotic protein that plays a central role in protection from tumor development and is frequently inactivated in human cancer, however inactivating mutations of p53 are rare in PV. Murine double minute homolog 2 (MDM2) regulates p53 through a negative feedback loop. More than 95% of patients with the haematopoietic stem cell malignancy polycythaemia vera (PV) have been found to have the constitutively activated JAK2 mutant V617F allele which dysregulates MDM2, leading to a decrease in p53 activation.
Idasanutlin (RO5503781) is a selective inhibitor of the p53 MDM2 binding which frees p53 from negative control and activates the p53 pathway. Therefore, it may allow for an increase in p53 activity and decrease of the malignant proliferation seen in PV.
This study will evaluate the efficacy of idasanutlin monotherapy in patients with HU resistant/intolerant PV and without prior ruxolitinib exposure and in all patients (with and without splenomegaly) by complete haematologic response.
40 patients will be recruited globally with approximately 4 patients recruited at 4 UK sites. The study will last approximately 1.5 - 2 years from first patient screened to last patient last visit.The study is sponsored by F. Hoffman La Roche
Research Summary; Version Number 3 dated July 2019REC name
North West - Haydock Research Ethics Committee
REC reference
19/NW/0554
Date of REC Opinion
18 Oct 2019
REC opinion
Further Information Favourable Opinion