Uh Oh. Side effects. (Thanks to rick for linking to the abstracts.) aacr/eortc 2005. Cool PDF format.
A259 Sensitivity of Proto-Oncogene c-Kit Mutant Carrying Cells to Kinase
Inhibitor EXEL-0862. Taghi Manshouri,1 Hagop Kantarjian,1 Peter Lamb,2 Frances J.
Giles,1 Cem Akin,3 Jorge E. Cortes,1 Srdan Verstovsek.1 U.T. M.D. Anderson Cancer
Center,1 Houston, TX, Exelixis, Inc.,2 San Francisco, CA, University of Michigan,3 Ann
Arbor, MI.
Both stem cells and mast cells express the tyrosine kinase receptor c-kit and proliferate
after exposure to c-kit ligand. Oncogenic mutations of the c-kit receptor occur in
gastrointestinal stromal tumor (GIST), systemic mastocytosis (SM), and in some cases of
acute mylogenous leukemia (AML). Imatinib Mesylate (GLEEVEC) is a tyrosine kinase
inhibitor effective against juxtamembrane domain c-kit mutation found in GIST, but
lacks activity against SM and AML that harbors a mutation at tyrosine kinase domain.
EXEL-0862 is a novel inhibitor of c-kit tyrosine kinase. We examined, and compared
to imatinib, the growth inhibitory effect of EXEL-0862 against two mastocytosis cell
lines: HMC-1 (560) has a mutation in the juxtamembrane domain (Gly-560-Val), and
HMC-1 (560-816) has both mutation in juxtamembrane and tyrosine kinase domain
(Asp-816-Val). As expected, in 3-day MTS assay imatinib was able only to inhibit the
growth of HMC-1 (560) cells, with IC50 of 74 nM. In contrast, EXEL-0862 was effective
against both cell lines, and was more potent against cells carrying intracellular than the
cells with juxtamembrane domain mutation (IC50 of 353 versus 514 nM, respectively).
EXEL-0862 inhibited the phosphorylation of c-kit in HMC-1 (560-816) cells in dose dependent
manner. EXEL-0862 exerted its activity against mastocytosis cells by affecting
the cell cycle progression at G2/M level and induced apoptosis, as evidenced by an
increase in the mitochondrial membrane potential and caspase 3 activity, as well as an
increase in annexin V positivity. Finally, EXEL-0862 was able to decrease the survival
of mast cells obtained from bone marrows of patients with SM.
A261 A Phase 1 Dose-escalation and Pharmacokinetic (PK) Study of a Novel
Spectrum-selective Kinase Inhibitor (SSKI), XL647, in Patients with Advanced
Solid Malignancies. Heather Wakelee,1 Alex A. Adjei,2 Joanne Halsey,1 Janet Lensing,
2 Julia Dugay,1 Lorelei Hanson,2 Joel Reid,2 Sylvia Hutchison,1 Jill Piens,2 Branimir I.
Sikic.1 Stanford University,1 Stanford, CA, Mayo Clinic,2 Rochester, MN.
Background: XL647 is an orally bio-available small molecule inhibitor of multiple receptor
tyrosine kinases (RTKs) involved in tumor cell growth, angiogenesis, and metastasis,
including EGFR (erbB1), erbB2, VEGFR-2, and EphB4, currently under development
by Exelixis, Inc. Methods: Patients (pts) with advanced solid malignancies were
enrolled in successive cohorts to receive XL647 orally as a single dose on day 1 with
PK sampling, followed by 5 continuous daily doses starting on day 4 with additional
PK sampling. Pts then continued to receive dosing for 5 continuous days followed by
a break with cycles repeated every 14 days. Tumor imaging was done at baseline, after
the first 3 or 4 cycles and then after every 4 cycles. Pts with stable or improving
disease were allowed to stay on study. Results: A total of 28 pts have been treated
across 8 dose levels to date: 0.06, 0.12, 0.19, 0.28, 0.39, 0.78, 1.56, 3.12 mg/kg.
