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

538s Lymphoma and Plasma Cell Disorders
TPS8114 General Poster Session (Board #40G), Mon, 1:15 PM-5:15 PM
A phase II randomized study of bortezomib/dexamethasone (Bort/Dex) with
or without elotuzumab (Elo) in patients (pts) with relapsed/refractory
multiple myeloma (RR MM) (CA204-009). Presenting Author: Andrzej J.
Jakubowiak, University of Chicago Medical Center, Chicago, IL
Background: MM is rarely curable and pts typically relapse or become
refractory to current treatments. Elo is a humanized monoclonal IgG1
antibody targeting the cell surface glycoprotein CS1, which is highly
expressed on �95% of MM cells with little to no expression on normal
tissues. The mechanism of action of Elo is primarily natural killer (NK)
cell-mediated antibody-dependent cellular cytotoxicity (ADCC) against
myeloma cells. Elo � Bort significantly enhanced antimyeloma activity in a
mouse xenograft model vs either agent alone. The addition of Bort
enhanced the ADCC activity of Elo in preclinical studies. In a phase I study
of Elo � Bort in pts with RR MM, objective response rate (ORR) was 48%,
median progression-free survival (PFS) was 9.5 months, and activity was
observed in 2/3 patients (67%) refractory to Bort (Jakubowiak et al. J Clin
Oncol, in press). This study will assess if the addition of Elo to Bort/Dex
improves PFS and, if so, whether magnitude of the improvement is linked
to Fc�RIIIa polymorphism. Methods: Pts (N�150) with RR MM after 1 or 2
prior therapies will be randomized in a 1:1 ratio to receive Bort 1.3 mg/m2 IV or SQ (Cycles 1-8: days 1, 4, 8, and 11; Cycles �9: days 1, 8, and 15)
and Dex with or without Elo. Elo dose and schedule is 10 mg/kg IV (Cycles
1-2: days 1, 8, and 15 [21-day cycles]; Cycles 3-8: days 1 and 11 [21-day
cycles]; Cycles �9: days 1 and 15 [28-day cycles]). In the arm without Elo,
Dex 20 mg PO is scheduled for Cycles 1-8: days 1, 2, 4, 5, 8, 9, 11, and
12; and Cycles �9: days 1, 2, 8, 9, 15, 16. In the arm with Elo, Dex 20 mg
PO is scheduled for Cycles 1-2: days 2, 4, 5, 9, and 11; Cycles 3-8: days 2,
4, 5, 8, 9, 12; Cycles �9: days 2, 8, 9, and 16) on weeks without Elo, and
on weeks with Elo, Dex 8 mg PO and 8 mg IV is scheduled on the same day
as Elo. Treatment will continue until disease progression, unacceptable
toxicity, or withdrawal of consent. Patients refractory or intolerant to Bort
will be excluded. Efficacy will be assessed on day 1 of each cycle by IMWG
criteria. The primary endpoint is PFS. Secondary endpoints include ORR
and PFS/ORR in pts with �1Fc�RIIIa V allele. As of February 1, 2012, 1 pt
was enrolled. NCT01478048.
TPS8116 General Poster Session (Board #41A), Mon, 1:15 PM-5:15 PM
Phase I/II open-label, multiple-dose, dose-escalation study to evaluate the
safety and tolerability of SNS01T administered by intravenous infusion in
patients with relapsed or refractory multiple myeloma. Presenting Author:
John Anthony Lust, Mayo Clinic, Rochester, MN
Background: Eukaryotic translation initiation Factor 5A (eIF5A) has been
implicated in the regulation of apoptosis and is the only known protein to be
modified by hypusination. Hypusinated eIF5A is the predominant form of
eIF5A in cancer cells. However, in its unhypusinated form, eIF5A is
pro-apoptotic. SNS01-T, designed to treat myeloma, consists of two
components: a plasmid DNA expressing eIF5AK50R (human eIF5A containing
a lysine to arginine substitution at position 50) which remains
pro-apoptotic because it cannot be hypusinated, and an siRNA against an
untranslated region of native eIF5A mRNA. When these two components
are combined with linear polyethyleneimine (PEI), the nucleic acids are
condensed into nanoparticles for protection from degradation in the blood
and enhanced delivery to tissues. The eIF5AK50R transgene is under the
control of the B29 promoter and enhancer, which restricts expression to B
cells. The mode of action of SNS01-T is to use an eIF5A-specific siRNA to
deplete the pool of hypusinated eIF5A in myeloma cells while simultaneously
adding pro-apoptotic eIF5AK50R . In vitro cell studies and in vivo
xenograft studies have demonstrated the efficacy of this approach. Methods:
Eligible patients are enrolled sequentially into four cohorts of increasingly
higher doses. Each cohort will receive SNS01-T by intravenous infusion
twice weekly for 6 consecutive weeks and then be observed every 4 weeks
during a 24-week follow-up period. Eligible patients must have been
diagnosed with multiple myeloma according to IMWG criteria, have
measurable disease, have relapsed disease after two or more prior treatment
regimens, have a life expectancy of at least 3 months, and not be
eligible to receive any other standard therapy known to extend life
expectancy. The primary objective is to evaluate the safety and tolerability
of multiple escalating doses of SNS01-T. Secondary objectives include
pharmacokinetics, immunogenicity studies, proinflammatory cytokine quantitation,
and therapeutic efficacy. Two of the planned 15 patients have
been enrolled. (Clinical Trials.gov Identifier: NCT01435720.)
