Daily Continuous Infusion Research Articles

High-dose continuous-infusion ifosfamide in advanced well-differentiated/dedifferentiated liposarcoma.

BackgroundLiposarcomas represent the most common histological type of soft-tissue sarcomas (STS). Its main subgroups, WD/DD, is known to be poorly sensitive to chemotherapy, with few active agents, i.e., anthracyclines +/- ifosfamide and trabectedin. High-dose ifosfamide (HDIFX >12 g/m2) is active in STS pts pretreated with standard-dose IFX, though with greater toxicity. A prolonged continuous-infusion (ci) through a portable external pump may be an alternative way to administer HDIFX.MethodsFrom March 2002 to August 2013, 28 pts (median age =60, range =37–73 yrs) with advanced disease (6 WD and 22 WD/DD) were given ciHDIFX, at the dose of 14 g/m2 as a 14-day continuous infusion every 4 weeks. Twenty-four pts (86%) were previously treated with chemotherapy (19 with anthracyclines and ifosfamide; 4 with anthracycline monotherapy; 1 with trabectedin).ResultsSeven PR (all in DDLPS), 2 minor response (MR) and 11 SD were observed. Of interest, 6 of 9 patients with PR or MR had had SD with the previous therapy with anthracycline plus ifosfamide. The median progression-free survival was 7 months. Most common side effects were mild myelosuppression (anemia G2-3 in 3 pts; G2-3 neutropenia in 3 pts and G4 in 1; G3 thrombocytopenia in 1 pt); nausea (G3 in 3 pts) and fatigue (G3 in 6 pts). One pts had transient G3 confusion.ConclusionsThese data suggest that ciHDIFX is active in WD/DDLPS, even in patients already treated with a combination of anthracyclines plus ifosfamide. In this series, ciHDIFX regimen was better tolerated than HDIFX in published studies.

Dacarbazine with or without oblimersen (a Bcl-2 antisense oligonucleotide) in chemotherapy-naive patients with advanced melanoma and low–normal serum lactate dehydrogenase

In a previous large randomized, open-label study, retrospective subset analysis revealed that the addition of the Bcl-2 antisense oligonucleotide oblimersen to dacarbazine (Dac) significantly improved overall survival, progression-free survival, and the response rate in chemotherapy-naive patients with advanced melanoma and normal baseline serum lactate dehydrogenase (LDH) levels. To confirm and expand on this observation, we conducted a prospective double-blind, placebo-controlled study to determine whether oblimersen augmented the efficacy of Dac in advanced melanoma patients with low-normal baseline LDH levels. A total of 314 chemotherapy-naive patients were randomly assigned to receive Dac (1000 mg/m(2)) preceded by a 5-day continuous intravenous infusion of either oblimersen sodium (7 mg/kg/day) or placebo every 21 days for less than eight cycles. Co-primary efficacy endpoints were overall survival and progression-free survival. Response and progression of the disease were assessed by independent blinded review of computed tomography scan images. No difference in overall nor progression-free survival was observed between the Dac-oblimersen and Dac-placebo groups. Although the overall (17.2 vs. 12.1%) and durable (10.8 vs. 7.6%) response rates numerically favored Dac-oblimersen over Dac-placebo, they did not differ significantly (P=0.19 and 0.32, respectively). The incidence of hematologic adverse events, particularly thrombocytopenia and neutropenia, was higher in the Dac-oblimersen group than in the Dac-placebo group. Withdrawals from the study because of treatment-related adverse events were low (i.e. <2.5%) in both groups. The addition of oblimersen to Dac did not significantly improve overall survival nor progression-free survival in patients with advanced melanoma and low-normal levels of LDH at baseline.

14-day continuous infusion ifosfamide in advanced refractory sarcomas.

10596 Background: Ifosfamide is commonly used to treat bone and soft tissue sarcomas (STS) and its efficacy appears to increase with doses >9g/m2/cycle. Due to the toxicity associated with bolus do...

