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

192s Developmental Therapeutics—Experimental Therapeutics
3076 General Poster Session (Board #17B), Mon, 8:00 AM-12:00 PM
A phase I study of HM781-36B, a novel pan-HER inhibitor, in patients (pts)
with advanced solid tumors. Presenting Author: Tae Min Kim, Department
of Internal Medicine, Seoul National University Hospital, Seoul, South
Korea
Background: HM781-36B is a pan-HER tyrosine kinase inhibitor, which
showed a potent activity against the gefitinib- or erlotinib-resistant, EGFR
L858R/T790M double mutant cells. A phase I study was conducted to
determine the MTD, pharmacokinetics, and antitumor activity. Methods:
Eligible pts had advanced malignancies refractory to standard therapies.
Standard 3�3 scheme was used in the dose escalation part, and additional
12 pts were enrolled in the expansion cohort of molecular enrichment.
Results: In dose-escalation part, 43 pts (median age: 55 yrs (range 25-82),
M:F�25:18, ECOG PS 0/1/2/3: 23/17/2/1, median prior chemotherapy: 4)
were treated. DLTs were G3 diarrheas in 5 pts, one at 12 mg, 16 mg, 24
mg, and two at 32 mg. The MTD was determined as 24mg. The most
common drug-related adverse events were diarrhea, stomatitis, rash,
pruritus, and anorexia. Among 41 evaluable pts, 4 pts achieved PR (1
unconfirmed, duration of response: 11.9 mo, 7.07 mo�, 4.5 mo�), and
19 pts had SD. Two of 4 PR pts were Her2-positive breast cancer pts. The
median duration of treatment in pts with PR or SD was 3.87 (2.47- 15.17)
months. In the dose range of 0.5 to 24 mg, it showed linear pharmacokinetics
proportional to dose-escalation, relatively short half-life, and little
accumulation. Additional 12 pts in the expansion cohort are under
treatment at 24 mg (6 pts: EGFR-mutant NSCLC, 3 pts: Her2-positive
gastric cancer, 2 pts: Her2-positive breast cancer, 1 pt: rectal cancer).
Conclusions: HM781-36B was safe and well tolerable in advanced solid
tumors. Preliminary evidence of anticancer activity has been observed.
Updated data will be presented at the meeting.
3078 General Poster Session (Board #17D), Mon, 8:00 AM-12:00 PM
Phase I pharmacokinetic study of dasatinib (BMS-354825) in patients
with advanced malignancies and varying levels of liver dysfunction: S0711,
a SWOG early therapeutics committee study. Presenting Author: John
Sarantopoulos, Institute for Drug Development, Cancer Therapy and
Research Center, University of Texas Health Science Center San Antonio,
San Antonio, TX
Background: Dasatinib (D) is a first in class Src kinase inhibitor, and inhibits
BCR-Abl, c-Kit, PDGFR-beta, EPHA2 and Src family kinases including Src,
Lck, Yes, Fyn at nanomolar concentrations. Initially FDA approved for use
in imatinib resistant CML. It is a small molecule targeted therapy
hepatically metabolized primarily by CYP3A4. We conducted a phase I
study to determine maximum tolerated dose (MTD) and pharmacokinetics
(PK) of D in patients (pts) with liver dysfunction (LD). Methods: Pts with
advanced solid tumors or lymphoma, Zubrod �2, no baseline ascites or
pleural effusions, adequate renal and bone marrow function, received PO D
daily. Cycles q28 days. Pts stratified into 4 LD groups: normal, mild,
moderate, severe, using Child-Pugh classification (CPC). Data also collected
for NCI ODWG Organ Dysfunction Working GroupCriteria. D dose was
escalated in sequential cohorts of pts within each LD category. Blood
analysis for D concentrations were determined during cycle 1 using a
validated LC-MC/MS assay. Study objectives included characterizing safety,
tolerability, PK, identifying the MTD and obtaining preliminary evidence of
efficacy. Results: 54 registered pts, 51 pts received 51 cycles of D at doses
starting at 100 mg in mild LD (50-140 mg). Median age 60, male 55%,
Zubrod 1 70%. CRC 27%. Groups: normal-17, mild-20, moderate-13,
severe-1 pt(s). Related AEs include fatigue 35%, diarrhea 27%, anemia
27%, nausea 25%, vomiting 21%, lymphopenia 13%, rash 13%, pleural
effusion 8%. 1 DLT of increased CK in a pt in moderate LD with past history
of similar episode with previous sorafenib. Previous linear PK disposition,
and no accumulation. No apparent PK differences between normal and
mild groups. Cycle 1 Day 1 D 140 mg Normal Group: Cmax 129 ng/mL. Mild
Group 140mg: Cmax 157 ng/mL. Prolonged disease stabilization (�4
cycles) in 6 pts, 3 CRC (4,5,8); 1 Pancreas, HCC, Bladder (4,5,6).
