Annual Meeting Proceedings Part 1 - American Society of Clinical ...

422s Leukemia, Myelodysplasia, and Transplantation
6524^ Poster Discussion Session (Board #16), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
Evaluation of the first-in-class antimitochondrial metabolism agent CPI-
613 in hematologic malignancies. Presenting Author: Timothy S. Pardee,
Wake Forest University Health Sciences, Winston-Salem, NC
Background: Altered metabolism is a hallmark of cancer, including hematologic
malignancies. Most tumor cells use glycolysis even under aerobic
conditions (the Warburg effect). This altered metabolism is a possible
therapeutic target. The novel lipoate derivative CPI-613 is a first-in-class
agent that targets a key mitochondrial enzyme, pyruvate dehydrogenase
complex (PDH). Methods: CPI-613 was tested against leukemia cell lines in
vitro and in vivo. It is also the subject of a phase I clinical trial for patients
with hematologic malignancies. Results: CPI-613 was active against HL60,
Jurkat, and K562 cells, with an average IC50 value of 14 �M (range 12.2 –
16.4). CPI-613 was synergistic with doxorubicin, with Combinatorial Index
(CI) values of 0.478 to 0.765. CPI-613 sensitivity increased with knockdown
of p53 or MN1 expression, despite their increased resistance to
standard therapy. CPI-613 was synergistic with nilotinib against BCR-ABLexpressing
cells and with sorafenib against Flt3 ITD-expressing cells. CI
values for nilotinib � CPI was 0.059 (�/-0.002) and for sorafenib � CPI
was 0.581 (�/-0.052). In vivo, CPI-613 synergized with doxorubicin;
median survival improved from 12 days with doxorubicin to 16 days with
CPI-613 plus doxorubicin (p�0.0001). In the phase I clinical trial, 7 of 13
evaluable patients had a response of stable disease or better, for an overall
response rate of 54% (see table). CPI-613 was well tolerated, with no
evidence of marrow suppression and no dose limiting toxicity identified.
Conclusions: The novel agent CPI-613 has activity against a variety of
hematological malignancies, including acute leukemias. The therapeutic
index appears high, with only minor toxicities observed.
Patient # Diagnosis Dose CPI-613 mg/m 2
Best response # of cycles
1 NHL 420 NE 0
2 AML 420 PD 1
3 Myeloma 840 PD 1
4 AML 840, 1386, 2100 CR 15
5 Hodgkin’s 840 PD 1
6 AML 1386 PD 0
7 Myeloma 1386 SD 3
8 Myeloma 1386 SD 4
9 AML 1386 PD 1
10 MDS 2100 SD 7
11 MDS 2100 SD 6
12 AML 2100 MLFS 2
13 AML 2940 NE 0
14 Burkitt’s 2940 SD 4
15 AML 2940 PD 1
SD� stable disease; CR�complete remission; MLFS�morphologically leukemia-free state;
PD�progressive disease; NE�not evaluable.
6526 Poster Discussion Session (Board #18), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
A phase II study of bortezomib added to standard daunorubicin and
cytarabine during induction therapy and to intermediate-dose cytarabine
(Int-DAC) for consolidation in patients with previously untreated acute
myeloid leukemia (AML) age 60-75 years: CALGB study 10502. Presenting
Author: Eyal C. Attar, Massachusetts General Hospital, Boston, MA
Background: We conducted a clinical trial to determine the complete
remission (CR) rate in older AML patients treated with bortezomib (Bz) plus
daunorubicin and cytarabine induction therapy and the maximal tolerated
dose (MTD) of Bz when added to Int-DAC consolidation therapy. Methods:
Ninety-five adults (60-75 yrs old; median, 67) with previously untreated
AML (including therapy-related and prior MDS) received Bz 1.3 mg/m2 IV
on days 1, 4, 8 and 11 with daunorubicin 60 mg/m2 on days 1-3 and
cytarabine 100 mg/m2 by continuous IV infusion on days 1-7. Patients who
achieved a CR received 2 courses of consolidation chemotherapy with
cytarabine 2 gm/m2 over 3 hours on days 1-5 (Int-DAC) with Bz administered
on days 1, 4, 8 and 11. Three cohorts with escalating dose levels of
Bz were tested (0.7, 1.0, and 1.3 mg/m2 ). Dose limiting toxicities were
assessed during the first cycle of consolidation. Predictors of response,
including CD74 expression, were assessed. Results: The CR frequency was
65% (62/95). An additional 4% (4/95) achieved CR with incomplete
platelet recovery. The CR rate according to ELN Genetic Groups was 90%
(9/10) for favorable, 71% (12/17) for Int-I, 52% (17/33) for Int-II, and
46% (5/11) for adverse. Six patients had grade 3 sensory neuropathy.
There were 6 treatment-related deaths during cycle 1 of induction and 2
during cycle 2. Bz plus Int-DAC proved tolerable at the highest dose tested.
The median disease-free (DFS) and overall survivals (OS) for patients on
this study were 8.2 and 12.1 months, respectively. Lower CD74 expression
was associated with CR/CRp (p�.04) but not with DFS or OS. Conclusions:
The addition of Bz 1.3 mg/m2 IV on days 1, 4, 8, and 11 to standard “3 �
7” daunorubicin and cytarabine induction chemotherapy for AML is well
tolerated and results in a remission rate at least as high as would be
expected with ”3�7” alone in older patients. The maximum tested dose of
Bz given in combination with Int-DAC for remission consolidation was 1.3
mg/m 2
and proved to be tolerable. Further testing of this regimen in a phase
III study is planned.
