A Phase 1 Study of PD 0332991: Complete
CDK4/6 Inhibition and Tumor Response in
Sequential Combination with Bortezomib
and Dexamethasone for Relapsed and
Refractory Multiple Myeloma
R Niesvizky,1 S Lentzsch,2 AZ Badros,3 AA Chanan-Khan,4
SB Singhal,5 JA Zonder,6 R Vij,7 X Huang,8 M DiLiberto,8
R Courtney,9 N Shaik,9 ST Kim,9 S Randolph,9 S Ely,8
S Chen-Kiang8
1Department of Medicine, Weill Cornell Medical College, New York, NY; 2University of Pittsburgh Hillman
Cancer Center, Pittsburgh, PA; 3University of Maryland Greenbaum Cancer Center, Baltimore, MD; 4Roswell
Park Cancer Institute, Buffalo, NY; 5Northwestern University Feinberg School of Medicine, Chicago, IL;
6Karmanos Cancer Institute, Detroit, MI; 7Washington University School of Medicine, St. Louis, MO;
8Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY;
9Pfizer Oncology, San Diego, CA
The Cell Cycle
Positive
Negative
Go
p16INK4a
p15INK4b
Cyclin D + CDK4/6
INK
M
p18INK4c
p19INK4d
G1
pS-Rb-E2F
G2
p21CIP1
p27KIP1
Cyclin E + CDK2
CIP/KIP
S
p57KIP2
pST-Rb
E2F release
CDK = cyclin-dependent kinase
Adapted with permission from Figure 1A of Ely S, et al.
p18INK4c (CDKN2C) = cyclin-dependent kinase 4 inhibitor C
Cancer Res 2005;65:1134511353
CDK4/CDK6-Specific Phosphorylation of Rb
and Cell Proliferation Increase with Disease
Progression in Multiple Myeloma
PT
1239
247-1
247-2
Retina
Tumor
Rb = retinoblastoma
Reprinted with permission from Figure 1C of Ely S, et al.
Cancer Res 2005;65:1134511353
Rationale for PD 0332991
in Multiple Myeloma
A selective, reversible, orally bioavailable inhibitor of cyclin-
dependent kinases 4 and 6 (CDK 4/6)1
low toxicity
simple and reproducible functional assay from
patient samples
1Fry DW, et al. Mol Cancer Ther 2004;3:14271438
2Baughn LB, et al. Cancer Res 2006;66:76617667
S Chen-Kiang, unpublished data
Hypothesis
Inhibition of CDK4/CDK6 by PD 0332991 is highly specific
Induction of prolonged G1 arrest by inhibition of CDK4 and CDK6
may disrupt the coupling of gene expression from the cell cycle,
thereby sensitizing tumor cells for cytotoxic killing in G1
Go
Cyclin D + CDK4/6
PD 0332991
M
G1
Rb
G2
S
S Chen-Kiang, unpublished data
Hypothesis
Inhibition of CDK4/CDK6 by PD 0332991 is reversible
Release from PD 0332991-induced G1 arrest may lead to
synchronous cell cycle progression and further sensitizes tumor
cells for cytotoxic killing in S phase
Go
Cyclin D + CDK4/6
PD 0332991
M
G1
pS-Rb
G2
S
S Chen-Kiang, unpublished data
Study Design
A multicenter, open-label, Phase 1 dose-escalation study of PD 0332991
combined with bortezomib and dexamethasone in MM
PD 0332991
daily
Schedule A
Bortezomib + dexamethasone
Patients with
Rb protein-positive,
symptomatic, relapsed
D1
D8 D11 D15 D18 D21 D28
and/or refractory MM
after 1 previous
Continue treatment
treatment
PD 0332991
until withdrawal
daily
criteria met
Bortezomib + dexamethasone
Schedule B
D1
D8 D11 D15 D18 D21
Both schedules: PD 0332991 starting dose 100 mg/day, with planned dose
