Annual Meeting Proceedings Part 1 - American Society of Clinical ...
Annual Meeting Proceedings Part 1 - American Society of Clinical ...
Annual Meeting Proceedings Part 1 - American Society of Clinical ...
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Developmental Therapeutics—<strong>Clinical</strong> Pharmacology and Immunotherapy<br />
2553 General Poster Session (Board #3B), Mon, 8:00 AM-12:00 PM<br />
Phase I pharmacokinetic (PK) and pharmacodynamic (PD) study <strong>of</strong><br />
intravenous dimethane sulfonate (DMS612, NSC 281612) in advanced<br />
malignancies. Presenting Author: Susan Elaine Bates, Center for Cancer<br />
Research, National Cancer Institute, Bethesda, MD<br />
Background: DMS612 is a dimethane sulfonate compound that was<br />
identified as preferentially cytotoxic to renal cell carcinoma (RCC) cell lines<br />
in a chemical screen <strong>of</strong> the NCI-60 panel. DMS612 has bifunctional<br />
alkylating activity in vitro. Objectives <strong>of</strong> this first-in-human phase I study<br />
included determining the dose-limiting toxicity (DLT), maximum tolerated<br />
dose (MTD), recommended phase 2 dose (RP2D), PK and PD <strong>of</strong> DMS612<br />
administered by 10 minute intravenous infusion on day 1, 8 and 15 <strong>of</strong> a 28<br />
day cycle. Methods: Eligibility criteria included adults with advanced solid<br />
malignancies or lymphoma with ECOG performance status 0-2, life<br />
expectancy � 3 months and adequate organ and marrow function. Patients<br />
were enrolled using a standard “3�3” dose escalation scheme. Plasma PK<br />
<strong>of</strong> DMS612 and metabolites was assessed by LC-MS/MS. DNA damage PD<br />
was assessed by �-H2AX immun<strong>of</strong>luorescence. Results: 35 subjects were<br />
enrolled (22 male, 13 female) with median age 59 years (41-75). Tumor<br />
types included colorectal (8), RCC (4), cervix (2), and urothelial (2). Doses<br />
administered were 1.5, 3, 5, 7, 9 and 12 mg/m2 . The MTD was determined<br />
to be 9 mg/m2 , with only one DLT <strong>of</strong> grade 4 thrombocytopenia in 12<br />
subjects enrolled. The maximum administered dose <strong>of</strong> 12 mg/m2 was<br />
considered to be intolerable after 1 <strong>of</strong> 3 subjects had grade 4 neutropenia<br />
and 1 had prolonged grade 3 thrombocytopenia. Prolonged thrombocytopenia<br />
in later cycles was observed in other subjects, including one patient<br />
naïve to prior cytotoxic chemotherapy. One subject with RCC had a<br />
confirmed partial response at 7 mg/m2 . DMS612 was rapidly converted into<br />
carboxy, chloroethyl and hydroxyethyl analogues and their glucuronides,<br />
some <strong>of</strong> which retained alkylating activity in vitro. Dose-dependent pharmacodynamic<br />
evidence <strong>of</strong> DNA damage induced by DMS612 in vivo was<br />
observed by �-H2AX immun<strong>of</strong>luorescance in both peripheral blood lymphocytes<br />
and plucked scalp hairs. Conclusions: The MTD <strong>of</strong> DMS12 administered<br />
by intravenous infusion on day 1, 8 and 15 <strong>of</strong> a 28-day cycle was 9<br />
mg/m2 . Pre-clinical and clinical observations suggest that further study <strong>of</strong><br />
DMS612 in RCC is warranted.<br />
2555 General Poster Session (Board #3D), Mon, 8:00 AM-12:00 PM<br />
Phase I development <strong>of</strong> a weekly dosing schedule for the oral taxane<br />
tesetaxel. Presenting Author: Amy Lang, South Texas Accelerated Research<br />
Therapeutics, LLC, San Antonio, TX<br />
Background: Tesetaxel (TST) has anticancer activity in patients (pts) with<br />
metastatic breast cancer (MBC) and gastric cancer when administered<br />