Lack of a sex difference in leptin‐mediated regulation of appetite, cardiovascular function and glucose homeostasis (1083.5)

Previous studies using male rodents have shown that the adipocyte‐derived hormone leptin acts in the brain to regulate cardiovascular function and energy homeostasis noted by modulation of appetite and energy expenditure and normalization of diabetes‐induced elevations in glucose levels. Because it is uncertain if leptin acts similarly in females, the aim of our study was to examine sex differences in leptin’s actions on blood pressure (BP), heart rate (HR), appetite, and glucose homeostasis. Female Sprague‐Dawley rats (n=6) and male controls (n=5) were instrumented with intracerebroventricular (ICV) cannulas in the lateral ventricle for continuous 7‐day infusion of leptin (15 μg/day) and telemetry probes for measurement of BP and HR 24‐hr/day. At baseline, female rats had significantly lower MAP (96±3 vs. 104±4 mmHg, p&lt;0.05) but higher HR (375±5 vs. 335±5 bpm, p&lt;0.05) compared to males but, following leptin treatment, we observed similar rises in BP (~3 mmHg) and HR (~25 bpm) in both sexes. Females had significantly reduced body weight (BW, 283±2 vs. 417±7 g, p&lt;0.05) and lower caloric intake (162±20 vs. 192±9 kcal/kg of BW, p&lt;0.05) compared to males, and leptin infusion reduced BW (‐10%) and caloric intake (‐62%) in both sexes alike. Also, in females and males, leptin infusion significantly reduced, to a similar extent, both fasting insulin (1.9±0.5 vs. 0.6±0.3 and 1.9±0.2 vs. 0.3±0.1 ng/ml, respectively) and blood glucose levels (100±6 vs. 75±6 and 80±4 vs. 73±5 mg/dl, respectively). In female rats with streptozotocin‐induced diabetes (n=5), chronic ICV leptin treatment for 7‐days also completely normalized the elevated glucose levels (315±33 vs. 83±13 mg/dl, p&lt;0.05). These results show that the effects of leptin on cardiovascular function, glucose regulation and energy homeostasis are similar in male and female rats. Therefore, our results provide no evidence of a sex difference in leptin’s cardiovascular or metabolic actions. (NHLBI‐PO1HL51971, NIGMS P20GM104357, AHA‐SDG5680016)Grant Funding Source: NIH: NHLBI‐PO1HL51971 and NIGMS P20GM104357; AHA: SDG5680016

Second-line FOLFOX chemotherapy in patients with metastatic gallbladder cancer and cholangiocarcinoma.

322 Background: After first-line treatment with gemcitabine-based regimen, there is not standard second-line chemotherapy for patients with metastatic gallbladder cancer (GB) and cholangiocarcinoma (CC). The aim of this study was to evaluate the activity, progression free survival (PFS), and overall survival (OS) of the FOLFOX4 regimen as second-line chemotherapy. Methods: We performed a retrospective analysis of all metastatic GB and CC that were treated with gemcitabine (Gem) based first-line chemotherapy, and second-line FOLFOX4 chemotherapy (oxaliplatin 85 mg/m2, day 1; leucovorin 200 mg/m intravenously, days 1 and 2; 5-fluorouracil 400 mg/m intravenous bolus, days 1 and 2; and 600 mg/m in 22 h intravenously, continuous infusion days 1 and 2; every 14 days) in our Institution since 2003. The response rate was evaluated every 2 to 4 months according to the RECIST criteria, and PFS/OS were calculated according to the Kaplan-Meier method. Results: Eighty patients (n=40 GB; n=40 CC) received Gem based first-line treatment (42 Gem alone; 38 Gem + platinum). There was no survival difference between Gem or Gem+platinum treatment (161 versus 254 days; p=0.09). Response rate (complete and partial response) was 16% and stable disease was 31%. Ca19-9 at presentation was predictive for OS: &lt;100U/ml =403 days versus &gt;100 U/ml =223 days (p=0.025). Eighteen patients (22%; n=10 GB and n=8 CC) were treated with second-line FOLFOX4. In the second-line group, stable disease was achieved in 4 patients (22%), and 11 patients progressed (66%). The median DFS and OS were 96 and 138 days respectively. The median OS for patients that received one versus both lines of chemotherapy were 161 versus 400 days (p=0.009). Conclusions: FOLFOX4 has activity in second line chemotherapy for patients with metastatic GB and CC. A prospective study is warranted to confirm this observation.