escalation to 125 mg/day and reduction to 75 mg/day;
bortezomib 1.0 mg/m2 and oral dexamethasone 20 mg on dosing days
Study Objectives
Primary: to determine the maximum tolerated dose
(MTD)* and recommended Phase 2 dose (RP2D) of
PD 0332991 combined with bortezomib plus
dexamethasone
Secondary:
Pharmacodynamic effects
Pharmacokinetics
Safety
Antitumor activity
*MTD defined as the dose level at which 1/6 patients experienced dose-limiting toxicity
Patient Baseline Characteristics
Schedule A
Schedule B
Total
(n=9)
(n=12)
(N=21)
Median age (range), years
60 (3771)
61 (3872)
60 (3772)
Male/female, n
4/5
11/1
15/6
ECOG performance status: 0/1/2, n
1/7/1
5/7/0
6/14/1
Median 2 microglobulin, mg/L
4.0*
2.9*
3.9*
Median hemoglobin, g/dL
10.5
11.1
10.9
Median platelets, 103/mm3
125
143
129
Median calcium, mg/dL
9.5
9.0
9.1
Median number of prior therapies (range)
4 (27)
4 (29)
4 (29)
Previous bortezomib therapy, n (%)
9 (100%)
9 (75%)
18 (86%)
Tumor volume (intertrabecular space,
47% (580)
33% (190)
38% (190)
CD138), % (range)
Median Ki67, % (range)
21% (1433)
16% (234)
18% (234)
*Data missing for one patient on each schedule
ECOG = Eastern Cooperative Oncology Group
DLTs and Dose Reductions
Dose
level PD 0332991 Bortezomib
Dex
n
DLTs*
Dose reductions
Schedule A (n=9)
1
100 mg
1.0 mg/m2
20 mg
3
2
PD 0332991 to 75 mg (n=3)
PD 0332991 to 50 mg (n=1)
1
75 mg
1.0 mg/m2
20 mg
6
2
Bortezomib to 0.7 mg/m2 (n=1)
Schedule B (n=12)
MTD/RP2D
PD 0332991 to 75 mg (n=3)
1
100 mg
1.0 mg/m2
20 mg
7
1
Bortezomib to 0.7 mg/m2 (n=1)
2
125 mg
1.0 mg/m2
20 mg
5
2
Bortezomib to 0.7 mg/m2 (n=1)
Dex = dexamethasone; DLT = dose-limiting toxicity
*All DLTs comprised inability to deliver 80% of the dose of PD 0332991/bortezomib due to grade 3/4 neutropenia and/or
thrombocytopenia (n=6) and metabolic acidosis (n=1)
Treatment-Related Adverse Events*
Event
Grade 1/2, n (%)
Grade 3, n (%)
Grade 4, n (%)
Thrombocytopenia
0
4 (19)
12 (57)
Neutropenia
3 (14)
6 (29)
5 (24)
Lymphopenia
4 (19)
0
1 (5)
Anemia
1 (5)
3 (14)
0
Constipation
3 (14)
0
0
Fatigue
3 (14)
0
0
Leukopenia
2 (10)
1 (5)
0
Nausea
3 (14)
0
0
Vomiting
3 (14)
0
0
Diarrhea
2 (10)
0
0
Hyperglycemia
2 (10)
0
0
Insomnia
2 (10)
0
0
Peripheral neuropathy
2 (10)
0
0
Rash
2 (10)
0
0
*Occurring in 10% of patients
One patient experienced grade 4 febrile neutropenia
Pharmacodynamics
PD 0332991 treatment completely (13/16 patients) or >80%
(3/16 patients) inhibited pS-Rb and Ki67 in bone marrow MM
cells before bortezomib and dexamethasone treatment began
on Day 8
Cell cycle progression followed PD 0332991 withdrawal on
Day 18 of Schedule B (7/7 patients)
pS-Rb = phosphorylation of the serine of
1Ely S, et al. Cancer Res 2005;65:1134511353
retinoblastoma protein
2Scholzen T and Gerdes J. J Cell Physiol 2000;182:311322
PD 0332991: Potent and Reproducible G1 Arrest In Vivo
PD 0332991
daily
Bortezomib/dex
Bone Marrow
D1
D8 D11 D15 D18 D21
Day 1
Day 8
pSRb / BOTH / MUM1