Conclusions: Recommended dose for Dasatinib given PO QD for pts with
mild, moderate, or severe LD using clinical criteria with CPC and no
baseline ascites, are 140 mg, 70 mg, insufficient pts, respectively. Dose
adjustment not necessary in pts with mild LD.
3077 General Poster Session (Board #17C), Mon, 8:00 AM-12:00 PM
Tumor drug distribution and target engagement of MLN9708, an investigational
proteasome inhibitor, in patients with advanced solid tumors.
Presenting Author: Alessandra Di Bacco, Translational Medicine, Millennium
Pharmaceuticals, Inc., Cambridge, MA
Background: MLN9708 is a potent investigational proteasome inhibitor,
which upon intravenous (IV) administration immediately hydrolyzes to the
active form MLN2238. MLN9708 is currently being evaluated in a phase 1
trial in solid tumors (NCT00830869). This trial has a dose-escalation arm
and five expansion cohorts: non-small cell lung cancer (NSCLC), soft tissue
sarcoma, head and neck cancer, prostate cancer, and a tumor biopsy cohort
of mixed histology. The purpose of the tumor biopsy cohort was to obtain
pre- and post-dose biopsies to determine drug distribution and target
engagement in post-dose tumor samples. The latter was measured by the
increase in levels of ATF-3, a marker of unfolded protein response/
endoplasmic reticulum stress, which is upregulated in response to proteasome
inhibition. Methods: The tumor biopsy cohort included 20 patients
dosed at the maximum tolerated dose who consented to core needle
biopsies during screening and after either the first or second dose of
MLN9708 (IV 1.76 mg/m2 ; 4–20 hours post-dose). Tumor biopsies were
individually weighed, homogenized, and analyzed for the presence of
MLN2238 using a quantified LC/MS/MS methodology. ATF-3 levels in
tumors were determined by an immunohistochemical assay (IHC) on six
sections for each tumor biopsy. Tumor area was identified using Aperio
Genie, a machine learning program for pattern recognition, and the
percentage of ATF-3 positive area in the tumor was measured. Results:
Biopsies from 20 patients were collected for assessment of drug distribution
and target engagement. Ten patients with paired pre- and post-dose
biopsies of sufficient size were considered evaluable for PK analysis;
MLN2238 was present in all 10 (100%) post-dose biopsies analyzed.
Tumor pairs from 7 patients passed quality control by H&E staining for
tumor content and were evaluable for ATF-3 IHC. Six of 7 paired samples
(86%) showed a statistically significant (p�0.05) increase in post-dose
ATF-3 levels. Conclusions: Overall, emerging data from MLN9708 phase 1
solid tumor analysis show that MLN2238 is present in tumors and
demonstrates target engagement upon inhibition of the proteasome in
tumor tissue biopsies.
3079 General Poster Session (Board #17E), Mon, 8:00 AM-12:00 PM
Phase I dose-finding study of golvatinib (E7050), a c-Met and Eph receptor
targeted multi-kinase inhibitor, administered orally BID to patients with
advanced solid tumors. Presenting Author: Toshihiko Doi, National Cancer
Center Hospital East, Kashiwa, Japan
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 antiproliferative activity in human cancer
xenograft models, warranting further investigation in the clinical setting.
Methods: Japanese patients (pts) with advanced solid tumors that had
progressed after approved therapy received oral golvatinib at escalating
doses of 50 to 100, 200 and 300 mg administered twice daily (BID) in
conventional 3 pt cohorts. The primary objective was to determine the MTD
of golvatinib when administered continually BID. The secondary objectives
were to evaluate the safety, PK, PD biomarkers, and efficacy. Results: 16pts
were enrolled (8 M, 8 F; med age 59 years; ECOG 0-1). Tumor types were
colorectal (5), gastric (4) and others (7). One DLT (Gr 3 ALT increase) and 1
equivalent DLT (Gr 2 vomiting, nausea and anorexia) appeared in 2 pts in
the 300 mg BID cohort and the dose escalation was terminated. The MTD
was determined to be 200 mg BID. Frequently observed adverse drug
reactions were proteinuria [50.0% (8/16)], ALT increased [43.8% (7/16)],
AST increased, nausea, vomiting [37.5% (6/16)], and blood alkaline
phosphatase increased, decreased appetite, diarrhea, leukopenia [31.3%
(5/16)], which were all mild to moderate in severity with � Gr 2. No related
severe adverse event was observed. Responses included 4 stable diseases
(84-113 days) in 3 pts with gastric cancer and 1 patient with NSCLC, 11
progressive diseases, and 1 non evaluable. The golvatinib plasma concentration
after first-dose reached Cmax at a median time of 2 to 4 hours, and
declined bi-exponentially with a t½ of approximately 40 hours. Cmax and
AUC0-inf increased with dose. Analysis of blood PD biomarker showed a
significant increase in soluble c-Met levels after golvatinib treatment.
Conclusions: The MTD of golvatinib was achieved at 200 mg BID. Golvatinib
was well tolerated with manageable toxicities at dose levels up to and
including the MTD. 4 of 16 pts showed stable disease after golvatinib
treatment.
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