Slide 1: CPI-818, an Oral Interleukin-2-Inducible T-Cell Kinase Inhibitor
CPI-818, an Oral Interleukin-2-Inducible T-Cell Kinase Inhibitor Pre-clinical Characterization and Interim Results of a Phase I/Ib Dose-Escalation Trial in Patients with Relapsed/Refractory T-Cell Lymphoma Mehrdad Mobasher, MD, MPH Chief Medical Officer
Slide 2: Inhibition of ITK for T Cell Lymphoma
Inhibition of ITK for T Cell Lymphoma T cells TCR • Rationale for Targeting ITK Signaling in Lymphomas CD3/4/8 – TCR signaling is maintained in most T cell lymphomas PIP2 PIP3 – Analogous to BCR and B cell lymphomas; ITK is the T cell PtdIns(4,5)P2 ITK homologue of BTK and is widely expressed in T
Slide 3: CPI-818 Selectivity Inhibits ITK and Blocks Cellular Signaling
CPI-818 Selectivity Inhibits ITK and Blocks Cellular Signaling Kinome Profile and pPLC𝛄𝛄1 Suppression Kinases with Cys-442 CPI-818 (µM): TCR 𝝰𝝰CD3: – + + + + + + + + CPI-818 Kd in nM pPLC𝛄𝛄1 Y783 ITK 2.5 BLK 4700 Total PLC𝛄𝛄1 CPI-818 BMX 9100 ITK BTK 1200 pERK Suppression 30 EGFR >10000 25…
Slide 4: CPI-818 Inhibits Lymphoproliferative Disease in Mice
CPI-818 Inhibits Lymphoproliferative Disease in Mice Lymphadenopathy Pathologic and Normal T cells in Spleens Lymphadenopathy Score CD4- CD8- (DN) CD4+ CD8+ 106 / Spleen Control CPI-818 Cyclophosphamide Cont 818 CTX Cont 818 CTX Cont 818 CTX MRL/lpr MRL MRL/lpr MRL MRL/lpr MRL Age (weeks) Treatment
Slide 5: CPI-818 Preferentially Inhibits Sézary Cells
CPI-818 Preferentially Inhibits Sézary Cells Gating Strategy Inhibition of Cell Division 𝝰𝝰CD3/CD28 DMSO DMSO 818 (1 µM) Pt 1 Pt 2 Pt 3 Healthy Donor Proliferation Score TCRV𝝱𝝱2+ Total CD4+ Cells TCRV𝝱𝝱2- CPI-818 (µM) Proliferation Dye CD8 Cells CD4 Cells Sézary Cells • Sézary cells were more…
Slide 6: Spontaneous T Cell Lymphoma in Companion Animals
Spontaneous T Cell Lymphoma in Companion Animals Evaluation of CPI-818 by Prof. Douglas Thamm (CSU) CTCL Patient 11 year old, Male Golden Retriever 4 months 6
Slide 7: CPI-818-001 Phase 1/1b Clinical Trial Design
CPI-818-001 Phase 1/1b Clinical Trial Design Dose escalation Dose Escalation Design • Initial enrollment in dose escalation with 3+3 (+ optional 3) design 1200mg BID • Up to 6 ascending dose levels of CPI-818 n = 3+3 • Enroll patients with various types of T-cell lymphoma (PTCL and CTCL) who have pr
Slide 8: CPI-818-001 Trial Dose Expansion
CPI-818-001 Trial Dose expansion Dose Expansion PTCL-NOS AITL CTCL Others* Stage 1 Stage 1 Stage 1 n=28 n=11 n=11 n=11 If ≥ 2 response observed in a disease cohort, add 17 subjects and proceed to Stage 2 Stage 2 Stage 2 Stage 2 n=17 n=17 n=17 * Other types include NKTCL, ALCL, ATLL, etc 8
Slide 9: CPI-818-001 Study Patient Characteristics
CPI-818-001 Study Patient Characteristics CPI-818 CPI-818 CPI-818 CPI-818 100mg BID 200mg BID 400mg BID 600mg BID (N=4) (N=3) (N=5) (N=4) Age (yrs), median (range) 51 (29, 75) 59 (57, 60) 69 (42, 80) 69 (34, 74) Gender, male N (%) 3 (75%) 1 (25%) 3 (60%) 2 (50%) No. of prior therapies, median (range