PD 0332991: Potent and Reproducible G1 Arrest In Vivo
Rb
pSRb
Ki67
100%
Cells 75%
MUM1+
in 50%
25%
Coexpression
0%
pre D8
pre
D8 D18
pre D8 D18
pre D8 D18
pre D8 D18 OFF8D
Patient 1
Patient 2
Patient 3
Patient 4
Patient 5
PD 0332991
Pre = pr
dailye-treatment; D = Day
Bortezomib/dex
Bone Marrow
D1
D8 D11 D15
D18
Pharmacokinetics
AUC(012) (n=10)
Cmax (n=10)
1,500
150
1,000
100
(ng·h/mL)
(ng/mL)
(012)
max
500
50
C
AUC
0
0
PD 0332991
PD 0332991 +
PD 0332991
PD 0332991 +
alone
dexamethasone
alone
dexamethasone
Treatment (n=10*)
PD 0332991
PD 0332991 + dexamethasone
Mean Cmax, ng/mL
52.0
57.3
Mean AUC(012), ng.h/mL
503
542
Median (range) Tmax, h
8.0 (48)
4.0 (48)
*Schedule A: 1 patient at 75 mg; Schedule B: 7 patients at 100 mg, 2 patients at 125 mg
Lines on figures represent individual patients; red dashes represent mean; AUC(012) = area under the plasma
concentrationtime curve from 0 to 12 hours; Cmax = maximum plasma concentration; Tmax = time to Cmax
Best Response by International
Myeloma Working Group1
2 VGPRs:
1 patient from Schedule A, DL 1 (PD 0332991 75 mg)
71-year-old female with t(4:14), diagnosed in 2005
Ki67: 16% (baseline) 1% (C1D8) 26% post 7 days off tx
Prior treatment regimens include lenalidomide (PR PD),
bortezomib (CR), carfilzomib (PR PD), and SCT
1 patient from Schedule B, DL 2 (PD 0332991 125 mg)
63-year-old male, diagnosed in 2006
Ki67: 7% (baseline) 0% (C1D8) 6% on C1D18
Prior treatment regimens include thalidomide (PR PD) and
lenalidomide
CR = complete response; DL = dose level; PD = progressive
disease; PR = partial response; SCT = stem cell transplant;
1
VGPR = very good PR
Durie BG, et al. Leukemia 2006;20:14671473
Conclusions
PD 0332991 100 mg plus bortezomib 1.0 mg/m2 and
dexamethasone 20 mg on Schedule B was determined as the
MTD and RP2D
Cytopenias were the most commonly reported adverse events,
consistent with the known safety profiles of PD 0332991 and
bortezomib
PD 0332991 completely (but reversibly) inhibited CDK4/6 and cell
cycle progression in multiple myeloma cells
Encouraging antitumor activity was observed in this heavily
pretreated multiple myeloma population
A Phase 2 part of this trial is underway
Targeting CDK4 and CDK6 in combination
therapy
-- a new class of cancer therapy
Weill-Cornell
Myeloma
Phase I/II combination therapy (08-date)
MCL
Phase I single drug study (07-10)
MCL
Phase I combination therapy (10--)
Leukemia
Preclinical
Solid tumors
Phase I single agent, completed
Breast cancer
Phase I/II front line combination
therapy(08--
Sarcoma
Phase I single agent, initiated 9/2010
Glioblastoma
Phase I single agent, initiated 10/2010
Acknowledgments
We would like to thank all of the participating patients
and their families, as well as the network of
investigators, research nurses, study coordinators,
and operations staff.
This study was sponsored by Pfizer Inc.
Medical writing/editorial support was provided by
Christine Arris at ACUMED® (Tytherington, UK) with
funding from Pfizer Inc.