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

10004 Oral Abstract Session, Mon, 3:00 PM-6:00 PM
A first-in-human, phase Ib combination study to assess safety, pharmacokinetics
(PK), and pharmacodynamics (PD) of a hedgehog inhibitor, GDC-0449, with a
Notch inhibitor, RO4929097, in patients with advanced sarcoma. Presenting
Author: Mrinal M. Gounder, Memorial Sloan-Kettering Cancer Center, New York,
NY
Background: Aberrant Hedgehog and Notch signaling is seen in sarcoma and
anti-tumor activity is enhanced by inhibiting both pathways. This first in man
Phase Ib study evaluated safety and efficacy of the combination of GDC-0449
(G), a smoothened inhibitor with RO4929097 (R), a gamma-secretase/notch
inhibitor. Methods: The study evaluated fixed dose G (150 mg qd) for 21 days
followed by G � R at either 10 mg (level 1) or 15 mg (level 2) QD. At MTD pts
were evaluated with G � R (without “lead in” G) or single agent R. Pre and post
treatment tumor biopsies were obtained to assess notch and hedgehog inhibition.
PK was assessed for each drug. Key eligibility: advanced sarcoma, ECOG
� 2, age � 18 and prior therapies � 4. RECIST response was assessed Q6 wks.
Results: 34 pts had a median age of 53 yrs (23-78), median priors 3 and various
histologies [liposarcoma (7), chondrosarcoma (7), leiomyosarcoma (4), osteosarcoma
(2), GIST (2) and other (12)]. No DLT was seen. Common (�10 %) grade
�3 toxicity was hypophosphatemia (18%). Systemic exposure (AUC0-24 and
Cmax) of G was similar to established studies (not shown). AUC0-24 and Cmax of R
was significantly lower (~70%) when administered with G (Table). However,
measurement of unbound, free drug (Cfree) of R showed comparable levels
between single agent R and G � R, but not when G was a “lead in” (Table).
Target inhibition of the notch pathway (cleaved notch) and pAkt was observed in
matched tumor biopsies with both arms. Durable SD was seen in both arms:
myxoid chondrosarcoma (56 wks), liposarcoma (24� wks), clear cell (21� wks),
desmoid (17� wks), spindle cell (15� wks) and chondrosarcoma (13� wks).
Conclusions: The combination of G�R is well tolerated and the RP2D is G 150
mg qd and R 15 mg qd without a “lead in” G. Despite reduction in total levels of
R in the combination, free drug was similar and inhibits target. Disease stability
was seen with R and R � G. Further clinical development of notch and hedgehog
inhibitors in sarcomas is warranted.
PK of R �Lead in G� then G � R G�R R
AUC0-24 714 3150 4477
Half life hr 21 17.5 28
Tmax hr 2.75 2 2
Cmax ng/mL 87.6 382 535
Trough total ng/mL 28 38 103
Trough free 0.5 0.9 1
10006 Oral Abstract Session, Mon, 3:00 PM-6:00 PM
An open-label international multicentric phase II study of nilotinib in
progressive pigmented villo-nodular synovitis (PVNS) not amenable to a
conservative surgical treatment. Presenting Author: Isabelle Ray-Coquard,
GINECO and Centre Leon Berard, Lyon, France
Background: PVNS, also known as tenosynovial giant cell tumor (TGCT), is a
rare pathological entity affecting the synovium in young adults. This
neoplastic disease is driven by a t(1;2) translocation which results in the
fusion of COL6A3 and M-CSF genes. Nilotinib has inhibitory properties on
M-CSF receptor pathway which could be of therapeutic interest in pts with
non resectable PVNS. Methods: In this open-label International, multicenter,
non-randomized, phase II study the primary objective is to evaluate
the efficacy of nilotinib treatment in patients (pts) with progressive or
relapsing PVNS not amenable to surgery or in whom surgery would be
mutilating, as measured by the 12-week progression-free rate (12-w PFR)
validated by an independent committee. Using a Bayesian design with a
stopping rule for futility, interim analyses were planned after the inclusion
of 10 pts and then every 5 pts. Results: From December 2010 to November
2011, 33 pts with progressive disease from 17 institutions from Europe
and Australia were enrolled. 14 pts (median age 37 y (range: 19-68), 7
males) were analyzed in the 2nd interim analysis. Median time since
diagnosis was 4.4 years (range: 0.2-26). Primary tumour was located on a
knee for 10 pts (71%) and on hip (1 pt, 7%), finger (7%), foot (7%), hand
(7%), respectively. 69% of pts had a inoperable PVNS and 31% had a
resectable tumour but requiring mutilating surgery. All pts started nilotinib
at the planned dose of 800 mg/day. At a median follow-up of 8.9 months
(range: 0.6-11), 2 pts had a dose reduction and 1 pt had discontinued
nilotinib after 14 days due to toxicity. Nilotinib was well tolerated, with only
2 pts experiencing grade 3 adverse events (anorexia: 1 pt; hepatic failure: 1
pt).The 12-w PFR was 85.7% (95%CI, 57.2%-98.2%), in favour of the
study continuation. No OR was observed at w-12; 1 pt (7%) was in PR at
w-30. Updated results will be presented after the 3rd interim analysis.
