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Annals of Oncology
Conclusions: The combination of PM01183 and GEM seems feasible with an
acceptable safety profile below the MTD: PM01183 3.5 mg+ GEM 1000 mg/m 2 .RD
cohort expansion is currently ongoing. The combination is showing promising
anti-tumour activity. Updated results will be presented in the meeting.
Disclosure: A. Velasco: membership PharmaMar. A. Soto-Matos: PharmaMar
membership. S. Szyldergemajn: PharmaMar membership. All other authors have
declared no conflicts of interest.
485P CHALLENGE IN THE PHARMACOKINETIC EVALUATION OF
DTS-108, A NEW TOPOISOMERASE I INHIBITOR, IN
PATIENTS WITH ADVANCED CARCINOMAS
O. Mir 1 , S. Faivre 2 ,C.Dreyer 3 , R. Coriat 4 , M. Bouattour 3 , F. Goldwasser 5 ,
E. Raymond 3
1 Oncology Department, Teaching Hospital Cochin, AP-HPUniversit, Paris Cedex,
FRANCE, 2 Internal Medicine, Hopital Beaujon, Clichy, FRANCE, 3 Oncology
Department, Beaujon University Hospital, Clichy, FRANCE, 4 Oncology
Department, CHU Cochin, Paris, FRANCE, 5 Oncology, Cochin Hospital, Paris,
FRANCE
Background: DTS-108 is a soluble pro-drug of SN38, the active metabolite of
irinotecan, where the SN38 moiety is covalently linked to a 20AA peptide through a
specific cross-linker that releases SN38 by esterase bond cleavage. DTS-108 was
designed to achieve therapeutic levels of SN38, while reducing diarrhea.
Methods: SN-38 and SN-38G levels were evaluate with fluorescence HPLC test and
LC/MS/MS methods. The pharmacokinetics of DTS-108, the adverse event (AE)
profile, the dose limiting toxicities (DLT) at cycle 1, the maximum tolerated dose
(MTD), and the recommended phase II dose (RD) of intravenous DTS-108 (1-2
hours) every two weeks (q2w) in patients (pts) with advanced/metastatic carcinomas
was conducted.
Results: Forty-Two pts received DTS-108 across 14 dosing cohorts (range: 3-416mg/
m2). All grade AEs were asthenia (43%), nausea (43%), diarrhea (41%), vomiting
(33%), anemia (31%), rash (21%), anorexia (21%), alopecia (19%), abdominal pain
(19%), and neutropenia (19%). Neutropenia was the dose limiting toxicity of
DTS-108. Neutropenia started to be observed at doses >56 mg/m2. At 416 mg/m2, 3/
6 pts had grade 4 neutropenia. Fluorescence HPLC was initially used to quantify
DTS-108 and its metabolites (SN-38 and SN-38G). Sample stability analysis of this
method showed that SN38 values were inaccurate as DTS-108 degraded forming
ex-vivo SN-38 during the blood collection, plasma storage, and/or sample extraction.
New processes and analytical LC/MS/MS methods for testing SN-38 were
implemented. At the dose of 313 mg/m2, mean DTS-108, SN38, and SN38G
AUCINF (CV%) were 439293 (24%), 1992 (34%), and 4538 (46%) h*ng/mL. Tumor
stabilization (RECIST) was observed in 9 pts and confirmed in 6 pts.
Conclusions: SN-38 concentration using Fluorescence HPLC failed to monitor
drug escalation in topoisomerase I inhibitor because of ex vivo degradation. SN-38
exposures using LC/MS/MS methods are consistent with less variables values and
allow drug monitoring. DTS-108 induced no dose-limiting diarrhea but
neutropenia and infusion skin reactions. The dose level 313 mg/m2 was declared
the MTD based on 5 of the 6 patients treated at this dose level having no
dose-limiting neutropenia and the overall improvement in the management of
infusion réactions.
Disclosure: All authors have declared no conflicts of interest.
486P PHARMACOKINETICS (PK) AND SAFETY OF TESETAXEL, A
NOVEL ORAL TAXANE, IN JAPANESE PATIENTS (PTS) WITH
ADVANCED SOLID TUMORS
K. Tanaka 1 , T. Kurata 1 , Y. Fujisaka 2 , H. Kawakami 1 , H. Hayashi 1 , T. Cousin 3 ,
W. Okamoto 1 , T. Kudoh 1 ,T.Satoh 1 , K. Nakagawa 1
1 Medical Oncology, Kinki University School of Medicine, Osaka, JAPAN,
2 Medical Oncology, Kinki University Faculty of Medicine, Osaka, JAPAN, 3 Clinical
Operations, Genta Incorporated, Berkeley Heights, NJ, UNITED STATES OF
AMERICA
Background: Tesetaxel is an orally administered taxane that, unlike IV analogs, is
not a Pgp substrate (a primary mechanism of taxane resistance). This novel agent has
a long plasma T½ (∼180 h), allowing administration once every 3 weeks (Q3W).
Tesetaxel is particularly active in breast and gastric cancers, with response rates of
50% and 20%, respectively, in 1st-line metastatic breast and 2nd-line gastric cancer.
Among > 500 pts treated to date, no hypersensitivity reactions have occurred, and
neurotoxicity has been distinctly uncommon. In Western pts, the maximally
tolerated dose (MTD) of tesetaxel is 27 mg/m 2 Q3W, and neutropenia is dose
limiting. We conducted a phase I intersubject dose-escalation study to evaluate safety
and PK in Japanese pts.
