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

3080 General Poster Session (Board #17F), Mon, 8:00 AM-12:00 PM
A phase I study of ombrabulin (O) combined with bevacizumab (B) in
patients with advanced solid tumors (NCT01193595). Presenting Author:
Gianluca Del Conte, Fondazione IRCCS Istituto Nazionale dei Tumori,
Milan, Italy
Background: O is a vascular-disrupting agent derived from combretastatin
A4-phosphate that induces rapid but transient tumor vascular shutdown. In
experimental models, the combination of O with VEGF-blockade induced
more regressions than O alone. This phase I study was performed to
determine the maximum tolerated dose (MTD), and assess the overall
safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary
antitumor activity of O plus B. Trial is funded by sanofi. Methods: Patients
(pt) with advanced solid tumors, ECOG PS �1, and adequate organ
function were eligible. Increasing doses of O (mg/m²) was administered
intravenously (IV) on day (d) 1; B (5 or 10mg/kg) was administered IV on
d2, in 21d cycles (C). A Bayesian design was applied to determine dose
escalation steps and MTD. PK sampling was performed in C1 and C2. PD
sampling for circulating endothelial cells (CEC) and progenitors (CEP) were
performed throughout. Dynamic contrast-enhanced ultrasound (DCE-US)
to assess tumor perfusion was performed before and after C1 and C2
dosing. Results: 25 pts (M:F 6:19; median age 49 years [range 27-75])
have been treated at 8 dose levels of O/B: 8/5 (3), 11.5/5 (4), 11.5/10 (3),
15.5/10 (3), 20/10 (3), 25/10 (3); 35/10 (3) and 42/10 (3). Ovarian
cancer was the most frequent tumor type (n�11). Median Cs received was
3 (1 to 14). No DLTs were observed during C1. Drug-related grade (g) 3-4
adverse events (AE) included hypertension in 2 pts (8/5; 11.5/5) and ileal
perforation in 1 pt with peritoneal carcinomatosis at laparotomy (11.5/10).
A case of duodenal perforation was unlikely related (25/10). Two pts with
ovarian cancer (11.5/5; 20/10) had confirmed partial responses (4.4
months (mo) and 7� mo). 13/23 (57%) pts with � 1 tumor assessment
had stable disease (n�8; median 4.3 mo [1.8-9.5]; 5 ongoing). Data from
cohorts 1 and 2 demonstrated no evidence of a PK interaction.17/25
patients demonstrated a peak in CEC, and 7/9 patients a peak in CEP. 4/7
DCE-US evaluable pts had �50% drop in tumor perfusion (AUC) at Day 8
of C1. Conclusions: O combined with B is well tolerated with early evidence
of clinical activity. The MTD has not been reached (current dose level
50/10); cohorts of O combined with B at 15 mg/kg will be tested.