orally once every 3 weeks (Q3W). This drug is not a Pgp substrate, does not<br />
cause hypersensitivity reactions, and may be associated with less neurotoxicity.<br />
The maximally tolerated dose (MTD) on the Q3W schedule is 27<br />
mg/m2 , and neutropenia is dose-limiting. Since taxane activity may be<br />
schedule-dependent, we conducted a weekly, dose-ranging, and PK evaluation<br />
<strong>of</strong> TST. Methods: Eligibility: advanced solid tumors; ECOG PS 0-2;<br />
adequate organ function. TST was given once weekly for 3 weeks in a<br />
28-day cycle, beginning at a total flat dose <strong>of</strong> 25 mg/cycle with progressive<br />
increases in total dose up to 75 mg/cycle. Subsequently, dosing was<br />
converted to a weight-based regimen at weekly doses <strong>of</strong> 12.5, 15, and 17.5<br />
mg/m2 (i.e., total per cycle dose up to 52.5 mg/m2 ). Serial plasma samples<br />
were assayed by HPLC. Results: 26 pts were treated in 8 dose cohorts. The<br />
MTD was 15 mg/m2 /wk (total cycle dose, 45 mg/m2 ). With repeated cycles,<br />
constitutional symptoms (fatigue and anorexia) rather than neutropenia<br />
proved dose-limiting at 17.5 mg/m2 /wk. Only 1 pt (at 12.5 mg/m2 /wk)<br />
developed grade 3 neutropenia; no other episodes <strong>of</strong> Grade 3-4 myelotoxicity<br />
were observed. One pt with MBC (who had progressed after 2 prior<br />
taxane regimens) achieved a PR; 1 pt with prostate cancer has maintained<br />
prolonged reduction <strong>of</strong> PSA (� 57%). PK analyses showed low but<br />
progressive increases in trough TST concentrations (0.4–4.6 nmol/mL) 7<br />
days after each succeeding dose, which was consistent with the prolonged<br />
T½ <strong>of</strong> this drug (~180 hrs). There was no substantial drug accumulation<br />
over multiple cycles. Conclusions: Weekly oral TST is safe, provides<br />
long-term low-level drug exposure, and increases the total delivered dose<br />
over 12 wks by 25%. Interestingly, this regimen is not associated with<br />
significant myelosuppression. Thus, weekly TST dosing provides a highly<br />
convenient, “dose-dense”, taxane regimen that is not associated with<br />
neutropenia, which should facilitate its integration into multiple chemotherapy<br />
regimens. An ongoing study is evaluating efficacy <strong>of</strong> weekly TST<br />
dosing in MBC.<br />
155s<br />
2554 General Poster Session (Board #3C), Mon, 8:00 AM-12:00 PM<br />
Phase I and pharmacokinetic (PK)/pharmacodynamic (PD) study <strong>of</strong><br />
LY2334737, an oral gemcitabine prodrug, in patients (pts) with advanced<br />
solid tumors. Presenting Author: Sandrine J. Faivre, Department <strong>of</strong> Medical<br />
Oncology, Beaujon University Hospital, Clichy, France<br />
Background: LY2334737 is a valproic acid-bound carboxylesterasesubstrate<br />
prodrug <strong>of</strong> gemcitabine that can be given orally. The primary<br />
objective was to define the recommended phase II doses and schedules<br />
(sch) <strong>of</strong> administration <strong>of</strong> LY2334737 in 28-day cycles. Methods: Eligible<br />
pts (ECOG�2) had adequate hematologic, renal, and hepatic functions. In<br />
sch-A, LY2334737 was given every other day for 21 days. In sch-B,<br />
LY2334737 was given daily every other week. Dose escalation (3�3) was<br />
based on CTCAE V3 toxicities. Secondary objectives were PKs (LY2334737,<br />
dFdC, dFdU), PD biomarkers (dFdC DNA incorporation, Cytokeratin 18 -<br />
M30), and antitumor activity. Results: 57 pts (38 males, 19 females,<br />
median age 60 yrs) were treated using 7 dose-levels (40–100 mg/day). Pts<br />
received a median <strong>of</strong> 2 cycles. Dose limiting toxicities (DLTs) at cycle 1<br />
