Wei Ai, M.D., Ph.D.
June 2012
I.
II.
III.
IV.
Lymphoma: bendamustine
CLL/SLL: Btk inhibitor
Pre-B ALL: Bite biphasic antibody
Multiple Myeloma: Carfilzomib
National LymphoCare Study 2004 -2007 N = 2728
R + chemotherapy:
Regimen
Users (%)
RCHOP
55.0%
RCVP
23.1%
R-fludarabine
15.5%
Other
6.4%
Friedberg, et al., JCO 2009



Newly diagnosed indolent lymphoma or
mantle cell lymphoma:
- Follicular lymphoma (grade 1-3a), small
lymphocytic lymphoma, marginal zone
lymphoma, wadenstroms, mantle cell
lymphoma (elderly)
Stage III and IV
Meet criteria for initiating treatment
Samantha Mary Jaglowski, et al.
The Ohio State University


BTK inhibitor, an oral agent, showed
promising activity as a single agent in
untreated elderly pts (>65 yo) with CLL/SLL
(John Byrd 2012 ASCO)
- N = 26
- ORR 81%, CR 12% with medium f/u 14 mos
Ofatumumab is active in fludarabine- or
alemtumumab-refractory CLL/SLL pts: ORR
approximately 50%
Wierda, et al., JCO 2010


Ibrutinib 420 mg po qd
Oftumumab
- 300 mg C2, day1
- 2000 mg C2,days 8, 15, 22
- 2000 mg C3, days 1, 8, 15, 22
- 2000 mg C4-8, day 1 only


To determine the toxicity of the combination
regimen
- Tolerability is defined as no more than 1
DLT in the first 6 pts treated for 2 cycles
To evaluate ORR at one year:
N = 27, including the initial 6
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CLL/SLL or Richter’s transformation
Two or more prior therapy, including a purine
analog- containing regimen
More than 10% CD20 expression on CLL cells
by flow cytometry
Adequate organ functions

Ibrutinib combined with ofatumumab is a well
tolerated and highly active regimen in
patients with relapsed and refractory CLL/SLL
Max Topp et al.
80%
15 ug/m2/24 hrs CIV x 4 weeks, 2 weeks off, q 6wk-cycle
Topp, et al., JCO 2011


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Dose-finding Phase:
- Cohorts: 1, 2a, 2b
Expansion Phase:
Dosing: CIV 4 wks on, 2 wks off, for up to 5
cycles
- CR/CRh within the first 2 cycles -> allo
Primary Endpoint: CR/CRh within 2 cycles


R/R ALL, > 5% blasts in BM
Ph+ and relapsed after allo were permitted

Selected dose for expansion cohort based on
lowest treatment-related AEs (3/5 pts):
5ug/m2/d CIV week 1, then 15ug/m2/d CIV
thereafter
N = 23
Median Age
31 (21 – 66)
Refractory
1 (4%)
Relapsed
21 (91%)
1st relapse <= 18
mos
9 (43%)
1st relapse > 18 mos
4 (19%)
>= 2nd relapse
8 (38%)
Prior SCT
10 (43%)
Ph +
2 (9%)
T (4,11)
1 (4%)
Blasts in BM
>60%
12 (52%)
10% - 60%
6 (24%)
< 10%
4 (17%)

Cytokine release syndrome
- Risks: high tumor burden ans without cytoreductive
phase
- Prevention: cytoreduction 5ug/m2 wk 1 and give
Dex for BM>50%


CNS Adverse Events:
- 3 seizures and 3 encephalopathy: fully
reversible
- all 6 pts continued at 5 ug/m2
One pt died of fungal infection





CR/CRh: 17/23 pts (74%)
All but 2 responders achieved molecular
remission
High remission rate in all pt groups, including
Ph+
13 pts received an allogeneic SCT
With a median follow-up of 4.5 months,
median duration of response was 8.9 for all
cohorts, not yet reached for the expansion
cohort




Well-tolerated at 5 ug/m2/d followed by
15 ug/m2/d CIV, 4 weeks on, 2 weeks off
High hematologic and molecular response
rate
Median duration of complete hematologic
response was 8.9 months
Median survival was 9 months
Carfilzomib Coming to the Front-line
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Disease status
- High risk, intermediate risk vs low risk
- special clinical scenarios: plasma leukemia,
renal failure
Patient factors
- Transplant eligibility
- PS and comorbidity
Clinical benefit
- response and OS
- QOL
Toxicity and convenience
Cost




Newly approved second-in-class proteasome
inhibitor
Well tolerated, no neurotoxicity
Overcome bortezomib resistance in vitro
Active alone and in combination regimens for
relapsed/refractory MM
Kuhn et al., Blood 2007, O’Connor Clin Cancer Res 2009, Wang,
M et al., JCO 2011 Abstract 8052, Vij, et al., Blood, 2012
CMP
carfilzomib,
melphalan,
prednisone
CYCLONE
carfilzomib,
cyclophosphamide
thalidomide
dexamethasone
CRd
carfilzomib,
lenalidomide
dexamethasone
Key Criteria
Transplant
ineligible
>65 yo
Transplant eligible
Transplant
ineligible or
eligible
Comparative or
Parent regimens
VMP
CyBorD
CTD
RVD,VTD, VTD

