Results of a Phase 2 Pharmacokinetic/Pharmacodynamic (PK/PD) Study of Combination
Voreloxin and Cytarabine in Patients With Relapsed or Refractory Acute Myeloid Leukemia
GJ Roboz1, JE Lancet2, LD Cripe3, F Ravandi4, RK Stuart5, AF List2, JA Fox6, G Michelson6, JE Karp7
University / NY Presbyterian Hospital, New York, NY; 2H Lee Moffitt Cancer Center, Tampa, FL; 3Indiana University Cancer Center, Indianapolis, IN; 4University of Texas MD Anderson Cancer Center, Houston,TX;
5Medical University of South Carolina, Charleston, SC; 6Sunesis Pharmaceuticals, Inc., South San Francisco, CA; 7Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD
Study Design
Phase 2 voreloxin in combination with cytarabine in primary refractory
and first relapse AML
Population
Primary refractory: failed to achieve CR or CRp following 1 or more
cycles of induction, or CR1 < 90 days
First relapse: relapse following CR1 ≥ 90 days and ≤ 24 months
Voreloxin
and Cytarabine
Dose Regimens
Objectives
ASCO 2010
80 or 90 mg/m2 voreloxin on days 1 and 4
by short ≤ 10 minute IV infusion
in combination with
400 mg/m2/d CIV cytarabine on days 1-5 or
1 g/m2/d 2-hr IV infusion cytarabine on days 1-5
Safety, pharmacokinetics, antileukemic activity
VORELOXIN: AN ANTICANCER QUINOLONE DERIVATIVE (AQD) (PLoS ONE, 2010)
● Novel, stable scaffold offers advantages
over anthracyclines
● Intercalates DNA and inhibits
topoisomerase II
Voreloxin
H3C
HN
● Evades common drug resistance
mechanisms
– Not a P-glycoprotein substrate
– Activity unaffected by p53, p63 or
p73 status
OH
N
N
Primary refractory
O
OH
H3C
OH
O
O
OH
O
4 CR
7 CR, 1 CRp, 1 CRi
Primary refractory
nr (260 – nr) days
First relapse
329 (175 – nr) days
N = 33
48%
34%  60 years
2 (1-6)
216 (140, 307) days
First relapse median OS
218 (131, 377) days
Primary refractory median OS
209 (124, 307) days
85%
Unf 21%
N = 23
33%
Early Mortality
N
%
N = 13
19%
30-day all-cause mortality
2 of 69
3%
61 (35-73)
64%  60 years
60-day all-cause mortality
6 of 69
9%
7.3 (3.3 – 23.7) mos
ECOG 0-1
89%
Fav 3%
Int 64%
Unf 28%
2-hr IV
Cytarabine
N = 38
None or
Consol. Only
N (%)
HSCT
N (%)
Other**
N (%)
Death
N (days)
Surviving
N (days)
Overall
N = 68
Prim. Refr.
N=7
0
7 (100%)
0
1 (307)
6 (222-611)
1st Relapse
N = 13
4 (31%)
6 (46%)
3 (23%)
8 (74-530)
5 (299-515)
Overall
N = 20
20%
65%
15%
45%
55%
20%
11%
15%
Febrile neutropenia
53%
34%
43%
Sepsis/Bacteremia*
30%
24%
27%
Infections*
10%
13%
12%
Pneumonia*
17%
8%
12%
Hypokalemia
27%
13%
19%
Hypophosphatemia
13%
0%
6%
*Includes multiple preferred terms
100
150
200
250
300
350
400
450
500
550
600
650
Time (Days)
Primary Refractory
Pref Censored
First Relapse
FRel Censored
All
All Censored
Median LFS of 329 days (10.8 mos)
CONCLUSIONS
CR*
mucositis*
50
● 20 patients continue in survival follow-up, with 12 patients to date surviving one
year or more
POSTREMISSION THERAPY AND OUTCOME
NONHEMATOLOGIC GRADE 3 OR HIGHER ADVERSE EVENTS  10%
CIV
Cytarabine
N = 30
0
Median Overall Survival (95% CI)
CR1 < 12 mos
Cytogenetics (NCCN 2010)
0.00
CLINICAL ACTIVITY WITH LOW EARLY MORTALITY TRANSLATES TO
FAVORABLE SURVIVAL OUTCOME
CR1 12 – 24 mos
Median age (range)
0.50
* Leukemia-free survival (LFS) is defined as time from complete remission (CR, CRp, or CRi) to
relapse or death. **nr = not reached, 11 CR patients continue in follow-up.
57.5 (18.5-71)
Int 58%
Median overall survival of 216 days (7.1 mos)
0.75
329 (222 – nr**) days
OH
N = 69
Fav 3%
KAPLAN-MEIER CURVES FOR OVERALL SURVIVAL AND LFS
1.00
0.25
Median Leukemia-Free Survival* (95% CI)
CH3
O
NH2
Median duration of CR1 (range)
Upper GI
6 CR, 1 CRp
First relapse (CR1 12 – 24 mos)
O
OH
ECOG 0-1
Adverse Event
25%
First relapse (CR1 < 12 mos)
Anthracycline
Core
Median prior induction cycles (range)
First Relapse
17 of 69
Doxorubicin
Overall
Cytogenetics (NCCN 2010)
CR Rate
N
DEMOGRAPHICS AND BASELINE CHARACTERISTICS
Median age (range)
29%
CH3
● Unlike anthracyclines, does not produce
in vitro substantial reactive oxygen
species implicated in cardiotoxicity
Primary Refractory
20 of 69
N
S
O
O
O
Quinolone
Core
COMPLETE REMISSIONS COUPLED WITH LONG-TERM LEUKEMIA-FREE SURVIVAL
CR Rate (CR+CRp+CRi)
Overall Survival
ABSTRACT - UPDATED
Background: Voreloxin, an anticancer quinolone derivative that inhibits topoisomerase II, is active in
ovarian cancer and acute myeloid leukemia (AML). Nonclinical studies showed synergistic activity of
voreloxin and cytarabine in vitro and in vivo (Scatena Cancer Chemother Pharmacol 2010). Methods:
Phase 1b results were presented previously (Proc ASCO 2009). Phase 2 expansions studied voreloxin
in combination with cytarabine in first relapsed or primary refractory AML. Dose regimens were 80 or 90
mg/m2 voreloxin administered by short IV infusion  10 minutes on days 1 and 4, in combination with
either 400 mg/m2/d CIV cytarabine for 5 days or 2-hr IV infusion 1 g/m2/d cytarabine (IDAC) for 5 days.