(any dose level) consisted <strong>of</strong> diarrhea (2pt), AST elevation (1pt), lower<br />
extremity edema (1pt), QTC prolongation (1pt), and general deterioration<br />
(1pt). A total <strong>of</strong> 2/7pts treated with 100mg in sch-A and 1/4pts treated with<br />
90mg in sch-B had DLTs. During dose escalation most frequent toxicities<br />
were 1) Sch-A (28 pts): nausea (10pts), pyrexia (9pts), vomiting (8pts),<br />
mucositis (6pts), anorexia (6pts), ALT elevation (5pts), asthenia (5pts),<br />
anemia (5pts), fatigue (4pts), chills (4pts), and lymphopenia (4pts). 2)<br />
Sch-B (29 pts): pyrexia (13pts), nausea (8pts), diarrhea (6pts), vomiting<br />
(5pts), chills (6pts), anemia (5pts), asthenia (6pts), AST elevation (6pts),<br />
ALT elevation (5pts), and fatigue (4pts). Nine pts had stable disease (3pts<br />
completed �6 cycles). PKs showed a dose-proportional increase in<br />
exposure <strong>of</strong> LY2334737 and dFdC with no accumulation after repeated<br />
dosing. dFdC is detected in the DNA <strong>of</strong> peripheral blood mononuclear cells<br />
(increasing amount with dose and over time after repeated cycle). In sch-A,<br />
we observed a significant increase in cytokeratin 18 M30 relative to<br />
baseline. Conclusions: LY2334737 displayed linear PK and acceptable<br />
safety pr<strong>of</strong>ile in both schedules. The dose <strong>of</strong> 90mg given every other day is<br />
the recommended dose for phase II trials with LY2334737 (dose expansion<br />
is ongoing).<br />
2556 General Poster Session (Board #3E), Mon, 8:00 AM-12:00 PM<br />
Effect <strong>of</strong> dexrazoxane on doxorubicin-induced testicular toxicity. Presenting<br />
Author: Irit Ben-Aharon, David<strong>of</strong>f Center, Rabin Medical Center, Petach<br />
Tikva, Israel<br />
Background: Seminal advances in anti-cancer therapy result in growing<br />
numbers <strong>of</strong> young male cancer survivors for whom treatment-induced<br />
infertility represents a major late-term concern. Doxorubicin (DXR) has<br />
been previously shown to exert toxic effect on the testicular germinal<br />
epithelium. Based upon the cardioprotective traits <strong>of</strong> dexrazoxane (DEX),<br />
we aimed to study its potential effect to reduce DXR-induced testicular<br />
toxicity. Methods: Male mice were injected intraperitoneally with 5mg/kg<br />
DXR or 100mg/kg DEX or the combination <strong>of</strong> both and scarified at one<br />
month post treatment. Saline-injected mice served as controls. Testes were<br />
excised, weighed and further processed. For oxidative stress determination<br />
glutathione assay was performed on testes’ lysates and P38 protein levels<br />
were determined by western blot analysis. Bax levels were used to assess<br />
apoptosis. Immunohistochemistry and confocal microscopy were used to<br />
study the effect <strong>of</strong> DXR, DEX and their combination, on the testis histology<br />
as well as on the spermatogonial reserve. Results: One month after DEX and<br />
DXR treatment, a striking decline in testicular weight was observed<br />
(decrease by 60% compared with control values; decrease <strong>of</strong> 54% in<br />
DXR-only treated mice; p�0.05). DEX prevented DXR-induced oxidative<br />
stress. However, DEX enhanced DXR-induced apoptosis within the testes<br />
and furthermore, the combination depleted the spermatogonial reserve one<br />
month after treatment. Conclusions: DEX activity in the testis may differ<br />
from its activity in cardiomyocytes. Adding DEX to DXR may exacerbate<br />
DXR-induced testicular toxicity.<br />
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