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

180s Developmental Therapeutics—Experimental Therapeutics
3028 Poster Discussion Session (Board #20), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
First-in-human phase I study: Results of a second-generation nonansamycin
heat shock protein 90 (HSP90) inhibitor AT13387 in refractory
solid tumors. Presenting Author: Daruka Mahadevan, Arizona Cancer
Center, Tucson, AZ
Background: AT13387 is a second-generation potent, novel non-ansamycin
HSP90 inhibitor (IC50 0.71 nM). AT13387 has good tissue distribution,
long tumor t1/2 resulting in extended knockdown of client proteins in cells
and animal models of gastric, prostate and melanoma. Methods: AT13387
was administered as a 1-hr IV infusion twice weekly on Days 1, 4, 8, 11, 15
and 18 (Part A) and then subsequently, weekly on Days 1, 8 and 15 (Part B)
of a 28-day cycle in a standard 3�3 dose-escalation design. The primary
endpoint was to determine the MTD; secondary endpoints included PK, PD,
safety and tolerability. Results: As of 1 Dec 2011, 53 patients received
1–12 cycles of AT13387 (median 2). In Part A, AT13387 was evaluated at
5 doses (10, 20, 40, 80, 120 mg/m2 ). In Part B, 4 additional doses (150,
220, 260 and 310 mg/m2 ) were explored. Common treatment related
toxicities (� 10%) included transient and reversible GI disturbance
(vomiting, nausea, dry mouth, diarrhea, abdominal pain), fatigue, local
infusion site irritation and systemic infusion-related symptoms including
chills, rash, itch, cardiovascular (tachycardia, bradycardia, hypertension,
hypotension), and visual changes (diplopia, transient flashes, delayed
light/dark accommodation, blurred vision). Severity of infusion-related
symptoms, GI toxicities, and fatigue at 310 mg/m2 prevented further dose
escalation. A dose of 260 mg/m2 has been identified as the once weekly
MTD and the study is currently accruing at this dose. Biological evidence of
HSP90 inhibition, demonstrated by an increase in HSP70 in PBMCs, was
detected at all doses and exhibited evidence of dose dependence. PK
demonstrated dose proportionality, without significant accumulation. One
durable RECIST PR (8 months) in an imatinib relapsed metastatic GIST
patient with c-kit mutations in exons 11 and 17 was observed. Three SD �
6 months (follicular cell thyroid carcinoma, metastatic uveal melanoma,
GIST) were also observed. Conclusions: The MTD of AT13387, administered
as a once weekly IV, is 260 mg/m2 . All drug-related toxicities were
generally reversible. Single-agent activity was observed. Dose expansion at
MTD and phase II studies are ongoing.
3030 Poster Discussion Session (Board #22), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Phase I dose-finding study of golvatinib (E7050), a c-Met and Eph receptor
targeted multi-kinase inhibitor, administered orally QD to patients with
advanced solid tumors. Presenting Author: Gennaro Daniele, Royal Marsden
Hospital and Institute of Cancer Research, Sutton, United Kingdom
Background: Golvatinib is a highly potent, small molecule ATP-competitive
inhibitor of the c-Met receptor tyrosine kinase and multiple members of the
Eph receptor family as well as c-Kit and Ron, based on isolated kinase
assays. Golvatinib showed preclinical evidence of anti-tumor activity. This
phase 1 study was performed to determine the MTD, safety, PK, PD and
preliminary activity of golvatinib. Methods: Patients (pts) with advanced
solid tumors, ECOG PS 0-1, � 18 years (yrs) and adequate organ function
were eligible. Golvatinib was administered orally, once daily (QD), continuously.
Blood samples for PK and PD analysis were collected at multiple
time-points. Mandatory tumor biopsies for PD analysis were taken pre and
post Cycle 1 in an expanded MTD cohort. Results: 34 pts (M/F: 21/13;
median age 63.5yrs [range 32-78]) were treated at 6 dose levels: 100,
200, 270, 360, 450 and 400 mg. Tumor types were colorectal (n�15),
lung (n�4), renal (n�4), esophageal (n�2), melanoma (n�2) and others
(n�7). Three DLTs were observed: Gr3 GGT and alkaline phosphatase
(n�1; 200mg) and repeated Gr2 (n�1) and Gr3 (n�1) fatigue, both at
450mg. The MTD was determined to be 400 mg QD. Frequently occurring
adverse events ([AEs]; all grades) were fatigue: 68% (Gr3: 15%), diarrhea:
65%, nausea: 62%, vomiting: 53%, decreased appetite: 47% (Gr3: 9%),
ALT increase: 38% and AST increase: 23%. No Gr4 AEs were observed.
Best response was stable disease in 6 pts lasting �84 days. PK showed
high variability and plasma concentration increased with dose. The Cmax was reached within a median time of 4 hours. Plasma PD analysis showed
an increase in soluble c-Met and Ang 2 levels after golvatinib treatment.
Tumor PD analysis in 5 pts at 400 mg demonstrated a baseline elevated
MET gene copy number, with c-Met overexpression and post treatment
decline in phospho(p)-c-Met expression in 1 pt; post-treatment decline in
p-c-Met in a 2nd pt, and post-treatment decline in p-ERK in a 3rd pt.
Conclusions: Golvatinib at an MTD of 400 mg QD has manageable toxicity.
Preliminary PD analysis demonstrated evidence of c-Met target modulation.
Further evaluation will continue in phase 2 combination studies.