Conclusions: Nilotinib treatment induces disease stabilisation in a large
proportion of PVNS patients with non resectable disease or in whom
resection would be mutilating.
Sarcoma
631s
10005 Oral Abstract Session, Mon, 3:00 PM-6:00 PM
GDC-0449 in patients with advanced chondrosarcomas: A French Sarcoma
Group (FSG)/French and U.S. National Cancer Institutes phase II collaborative
study. Presenting Author: Antoine Italiano, Institut Bergonié, Bordeaux,
France
Background: Chondrosarcomas (CS) exhibit a strong activation of hedgehog
(Hh) signaling which plays a crucial role in cartilage tumorigenesis.
Preclinical data show that hedgehog blockade reduces strongly chondrosarcoma
cell proliferation and tumour size. GDC-0449 is a small-molecule
antagonist of the Hh pathway. Methods: This is a multicentric single-arm
phase 2 clinical trial based on two-stage Simon’s design which assesses
safety and efficacy of GDC-0449 in patients (pts) with advanced CS. All pts
had to have documented progressive disease (PD) as per RECIST 1.1 before
study entry. Pts receive GDC-0449 150mg (oral route), daily until PD or
unacceptable toxicity. The primary endpoint is the 6-month non-PD rate
according to RECIST. Based on the following hypotheses: 20% 6-month
non-PD rate (H0), 40% acceptable 6-month non-PD rate (H1), 10% type I
error rate, 90% power, a total of 37 assessable pts are necessary (17 for the
first stage � 20 for the second stage). Following the inclusion of the first 17
pts, if � four pts are progression-free at 6 months, the accrual will
continue. In order to account for not assessable pts (�/- 10%), 41 pts will
be recruited. Accrual started in February 2011 in six centers of the FSG.
Results: As of January 24 2012, 40 pts (28 males, 12 females) have been
included in the study. Median age is 59 years (30-86). The most frequent
histological subtype is conventional CS (n�32). Twenty eight pts (70%)
had grade 1 or 2 adverse events (AE) possibly related to the drug whereas 3
pts (7.5%) had grade 3 or 4 AE. The planned interim statistical analysis
performed after central histological and radiological review showed that
four patients out of the first 17 evaluable patients had stable disease
indicating that GDC-0449 had reached the primary endpoint to justify
continuing accrual after the 1st step of the study. 15 pts are still on
treatment. Molecular analyses are available for 21 pts. No mutation of SMO
was detected. qRT-PCR experiments and PTCH sequencing are ongoing.
Conclusions: GDC-0449 is well tolerated and shows some activity in a
subset of pts with advanced CS. Final clinical and molecular data will be
presented at the meeting.
10007 Oral Abstract Session, Mon, 3:00 PM-6:00 PM
Masitinib mesylate in imatinib-resistant advanced GIST: A randomized
phase II trial. Presenting Author: Antoine Adenis, Centre Oscar Lambret,
Lille, France
Background: Masitinib is an oral tyrosine kinase inhibitor with greater in
vitro activity and selectivity than imatinib against wild-type and juxtamembrane
mutations of KIT (Dubreuil, 2009, PLoSONE). This trial studied
efficacy and safety of masitinib at 12 mg/kg/day and sunitinib at 50 mg/day
for the treatment of imatinib-resistant GIST. Methods: Patients with
inoperable, locally advanced or metastatic GIST and showing disease
progression while treated with imatinib 400 mg/day received either
masitinib or sunitinib until progression. Primary endpoint was PFS evaluated
with RECIST with OS as a secondary endpoint. Based upon an 80%
power to detect with a Fleming design a median PFS �3 months (alpha
10%, unilateral), a population of 44 patients (22 per arm) was required.
Stratification was applied based on mutation status. Results: 44 patients
(exon 11 [66%], exon 9 [11%], wild-type or other [5%], not done at
baseline [18%]) were randomized into masitinib (n�23) or sunitinib
(n�21) treatment-arms from 9 centers between 02/2009 and 09/2011.
After a median follow-up of 14 months, median PFS was 3.9 months
(95%CI [2.6;8.1]) for masitinib vs 3.8 months [1.9;11] for sunitinib. Of
those patients progressing under masitinib, 88% received sunitinib in third
line. Median OS was not reached (NR) (95%CI [21;NR]) for masitinib vs 15
months [9.4;22] for sunitinib. The 18-month and 24-month OS rates for
masitinib vs sunitinib were 79% (95%CI [53;92]) vs 20% [1.5;55], and
53% (95%CI [9.5;84]) vs 0%, respectively. Similar results were seen in
the exon 11 subpopulation with median OS for masitinib NR (95%CI
[NR;NR]) vs 15 months [9.6;22] for sunitinib. The safety profile of
masitinib was better than sunitinib with a lower occurrence of severe
related adverse events (AEs) (17% vs 52%) and related AEs leading to
discontinuation (0% vs 9.5%). In masitinib treated patients, nausea,
diarrhea and asthenia were the most common related AEs. Conclusions:
Although PFS curves looked similar, this study apparently showed a longer
survival in the masitinib treatment-arm with a better safety profile than
sunitinib. Masitinib may potentially offer patients a new active compound
for advanced GIST in the second-line setting.
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