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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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