Issues with Novel Agents Need to revise Response Criteria
Dosing: No more MTD dosing Threshold dosing Fixed dosing / wide
therapeutic window Differences
Slide 6
Issues with Novel Agents Need to revise Response Criteria
Dosing: No more MTD dosing Threshold dosing Fixed dosing / wide
therapeutic window Differences
Slide 7
Lymphocytosis + Nodal Reduction with BCR Antagonists
Slide 8
Redefining Clinical End Points Cheson 2012 Standard response
criteria: measure of treatment efficacy For novel agents, response
criteria dont measure effect: Thalidomide / lenalidomide: tumor
flare BCR Antagonists: lymphocytosis (Not tumor flare) Need to
provide means for determining need for treatment discontinuation
LRF sponsored committee: May 2011 Cheson BD. JCO 2012.
Slide 9
Cheson 2012: Recommendations 1.For IMID compounds: Assessment
of PD should use repeat observations and incorporate indicators of
PD not associated with tumor flares. 2.For BCR-targeted agents:
lymphocytosis alone should not be considered an indicator of PD.
Need to demonstrate other CLL-related signs or symptoms of PD.
3.Lymphocytosis is distinct from tumor flare
Slide 10
Issues with Novel Agents Need to revise Response Criteria
Dosing: No more MTD dosing Threshold dosing Fixed dosing / wide
therapeutic window Differences
Issues with Novel Agents Need to revise Response Criteria
Dosing: No more MTD dosing Threshold dosing Fixed dosing / wide
therapeutic window Differences
Slide 13
Kinase PCI-32765 IC 50 (nM) Kinase PCI-32765 IC 50 (nM)
Btk0.46FGR2.31 Ikt10.70Fyn95.55 Bmx/Etk0.76HCK3.67
TEC77.76Lyn200.45 EGFR5.55ABL86.12 JAK316.13Brk3.34
BLK0.52JAK2>10,000 LCK33.24SYK>10,000 IC50 Values of
PCI-32765 and Related Kinases
Slide 14
Brutons Tyrosine Kinase (Btk) B-cell antigen receptor (BCR)
signaling required for B cell survival Brutons Tyrosine Kinase
(Btk) is an essential element of the BCR signaling pathway
Inhibitors of Btk block BCR signaling and induces apoptosis
Slide 15
Ibrutinib: Inhibitor of Brutons Tyrosine Kinase Forms an
irreversible bond with cysteine-481 in Btk Potent Btk inhibition IC
50 =0.5 nM Orally bioavailable Daily dosing resulting in 24-hr
target inhibition No impact on T-cells or NK cells Possible impact
upon bmx, blk, and platlets N N N N NH 2 O N O
Slide 16
Ibrutinib in CLL: PCYC-1102 Furman RR. iWCLL 2013
Slide 17
PCYC-1102: Patient Demographics Furman RR. iWCLL 2013
Characteristic TN 65 Years n = 31 R/R n = 85 Median age, years
(range) 70 years, n (%) 71 (65, 84) 23 (74) 66 (37, 82) 30 (35)
Male, n (%) Female, n (%) 19 (61) 12 (39) 65 (76) 20 (24) Prior
Therapies, n (%) < 3 > 3 NA Median = 4 (1-12) 24 (28) 61 (72)
2 M > 3.0 mg/L, n (%)8 (26)39 (46) Rai stage III/IV, n (%) 17
(55) 52 (61) Prognostic markers, n (%) IgV H unmutated del(17p)+
del(11q)+ 15 (48) 2 (6) 1 (3) 65 (76) 29 (34)
Slide 18
PCYC-1102: Patient Disposition Furman RR. iWCLL 2013 TN 65
Years n = 31 R/R n = 85 Median time on treatment, months (range)
21.3 (0.3, 26.6)16.3 (0.3, 28.7) Median time on study, months
(range)22.1 (2.5, 28.9)22.1 (0.7, 29) Patients still on treatment,
n (%)26 (84)53 (62) Patients discontinuing treatment, n (%)5 (16)32
(38) Reasons for treatment discontinuation, n (%) AE
Treatment-related AE Death due to AE 2 (6) 1 (3) 0 10 (12) 1 (1) 1
(1) a Disease progression b 1 (3)10 (12) SCT (while in response)
Investigator decision (not SCT) Patient decision Lost to Follow-up