TPS8115 General Poster Session (Board #40H), Mon, 1:15 PM-5:15 PM
A single-arm, open-label, multicenter phase I/II study of the combination of
panobinostat (pan) and carfilzomib (cfz) in patients (pts) with relapsed/
refractory multiple myeloma (RR MM). Presenting Author: Jesus G.
Berdeja, Tennessee Oncology, PLLC/Sarah Cannon Research Institute,
Nashville, TN
Background: Despite novel therapies, MM remains an incurable disease.
Changes in histone modification are commonly found in human cancers
including MM. Preclinical studies demonstrate synergistic anti-MM activity
with histone deacetylase inhibitors (HDACi) and proteasome inhibitors (PI)
through the dual inhibition of the proteasome and aggresome pathways.
Pan is an oral pan-HDACi which has shown synergy with bortezomib in
clinical studies. Cfz is a 2nd generation PI which has shown marked
anti-MM activity with an improved safety profile. In this trial we evaluate
the safety and efficacy of the combination of pan and cfz in pts with RR
MM. Methods: This multi-center US study plans to enroll up to 52 adults
with RR MM. The phase I study will determine the MTD of the combination
of cfz and pan and follow a standard dose escalation design. Pan will be
administered orally three times weekly during weeks 1 and 3 of each
28-day cycle (Days 1, 3, 5, 15, 17, 19) at a starting dose of 20 mg. Cfz will
be administered intravenously on Days 1, 2, 8, 9, 15, and 16 of each
28-day cycle. Cfz starting dose will be 20mg on days 1,2 of cycle 1 with
escalation to the corresponding dose level beginning at 27 mg , if well
tolerated. Dose modifications will not be permitted during cycle 1 unless a
pt experiences a DLT. A maximum of four dose levels will be evaluated.
Approximately 24 pts will be enrolled during the phase I portion to
establish the MTD. In the phase II portion of this study, pts with RR MM will
receive treatment with the optimal dose of pan and cfz established during
phase I. Pts will be assessed for response to treatment after each cycle (4
weeks). Pts with objective response or stable disease will continue
treatment until disease progression or unacceptable toxicity occurs. The
primary endpoint is to establish the optimal doses of cfz and pan that can
be administered to pts with RR MM (phase I) and to evaluate the overall
response rate (phase II). Secondary endpoints include time-to-progression,
progression-free survival, overall survival and safety. Approximately 25 pts
are planned for the phase II portion. Current status: As of 1/27/12 3
patients have been enrolled.
TPS8117 General Poster Session (Board #41B), Mon, 1:15 PM-5:15 PM
Recruitment in a randomized, double-blind, placebo-controlled study to
assess siltuximab (CNTO 328), an anti-IL-6 monoclonal antibody, in
patients with multicentric Castleman’s disease. Presenting Author: Frits
Van Rhee, University of Arkansas for Medical Sciences, Little Rock, AR
Background: Multicentric Castleman’s disease (MCD) is a rare lymphoproliferative
disorder in which dysregulated production of interleukin (IL)-6
results in lymph node enlargement and debilitating symptoms, including
systemic inflammatory manifestations (eg, fever, fatigue, weight loss),
autoimmune phenomena, and markedly abnormal laboratory findings (eg,
anemia, hyper-�-globulinemia, hypoalbuminemia, thrombocytosis, increases
in acute-phase proteins such as CRP, ESR, fibrinogen). There is
currently no approved systemic treatment for MCD in the US or EU.
Siltuximab (CNTO 328) is a chimeric mAb with high affinity for soluble
IL-6. In a previous phase 1 study, high objective tumor response rate (64%)
has been observed in patients with MCD (van Rhee F et al. Blood
2008;112:1008), and the long-term safety profile looks favourable (Kurzrock
R et al. Blood 2011;118:3959). These results have prompted a
randomized, double-blind, placebo-controlled study to definitively assess
the efficacy and safety of siltuximab in combination with best supportive
care (BSC) compared with BSC in patients with MCD. Methods: Eligibility
includes HIV- and HHV-8-negative, symptomatic, measurable MCD patients.
Patients with prior lymphoma or prior exposure to treatment
targeting IL-6 or its receptor are excluded. Patients can be enrolled when
receiving stable doses of corticosteroids (�1 mg/kg/d of prednisone or
equivalent). Patients will be randomized in a 1:2 ratio to placebo � BSC or
to 11 mg/kg siltuximab � BSC and will receive siltuximab/placebo in a
1-hour IV infusion every 3 weeks. The primary objective is to evaluate
durable tumor and symptomatic response in the intent-to-treat population.
Secondary objectives include additional efficacy measures, safety, patient
reported outcomes, and pharmacologic assessment. Status: 67/78 patients
have been randomly assigned. This is the first randomized, placebocontrolled
study to be conducted in MCD. The rarity of the disease has
posed unique challenges, and various enrollment strategies have been
successfully implemented, with projected completion of enrollment in
March 2012.
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