Preliminary Results from an Open-Label, Phase 2 Study of Tipifarnib in Chronic Myelomonocytic Leukemia (CMML)

Background

Tipifarnib is a potent and selective inhibitor of farnesyltransferase (FT). FT catalyzes post-translational attachment of farnesyl groups required for localization of signaling molecules to the inner cell membrane. While all RAS isoforms (KRAS/NRAS/HRAS) are FT substrates, only HRAS is exclusively dependent upon farnesylation for membrane localization and signaling activation. KRAS and NRAS, on the other hand, can undergo an alternative pathway for prenylation, i.e. geranylgernylation, enabling these cancer cells to overcome signaling inhibition by FT inhibition alone. Oncogenic RAS pathway mutations (NRAS, KRAS, CBL and PTPN11) are seen in approximately 30% of CMML patients (Patnaik BCJ 2016) and are associated with a proliferative phenotype. Tipifarnib has previously been shown to be well tolerated and to have a 32% response rate in patients (pts) with myelodysplastic syndromes, including 3 (17%) complete responses in 17 pts with CMML (Fenaux Blood 2007). Given the known resistance mechanisms and reported clinical activity, we hypothesize that tipifarnib might have greater activity in RAS wild type CMML patients. We report the efficacy, safety and biomarker data from our ongoing Phase 2 study in CMML.

Methods

This Phase 2 study is a multi-institutional, single-arm, open-label study to determine the efficacy and safety of tipifarnib in pts with CMML (N=20). Pts aged ≥ 18 years old and with a performance status of 0-1 were eligible and retrospectively stratified based on KRAS/NRAS mutational status. At study initiation, pts received 1200 mg orally twice daily, but due to frequent myelosuppression and azotemia, the trial was amended and 900 mg twice daily on days 1-7 and 15 -21 of 28-day treatment cycles was selected as the optimal dose. The primary endpoint was overall response rate (ORR) per Myelodysplastic/Myeloproliferative International Working Group (MDS/MPN IWG) criteria (Savona Blood 2015) with the probability that the TRUE underlying ORR rate exceeds historical control rate 0.1 computed via Bayesian methodology. Secondary endpoints included safety and tolerability, duration of response (DOR) and progression free survival (PFS). Biomarker studies included, serial next-generation sequencing, gene expression profiling of pre- and on-treatment bone marrow samples by RNASeq and flow cytometry based monocyte and immune cell subsets analyses. Clinical trial information: NCT02807272.

Results

At data cut-off (July 2017), 15 pts (11 CMML-1, 4 CMML-2) were treated with tipifarnib, with 10 pts continuing on treatment in cycles 1 - 6. Most common treatment related AEs (all grades) were thrombocytopenia (33%); diarrhea and nausea (27%); neutropenia, fatigue and vomiting (20%). 1 pt experienced tumor lysis syndrome during the first cycle of tipifarnib treatment that resolved with sequelae. Of the 7 pts evaluable for response, marrow response and symptom response have been observed in 1 pt each, 4 pts have stable disease and 1 pt progressed. Five of those pts received prior therapy with hypomethylating agents (HMA). DNA sequencing data are available for 10 pts. Most commonly observed mutations at study entry were TET2 (80%), SRSF2 (50%), ASXL1 (50%), NRAS (50%), CBL (40%), RUNX1 (40%), EZH2 (30%), and KRAS (20%). Two of the 5 pts with NRAS mutations were evaluable beyond cycle 2 and an increase in NRAS allele frequency was observed (15 to 32%, p = 0.04 and 13 to 20%, p = ns). No meaningful changes were observed in the allele frequency of other mutations. Early decreases in monocytes counts were observed in several pts with a responding patient having normalization of CD14+/CD16- classical monocytes.

Conclusion

In this ongoing Phase 2 trial, preliminary data suggest that tipifarnib was generally well-tolerated and has antitumor activity in pts with CMML in a post-HMA setting.