Carfilzomib:
20mg/m2 first week, 27mg/m2 thereafter
Stringent complete response (sCR) in patients
with newly diagnosed multiple myeloma
(NDMM) treated with carfilzomib (CFZ),
lenalidomide (LEN), and dexamethasone (DEX)
AJ Jakubowiak,1 K Griffith,2 D Dytfeld,3 DH Vesole,4 S Jagannath,5 T Anderson,2
B Nordgren,2 K Detweiler-Short,2 D Lebovic,2 K Stockerl-Goldstein,6 T Jobkar,2
S Wear,
7
A Al-Zoubi,
2
A Ahmed,
2
M Hussein,8 H Yeganegi,9 R Vij6
1University
M
of Chicago, Chicago, IL; 2University of Michigan Comprehensive Cancer Center,
Ann Arbor, MI; 3Poznan University of edical Sciences, Poznan, Poland; 4John Theurer Cancer
Center, Hackensack, NJ; 5Mount Sinai Medical Center, New York, NY; 6Washington University
School of Medicine, St. Louis, MO; 7Multiple Myeloma Research Consortium, Norwalk, CT;
8
Celgene, Inc, Summit, NJ;
9
Onyx Pharmaceuticals, South San Francisco, C
Objectives
Primary
• Phase 1: MTD of CRd
• Phase 1/2: rate of ≥nCR
Secondary
• Overall response rate (≥PR)
• TTP, DOR, PFS, and OS
• Tolerability and toxicity
• For transplant candidates, evaluate the impact of CRd on
stem cell mobilization
• Evaluate prognostic factors and markers of response
4
Eligibility
Key inclusion criteria
• Newly-diagnosed MM requiring first-line therapy1
- Transplant-eligible and -ineligible
• Measurable disease per IMWG Criteria1
• ECOG performance status 0-2
Key exclusion criteria
• Grade 3/4 peripheral neuropathy
• ANC <1.0x109/L, Hgb <8.0 g/dL, platelets <75,000/µL
• Creatinine clearance <50 mL/min or serum creatinine ≥2 g/dL
• Serious co-morbidities
1. Durie BGM, et al. Leukemia. 2006;20:1467-1473.
5
Treatment Schema
CRd
Induction
Transplanteligible and -ineligible CRd Cycles 1-4
patients
CRd
Maintenance
CRd Cycles 5-8
Transplant-eligible
≥PR
ASCT
CRd Cycles 9-24
Lenalidomide
(off protocol)
LEN Cycles 25+
Until disease progression or
unacceptable toxicity
Stem cell collection
• Assessments on D1 and 15 of C1 and D1 thereafter using modified IMWG Criteria with nCR
Cycles 1-8
• CFZ 20-27-36 mg/m2 Days
1-2, 8-9, 15-16
1
• LEN 25 mg Days 1-21
• DEX 40 mg weekly Cycles 14, 20 mg weekly Cycles 5-8
Cycles 9-24
• CFZ on Days 1-2 and 1516 only
• CFZ, LEN, DEX at last
best tolerated doses
1. Jakubowiak AJ, et al. Blood. 2011;118: abstract 631.
Cycles 25+
• LEN at last best
tolerated dose
6
Best Response
Median 12 cycles (range 1-25)
≥PR
≥VGPR
≥nCR
sCR
100
98
80
60
40
81
62
42
20
0
All patients N=53
There was no difference by disease stage and cytogenetics
9
Progression-free Survival
Median follow-up of 13 months (range 4-25)
2 patients progressed
All patients with sCR have maintained response for median 9 months
(range 1-20)
12
Updated Toxicity of CRd Induction
Thrombocytopenia
Anemia
Neutropenia
Grade 3/4
Any grade
Hyperglycemia
Edema
Hypophosphatemia
Fatigue
Muscle cramping
LFTs
Rash
Diarrhea
Infection
Phlebitis
Peripheral neuropathy
Dyspnea
DVT/PE
Renal
Constipation
Mood alterations
0
20
40
Patients (%)
60
80
100
• Toxicity for cycles 1-8 is similar to previously reported1
• Limited dose modifications
1. Jakubowiak AJ, et al. Blood. 2011;118: abstract 631.
13
CMP
carfilzomib,
melphalan,
prednisone
CYCLONE
carfilzomib,
cyclophosphamide
thalidomide
dexamethasone
N = 24
CRd
carfilzomib,
lenalidomide
dexamethasone
Transplant ineligible
>65 yo
Transplant eligible
Transplant
ineligible or
eligible
VMP
CyBorD
CTD
RVD,VTD, VTD
31(89%)
1 (3%)
23 (96%)
7 (29%)
14 (40%)
16 (46%)
11 (46%)
5 (21%)
52 (98%)
33 (62%)
22 (42%)
11 (20%)
10 (19%)
9 (17%)
N = 35
Comparative or
Parent regimens
ORR
- CR
- sCR
- nCR
- VGPR
- PR
N = 53



Highly active as a first-line treatment for MM
The quality of response seems improved in
some studies
Tolerability seems improved with minimum
peripheral neuropathy, although comparison
with SQ bortezomib remain to be investigated
Lymphoma and CLL/SLL
 The Stil trial established R-Benda as the
preferred first-line treatment for FL and MCL
 Ofatumumab + ibrutinib (Btk inhibitor) is
highly active in relapsed/refractory CLL/SLL
 Acute Leukemia
Blinatumumab (Bite biphasic antibody) is
highly active in relapsed/refractory ALL
 Multiple Myeloma
Carfilzomib is moving to the front line

CHOP-R
N =253
BR
N = 261
Neutropenia
69%
29%
lymphopenia
43%
74%
Grade 3/4
Topp, et al., JCO 2011