3029 Poster Discussion Session (Board #21), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Clinical pharmacokinetics of the Smac-mimetic birinapant (TL32711) as a
single agent and in combination with multiple chemotherapy regimens.
Presenting Author: Gerald J. Fetterly, Roswell Park Cancer Institute,
Buffalo, NY
Background: Birinapant is a novel small molecule Smac-mimetic that
targets members of the inhibitor of apoptosis proteins (cIAP1, cIAP2 and
XIAP) involved in the blockade of apoptosis. A population PK model was
developed to characterize the interpatient variability in birinapant PK and
to evaluate the effect of multiple combination regimens on birinapant
disposition and safety. Methods: Birinapant was administered alone or in
combination to 114 patients (55M/59F; 89% Caucasian) with advanced
malignancies. Birinapant was administrated by a 30 min IV infusion QW
alone (30 pats), or approx. 30 min. after chemotherapy with irinotecan (19
pats), docetaxel (20 pats), gemcitabine (17 pats), liposomal doxorubicin
(13 pats), or paclitaxel/carboplatin (15 pats). Birinapant dose levels ranged
from 0.18 to 35 mg/m2 . Population PK modeling was performed to
investigate the effect of the following patient covariates: [BW (38.5-127.5
kg), age (27.5-86.0 yrs), CrCL (36.4-219.2 ml/min), ALT (6-121 IU/L),
and TBIL (0.1-1.7 mg/dL)]. Results: A 3-compartment PK model described
the time course of birinapant disposition with predicted values for T1/2,
CL, and Vd of 40 h, 21 L/h and 10.2 L, respectively. Birinapant displayed
linear PK across the dose range with no significant accumulation in plasma
following weekly dosing. Goodness of fit plots supported the model fit, with
residual variability of 23%. The PK of birinapant remained unchanged
when combined with irinotecan, docetaxel, gemcitabine and liposomal
doxorubicin. Concomitant administration with paclitaxel/carboplatin resulted
in a 2-fold increase in birinapant AUC possibly due to reduced
OATP1B3 mediated tissue uptake. Conclusions: These data show that
birinapant possesses an excellent PK profile with dose proportional
kinetics, a long terminal half-life for target coverage, low/moderate interpatient
variability in CL and no significant accumulation following weekly
dosing. Importantly, the PK of birinapant remained unchanged when
combined with multiple chemotherapy regimens and the increased exposure
with paclitaxel/carboplatin was not associated with any change in
birinapant tolerability.
3031 Poster Discussion Session (Board #23), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Proof of mechanism (POM) in the first-in-human trial of two novel
indenoisoquinoline, non-camptothecin topoisomerase I (TOP1) inhibitors.
Presenting Author: James H. Doroshow, Division of Cancer Treatment and
Diagnosis, National Cancer Institute, Bethesda, MD
Background: Indenoisoquinolines LMP 400 and LMP 776 form stable
DNA-top1 cleavage complexes, have a preference for unique DNA cleavage
sites, and are not substrates for ABC transporters compared to camptothecins.
We conducted a randomized phase I trial of LMP 400 and LMP 776
in patients (pts) with refractory tumors to establish safety and MTD of LMP
400 and LMP 776 administered IV daily x5d,q28d; determine PK;
evaluate TOP1 and �H2AX levels in tumor biopsies (bx); and compare
pharmacodynamic responses of LMP400 and LMP776. Methods: Pts had
refractory malignancies; � 18 yrs old; KPS � 70%; adequate organ
function. DLT: drug-related gr � 3 non-hem or gr 4 hem toxicities during
C1. Pts assigned to receive either LMP 400 or LMP 776. Dose level (DL) in
mg/m2 /day for LMP 776: 1, 2, 3, 4.5 mg; LMP 400: 2.5, 5, 10, 20, 40,
80. Accelerated titration design with one pt per dose level (DL), 100% dose
escalation until one DLT or 2 gr 2 toxicities, then 3�3 design. Tumor bx
and circulating tumor cells (CTCs) were obtained at baseline and C1D3.
Results: Twenty pts accrued to date [LMP 400 (11 pts); LMP 776 (9 pts)];
M/F 7/13; median age 59 (range 32-71 yrs); diagnosis (# of pts): colorectal
(10), vaginal adenocarcinoma (1), head and neck (2), bladder (1),
melanoma (1), pancreas (1), thyroid (1), small cell lung (1), sarcoma (1),
lymphoma (1). DLTs: LMP 400- gr 4 myelosuppression, gr 3 fatigue at DL
6; DL 5 expanded to establish MTD; LMP 776 (DL2)- gr 4 hypercalcemia,
no other DLTs, dose escalation continuing. One pt with irinotecanrefractory
colon cancer had shrinkage of lung nodules post one cycle of
LMP 400. Relative to baseline, 5 of 6 tumor bx demonstrated 20-50%
reduction in TOP1 levels (LMP 776); an increase in �H2AX foci in tumor
was observed in 2/6 LMP 776 and 1/1 LMP 400 pts. An increase in �H2AX
was also observed in hair bulbs (3/3 pts) and CTCs (9/20 pts). PK for LMP
400 and LMP 776: mean T1/2 48 and 36 h; Cl 1.5 and 2.0 L/h/m2 ;Vc30
and 31 L/m2 , respectively. Conclusions: POM, as assessed by reduction in
TOP 1 levels and increase in �H2AX in tumor and CTCs, and preliminary
evidence of activity, has been demonstrated in this first-in-human trial of
indenoisoquinoline-class of TOP1 inhibitors. Accrual is ongoing.
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