One subject at 3.12 had asymptomatic QTc prolongation on electrocardiogram. The
MTD has not yet been reached and dose escalation continues. Additional schedules
(continuous) are under investigation. Preliminary PK analysis indicate XL647 shows
approximately dose-proportional exposure with a mean time to maximal concentration
(Tmax) of approximately 6-9 hours, and an elimination half-life of approximately
70 hours. To date, 1 pt (NSCLC) from cohort 1 had a partial response and 7 others
(NSCLC-2, chordoma-2, adenoid cystic carcinoma, adrenocorticalcarcinoma, colorectal)
have had prolonged stable disease (> 3 months). Conclusions: XL647 has been
well tolerated with accrual to higher dose cohorts and exploration of additional schedules
ongoing.
C82 A Phase 1 Dose-escalation and Pharmacokinetic (PK) Study of a Novel
Spectrum Selective Kinase Inhibitor (SSKI), XL999, in Patients with Advanced
Solid Malignancies. Kyriakos P. Papadopoulos,1 Monica M. Mita,1 Janet Curtright,1
Afshin Dowlati,2 Susan Flick,2 Alejandro Ricart,1 Chris Takimoto,1 Harold Keer,3 Josh
Cooper.1 Institute for Drug Development,1 San Antonio, Texas, Case Western Reserve
Univ,2 Cleveland, Ohio, Exelixis Inc,3 San Francisco, California.
Background: XL999 is a small molecule inhibitor of multiple kinases involved in
tumor cell growth, angiogenesis, and metastasis, including VEGFR2 (KDR), PDGFR,
FGFR1, FLT-3, and SRC. In tumor cell culture, XL999 induces a cell-cycle block by a
mechanism distinct from those previously identified and exhibits broad antitumor activity
in xenograft models. Methods: Patients (pts) with advanced solid malignancies
were enrolled in successive cohorts to receive XL999 intravenously as a single 4 hour
infusion on day 1 with PK sampling. Real time PK evaluation, in concert with clinical
parameters, guided cohort dose escalation. If treatment was well tolerated, subjects
were eligible to receive further XL999 every 2 weeks in the absence of unacceptable
toxicity or disease progression. Disease reassessment by RECIST was performed every
8 weeks unless earlier evaluation was clinically indicated. Results: A total of 23 pts
have been treated across 6 dose levels to date: 0.2, 0.4, 0.8, 1.6, 3.2, and 6.4 mg/kg.
Both subjects treated at 6.4 mg/kg experienced hypertension and grade 3-4 elevations
in hepatic transaminases, one with fatal cardiogenic pulmonary edema and this was
determined to be the maximum administered dose. At 3.2 mg/kg side effects observed
included peri-infusion hypertension, perioral dyesthesias and dizzyness, and grade £ 2
elevation of hepatic transaminase values. In general toxicities resolved within 24 hours
excepting transaminase changes. One patient required prophylactic antihypertensive
therapy prior to XL999 dosing. Further evaluation of dose and schedule is ongoing.
Preliminary PK analyses show dose proportionality across all levels. Cmax at 3.2 mg/kg
is approximately 400 ng/mL, with an average AUCinf of ~3450 hr*ng/mL. The approximate
CL and Vss for the 22 patients with evaluable PK parameters were 60L/hr (range,
27-207 L/hr) and 1600 L (range, 600-4300 L) respectively and appeared to be independent
of dose. Elimination is linear with an elimination half-life for all dose levels of
~24 hours (range, 12-42 hours). In 22 evaluable pts who to date have been followed
for 8 or more weeks, there have been 2 PRs ( 1 unconfirmed), 1 minor response (28%
reduction), and 4 subjects with stable disease for 3 - 7 months. Conclusions: A single
dose of XL999 at 3.2 mg/kg was generally well tolerated. When administered every 2
weeks, XL999 demonstrated preliminary evidence of clinical activity with no cumulative
toxicities. Based on safety and PK data, a weekly dosing schedule is being explored.
__________________________
___________________________
(Co already said 647 and 999--from its POV--are headed for P2.) |
