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

450s Leukemia, Myelodysplasia, and Transplantation
TPS6636 General Poster Session (Board #29C), Mon, 1:15 PM-5:15 PM
A single-arm, open-label, multicenter study of complete molecular response
(CMR) in patients with newly diagnosed Philadelphia chromosome–
positive (Ph�) chronic myeloid leukemia in chronic phase (CML-CP)
treated with nilotinib. Presenting Author: Michael R. Savona, Sarah
Cannon Center for Blood Cancers, Tennessee Oncology, PLLC, Nashville,
TN
Background: With more-potent tyrosine kinase inhibitors, increasingly
sensitive methods are required to monitor treatment response and quantify
minimal residual disease (MRD). Molecular monitoring is recommended by
National Comprehensive Cancer Network and European LeukemiaNet
guidelines; major molecular response (MMR) correlates with optimal
long-term outcomes. CMR, while implying absence of BCR-ABL transcripts,
is defined by levels undetectable by current technology (generally
�4.5 logs reduced below a standardized baseline using quantitative
real-time polymerase chain reaction [RT-PCR]). Newer technologies that
can detect larger reductions will be important in analyzing correlations
between decreased disease burden and long-term outcomes and may assist
in selecting patients for “stopping” therapy. Methods: This US study plans
to enroll 100 adults with newly diagnosed Ph� CML-CP within 6 months of
diagnosis to receive nilotinib 300 mg twice daily (BID) for up to 2 years.
BCR-ABL transcripts are quantified using RT-PCR at a central laboratory.
An exploratory molecular assay (digital detection [DiD]) with an additional
�1-log sensitivity and mutation detection and quantification will be
evaluated. Primary endpoint: the rate of confirmed CMR at 24 months
(CMR confirmed by second PCR sample within 3 months; �4.5-log
reduction of BCR-ABL from standardized baseline on the international
scale [IS], equivalent to BCR-ABL �0.0032% IS). Dose escalation to 400
mg BID is allowed per protocol. Secondary endpoints: rate of, time to, and
duration of complete cytogenetic response (CCyR), MMR, and CMR; rate of
and time to loss of CCyR, MMR, and CMR and to progression to accelerated
phase/blast crisis; rate of CMR in dose-escalated patients; and event-free,
progression-free, and overall survival. Exploratory endpoints: BCR-ABL
trends and correlation of mutations with response. The DiD assay data will
provide information on BCR-ABL trends below the current CMR threshold
and assist in evaluating lower levels of MRD.
TPS6638 General Poster Session (Board #30B), Mon, 1:15 PM-5:15 PM
Prospective, observational registry of branded imatinib (IM) and nilotinib
(NIL) exposure in pregnant women: Voluntary post-authorization safety
study. Presenting Author: Matthews Juma, Novartis Pharmaceuticals, East
Hanover, NJ
Background: Family planning decisions for cancer patients of childbearing
age are impacted by their diagnosis. IM and NIL are category D drugs
(demonstrated risk to the fetus based on mechanism of action and findings
in animals; however, the benefits of therapy may outweigh the potential risk
to the fetus); women should be advised not to become pregnant when
taking these drugs. Limited data exist concerning safety of these drugs
during pregnancy and consequences of interrupting treatment. The registry
does not recommend patients receiving IM or NIL become pregnant, but
serves only to document exposures that occur, and collect information on
pregnancy outcome, maternal course of disease, and infant follow-up.
Methods: The registry intends to enroll 150 women (�18 years) treated with
branded IM and NIL within 6 mo before or during pregnancy (generic IM
and NIL reports are excluded). Schedule of visits and treatment is
according to local standard of care. Women are divided into 2 exposure
cohorts: 1) pregnancy/fetal: received tyrosine kinase inhibitors (TKIs)
within 14 d of conception or at any time during pregnancy; 2) interrupted
TKI: received TKIs within 6 mo before conception but interrupted TKIs in
preparation for/due to pregnancy. To identify signals of teratogenicity, the
registry uses a general population baseline rate of birth defects, and the
prevalence of defects in cohorts 1 and 2 may be compared. Cases are
quantitatively analyzed for the emergence of unique defects or patterns of
defects. Primary objective: monitor TKI-exposed pregnancies to estimate
the prevalence of birth defects (calculated by dividing number of birth
defects by total number of exposed live births from cohort 1). Secondary
objectives are to: 1) determine the impact of treatment interruption on
maternal disease status; 2) assess and estimate the prevalence of serious
adverse pregnancy outcomes; and 3) assess and estimate the prevalence of
developmental delays and functional deficits among infants during the first
year of life. Maternal disease status is analyzed, comparing disease status
at registration, pregnancy outcome, and 1 y after birth, stratified by length
of TKI interruption.
