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

3024 Poster Discussion Session (Board #16), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
PX-866 and docetaxel in patients with advanced solid tumors. Presenting
Author: Antonio Jimeno, Division of Medical Oncology, University of
Colorado Denver, Aurora, CO
Background: PX-866, an irreversible pan-isoform inhibitor of Class 1 PI-3K
has additive to synergistic effects when combined with docetaxel in
xenograft models of NSCLC and SCCHN. A phase I/II study of PX-866 and
docetaxel was initiated to further evaluate this combination. Enrollment in
phase I is complete, and the randomized, controlled phase II portion is now
enrolling patients with either NSCLC or SCCHN. Phase I safety and
pharmacokinetics were previously described; the recommended phase II
dose of PX-866 was 8 mg daily, the same as the single agent MTD (Jimeno
A, et al. AACR-NCI-EORTC, 2011). Updated phase I antitumor and
biomarker results are presented here. Methods: Phase 1 consisted of dose
escalation of PX-866 at 4, 6, or 8 mg po qd in combination with docetaxel
75 mg/m2 IV once every 21 days (d). Patients had advanced solid tumors
for which docetaxel was compendia listed. Tumor restaging was performed
every 2 cycles. Archived tumor biopsies were collected for assessment of
potential biomarkers of response, including PIK3CA and KRAS mutations
and PTEN expression. Results: 43 pts were enrolled: NSCLC (n�6),
prostate (n�5), ovarian (n�5), SCCHN (n�3), and pancreatic (n�3) were
the most common tumor types. Median time on study (TOS) was 81 d
(5-361), with 9 pts still on study. 16 pts received � 6 cycles (6-17),
including 3 pts with NSCLC, and 4 pts with ovarian cancer. Biomarker data
are available for 20 evaluable pts. Median days on study by mutational
status was: PIK3CA/KRAS WT (n�13): 91 d (28-286); PIK3CA-MUT
(n�5): 183 d (64-342); KRAS-MUT (n�3): 141 d (125-361); and
PIK3CA/KRAS-MUT (n�2): 96 d (86-105). A trend toward longer TOS was
observed in pts with PIK3CA-MUT vs PIK3CA/KRAS-WT (p�0.14). Assessment
of PTEN is ongoing. Best response in 32 evaluable pts was 2 PR
(6%), 22 SD (69%), and 8 PD (25%). The PRs were in NSCLC and ovarian
cancer (both PIK3CA/KRAS WT). 8 other pts had �15% tumor shrinkage,
including NSCLC (n�2). Conclusions: PX-866 with docetaxel was associated
with a disease control rate of 75%, with 50% of evaluable pts
demonstrating SD or better for � 6 cycles. Based on available data, a trend
for a longer TOS was seen with PIK3CA-MUT pts. This relationship will be
further evaluated in phase II.
3026 Poster Discussion Session (Board #18), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
A phase I study of Debio 0932, an oral HSP90 inhibitor, in patients with solid
tumors. Presenting Author: Nicolas Isambert, Centre Georges François Leclerc,
Dijon, France
Background: Debio 0932 is an oral second-generation heat shock protein 90
(HSP90) inhibitor that has shown extended tumor retention, blood-brain-barrier
penetration, and promising anti-tumor activity both as monotherapy and combination
against a broad range of tumors in pre-clinical models. Here we report the
results of the dose escalation part of a phase I study in patients with advanced
solid tumors or lymphoma (NCT01168752). Methods: This was an open-label,
non-randomized, 3 � 3 dose-escalation study to determine the maximum
tolerated dose (MTD) of Debio 0932 when given QD or Q2D during the first 30
days of treatment in patients with advanced solid tumours or lymphoma resistant
to standard therapy. The starting dose in both treatment groups was 50mg.
Doses were increased according to an algorithm based on observed toxicity and
dose limiting toxicities (DLT). Tumor assessments were performed every 8
weeks. Results: Patient characteristics and results are summarized below. DLTs
occurred at 1600mg in both dose groups. Adverse events (AE) were mostly
CTCAE grade 1 or 2, with no apparent dose relationship. No ocular or cardiac
toxicity was observed. The main reason for treatment withdrawal was progressive
disease. Investigator-reported cases of SD and PR were observed. Conclusions:
Debio 0932 mono-therapy was generally well tolerated and showed promising
signs of efficacy in patients with advanced solid tumors. The recommended
phase II dose, established at 1000mg QD, will be tested in an additional 30
patients in an ongoing expansion study. A phase I-II study of Debio 0932 in
combination with standard of care in the first- and second-line treatment of
NSCLC is planned.
Q2D dosing
N � 23
QD dosing
N � 28
Mean age (range) (yrs) 58 (39-72) 55 (27-74)
Gender M / F % 48/52 68/32
Predominant cancer types % Colorectal 26
Colorectal 29
Lung 17
Pancreas 13
Lung 18
>3 previous treatment regimens % 83 86
Days on treatment (range) 69 (1 – 223) 66 (6 – 252)
DLTs / dose Febrile neutropnia / 1600mg Diarrhea / 1600mg
Asthenia / 1600mg
Most frequent AEs %
.
.
Constipation
44
36
Diarrhea
26
61
Nausea
39
46
Vomiting
39
43
Asthenia
61
71
Decreased appetite
35
50
Best overall tumor response
.
.