Efficacy and tolerability of chemotherapy with modified dose-dense TCF regimen (TCF-dd) in locally advanced or metastatic gastric cancer: final results of a phase II trial

We previously studied a dose-dense TCF (TCF-dd) regimen demonstrating its feasibility and an activity comparable to epirubicin-based chemotherapy and TCF q3w in terms of overall survival and time to progression (TTP). We report here the final results of a phase II study of chemotherapy with a modified TCF-dd regimen in locally advanced or metastatic gastric cancer (MGC). Patients with histologically confirmed measurable MGC, not previously treated for advanced disease, received docetaxel 70mg/m(2) day 1, cisplatin 60mg/m(2) day 1, l-folinic acid 100mg/m(2) days 1 and 2, followed by 5-fluorouracil (5-FU) 400mg/m(2) bolus days 1 and 2, and then 600mg/m(2) as a 22-h continuous infusion days 1 and 2, every 14days, plus pegfilgrastim 6mg on day 3. Patients aged ≥65years received the same schedule with a dose reduction of 30%. Study duration: December 2007-November 2010. Forty-six consecutive patients were enrolled (78% male, 22% female; median age, 66 years, range, 38-76 years; ECOG PS: 0, 48%, 1, 46%). Primary endpoint was overall response rate (ORR). A median of four cycles (range, one to six) was administered. Forty-three patients were evaluated for response (93.5%) and all for toxicity: 3 complete response (CR), 25 partial response (PR), 10 stable disease (SD), and 5 progressive disease (PD) were observed, for an ORR by intention to treat (ITT) of 61% (95% CI 47-75). Median overall survival (OS) was 17.63months (95% CI, 13.67-20.67); median progression-free survival was 8.9months (95% CI, 6.5-13.4). Twenty-one patients (46.0%) were treated at full doses without any delay, thus respecting the dose-dense criterion. Most frequent grade 3-4 toxicities were neutropenia (20%), leukopenia (4%), thrombocytopenia (2%), anemia (2%), febrile neutropenia (6%), asthenia (22%), diarrhea (4%), nausea/vomiting (11%), and hypokalemia (6%). Overall, TCF-dd was shown to be safe. The TCF-dd regimen in locally advanced or MGC is confirmed to be feasible and very active and needs to be further tested in randomized studies.

A Phase 1 Study Of TH-302, An Investigational Hypoxia-Targeted Drug, In Patients With Advanced Leukemias

BackgroundTH-302 is a 2-nitroimidazole prodrug of the DNA alkylator bromo-isophosphoramide mustard designed to be selectively activated in hypoxic conditions. Preclinical data in mice with acute lymphoblastic leukemia (ALL) have demonstrated marked expansion of hypoxia in areas of marrow leukemia infiltrates (Benito et al., PLoS One 2011). TH-302 also exhibited specific hypoxia-dependent cytotoxicity when tested against primary ALL and acute myelogenous leukemia (AML) samples in vitro (Benito et al., ASH 2012). Based on these findings, a phase 1 study of TH-302 was designed for advanced leukemias. MethodsEligible patients had ECOG ≤ 3, relapsed/refractory leukemias for which no standard therapy options were available, and acceptable hepato-renal function. A standard 3+3 dose-escalation design was used with 40% dose increments. TH-302 was administered IV over 30-60 min daily, either by 30 min-bolus administration or as a continuous infusion on days 1-5 of a 21-day cycle. The objectives were to determine the maximum tolerated dose (MTD) and pharmacokinetic (PK) profile of TH-302 with these schedules and to assess preliminary clinical activity of TH-302. ResultsA total of 49 patients with previously treated AML (n=39), ALL (n=9) or CML in blast phase (n=1) received TH-302 at bolus doses of 120 (n=4), 170 (n=4), 240 (n=3), 330 (n=3), 460 (n=20), 550 (n=4) mg/m2 or continuous doses of 330 (n=8) or 460 (n=3) mg/m2. Two of 3 evaluable patients treated with bolus TH-302 (550 mg/m2) experienced DLTs of grade 3 esophagitis; bolus administration MTD was established at 460 mg/m2. Two of 3 patients treated with continuous infusion of TH-302 (460 mg/m2) experienced DLTs of grade 3 mucositis or grade 3 hyperbilirubinemia; continuous administration MTD was established at 330 mg/m2. Thirteen patients received greater than 1 cycle. Generally, a significant rapid cytoreduction was evident early in the cycle, but was not maintained prior to initiation of the next cycle. Two AML patients who received 550 mg/m2 bolus TH-302 had complete resolution of leukemia cutis. One AML patient at 550 mg/m2 bolus TH-302 had a complete response with incomplete platelet recovery (CRp), and one AML patient at 440 mg/m2 bolus TH-302 had a CR. ConclusionsIn patients with advanced leukemias, MTDs were established for daily bolus infusion and 5-day continuous infusion of TH-302 at 460 mg/m2 and 330 mg/m2, respectively. Increased incidence of skin and mucosal toxicity were observed at higher dose levels with both administration schedules. Clinical activity of single-agent TH-302 has been noted with a few objective responses, but the majority of cytoreductions were transient. Disclosures:Konopleva:Threshold Pharmaceuticals: Research Funding. Handisides:Threshold Pharmaceuticals: Employment, Equity Ownership. Kroll:Threshold Pharmaceuticals: Employment, Equity Ownership. Kantarjian:Ariad: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; BMS: Research Funding.

