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

3032 Poster Discussion Session (Board #24), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Phase Ib safety trial of CVX-060, an intravenous humanized monoclonal
CovX body inhibiting angiopoietin 2 (Ang-2), with sunitinib. Presenting
Author: Lee S. Rosen, UCLA School of Medicine, Santa Monica, CA
Background: CVX-060 (CVX) is a humanized monoclonal antibody fused to
two Ang2 binding peptides. The recommended phase 2 dose (RP2D) is15
mg/kg/wk by intravenous (IV) infusion. Sunitinib (Sun), a kinase with many
targets including VEGFR1-3, is dosed 50 mg/day orally x 4/6 wks. Methods:
Patients (pts) with solid tumors were to receive CVX at doses of 6, 12, or 15
mg/kg/wk with Sun 50 mg/day x 4/6 wks in successive cohorts. Standard
definitions of dose limiting toxicities (DLTs) were used. Serum PK was
assessed by ELISA. Results: Thirty-four pts were treated at 5 dose levels
(DL) –see table. The median age was 62 years (29-76), ECOG performance
status 0-1. The safety of CVX plus lower Sun dose was established in DL 1.1
due to DLTs at the initial cohort. The safety of full dose Sun was further
established in 1.2 before further escalating the CVX dose. Overall, DLTs
related to CVX and Sun included hemorrhage (DL 1.0), asymptomatic
proteinuria (DL 1.2), ischemic colitis/lower GI bleed/recurrent lower GI
bleed (DL 3.0) and abdominal pain/microperforation on CT (DL 3.0). The
most common adverse events (AEs) related to either agent were fatigue
(68%), diarrhea (50%), nausea (47%), hypertension (35%), and dysgeusia
(32%). The majority of AEs were Gr 1 to 2. There were no PK interactions
between CVX and Sun. Total serum Ang2 (bound plus free) increased with
CVX treatment. Of the 34 patients, 24 (71%) remained on study � 8 weeks
and 2 patients continue on treatment � 9 months. Anti-drug antibodies
were seen in 16 patients at low titers without effects on PK or safety.
Conclusions: In pts with advanced disease, CVX is able to be combined at
the RP2D with Sun at its labeled dose without exacerbation of Sunassociated
toxicities. Combination trials of CVX and other VEGF inhibitors
are planned.
Dose levels evaluated.
Dose level CVX-060 mg/kg/wk Sunitinib mg/d x 4/6 wks Pts
1.0 6.0 50.0 6
1.1 6.0 37.5 3
1.2 6.0 50.0 6
2.0 12.0 50.0 3
3.0 15.0 50.0 16
3034 General Poster Session (Board #11H), Mon, 8:00 AM-12:00 PM
A phase Ib dose-escalation study of TRC105 in combination with bevacizumab
for advanced solid tumors. Presenting Author: David S. Mendelson,
Pinnacle Oncology Hematology, Scottsdale, AZ
Background: CD105 (endoglin) is an endothelial cell membrane receptor
highly expressed on angiogenic tumor vessels that is essential for angiogenesis
and upregulated by hypoxia and VEGF inhibition. TRC105 is a
human/mouse chimeric anti-CD105 monoclonal antibody that completed
phase I testing and is being studied in multiple phase II trials. Methods: Pts
with advanced solid tumors (non-CNS), ECOG PS 0-1, and normal organ
function were treated with escalating doses of intravenously administered
TRC105 plus bevacizumab (BEV) at 15 mg/kg q3wk or 10 mg/kg q2wk and
assessed for safety, PK, and response. Results: Twelve pts were treated (3
with TRC105 at 3 mg/kg q1wk � BEV at 15 mg/kg q3wk, 5 with TRC105 at
6 mg/kg q1wk � BEV at 15 mg/kg q3wk, and 4 with TRC105 at 6 mg/kg
q1wk � BEV at 10 mg/kg q2wk), and 10 have completed the DLT
evaluation period. TRC105 at 6 mg/kg q1wk � BEV at 15 mg/kg q3wk
resulted in grade 1-3 headaches with sinus congestion following the cycle 1
day 1 (C1D1) dose in 5 of 5 pts that improved with continued dosing.
Treatment with BEV 10 mg/kg q2wk and sequential dosing with Bev
starting on C1D1 and TRC105 on C1D8 resulted in decreased frequency
and severity of headaches, allowing dose escalation to continue. TRC105
serum concentrations that saturate CD105 binding sites (�200 ng/mL)
were achieved continuously at 6 mg/kg q1wk. At 3 mg/kg q1wk TRC105 �
15 mg/kg q3wk BEV, one pt with BEV-resistant ovarian cancer had stable
disease for 6 cycles and one pt with refractory hepatocellular cancer who
failed sorafenib and sunitinib had an AFP decrease from 1578 at baseline
to 179 at the end of cycle 3. Two of three evaluable pts at 6 mg/kg q1wk
TRC105 � 15 mg/kg q3wk BEV with VEGF-refractory tumors (HCC and
CRC) are ongoing in C4 with stable disease. Dose escalation continues and
TRC105 dose levels of 8 and 10 mg/kg are planned. Conclusions: The
combination of TRC105 and BEV was tolerated with early evidence of
activity in VEGF-refractory pts by sequential administration during initial
dosing in C1.
