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

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