Development and validation of a sensitive LC–MS/MS method for the determination of d-serine in human plasma

A validated LC–MS/MS method was developed for the determination of d -Serine in human plasma. The method was fully validated for use with human plasma samples and was linear from 0.19 nmol/ml to 25 nmol/ml. The coefficient of variation was ≤5% for the high QC standards and ≤8% for the low QC standards in plasma. d -Serine and l -serine were resolved by pre-column derivatization using (R)-1-Boc-2-piperidine carbonyl chloride as the derivatizating agent. The method was used to determine the concentration of d-serine in plasma samples obtained in patients receiving a continuous 5-day intravenous infusion of (R,S)-ketamine. The changes in d-Ser levels varied in the six patients, with circulating d-Ser levels increasing as much as 35% in a patient, while decreasing 20% in a patient. While only preliminary data, the results suggests the potential importance in determining the d-Ser levels in plasma and their potential role in physiological response.

FOLFIRI in patients with locally advanced or metastatic pancreatic or biliary tract carcinoma

Pancreatic and biliary tract carcinomas are very chemoresistant. After a first-line treatment with a gemcitabine-based regimen, no second-line scheme is consolidated in clinical practice. The aim of this study was to evaluate the toxicity and the activity of the FOLFIRI regimen as first-line or second-line chemotherapy in patients with pancreatic or biliary tract tumors. Fifty-four patients (30 with pancreatic tumor, nine with gallbladder tumor, and 15 with biliary tract tumor) were treated with FOLFIRI (irinotecan 180 mg/m², day 1; leucovorin 100 mg/m² intravenously, days 1 and 2; 5-fluorouracil 400 mg/m² intravenous bolus, days 1 and 2; and 600 mg/m² in 22 h intravenously, continuous infusion days 1 and 2; every 14 days). Toxicity was recorded at each cycle according to the NCI-CTC V3.0 criteria, the response rate was verified each four cycles according to the RECIST criteria, and the progression-free survival rates as well as the overall survival rates were calculated according to the Kaplan-Meier method. Overall, the toxicity was mild. Grade 3-4 neutropenia occurred in 42.6% of patients. Grade 3-4 gastrointestinal toxicity was rare. FOLFIRI as a first-line treatment produced a response rate of 25%. In the second-line group, 9/21 patients (42.9%) obtained a stable disease as best response. In the entire population, the median progression-free survival rates were 3.1 months [95% confidence interval (CI), 1.9-4.4] and 3.5 months (95% CI, 2.6-4.4), respectively, in the first-line and the second-line cohort of patients. The median overall survival rates were 14.5 months (95% CI, 7.0-22.1) and 6.2 months (95% CI, 5.4-7.0), respectively, in the first-line and the second-line cohort of patients. FOLFIRI is feasible and well tolerated in patients with pancreatic or biliary tract tumors; it has a good activity in first line and mostly in patients with pancreatic cancer.