Developmental Therapeutics—Experimental Therapeutics
181s
3033 Poster Discussion Session (Board #25), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
NKP-1339: Maximum tolerated dose defined for first-in-human GRP78
targeted agent. Presenting Author: Dana Shelton Thompson, Sarah Cannon
Research Institute/Tennessee Oncology, PLLC, Nashville, TN
Background: NKP-1339 is a first-in-class small molecule anti-cancer
compound that down-regulates GRP78, a key regulator of misfolded
protein processing and tumor survival/anti-apoptosis. GRP78 up-regulation
occurs in many tumors, and is associated with intrinsic and chemotherapyinduced
resistance. Preclinically, single agent NKP-1339 demonstrates
activity against multiple tumor types, including chemoresistant lines. This
phase I trial evaluates the safety, tolerability, maximum tolerated dose
(MTD), pharmacokinetics, and pharmacodynamics (PD) of NKP-1339.
Methods: Patients (pts) with advanced solid tumors, adequate organ
function, ECOG 0-1 are enrolled. NKP-1339 is infused on day 1, 8, and 15
of 28 day cycles. Single pt cohorts are enrolled until grade 2 toxicity, then
adjusted to standard 3�3 design. Doses from 20-780 mg/m2 are evaluated.
PD samples for plasma GRP78 are collected. At MTD, an expanded
cohort of 25 pts is enrolled. Results: 34 pts are enrolled for dose escalation:
30 evaluable for dose determination; 4 replaced due to tumor progression
in cycle 1. Demographics: 19M/15F; median age 62 yrs (range 28 to 79).
Tumor types: colorectal (CRC, 10), non-small cell lung (NSCLC, 8);
neuroendocrine (NET, 5); head and neck (H&N, 3); and other cancer (8).
Dose limiting toxicity of grade (gr) 2-3 nausea, with gr 2 creatinine in 1 pt,
occurred at 780 mg/m2 ; MTD is 625 mg/m2 . Gr 1 fever/chills is observed
above 420 mg/m2 , but is prevented by steroid premedication. The most
common drug-related events are gr 1 nausea, gr 1-2 vomiting, and gr 1-2
fatigue. No lab abnormalities were noted except reversible creatinine
elevation in 4 pts: 3 pt with gr 1; 1 pt with gr 2 secondary to DLT. Partial
response was in 1 pt (NET); stable disease in 7 pts, including NET (2),
NSCLC (2), CRC (1), sarcoma (1), and unknown primary (1). Therapy
duration 14�-88� weeks. Soluble GRP78 is detected in the plasma of
patients at baseline. Conclusions: NKP-1339is well tolerated with manageable
side effects. Single agent activity is noted in multiple tumors including
NET. Results from the expanded cohort and pre/post-therapy PD will be
presented. Phase II single agent NKP-1339 and phase I NKP-1339
combination trials are planned.
3035 General Poster Session (Board #12A), Mon, 8:00 AM-12:00 PM
The effect of bevacizumab on targeting of anti-epidermal growth factor
receptor and anti-insulin-like growth factor 1 receptor antibodies. Presenting
Author: Sandra Heskamp, Department of Medical Oncology, Radboud
University Nijmegen Medical Centre, Nijmegen, Netherlands
Background: Bevacizumab and cetuximab are approved antibodies for
treatment of patients with metastasized colorectal cancer. However, the
combination of bevacizumab and cetuximab does not improve progression
free survival (Tol et al. NEJM 2009). This may be explained by the
disruption of tumor vascularity by bevacizumab, thereby reducing targeting
of other antibodies to the tumor. The aim of this study was to determine the
effect of bevacizumab on the targeting of anti-EGFR and IGF-1R antibodies
in tumors with SPECT/CT imaging. Methods: Mice with subcutaneous EGFR
and IGF-1R-expressing SUM149 xenografts were injected intraperitoneally
with a single dose of bevacizumab (10 mg/kg). After four days, mice
received an intravenous injection of 17 MBq 111In-labeled cetuximab, an
anti-EGFR antibody, or R1507, an anti-IGF-1R antibody. A control group
was injected with labeled hLL2 anti-CD22, an irrelevant IgG . Three days
after injection, SPECT/CT images were acquired and mice were dissected
for ex vivo biodistribution. Tumors were analyzed immunohistochemically
to determine vascular density (CD34), EGFR and IGF-1R expression.
Results: SPECT imaging revealed that bevacizumab treatment reduced
targeting of anti-EGFR and anti-IGF-1R antibodies by 42% and 35%,
respectively. Ex vivo biodistribution showed that uptake of 111In-cetuximab in untreated tumors was 35.2 � 1.6 %ID/g, compared with 19.7 � 5.3
%ID/g for bevacizumab treated tumors (p � 0.009). A similar effect was
observed for 111In-R1507 (control: 26.7 � 2.8 %ID/g, bevacizumab:18.9
� 2.8 %ID/g, p �0.009). No significant differences in tumor uptake were
observed in mice that received the irrelevant IgG. Immunohistochemical
analysis showed that vascular density decreased with 40%, while EGFR
and IGF-1R expression was unaltered. Conclusions: Bevacizumab treatment
can significantly reduce targeting of other antibodies to tumors. This
underlines the importance of timing and sequencing of bevacizumab
therapy in combination with other antibodies.
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