TPS6637 General Poster Session (Board #30A), Mon, 1:15 PM-5:15 PM
VALOR, an adaptive design, pivotal phase III trial of vosaroxin or placebo in
combination with cytarabine in first relapsed or refractory acute myeloid
leukemia. Presenting Author: Farhad Ravandi, University of Texas M. D.
Anderson Cancer Center, Houston, TX
Background: The promising phase 2 activity/tolerability profile of vosaroxin
with cytarabine in first relapsed or refractory AML (N�69) with median
overall survival (OS) 7.1 mo, combined CR 28% (CR 25%), median LFS 25
mo and 30-day all-cause mortality 3%, supported phase 3 trial. VALOR
(NCT01191801), a phase 3, randomized, controlled, double-blind trial,
evaluates vosaroxin and cytarabine versus placebo and cytarabine in
patients with first relapsed or refractory AML and incorporates an adaptive
design. Primary objective is OS; secondary/tertiary objectives include CR
rates, safety, EFS, LFS, and transplantation rate. Key eligibility criteria:
persistent AML or first relapsed AML after 1 or 2 induction cycles that
include at least 1 regimen of cytarabine with an anthracycline/anthracenedione;
adequate cardiac, hepatic, renal function; and adults with no upper
age restriction. Methods: VALOR is recruiting patients at over 100 sites in
14 countries in North America, Europe, and Australia/NZ. Enrollment
opened Dec 2010; 183 patients enrolled through Dec 2011. Adaptive
design: Base case assumed 40% improvement in median OS (hazard ratio,
HR�0.71), 90% power, 2-sided alpha of 0.05. At the interim analysis
(50% events), DSMB may recommend a 50% sample size increase from
450 to 675 evaluable patients if results indicate a larger sample size is
required to reduce the risk of failing to confirm a clinically meaningful OS
benefit (Mehta, Pocock, Stat Med 2010). In consideration of FDA and EMA
guidance on Data Monitoring Committees and adaptive design with respect
to trial integrity, operational bias, firewalls, and data confidentiality and
archival, VALOR uses the Access Control Execution System (ACES ) to
store, share, and archive confidential DSMB reports in a secure environment
with an audit trail, and to facilitate communication between the
DSMB and trial sponsor. The DSMB periodically reviews a combination of
blinded and unblinded analyses while the study team remains blinded as
specified in the DSMB charter. The DSMB recommended VALOR continue
as planned after reviewing safety data in Dec 2011.
TPS6639 General Poster Session (Board #30C), Mon, 1:15 PM-5:15 PM
JAKARTA: A phase III, multicenter, randomized, double-blind, placebocontrolled,
three-arm study of SAR302503 in patients with intermediate-2
or high-risk primary myelofibrosis (MF), post-polycythemia vera (PV) MF, or
post-essential thrombocythemia (ET) MF with splenomegaly. Presenting
Author: Animesh Dev Pardanani, Mayo Clinic, Rochester, MN
Background: SAR302503 is an orally administered selective JAK-2 inhibitor
being evaluated for the treatment of MF. In a phase 1 study,
SAR302503 reduced spleen size and disease-related symptoms and
provided clinical benefit, including a reduction in the JAK2V617F allele
burden, with an acceptable safety profile in patients with primary MF,
post-PV MF, or post-ET MF (J Clin Oncol 2011;29:789). An ongoing
open-label extension of this trial confirmed the durability of those results
and found that doses between 400–500 mg/day of SAR302503 represented
the optimal balance between safety and efficacy (Pardanani, ASH
2011;Abs 3838). These results led us to initiate a Phase 3 trial in
December 2011 to evaluate SAR302503 at doses of 400 mg/day and 500
mg/day, compared with placebo, for the treatment of patients with MF
(NCT01437787; EFC12153). Methods: Eligibility criteria include age of at
least 18 years, platelets �50,000/�l, ECOG PS 0–2, and a diagnosis of
high- or intermediate-risk 2 primary MF, post-PV MF, or post-ET MF
according to IPSS criteria (Blood 2009;113:2895). Patients are being
randomized (1:1:1) to receive 400 mg or 500 mg of SAR302503 or
placebo orally once a day for at least 6 consecutive 28-day cycles. Assigned
treatment will continue as long as patients are deriving benefit or until
progression or unacceptable toxicity. Cross-over is allowed after 6 cycles or
in case of progression before completion of 6 cycles according to predefined
criteria. The primary endpoint is spleen response (�35% reduction
in spleen volume by MRI/CT at the end of cycle 6). Key secondary
objectives are symptom response rate and durability of spleen response.
Additional secondary endpoints include assessment of allele burden and
bone marrow fibrosis reduction. It is planned to randomize 75 patients per
treatment group at approximately 130 sites worldwide.
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