6525 Poster Discussion Session (Board #17), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
Initial salvage therapy in first relapse AML: A phase IIb study of CPX-351
versus investigator’s choice—A subset analysis by prognostic group.
Presenting Author: Stuart Goldberg, John Theurer Cancer Center, Hackensack,
NJ
Background: CPX-351 encapsulates cytarabine and daunorubicin within
liposomes at a 5:1 molar ratio, shown in vitro to maximize synergy.
Liposomal encapsulation enables preferential uptake of drug within leukemic
blasts followed by intracellular release enhancing efficacy in AML. A
randomized Phase 2b study in 1st relapse AML completed 1-year follow up
with improvement in event free (EFS) and overall survival (OS). This report
describes patient outcomes with a focus on the unfavorable subset per the
European Prognostic Index (EPI) (Breems DA, et al. J Clin Oncol, 2005 Mar
20;23:1969-1978). Methods: Patients (pts) �65yo in 1st relapse AML
after an initial CR �1 month, ECOG PS� 0-2, serum creatinine� 2.0
mg/dL, total bilirubin � 2.0 mg/dL, ALT/AST � 3 x ULN, and LVEF �50%
were eligible. Pts with APL, daunorubicin exposure �368 mg/m2 (or other
anthracycline equivalent), active CNS leukemia, uncontrolled infections
were excluded. Pts were randomized 2:1 to receive up to 2 inductions and 2
consolidation courses of CPX-351 (100 u/m2 ; D 1, 3, 5) or investigators
choice of intensive salvage treatment. Post remission allo-transplantation
was permitted. 126 pts were stratified by EPI into favorable, intermediate,
and unfavorable groups (with projected 1-year OS of 70%, 49%, and 16%).
The primary efficacy endpoint was % survival at 1-year. Results: CPX-351
increased the rate of morphologic leukemia-free state (77% vs. 60%), the
rate of CR � CRi (51% vs. 41%), and the median EFS (4.0 vs. 1.4 mo) and
OS (8.5 vs. 6.3 mo) in the overall patient population. Significant survival
improvement occurred amongst those with unfavorable EPI scores
(HR�0.55, p-value�0.02) with improved 1-year survival (29% vs. 10%).
CPX-351 treatment resulted in more prolonged cytopenias with increased
febrile neutropenia and grade 3-4 infections, but not in the D 60 mortality
(overall: 15% vs. 16%; unfavorable: 16% vs. 24%). Conclusions: CPX-351
is highly active in AML and induces remission even in patients with prior
cytarabine and anthracycline exposure. Efficacy was evident in every
prognostic group, particularly in the unfavorable EPI group where a
statistically significant improvement in 1-year survival was observed.
6527 Poster Discussion Session (Board #19), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
Stage I findings of a two-stage phase II study to assess the efficacy, safety,
and tolerability of barasertib (AZD1152) compared with low-dose cytosine
arabinoside (LDAC) in elderly patients (pts) with acute myeloid leukemia
(AML). Presenting Author: Giovanni Martinelli, Department of Hematology/
Oncology Seràgnoli, Bologna, Italy
Background: Barasertib is the pro-drug to barasertib-hQPA, a selective
Aurora B kinase inhibitor with preliminary anti-AML activity in a Phase I/II
study (Löwenberg et al. Blood 2011;118:6030). Methods: AML pts aged
�60 y considered unsuitable for intensive chemotherapy were randomized
2:1 to open-label barasertib 1200 mg (7-day iv infusion) or LDAC 20 mg
(sc twice daily for 10 days) in 28-day cycles (NCT00952588). The primary
endpoint was improved objective complete response rate (OCRR: CR � CRi
[Cheson criteria, but requiring CRi confirmation �21 days after first
appearance, with partial recovery of platelets and neutrophils]). Secondary
endpoints included duration of response (DoR), overall survival (OS) and
safety. Results: 74 pts (barasertib, 48; LDAC, 26) received treatment and
all completed �1 cycle. A significant improvement in OCRR was observed
with barasertib (35.4% [17/48] vs 11.5% [3/26]; difference, 23.9% [95%
CI, 2.7-39.9]; P�0.05); barasertib responses were seen in all cytogenetic
risk groups and appeared to be durable (median DoR [range], 82 [28-321]
days; vs LDAC 30-85 days). Although not formally sized to compare OS
data, a trend favoring barasertib was observed (HR�0.88, 95% CI,
0.49-1.58; P�0.663; median OS, 8.2 vs 4.5 mo). Stomatitis and febrile
neutropenia were the most common adverse events (AEs) in the barasertib
arm with higher incidences vs LDAC (71% vs 15%; 67% vs 19%,
respectively). Grade �3 AEs with a greater incidence in the barasertib arm
were febrile neutropenia (50% vs 19%), stomatitis (29% vs 0%) and
pneumonia (25% vs 8%); grade �3 infection rates were also higher with
barasertib (40% vs 23%). For both arms, there were similar discontinuation
rates due to AEs (barasertib 8.3% vs LDAC 7.7%), deaths due to AEs
(12.5% vs 11.5%) and 30-day mortality (12.5% vs 15.4%). Cumulative
toxicities were not observed with barasertib treatment. Conclusions: In this
population with poor prognosis using standard chemotherapy, barasertib
showed a significant improvement in OCRR vs LDAC, and a safety profile
that was manageable and consistent with previous studies.
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