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

TPS10100 General Poster Session (Board #54E), Sun, 8:00 AM-12:00 PM
Randomized phase III, multicenter, open-label study comparing TH-302 in
combination with doxorubicin versus doxorubicin alone in subjects with
locally advanced unresectable or metastatic soft tissue sarcoma. Presenting
Author: Sant P. Chawla, Sarcoma Oncology Center, Santa Monica, CA
Background: A hypoxic microenvironment characterizes solid tumors including
soft tissue sarcoma (STS) and is associated with chemotherapy
resistance. TH-302, a prodrug of the alkylating agent bromo-isophosphoramide
mustard (BR-IPM) is reduced in hypoxic environments, releasing
Br-IPM. Combining D with TH-302 should effectively target both the
normoxic and hypoxic regions of STS. TH-302 was investigated with
full-dose D (75 mg/m2 ). The regimen was well tolerated, �60% completed
6 cycles. DLTs at higher doses were infection with neutropenia and grade 4
thrombocytopenia. The efficacy was higher than generally reported with
single agent D (Sleijfer, The Oncologist, 2005). At MTD (75 mg/m2 D and
300 mg/m2 TH-302) best response were 2 (2%) CR, 30 (34%) PR, 43
(48%) SD. Median PFS and OS were 6.7 and 17.5 months, respectively.
Based upon these data, a study (NCT01440088) is ongoing to assess the
benefit of adding TH-302 to the standard D as first-line therapy of STS.
Methods: The randomized (1:1) phase III study of TH-302 (300 mg/m2 )
with D versus D alone was initiated September 2011. Target goal is 450
patients. TH-302 is administered IV over 30-60 minutes on Days 1 and 8
(21-day cycle). D (75 mg/m2 , bolus or continuous) is administered Day 1
starting 2-4 hrs after TH-302 when used in combination. Patients receiving
TH-302 plus D without progression after 6 cycles may continue on TH-302
alone. Key eligibility criteria: locally advanced unresectable or metastatic
STS untreated with chemotherapy (adjuvant allowed), ECOG 0/1, measurable
disease (RECIST 1.1) and adequate hematologic, hepatic, renal
function. A FDA Special Protocol Agreement was reached on study design
and analyses. Primary efficacy endpoint is overall survival (OS) comparison
of the combination vs D. The study is designed to detect a 40%
improvement in OS with 85% power and one-sided alpha of 2.5%. An
interim futility PFS analysis is scheduled after 113 PFS events. Significant
improvement in PFS (one-sided p � 0.10) is required to continue. A further
analysis for early efficacy stoppage is scheduled after 175 OS events. IDMC
will monitor safety and efficacy.
TPS10102^ General Poster Session (Board #54G), Sun, 8:00 AM-12:00 PM
Masitinib in comparison to imatinib as first-line therapy of patients with
advanced gastrointestinal stromal tumor (GIST): A randomized phase III
trial. Presenting Author: Antoine Adenis, Centre Oscar Lambret, Lille,
France
Background: Masitinib is an oral tyrosine kinase inhibitor (TKI) that has
greater in vitro kinase activity and/or selectivity than imatinib against KIT
and PDGFRA/B. A phase 2 study has previously reported that masitinib
treatment produced clinically relevant activity in imatinib-naïve patients
with advanced GIST. Considering the promising long term response
observed in overall survival (OS) (see Table) there is compelling evidence to
compare masitinib against imatinib (the current standard of care) in the
first-line setting. Methods: A multicenter, randomized, open label, phase 3,
1:1 study to compare efficacy and safety of masitinib (7.5 mg/kg/day) to the
active control of imatinib (400 or 600 mg/day) in first-line treatment of
patients with advanced GIST. Primary endpoint is progression-free survival
(PFS), with secondary endpoints including OS, time to progression (TTP),
and clinical response rates (RECIST). Based on a planned sample size of
222 patients (111/arm) this 15% non-inferiority study was designed to
have an 85% power using a 95% two-sided CI of the hazard ratio. Patient
eligibility criteria include: histologically proven, metastatic or locally
advanced nonresectable, or recurrent post-surgery GIST; TKI naïve patient
or patient previously receiving imatinib only as a neoadjuvant or adjuvant
therapy; and confirmed KIT-positive or PDGFRA-positive tumors. Recruitment
is ongoing. On 09/2011, the DMC recommended continuation of this
study. Clinicaltrial.gov: NCT00812240.
Masitinib phase 2 a
Imatinib phase 3 b
{Meta-analysis data} c
Dose 7.5 mg/kg/d 400 mg/d 800 mg/d
Population, N 30 345 {818} 349 {822}
Median follow-up (months) 65 54
Median OS (months) [95%CI] Not reached [53; -] 55 {49} 51 {49}
Month-12 97% 86% {90%} 86% {90%}
24 90% 76% {80%} 72% {80%}
36 87% 64% {60%} 62% {61%}
48 76% 56% {56%} 56% {56%}
60 62% 48% {45%} 49% {45%}
Confirmed exon 11, n 9/30 (30%) 283/397 (71%) d
Median OS(months) [95%CI] Not reached [65; -] 60
Month-12 100% 93%
24 89% 80%
36 89% 70%
48 89% 63%
60 89% 51%
a Blay, JCO 29: 2011 (suppl 4; abst 85); b Blanke, JCO 2008, 26:626; c GSTMA Group. JCO 2010, 28:1247; d
Heinrich, JCO 2008, 26:5360.