3082 General Poster Session (Board #17H), Mon, 8:00 AM-12:00 PM
A phase I study of R04929097, an oral gamma secretase inhibitor, in
combination with gemcitabine in patients with advanced solid tumors
(PHL-078/CTEP 8575). Presenting Author: Suzanne Richter, Princess
Margaret Hospital, Toronto, ON, Canada
Background: RO4929097 (RO) is an oral inhibitor of �-secretase that
disrupts Notch signaling. Gemcitabine (GEM) is active against many solid
tumors with a favorable toxicity profile suited to combination. The primary
objective of this trial is to establish the recommended phase II dose (RP2D)
of RO in combination with GEM; secondary objectives include the evaluation
of safety, tolerability, pharmacokinetics (PK), biomarkers of Notch
signaling and preliminary anti-tumor activity. Methods: Patients (pts) with
advanced solid tumors were enrolled in escalating RO dose levels (DL) as
follows: DL1 20mg, DL2 30mg; DL3 45mg and DL4 90mg using a 3�3
design. Treatment with RO was administered once daily on days (d) 1-3,
8-10, 15-17, 22-24 and GEM 1000mg/m2 on d1, 8, and 15 in 28d cycles
(c). Dose limiting toxicities (DLTs) during c1 were defined as CTCAE v4
grade (g) 3 non-hematological or g4 hematological toxicities, failure to start
c2 within �14 days, or failure to receive �75% doses of RO or d8 GEM in
c1. Serial plasma samples for RO PK were collected on d1 and 10. Results:
As of January 2012, 15 pts (median age 55) have been treated. DLTs were:
DL1 0/3, DL2 1/7 (g3 ALT), DL3 0/3, DL4 2/2 (g3 AST/ALT and failure to
receive ³75% doses); all were reversible. One death (perforated viscus)
related to disease progression was observed. Most common g1/2 toxicities
were nausea (9), vomiting (6), fatigue (5), hypophosphatemia (5), transaminitis
(3) hypomagnasemia (2) and maculopapular rash (2). G3 hypophosphatemia
(1) was observed beyond C1. RO PKs demonstrated comparable
exposures at 30mg and 45mg (Table). Best response (RECIST 1.1) was
stable disease � 4 months in 3 pts (pancreas, tracheal, breast CA).
Conclusions: RO and GEM can be safely combined. RO levels achieved
exceeded the AUC0-24 for efficacy in preclinical models using daily dosing.
The maximum tolerated dose was exceeded at 90mg RO. Dose expansion at
45mg RO is ongoing to confirm the RP2D.
DL n
Cmax ng/ml
(SD) D1
Cmax ng/ml
(SD) D10
AUC 0-24
(ng*hr/mlx10 4 )
(SD) D1
AUC 0-24
(ng*hr/mlx10 4 )
(SD) D10
1 3 552 (100) 615 (382) 6.8 (1.0) 9.9 (7.2)
2 7 833 (352) 1221 (315) 12.6 (4.8) 19.2 (5.9)
3 3 986 (153) 1315 (332) 12.8 (1.2) 16.5 (8.2)
Developmental Therapeutics—Experimental Therapeutics
3081 General Poster Session (Board #17G), Mon, 8:00 AM-12:00 PM
A phase I study to assess oral bioavailability of a novel oral soft gelatin
capsule formulation of rigosertib (ON 01910.Na) under fasted and fed
conditions in patients with myelodysplastic syndromes. Presenting Author:
Azra Raza, Columbia Presbyterian Medical Center, New York, NY
Background: Rigosertib (ON 01910.Na) is a novel multikinase inhibitor,
with selective cytotoxic effects on tumor cells without impact on normal
cells. Rigosertib, administered as a 3-day continuous infusion, is now
undergoing phase 3 evaluation in higher risk MDS patients refractory to
hypomethylating agents. Here, we report the results of the effect of food on
the absolute bioavailability of a novel rigosertib oral formulation (soft
gelatin capsule) in MDS patients. Methods: This was a single-dose,
three-treatment, three-period sequential design for studying the effects of
food on the bioavailability of an immediate-release soft gelatin capsule
formulation. The following dosing groups were tested in 12 patients: IV
Dose 800 mg/m2 over 24 hours and oral dose 560 mg (2 x 280 mg
capsules) under fasting and fed conditions. The oral dose was the
recommended phase 2 dose, as reported previously (R.S. Komrokji et al.,
Oral Formulation of Rigosertib (ON 01910.Na) in Patients with Myelodysplastic
Syndrome (MDS) – Phase I Study Results. Blood 2011, 118:
Abstract #3797). Plasma samples were collected pre-dose, and over 32
hours (IV dose) or 8 hours (oral dose) after dose initiation. Rigosertib
plasma levels were analyzed by a validated LC/MS/MS method. Pharmacokinetic
parameters were estimated by noncompartmental analysis (WinNonlinÒ).