0 2 (6) 0 4 (5) 3 (4) 1 (1) a Cryptococcal pneumonia b 7 patients
(1 TN and 6 R/R) had disease progression with Richters
transformation
Slide 19
PCYC-1102: Overall Response Among those patients whose initial
response was PR-L, the majority achieved classic response by iwCLL
criteria: TN: 9/13 (69%) R/R: 38/49 (78%) Combined ORR + (PR-L) in
TN (84%) and R/R (88%)
Slide 20
Ibrutinib Pivotal Study Schema: PCYC-1112 Patients will be
randomized 1:1 to either arm A or B Treatment Arm A: Ofatumumab IV
12 IV doses over 24 weeks or until PD Week 1: 300 mg initial dose
Week 2 through 8: 2,000 mg (once weekly) Week 12, 16, 20 and 24:
2,000 mg (every 4 weeks) Treatment Arm B: Ibrutinib PO 420 mg (3 x
140mg) orally daily until PD
Slide 21
PI 3 Kinase Signaling in B Cells Lannutti, B. Blood, 2011 BCR
PI3K Delta CD40 STAT T308S473 AKT JAK TRAF6 NF-k pathway JAK mTOR
BTK PLC 2 PKC GSK-3 LYN SYK LYN/SYK T-cell Signalingstimulus gp130
STAT BTK PLC 2 p70s6k elf4E B-cell membrane CXCR4/5 BAFFR Stromal
cell IL-6R CXCL12/13 BAFF IL-6
Slide 22
Idelalisib: Specific Inhibitor of p110 Tyrosine Phosphorylation
PI3K Isoforms ExpressionBroad Leukocytes Gene KO effectLethal
Benign Physiological role Insulin signaling Angiogenesis unknown
B-cell signaling, development & survival Neutrophil, T-cell
development IC50 (nM)21544278182
Slide 23
Phase I Study of Idelalisib in Patients with Hematologic
Malignancies Idelalisib 50 mg to 350 mg BID Continuous oral dosing
(28-day cycles) 48 weeks Endpoints: Phase 2 dose Safety
Pharmacodynamics Pharmacokinetics Antitumor activity Previously
treated hematologic malignancies: CLL (N=54) iNHL (N=30) MCL (N=21)
DLBCL (N=9) myeloma (N=12) AML (N=12)
Slide 24
CLL Patients Treated with Idelalisib 150 mg BID Brown J. ASCO
2013 Response Rate Nodal Response 39% 33% 81% 72% Overall Response
Decrease by 50% of nodal SPD PR with lymphocytosis (Cheson 2012) PR
by IWCLL criteria (Hallek 2008)
Slide 25
CLL Patients Treated with Idelalisib 150 mg BID Brown J. ASCO
2013 ALC SPD
Slide 26
Single Agent Idelalisib in CLL Brown J. ASCO 2013
Slide 27
Improvement in Baseline Cytopenias Brown J. ASCO 2013
Slide 28
Idelalisib in CLL Brown J. ASCO 2013 Median PFS = 17.1
monthsMedian OS not reached Progression Free SurvivalOverall
Survival
Slide 29
Adverse Events (> 15%) and Selected Lab Abnormalities (N=54)
Brown J. ASCO 2013 AE, n (%)Any Grade (%) Grade 3 (%) Fatigue17
(32)1 (2) Diarrhea16 (30)3 (6) Pyrexia16 (30)2 (4) Cough13 (24)2
(4) Back pain12 (22)0 Rash12 (22)0 URI12 (22)0 Pneumonia11 (20)10
(19) Night sweats10 (19)0 Chills 9 (17)0 Laboratory abnormality, n
(%) AST, increased*13 (24)1 (2) ALT, increased*10 (19)1 (2) *15
subjects total with transaminase elevations
Slide 30
Idelalisib + Coutre S. ASH 2012, Abs 191 LNR = Nodal Response
OR = Response by IWCLL criteria (Hallek 2008) Response Rate 95% CI
LNRORLNROR +R +B +BR LNROR
Slide 31
Idelalisib Pivotal Study Schema: GS-US-312-0116
Slide 32
IPI-145 IPI-145: Potent Inhibitor of PI3K- and Potent oral
inhibitor of both PI3K- and PI3K- Selective for PI3Ks over other
protein and lipid kinases Inhibits malignant B and Tcell survival
Affects tumor cells directly Disrupts tumor cell interactions
within the microenvironment Patel et al ASCO 2013
Slide 33
Complete Inhibition of PI3K- and >50% Inhibition of at Doses
> 25 mg BID Patel. ASCO 2013.
Slide 34
IPI-145: Clinical Response Patel, et al. ASCO 2013