Sarcoma
655s
TPS10101 General Poster Session (Board #54F), Sun, 8:00 AM-12:00 PM
Randomized multicenter phase III trial of trabectedin (T) versus doxorubicinbased
chemotherapy as first-line therapy in patients with translocationrelated
sarcoma (TRS). Presenting Author: Jean-Yves Blay, Centre Léon
Bérard, Lyon, France
Background: One third of sarcoma histotypes have specific chromosomal
translocations which result in abnormal transcription factors, integral to the
change to a malignant phenotype. T is the first of a new class of anti-tumor
agents with a transcription-targeted mechanism of action. In vitro evidence
exists of the ability of T to interfere with the aberrant transcription factor’s
binding to DNA promoters in TRS. Patients with TRS, such as myxoid/round
cell liposarcomas (MRCL) have benefited from long-lasting tumor control in
response to T. Methods: A randomized, phase III study of T (1.5 mg/m2 in
24-h intravenous infusion every 3 weeks [q3wk]) vs doxorubicin 75 mg/m2 q3wk, or doxorubicin 60 mg/m2 with ifosfamide 6-9 g/m2 q3wk) as first line
treatment in patients with advanced TRS. Primary aim: to determine the
efficacy of T vs doxorubicin-based therapy by comparing progression-free
survival (PFS) in each arm. Secondary aims: comparison of PFS rates at six
months, response rate (RR), PFS and RR by histological type (MRCL vs
other subtypes), overall survival, safety, exploratory response evaluation by
Choi criteria and pharmacogenomic analyses. Patients with confirmed TRS
of the following subtypes: MRCL, alveolar soft part sarcoma,angiomatoid
fibrous histiocytoma, clear cell sarcoma, desmoplastic small round cell
tumor, low grade endometrial stromal sarcoma, low grade fibromyxoid
sarcoma,myxoid chondrosarcoma and synovial sarcoma, are stratified by
performance status (PS 0 vs 1-2) and sarcoma subtype (MRCL vs other
subtypes) and randomized (1:1 ratio) to T or doxorubicin � ifosfamide.
Confirmation of the translocation by fluorescence in situ hybridization is
compulsory for inclusion in the primary efficacy analysis. An adaptive
design was chosen to test the reduction in relative risk of progression or
death with T, an interim analysis will be conducted with 45 PFS events
from 80 evaluable patients. To date 117 patients have been enrolled from
six countries and 29 centers. An independent data monitoring committee
met on 15 November 2011 and concluded that the trial should continue as
planned.
TPS10103 General Poster Session (Board #54H), Sun, 8:00 AM-12:00 PM
Randomized multicenter double-blind phase II trial: The immunological
adjuvant OPT-821 with or without a trivalent ganglioside vaccine in
metastatic sarcoma patients following metastasectomy. Presenting Author:
Richard D. Carvajal, Memorial Sloan-Kettering Cancer Center, New York,
NY
Background: The gangliosides GM2, GD2, and GD3 are strongly expressed
in sarcoma and represent novel antitumor targets. We have demonstrated
the safety and immunogenicity of individual monovalent ganglioside
conjugate vaccines when administered with OPT821, a synthetic saponin
adjuvant that augments the T-cell response. Antitumor effects are observed
with anti-ganglioside antibodies in preclinical models, with greatest benefit
seen in the micrometastatic setting. Patients (pts) with metastatic sarcoma
rendered disease-free by surgery are at high risk for disease recurrence,
with no therapy demonstrated to improve outcomes. Therefore, this
population is ideally suited to test the efficacy of vaccine induced
anti-ganglioside antibodies. We thus initiated this randomized doubleblind
phase II study of OPT821 with or without a trivalent ganglioside
vaccine composed of GM2, GD2 lactone and GD3 lactone conjugated to
KLH, an immunogenic carrier protein. Methods: A total of 134 pts will be
randomized on a 1:1 basis stratified by disease state (relapsed disease vs
metastasis at time of diagnosis), disease-free interval and number of
relapses. Key inclusion criteria include stage IV sarcoma (locoregional
recurrence is not sufficient) rendered disease-free following surgery or
multi-modality therapy, no more than 8 weeks since surgery, and no
continuous use of anti-inflammatory medications. Pts with Ewings sarcoma,
GIST and rhabdomyosarcoma (except pleomorphic/anaplastic) are
ineligible. Eligible pts will receive 10 subcutaneous injections in the
outpatient setting over 84 weeks. The primary endpoint is progression-free
survival (PFS). Secondary objectives include overall survival (OS) and 1and
3-year PFS rate. Exploratory objectives include correlation of serologic
response to outcome, comparison of tumor ganglioside expression at
baseline and at recurrence, and analysis of circulating tumor cells.
Enrollment began in July 2010. As of January 1, 2012, 83 patients had
been recruited from 12 participating sites. Clinicaltrials.gov#:
NCT01141491. Funded by Mabvax Therapeutics and NIH (R21CA13386).
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