Patients could complete up to 4 cycles of therapy (2 induction and 2 consolidation). Response was
determined by IWG criteria. Blood, urine, and bone marrow aspirate (BMA) were collected for PK or PD
analysis. Results: Safety and activity were similar for both cytarabine schedules and thus phase 2 data
were pooled for 69 patients. Thirty-three patients with primary refractory AML (defined as persistent
AML after induction therapy or relapsed < 90 days after initial CR1) and 36 patients with first relapsed
AML (defined as CR1  90 days to 24 months) were studied; most had a poor prognosis (81% primary
refractory or first relapse with CR1 < 12 months). The overall median age was ~60 years; most patients
were male, and 85% had an ECOG performance status of 0 or 1. Primary refractory patients had
induction failure with a median 2 attempts (range, 1–6). First relapsed patients had a median duration of
CR1 of 7.3 months. Nonhematologic grade 3 or higher adverse events ≥ 10% included upper GI
mucositis 15%, febrile neutropenia 43%, sepsis/bacteremia 27%, infections 12%, pneumonia 12%, and
hypokalemia 19%. All-cause mortality was low, 3% (2 of 69) at 30 days and 9% (6 of 69) at 60 days.
CR+CRp+CRi (ORR) was 29% (20 of 69). The vast majority (17 of 20) were CR, for a CR rate of 25%
(17 of 69). By study population, ORR for primary refractory was 21% (7 of 33; 6 CR, 1 CRp) and for first
relapse was 36% (13 of 36). For first relapse, CR was achieved in 4 patients with CR1 < 12 months and
9 with CR1 ≥ 12 months (7 CR, 1 CRp, 1 CRi). Postremission, 13 of 20 patients went to transplant and
3 received maintenance therapy with azacitidine or decitabine. One with partial remission and one with
treatment failure also went to transplant, for a total of 15 of 69 patients (22%). Median overall survival
was 216 days or 7.1 months (95% CI 4.6–10.1 months) and was similar for both primary refractory and
first relapse; median leukemia-free survival was 329 days or 10.8 months (95% CI 7.3 – not reached).
Twenty of 69 patients remain in survival follow-up (range, 211-611 days), with 12 surviving a year or
more thus far. PK/PD: voreloxin PK was dose proportional and unaffected by cytarabine. Voreloxin
elimination is nonrenal, < 5% of voreloxin total dose was in urine. DNA damage response was seen in
BMA consistent with voreloxin’s mechanism of action (ASH 2009) Conclusions: Activity of voreloxin in
combination with cytarabine is promising in this difficult to treat patient population and was well-tolerated
with a 29% ORR, median overall survival of 7.1 months, and low early mortality (3% at 30 days and 9%
at 60 days). Twenty of 69 patients remain in survival follow-up, with 12 surviving a year or more thus far.
The regimen allowed a bridge to bone marrow/stem cell transplant. Safety and activity profile in this
population compares favorably with recent data for other AML therapies. A multinational, randomized,
double-blind, placebo-controlled, pivotal phase 3 study of voreloxin or placebo in combination with IDAC
in patients with relapsed or refractory AML (persistent AML after 1-2 cycles of therapy or relapsed
< 90 days after initial CR1 or CR1 3-24 months) is planned.
STUDY DESIGN
Leukemia Free Survival or
Overall Survival
1Cornell
*Complete Remissions: 17 CR, 2 CRp, 1 CRi
**3 patients received a hypomethylating agent as maintenance therapy; one additional patient received a
hypomethylating agent while awaiting transplant.
● Majority of CR patients went to transplant
http://www.sunesis.com/products-in-development/presentations_and_publications.php
● Voreloxin demonstrated encouraging clinical activity and tolerability in this study
of patients with relapsed or refractory AML
● Voreloxin can be readily combined with CIV or 2-hour IV cytarabine regimens
● Favorable median overall survival of 7.1 months with 20 of 69 patients continuing
in survival follow-up, reflecting
 29% remission rate (CR + CRp + CRi) and 25% CR rate
 Leukemia-free survival (median 10.8 months)
 Low 30- & 60-day all-cause mortality of 3% and 9%, respectively
● The combination of voreloxin and cytarabine was successfully used as a “bridge
to transplant” for relapsed/refractory patients in this study
● A multinational, randomized, double-blind, placebo-controlled, pivotal phase 3
study in relapsed or refractory AML is planned to initiate in 2H 2010
This poster and poster 6525, board # 17 (single agent voreloxin in frontline, poor-risk AML) will be discussed: RM E354a 5 – 6PM.