Decorin prevents the development of juvenile communicating hydrocephalus

In post-haemorrhagic and other forms of communicating hydrocephalus, cerebrospinal fluid flow and drainage is obstructed by subarachnoid fibrosis in which the potent fibrogenic cytokine transforming growth factor-β has been aetiologically implicated. Here, the hypothesis that the transforming growth factor-β antagonist decorin has therapeutic potential for reducing fibrosis and ventriculomegaly was tested using a rat model of juvenile communicating hydrocephalus. Hydrocephalus was induced by a single basal cistern injection of kaolin in 3-week-old rats, immediately followed by 3 or 14 days of continuous intraventricular infusion of either human recombinant decorin or phosphate-buffered saline (vehicle). Ventricular expansion was measured by magnetic resonance imaging at Day 14. Fibrosis, transforming growth factor-β/Smad2/3 activation and hydrocephalic brain pathology were evaluated at Day 14 and the inflammatory response at Days 3 and 14 by immunohistochemistry and basic histology. Analysis of ventricular size demonstrated the development of hydrocephalus in kaolin-injected rats but also revealed that continuous decorin infusion prevented ventricular enlargement, such that ventricle size remained similar to that in intact control rats. Decorin prevented the increase in transforming growth factor-β1 and phosphorylated Smad2/3 levels throughout the ventricular system after kaolin injection and also inhibited the deposition of the extracellular matrix molecules, laminin and fibronectin in the subarachnoid space. In addition, decorin protected against hydrocephalic brain damage inferred from attenuation of glial and inflammatory reactions. Thus, we conclude that decorin prevented the development of hydrocephalus in juvenile rats by blocking transforming growth factor-β-induced subarachnoid fibrosis and protected against hydrocephalic brain damage. The results suggest that decorin is a potential clinical therapeutic for the treatment of juvenile post-haemorrhagic communicating hydrocephalus.

Phase I Study Assessing the Safety and Tolerability of Barasertib (AZD1152) With Low-Dose Cytosine Arabinoside in Elderly Patients With AML

Barasertib is the pro-drug of barasertib-hydroxy-quinazoline pyrazole anilide, a selective Aurora B kinase inhibitor that has demonstrated preliminary anti-AML activity in the clinical setting. This Phase I dose-escalation study evaluated the safety and tolerability of barasertib, combined with LDAC, in patients aged 60 years or older with de novo or secondary AML. Barasertib (7-day continuous intravenous infusion) plus LDAC 20 mg (subcutaneous injection twice daily for 10 days) was administered in 28-day cycles. The MTD was defined as the highest dose at which ≤ 1 patient within a cohort of 6 experienced a dose-limiting toxicity (DLT) (clinically significant adverse event [AE] or laboratory abnormality considered related to barasertib). The MTD cohort was expanded to 12 patients. Twenty-two patients (median age, 71 years) received ≥ 1 treatment cycle (n = 6, 800 mg; n = 13, 1000 mg; n = 3, 1200 mg). DLTs were reported in 2 patients (both, National Cancer Institute Common Terminology Criteria for Adverse Events grade 3 stomatitis/mucositis; 1200 mg cohort). The most common AEs were infection (73%), febrile neutropenia (59%), nausea (50%), and diarrhea (46%). Barasertib plus LDAC resulted in an overall response rate (International Working Group criteria) of 45% (n = 10/22; according to investigator opinion). The MTD of 1000 mg barasertib in combination with LDAC in older patients with AML was associated with acceptable tolerability and preliminary anti-AML activity.

Approval Summary: Cetuximab in Combination With Cisplatin or Carboplatin and 5-Fluorouracil for the First-Line Treatment of Patients With Recurrent Locoregional or Metastatic Squamous Cell Head and Neck Cancer

On November 7, 2011, the U.S. Food and Drug Administration approved cetuximab in combination with cisplatin or carboplatin and 5-fluorouracil for the first-line treatment of patients with recurrent locoregional or metastatic squamous cell head and neck cancer. Approval was based on a randomized study of 442 patients conducted outside the U.S. Cisplatin (100 mg/m2 intravenously) or carboplatin (area under the curve 5 intravenously) on day 1 with 5-fluorouracil (1,000 mg/m2/day continuous intravenous infusion days 1-4) were administered every 3 weeks. Cetuximab, 400 mg/m2 intravenously, was administered initially followed by cetuximab, 250 mg/m2 intravenously weekly. After completion of six planned treatment courses, cetuximab patients without progression continued cetuximab 250 mg/m2 weekly. The study used European Union (EU)-approved cetuximab rather than U.S.-approved cetuximab. U.S.-approved cetuximab provides approximately 28% higher exposure relative to EU-approved cetuximab in a pharmacokinetic comparability study in monkeys. Overall survival, the primary efficacy endpoint, was significantly improved in cetuximab-treated patients (hazard ratio [HR]: 0.80; 95% confidence interval [CI]: 0.64-0.98; p = .034, stratified log-rank test). Median survival times were 10.1 and 7.4 months, respectively. Progression-free survival (PFS) was also significantly improved in patients receiving cetuximab (HR: 0.57; 95% CI: 0.46-0.72; p < .0001). Median PFS times were 5.5 and 3.3 months, respectively. Response rates were 35.6% and 19.5% (odds ratio: 2.33; 95% CI: 1.50-3.60; p = .0001). Adverse reactions (≥25%) from cetuximab plus chemotherapy treatment included nausea, anemia, vomiting, neutropenia, rash, asthenia, diarrhea, and anorexia. Conjunctivitis occurred in 10% of cetuximab patients. Other adverse reactions, sometimes severe, included infusion reactions, hypomagnesemia, hypocalcemia, and hypokalemia.

