A Phase II Trial of the FLT3 Inhibitor CEP701 as First Line Treatment for Older Patients with Acute Myeloid Leukaemia Not Considered Fit for Intensive Chemotherapy.
Authors: Knapper Steven , Burnett Alan K. , Kell Jonathan , Chopra Raj , Clark Richard , Craig Jenny , Culligan Dominic , Levis Mark J. , Russell Nigel H. , Small Donald 
Published: October 2019

Abstract
Activating mutations of the receptor tyrosine kinase FLT3 are present in approximately one-third of cases of AML and are associated with an adverse prognosis. Activated FLT3 is also frequently expressed in wild type (WT) patients. The indolocarbazole derivative CEP701 (Cephalon Inc) has been shown to potently inhibit phosphorylation of both mutant and WT FLT3 in vitro causing cytotoxicity in primary AML blasts and prolonging survival in mouse AML models. We present results from the first phase II trial of CEP701 given as first line treatment in AML in patients aged over 70 years (or aged 60–69 with a poor performance score or cardiac toxicity) and not considered fit for intensive chemotherapy, irrespective of FLT3 mutation status. Patients with presenting white blood cell (WBC) count of over 30x109/l received hydroxycarbamide for up to 21 days to reduce the WBC to less than 10x109/l before starting CEP701. CEP701 was administered orally for 56 days, initially at a dose of 60mg bd with dose increase to 80mg bd from day 28. Response was assessed by BM and peripheral blood examination on days 14, 28 and 56. 24 patients entered the study: 12 male and 12 female with a median age of 73 (range 67–84). 5 are too early in treatment to assess response. 1 patient died from intracerebral haemorrhage and 2 were withdrawn due to toxicity (emesis) before response could be assessed. Of the sixteen fully evaluable patients 4 were FLT3 mutants (2 ITD, 2 point mutations) and the remaining 12 had WT FLT3. Bone marrow response (BMR) was defined as a greater than 50% reduction in bone marrow blasts without haematological recovery. Haematological response (HR) was defined as disappearance of blasts from the peripheral blood not attributable to hydroxycarbamide. 3 of the 4 FLT3 mutant cases responded to CEP701. A 72 year-old male point mutant (deletion 836) achieved a late HR with normalisation of counts lasting 6 months. A 74 year-old male point mutant (D835) continues CEP701 after achieving a HR on 60mg bd associated with transfusion independence and normalisation of counts. A 74 year-old female ITD mutant achieved a HR on 60mg bd followed by rapid disease progression after the drug was withdrawn due to profound fatigue. 3 of the 12 wild type cases responded including 1 BMR and 1 HR (both transient) on 80mg bd. A third wild type case had a transient BMR on 60mg bd and a further transient BMR following dose increase to 80mg bd. No patient achieved a conventional complete remission. 11 of the first 24 patients (46%) experienced grade 1/2 gastrointestinal toxicity. Cases have been further categorised by Affymetrix gene expression analysis to identify gene signatures associated with drug responsiveness. 2 clinical CEP701 responders among the first 10 cases analysed fit a previously-defined gene expression signature associated with high in vitro CEP701 responsiveness (Knapper et al. Blood 102:11). Flow cytometric surface FLT3 expression assay, MTS cytotoxicity assay and ex vivo surrogate bioassay of plasma FLT3 inhibitory activity show limited correlation with clinical response. The preliminary trial results suggest that CEP701 has haematological activity in both mutant and WT patients. In view of the modest response of WT cases it is proposed to amend the trial to assess sequential low dose cytarabine and CEP701 as a combined approach.