Methods: Eligibility criteria included age ≥ 20 years, advanced or metastatic solid
tumors, ECOG PS ≤ 1, and adequate organ function. Tesetaxel 24 mg/m 2 was given
on day 1 of a 21-day cycle to the first cohort. The dose was escalated to 27 mg/m 2
and 31 mg/m 2 in successive cohorts absent dose-limiting toxicity (DLT). Serial blood
samples were obtained for PK analysis and assayed by HPLC.
Results: Twelve pts (9 men, 3 women; age 39-74 yr) were enrolled (3 each in the 24
and 31 mg/m 2 cohorts and 6 in the 27 mg/m 2 cohort). Most pts were heavily
pretreated; the median number of prior chemotherapy regimens was
4. Neutropenia ≥ grade 3 occurred in 1 pt in the 24 mg/m 2 and 27 mg/m 2 cohorts
and 2 pts in the 31 mg/m 2 cohort. DLT (febrile neutropenia) was observed in 1 pt at
the 31 mg/m 2 dose. Mean PK data (see table) were similar in Western and Japanese
pts, with an expected dose-dependent increase in exposure.
Dose level Patients (n) C max T max AUC 0-168 h
24 mg/m 2
27 mg/m 2
*31 mg/m 2
Western (11) 29.7 2.5 594
Japanese (3) 29.0 2.7 658
Western (7) 31.2 2.1 869
Japanese (3) †
46.6 4.7 818
Japanese (3) 57.0 2.0 1036
† Results of PK analyses for last 3 pts enrolled not yet available * Dose not studied in
Western pts
Conclusion: This study indicates that tolerability and PK of tesetaxel is similar in
Western and Japanese pts. Final data will be presented.
Disclosure: T. Cousin: I am an employee of Genta Incorporated, the company that is
developing tesetaxel. All other authors have declared no conflicts of interest.
487P CORRELATION OF INFUSION-RELATED REACTIONS (IRR)
AND OUTCOME IN PATIENTS RECEIVING NGR-HTNF
TREATMENT
G. Rossoni1 , V. Gregorc1 , A. Bulotta1 , M.G. Viganò1 , G. Todisco1 , A. Lambiase2 ,
C. Bordignon2 1 2
Oncologia, IRCCS San Raffaele, Milano, ITALY, Clinical Development, MolMed,
Milan, ITALY
Background: NGR-hTNF (asn-gly-arg-human tumor necrosis factor) induces
systemic release of cytokines and intratumoral infiltration of effector T cells.
Intravenous infusion of NGR-hTNF is characterized by onset of IRR, mostly
consisting of transient grade 1-2 chills. Incidence, predictors of development, and
relationships with outcome of IRR were assessed across 5 phase 2 single-arm trials of
NGR-hTNF.
Methods: 205 patients (pts) with solid tumors received NGR-hTNF 0.8 µg/m 2 every
3 weeks (q3w) given either alone in colon cancer (n = 45), liver cancer (n = 40), and
mesothelioma (n = 55), or with doxorubicin in small-cell lung cancer (n = 28) and
ovarian cancer (n = 37). Tumor assessment by RECIST was done q6w until
progressive disease (PD). Logistic and Cox proportional-hazards regression models
were used to analyze associations between IRR and outcome, in terms of response
rate (RR, complete and partial response), disease control rate (DCR, rate of pts
without PD at 6 weeks), and progression-free survival (PFS).
Results: Overall, 137/205 pts (67%) experienced IRR on treatment, while 68 pts
(33%) did not report IRR. In the IRR group, 63% of pts had grade 1 and 37% grade
2. By time of onset, 88% of pts developed IRRs within first 6 weeks and 12% later.
Baseline characteristics in the IRR v non-IRR groups were: median age 66 v 64; male
50% v 56%; PS 1-2 34% v 35%, range of prior lines 1-4 v 1-5. Among baseline
factors, only a low number of prior regimens predicted for IRR (odds ratio, OR 1.4 p
= .02). The RR was 12% (95% CI 7-18) in the IRR group and 3% (1-10) in the
non-IRR group (OR 4.4 p = .05), while DCR was 50% (42-59) in pts who had IRR
and 34% (23-46) in pts who did not (OR 2.0 p = .02). On landmark analysis set at
6-week time point, PFS was significantly improved in pts with IRR (hazard ratio, HR
0.63 p = .007). Six-month PFS rates were 17% (11-23) for the IRR group and 6%
(1-12) for the non-IRR group (log-rank p = .005). In multivariable analyses
(adjusting for age, sex, PS, prior lines, and tumor types), the onset of IRR remained
independent predictor of higher likelihood of response (OR 4.8 p = .05) and lower
risk of progression or death (HR 0.62 p = .009).
Conclusions: Occurrence of IRR may identify pts who are more likely to gain benefit
from NGR-hTNF treatment.
Disclosure: A. Lambiase: Employment- MolMed. C. Bordignon: Employment -
MolMed. All other authors have declared no conflicts of interest.
488P IMPACT OF SOLUBLE TUMOR NECROSIS
FACTOR-RECEPTORS (STNF-RS) SHEDDING ON OUTCOME IN
PATIENTS TREATED WITH NGR-HTNF
P.A. Zucali 1 , M. Simonelli 1 , F. De Vincenzo 1 , E. Lorenzi 1 , A. Santoro 1 ,
A. Lambiase 2 , C. Bordignon 2
1 Department of Oncology, Humanitas Cancer Center IRCCS, Rozzano, ITALY,
2 Clinical Development, MolMed, Milan, ITALY
Background: NGR-hTNF (asn-gly-arg-human tumor necrosis factor) displays a
biphasic dose-response curve with activity shown at very low or high doses.
Volume 23 | Supplement 9 | September 2012 doi:10.1093/annonc/mds395 | ix167