Slide 1: Tipifarnib in Relapsed or Refractory AITL and CXCL12+ PTCL: Preliminary Results
Tipifarnib in Relapsed or Refractory Angioimmunoblastic T-cell Lymphoma (AITL) and CXCL12+ Peripheral T-cell Lymphoma (PTCL): Preliminary Results from an Open-Label, Phase 2 Study Thomas Witzig1, Lubomir Sokol2, Won Seog Kim3, Francine Foss4, Eric Jacobsen5, Fatima de la Cruz Vicente6, Dolores Cabal
Slide 2: Disclosures
Disclosures • Clinical Trials Support to conduct the trials: Acerta, Celgene, Kura Oncology, Spectrum • Advisory Boards (personally uncompensated): Incyte, Seattle Genetics, Abbvie, Morphosys, Spectrum, Celgene • Advisory Boards (personally compensated): Immune Design, Karyopharm, Epizyme (April 201
Slide 3: Tipifarnib is a Farnesyltransferase (FT) Inhibitor
Tipifarnib is a Farnesyltransferase (FT) Inhibitor • FT adds a 15 carbon farnesyl group to proteins with CAAX motif – C = cysteine; A = aliphatic a.a. X= determines which enzyme does the prenylation • Tipifarnib is an oral FTI that has been tested in >5000 unselected patients with a variety of solid
Slide 4: ORR in all patients = 20%
ORR in all 93 patients = 20% NCT00082888; LS038B Iowa/Mayo SPORE trial 15-ICML International Conference on Malignant Lymphoma, Abstract 032 4
Slide 5: Goals of this Presentation
Goals of this Presentation • To review preliminary data from a new ongoing phase 2 study (KO-TIP- 002) of single-agent tipifarnib – Drug in-licensed to Kura Oncology from Janssen/Johnson & Johnson – Single-agent tipifarnib at two different schedules: • 300 mg po bid days 1-21 q28 days • 600 - 900 mg
Slide 6: Tipifarnib is a CXCL12/CXCR4 Pathway Inhibitor
Tipifarnib is a CXCL12/CXCR4 Pathway Inhibitor • Key characteristics of CXCL12 – CXCL12 and its receptors (CXCR4, CXCR7) are key factors linking cancer cells with the tumor microenvironment • High CXCL12 expression defines poor prognosis in PTCL – 50% of AITL and 35% of PTCL-NOS have high CXCL12 exp
Slide 7: Study Design of KO-TIP-002
Study Design of KO-TIP-0021 Protocol Stages 1 and 2 • Unselected R/R PTCL, including AITL and PTCL-NOS • Tipifarnib 600 - 900 mg orally (po) twice daily (bid) on days 1-7 Wild type (wt) CXCL12 3’UTR Cohort (N=12) and days 15-21 every 28 days • R/R PTCL, ≥ 1 prior therapy, measurable disease, ECOG 0-
Slide 8: Patient Demographics for Ongoing KO-TIP-002
Patient Demographics for Ongoing KO-TIP-002 wt CXCL12 3’UTR Cohort 1 AITL Cohort Total Patients Treated, n (%) 15 (100) 16 (100) Total Evaluable for Efficacy 2, n (%) 12 (80.0) 11 (68.8) Histology AITL, n (%) 4 (26.7) 16 (100) PTCL-NOS, n (%) 11 (73.3) 0 Other, n (%) 0 0 Age, yrs Median 65.2 66.9 Mi
Slide 9: Proof of Concept for Tipifarnib in wt CXCL12 3'UTR PTCL
Proof of Concept for Tipifarnib in wt CXCL12 3’UTR PTCL wt CXCL12 3’UTR Cohort: wt CXCL12 3’UTR Cohort: Variant CXCL12 3’UTR All patients PTCL-NOS PTCL-NOS enrolled in S1/2 Total treated 15 11 6 Total efficacy evaluable 12 9 6 Overall Best Response Complete Response (CR) 3 1 - Partial Response (PR)