PR %
4
0
SD %
17
29
PD %
57
61
Not evaluable %
13
3
Not assessed %
9
7
Developmental Therapeutics—Experimental Therapeutics
179s
3025 Poster Discussion Session (Board #17), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
A first-in-human phase I study to evaluate the fully human monoclonal
antibody OMP-59R5 (anti-Notch2/3) administered intravenously to patients
with advanced solid tumors. Presenting Author: Anthony W. Tolcher,
South Texas Accelerated Research Therapeutics, LLC, San Antonio, TX
Background: The Notch pathway plays a central role in embryonic development,
the regulation of stem and progenitor cells, and is implicated
centrally in many human cancers. OMP-59R5 is a fully human IgG2
originally identified by binding to Notch2. It inhibits the signaling of both
Notch2 and Notch3 receptors. Mouse xenograft studies using minimallypassaged,
patient-derived xenografts show that OMP-59R5 impedes tumor
growth and eliminates cancer stem cells (CSCs) in many tumor types.
OMP-59R5 modulates the expression of stromal genes and genes associated
with the function of tumor vascular pericytes. As such, OMP-59R5 is a
novel anti-cancer agent that inhibits tumor growth through direct actions on
tumor cells, including CSCs, and effects the stroma and vasculature.
Methods: A phase I dose escalation study (3�3 design) was initiated in
solid tumor patients. OMP-59R5 was administered to study safety, pharmacokinetics
(PK), pharmacodynamics (PD), preliminary efficacy, and to
determine the maximum tolerated dose (MTD). Results: Twenty-four patients
have been enrolled in 5 dose-escalation cohorts at doses of 0.5, 1,
2.5, and 5mg/kg administered weekly (QW) and 5mg/kg administered every
other week (QOW). The most frequently reported drug-related adverse
events were: mild to moderate diarrhea, fatigue, nausea, vomiting, decreased
appetite, and constipation. Diarrhea was dose related and occurred
at doses �2.5mg/kg weekly and appears less pronounced with every other
week dosing. Two dose-limiting toxicities (grade 3 diarrhea and grade 3
hypokalemia) occurred at 5mg/kg QW and 2.5mg/kg was established as an
MTD for QW dosing. A QOW dosing schedule is currently under investigation.
The PK of OMP-59R5 was characterized by fast and dose-dependent
clearance. Two patients (Kaposi’s sarcoma at 5mg/kg and adenoid cystic
carcinoma at 2.5mg/kg) had prolonged stable disease for �110 days. PD
analyses for Notch pathway modulation are ongoing. Conclusions: OMP-
59R5 is generally well tolerated. An MTD of 2.5mg/kg QW has been
established and a QOW schedule is currently under study. Updated results
will be presented.
3027 Poster Discussion Session (Board #19), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Rational molecularly targeted combinations: A parallel-arm phase I trial of
the humanized anti-IGF-1R antibody dalotuzumab (D) in combination with
the allosteric AKT inhibitor MK-2206 or the gamma secretase inhibitor
MK-0752, in patients with advanced solid tumors. Presenting Author:
Irene Brana, Princess Margaret Hospital, Toronto, ON, Canada
Background: Two rational strategies to interrogate the IGF-1R pathway were
investigated in this parallel-arm phase I trial: 1) vertical inhibition with D
and MK-2206 to potentiate PI3K pathway targeting, 2) horizontal crosstalk
inhibition with D and MK-0752 to exert effects against cellular proliferation,
angiogenesis and stem cell propagation. Methods: Patients (pts) with
advanced solid tumors and no prior exposure to agents of the same targets
were eligible. Dose escalation was based on a modified toxicity probability
interval method (Ji et al, 2010). Arm A is comprised of fixed D dose of 10
mg/m2 IV weekly plus MK-2206 at escalating doses of 90-200 mg PO
weekly. Arm B is comprised of fixed MK-0752 dose of 1800 mg PO weekly
plus D at escalating doses of 7.5-10 mg/m2 IV weekly. Each cycle � 4
weeks in both arms. Primary objectives were to determine DLT and RP2D of
these combinations. Results: 30 patients were enrolled in the dose
escalation phase (18 in Arm A and 12 in Arm B) with: median age � 56
(range 36-74); M:F � 13:17; ECOG 0:1 � 12:18; primary diagnosis �
colorectal (CRC) (9), NSCLC (3), others (17); prior metastatic regimens �
3 (range 1-4). In Arm A, 1/6 DLT was observed with MK-2206 at 135 mg
(G3 serum sickness-like reaction); 2/3 DLTs with MK-2206 at 200 mg (G4
leukopenia/neutropenia; G3 rash). No other G4 or worse adverse events
(AEs) were observed. RP2D of Arm A � D 10mg/m2 IV weekly and
MK-2206 150 mg PO weekly. Other common AEs in Arm A included:
fatigue, rash and nausea. In Arm B, 2/6 DLTs were observed with D at 10
mg/m2 (G3 rash; G3 nausea/vomiting). RP2D of Arm B � D 10mg/m2 IV
weekly and MK-0752 at 1800 mg PO weekly based on Ji et al. Other
common AEs in Arm B included: anorexia, nausea and fatigue. No PR was
observed and SD � 4 months occurred in 4 pts (all in Arm A). PK analyses
are ongoing. Conclusions: Targeted combinations of D with MK-2206 or
with MK-0752 were both tolerable. Expansion cohorts based on biomarker
selection are underway, specifically ovarian cancer with high IGF1 expression/low
RAS score for Arm A; and KRAS wild-type CRC with high IGF1/low
IGF2 expression for Arm B.
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