Results: Rigosertib pharmacokinetic parameters are presented in the
table below. The results of the present study demonstrate good oral
bioavailability under fasting condition.Oral administration of rigosertib
after a meal decreased Cmax and AUC by 77% and 61%, respectively,
compared to fasting conditions. Conclusions: The results of this study
support the potential for oral delivery of rigosertib, which could become a
preferred therapy over a 3-day continuous intravenous infusion.
Parameter
800 mg/m 2 IV
(24-hr infusion)
Dosing group
560 mg oral
(fasting)
193s
560 mg oral
(fed)
C max (�g/ml) 3.14 � 1.13 2.42 � 1.26 0.56 � 0.31
AUC (�g-hr/ml) 52.7 � 19.2 6.89 � 3.98 2.71 � 1.51
T max (hr) 2.91 � 1.30 1.00 � 0.45 2.82 � 1.15
t 1/2 (hr) 3.25 � 0.97 2.79 � 1.23 2.61 � 0.93
Bioavailability (%) N/A 34.9 � 17.6 13.8 � 6.04
3083 General Poster Session (Board #18A), Mon, 8:00 AM-12:00 PM
A phase I dose-escalation study of the HSP90 inhibitor AUY922 and
erlotinib for patients with EGFR-mutant lung cancer with acquired resistance
(AR) to EGFR tyrosine kinase inhibitors (EGFR TKIs). Presenting
Author: Melissa Lynne Johnson, Feinberg School of Medicine, Northwestern
University, The Robert H. Lurie Comprehensive Cancer Center, Chicago,
IL
Background: AUY922 is a highly potent, non-geldanamycin analog, HSP90
inhibitor that degrades mutated EGFR and MET. Preclinical studies
demonstrate that HSP90 inhibitors have anti-tumor activity in EGFR
mutant, EGFR TKI-sensitive and TKI-resistant lung cancer xenograft
models. To prevent disease flare after stopping EGFR TKIs in patients (pts)
with EGFR mutated lung cancer, erlotinib (E) is often continued with
subsequent lines of treatment for AR. This phase I study will determine the
maximally tolerated dose (MTD) of AUY922 and E for pts with mutated
EGFR and RECIST progression on EGFR TKIs. Methods: All pts have EGFR
mutant lung cancer, with development of AR (per Jackman, JCO 2010)
after treatment with an EGFR TKI. Pts underwent repeat tumor biopsies
after development of AR and prior to study entry. Pts receive AUY922 IV
weekly and E oral daily in 28-day cycles, with dose escalation using
standard 3�3 design. Pharmacokinetics, serial ophthalmology evaluations
and weekly assessment for toxicity are required. Tumor tissue from
re-biopsy at study entry is analyzed for EGFR T790M and MET. Results:
Since April 2011, 11 pts have been enrolled, in 4 of 5 planned cohorts
(AUY922 25 mg/m2 � E 75 mg; AUY922 25 mg/m2� E 150 mg; AUY922
37.5 mg/m2� E 150 mg; AUY922 55 mg/m2�E 150 mg). Prior to
developing AR, pts were treated with EGFR TKIs for a median of 9 months
(range 8-32). Of 9 pts with tissue analyzed thus far, 6 had EGFR T790M.
Pts have received a median of two cycles (range 1-7), and 5 remain on
study. There have been no dose-limiting toxicities. Adverse events reported
in � 20% of pts were diarrhea, nausea, vomiting, fatigue, and rash, all
graded 1 or 2. No cardiovascular, renal or hepatic toxicities have been
observed. Three pts have reported “flashing lights” and 2 pts transient
night blindness, all grade 1. Dose escalation continues. No partial
responses have been seen in 6 evaluable pts, 4 patients have confirmed
stable disease at 8 wks. Conclusions: AUY922 and E is a well-tolerated
combination at dose levels up to AUY922 55 mg/m2� E 150 mg. Further
dose-escalation, MTD, and correlation with markers of AR will be reported.
Supported by Novartis, Inc.
Visit abstract.asco.org and search by abstract for the full list of abstract authors and their disclosure information.