RAD001, An Inhibitor of mTOR, Shows Clinical Activity in a Phase I/II Study in Patients with Primary Myelofibrosis (PMF) and Post Polycythemia Vera/Essential Thrombocythemia Myelofibrosis (PPV/PET MF).
Authors: Vannucchi Alessandro M. , Guglielmelli Paola , Gattoni Elisabetta , Antonioli Elisabetta , Bogani Costanza , Tozzi Lorenzo , Pieri Lisa , Bosi Alberto , Rambaldi Alessandro , Barbui Tiziano , Barosi Giovanni 
Published: October 2019

Abstract
Abstract 307
Constitutive and enhanced activation of JAK/STAT pathway is found in patients (pts) with myeloproliferative neoplasms (MPN), particularly but not exclusively in those with mutation in the Janus tyrosine kinase 2 gene (JAK2V617F) or the MPL gene (MPLW515L/K/A). Activation of the Erk and PI3K/Akt pathways have also been described in cells harboring the JAK2V617F mutation. In in-vitro studies performed in our laboratory (AM Vannucchi et al, ASH 2009, abstract submitted) we observed that RAD001, a specific inhibitor of the serine/threonine kinase mTOR (mammalian target of rapamycin) that is a downstream target of PI3K, remarkably inhibited proliferation of JAK2V617F mutant cell lines and reduced the clonogenic activity of CD34+ cells from MPN pts. The PI3K/Akt/mTOR pathway has become an important focus for cancer therapy, and mTOR inhibitors have demonstrated activity against solid tumors and lymphomas. A phase I/II trial of RAD001 is being conducted in pts with PMF and PPV/PET MF, including JAK2V617F or MPL mutated as well as wild-type pts with intermediate/high risk score according to Lille criteria. Diagnosis of PMF and of PPV/PET-MF was made following the WHO and International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria, respectively. Phase I is a dose escalation of RAD001 involving 3 sequential cohorts of 3 pts each at 5.0, 7.5, and 10 mg daily, orally, for 3 months, to define maximum tolerated dose (MTD). Phase II involves the use of MTD for 4 months, according to a two-stage Simon design, aimed at assessing efficacy of the drug. Responses are evaluated using the EUMNET criteria for treatment response in myelofibrosis (Barosi G et al, Blood 2005). At the time of writing, 8 of 9 pts included in the Phase I have completed the 3-month study period without dose-limiting toxicities or other significant adverse events; the ninth pt at 10 mg is completing the last month of treatment. There were seven pts with PMF and 2 with PPV-MF. Main toxicities were represented by grade 2 mouth ulcers in 3 pts and transient grade 1/2 hypertrigliceridemia in 5 pts, that occurred irrespective of the dose. One pt at 10 mg presented transient muscular weakness and arthralgia. The initial dose of 5.0 mg resulted in a reduction in spleen size consistent with a complete response (CR) in one pt (from 4 to 0 cm below the left costal margin) and partial responses (PR) in two pts (from 10 and 13 cm to 1 and 9 cm, respectively). In the 7.5 mg cohort, there were one CR (from 4 to 0 cm) and one PR (from 16 to 8 cm) in splenomegaly; none of the 2 pts at 10 mg had a response in splenomegaly. In 1 pt CR in splenomegaly was maintained at +4 mo after suspension of drug while in the other responding pts there was a progressive re-enlargment of the spleen to baseline level. A complete resolution of systemic symptoms was achieved in 2 of 3 pts while aquagenic pruritus disappeared in all the 5 pts who complained of it. Overall, there were 2 major and 3 moderate responses, while 3 pts did not show a measurable response. At the end of therapy, the absolute count of circulating CD34+ cells had decreased in all but one pt of a median value of 39% from baseline (range 16% to 72%). There was no significant decrease in the burden of granulocyte V617F allele at the end of treatment in the 8 mutated pts. Single-colony JAK2V617F genotyping was performed in 4 pts, 2 each from the 5.0 and 7.5 mg cohort. In one patient receiving 7.5 mg the percentage of homozygous BFU-E and CFU-GM decreased from 14% and 45%, respectively, at baseline to 0 and 18% at the end of therapy; in the other 3 pts changes were minimal. In conclusion, initial results showed rapid reduction of splenomegaly and symptomatic improvement, without relevant toxicity, in pts with myelofibrosis receiving RAD001. The drug also reduced the circulating CD34+ cell count and V617F-homozygous progenitor cells appeared to be decreasing at least in some patients, although the allelic burden measured in granulocytes did not modify. Updated results on current patients and future patients enrolled in Phase II will be presented at the meeting.

Disclosures:
No relevant conflicts of interest to declare.