Slide 10: All Adverse Events
All Adverse Events No grade 3/4 AEs Adverse Events N (%) 100mg (N=4) 200mg (N=3) 400mg (N=5) Total (N=12) Patients with any TEAE 4 (100%) 3 (100%) 3 (60%) 10 (83.3%) Abdominal distension 1 ( 25.0%) 0 0 1 ( 8.3%) Diarrhea 1 ( 25.0%) 0 0 1 ( 8.3%) Nausea 1 ( 25.0%) 0 1 (20%) 2 ( 16.7%) Retching 1 ( 25
Slide 11: Safety
Safety No DLTs • No DLTs observed so far and MTD not reached • 100mg cohort: – No treatment related Grade ≥ 2 AEs or SAEs – Treatment related AEs: diarrhea, nausea, retching (all n=1; Grade 1). – Other AEs: abdominal pain, vomiting, chills, weight decreased, decreased appetite, hypercalcemia, hyperu
Slide 12: PK and Occupancy Summary from Cohorts 1, 2 and 3
PK and Occupancy Summary from Cohorts 1, 2 and 3 Occupancy is increasing as a function of dose, BID Dosing Required The Pharmacokinetic profile of CPI-818 and ITK Trough ITK Occupancy for Cycle 1 Occupancy in PBMCs following a 100 QD dose with BID Dosing of CPI-818 100 100 100 mg Plasma CPI-818 Occu
Slide 13: Preliminary Patient Status in Dose Escalation
Preliminary Patient Status in Dose Escalation CPI-818-001 Study Trough ITK Occupancy AITL (4) PTCL-NOS (3) 58% Histology (No. of Prior Lines) ALCL (4) ATLL (2) PTCL-NOS (2) CTCL SEZARY (3) AITL (6) 76% 100 mg CTCL SEZARY (3) 200 mg CTCL SEZARY (5) skin 400 mg 600 mg 88% CTCL SEZARY (9) Ongoing CTCL
Slide 14: CTCL/SS Patient on 200mg Cohort with Nodal CR
CTCL/SS Patient on 200mg Cohort with Nodal CR Summary • 60 year old Caucasian female with SS Pre-Treatment Post-Treatment(C4D1) • FDG avid adenopathy in cervical, axillary, inguinal Paratracheal nodes bilaterally at diagnosis in 2017 • Enrolled in 200mg BID cohort since 21 Oct, 2019 • Screening PET:
Slide 15: CTCL/SS Patient on 400mg cohort with Skin Improvement
CTCL/SS Patient on 400mg cohort with Skin Improvement Summary • 80 year old Caucasian male CTCL (Sézary Syndrome) • Started C1D1 on 400mg BID cohort on 25-Nov-2019 • Screening: no visceral disease or target lesions on CT, absolute Sézary count 5.6x109/L • Patient reported decreased skin redness with
Slide 16: Conclusion
Conclusion • CPI-818 is a selective, covalent inhibitor of ITK (sparing RLK and BTK) • Blocks signal transduction in endpoints downstream of T-cell activation • Inhibits lymphoproliferative disease in MRL mouse model • Preferentially inhibits the proliferation of malignant cells sparing normal T cel
Slide 17: Acknowledgements
Acknowledgements National Cancer Seoul National • Participating Centers and Investigators: Centre University Hospital Asan Medical Center Seoul St Mary Hospital Dartmouth Gachon University Gil Medical Center Hackensack University Samsung Medical United States Medical Center Yale Pusan National Unive