Slide 10: Tumor Reduction in PTCL-NOS, wt CXCL12 3'UTR
Tumor Reduction in PTCL-NOS, wt CXCL12 3’UTR • 77 yo; PTCL-NOS Stage IV • CHOP x 5 with response then PROG biopsy-proven PTCL relapse in multiple skin nodules • Rapid PR after two cycles of tipifarnib Baseline End of Cycle 2 15-ICML International Conference on Malignant Lymphoma, Abstract 032 10
Slide 11: Proof of Concept for Tipifarnib in AITL
Proof of Concept for Tipifarnib in AITL AITL Cohort All AITL in KO-TIP-0021 Total treated 16 23 Total efficacy evaluable 11 17 Overall Best Response Complete Response (CR) 3 5 Partial Response (PR) 2 4 Stable Disease (SD) 3 3 Progressive Disease (PD) 3 5 Not efficacy evaluable (NE) 5 6 PPS2 mITT PPS
Slide 12: AITL: Tipifarnib treatment resulted in durable clinical responses
AITL: Tipifarnib treatment resulted in durable clinical responses and enabled subsequent transplant in patients achieving a CR Maximum Change in Tumor Burden Time on Treatment 40 20 % Change in SPD 0 -20 -40 Allo BMT Median 5.5 months (95% CI 3.7-30.6) -60 Allo BMT for AITL patients with SD/PR/CR -8
Slide 13: Tipifarnib is Active in High CXCL12 Expressing AITL and PTCL NOS Tumors
Tipifarnib is Active in High CXCL12 Expressing AITL and PTCL NOS Tumors sample HISTOL RESP CXCL12/CXCR4 6 AITL PR 7.42 Maximum Change in Tumor Burden 28 AITL CR 2.4 34 AITL PD/NE 1.5 36 NOS SD 1.3 40 17 NOS SD 0.85 Tipifarnib targets 32 AITL PD/NE 0.8 37 NOS SD 0.6 CXCL12 and is active in 20 1 AITL
Slide 14: High Activity of Tipifarnib in AITL with KIR3DL2 mutations
High Activity of Tipifarnib in AITL with KIR3DL2 mutations Best Response to Tipifarnib (N=16 AITL with sequenced tumors) KIR3DL2 Mutant KIR3DL2 Wild Type N 8 8 Overall Best Response Complete Response (CR) 4 - Partial Response (PR) 2 2 Stable Disease (SD) 2 - Progressive Disease (PD) - 6 Not evaluabl
Slide 15: KIRs
KIRs Killer-cell immunoglobulin-like receptors (KIRs) are transmembrane glycoproteins expressed in NK and T cells that play key regulatory functions, including the control of chemokine/cytokine release and angiogenesis. See poster at this meeting by A. Gualberto et al Abstract 156-P 15-ICML Internat
Slide 16: Drivers of Tipifarnib's Activity
Drivers of Tipifarnib’s Activity High CXCL12 expression, Low CXCL5 expression confer high clinical activity AITL Genetics Mechanism of Action PTCL-NOS Genetics High CXCL12 expression in AITL histology Tipifarnib downregulates CXCL12 secretion High CXCL12 in subjects with wt CXCL12 3’UTR Histology CX
Slide 17: Conclusions
Conclusions • The AITL and wt CXCL12 3’UTR cohorts met pre-specified statistical hypotheses supporting proof-of-concept for tipifarnib in PTCL. • Tipifarnib is active in AITL pts and in PTCL-NOS pts with wt CXCL12 3’UTR – AITL: 53% ORR (all subjects, PPS) – PTCL-NOS with wt CXCL12 3’UTR: 33.3% ORR (
Slide 18: Acknowledgements
Acknowledgements • Patients, their families and caregivers • Study Investigators and their study teams • Kura Oncology 15-ICML International Conference on Malignant Lymphoma, Abstract 032 18