Physical and chemical stability of high-dose ifosfamide and mesna for prolonged 14-day continuous infusion

Ifosfamide plus mesna have been used recently in a high-dose regimen that allows this chemotherapy to be given to outpatients with less toxicity over 14 days using a portable pump. However, there is a need for published stability information. The aim of this study was to investigate the physicochemical stability of ifosfamide with mesna in normal saline at room temperature over a prolonged period of 14 days. Infusion solutions of 1:1 ifosfamide and mesna at final concentrations of 10, 20 and 30 mg/mL were prepared with 0.9% sodium chloride in PVC bags. Solutions were stored at room temperature. Concentrations of ifosfamide and mesna were measured at 0 and 1, 3, 7 and 14 days using a stability-indicating reversed phase high-performance liquid chromatography (HPLC) assay with ultraviolet detection. Ifosfamide and mesna were both physicochemically stable (>94%) for 14 days in all tested infusion solutions (10, 20 and 30 mg/mL). Our stability data indicate that ifosfamide and mesna (1:1) combination can be administered as a prolonged continuous infusion with portable pump in an outpatient setting without replacement of the infusion bag. We suggest 20 mg/mL as a reasonable concentration for infusion rates of about 2-4 cc/hr over prolonged periods of time.

A phase I/II study of ABT-888 in combination with 5-fluorouracil (5-FU) and oxaliplatin (Ox) in patients with metastatic pancreatic cancer (MPC).

147 Background: The PARP inhibitor, ABT-888 is a potent sensitizing agent for, and has been safely combined with DNA-damaging chemotherapies. The sensitizing effects of ABT-888 are magnified when cancer cells harbor underlying defects in DNA repair mechanisms, such as BRCA2 mutations. Methods: We have initiated a Phase I/II trial, and we present here the data from the Phase I portion. Patients (pts) with MPC who had any number of prior therapies were eligible. A standard 3+3 dose escalation of ABT-888 was employed, in cohorts of 40, 60, 80, 100, 150, 200, 250, and 300mg orally twice a day, days 1-7 of a 14 day cycle. Pts also received 85mg/m2 of Ox, 400mg/m2 of 5-FU, and 400mg/m2 of leucovorin on Day 1, and 2400mg/m2 of 5-FU continuous infusion Days 1-3. Restaging studies were performed every 4 cycles. The primary objective was to determine the Recommended Phase II Dose (RP2D) of ABT-888 combined with 5-FU and Ox. Secondary clinical objectives included an assessment of the pharmacokinetics (PKs) of ABT-888 metabolism, as well as response rate (RR), progression-free survival (PFS), and overall survival (OS). Results: Between 01-2011 and 09-2012, 22 pts received treatment. 55% were male; median age = 64, most with an ECOG PS of 1. 55% were previously untreated. The first 6 pts experienced persistent ≤Grade 2 myelosuppression, primarily thrombocytopenia, prompting an amendment to drop the 5-FU bolus. In the latter 16 pts, the combination of ABT-888 plus 5-FU and Ox was well tolerated, with no DLTs. The RP2D is expected to be 300mg BID of ABT-888, with the final analysis including ABT-888 PKs to be presented. For the 22 pts, the RR was 14%, and the PFS and OS were 2.9 and 5.4 months, respectively. Of the 11 previously untreated pts, the RR was 18%, and the PFS and OS were 4.3 and 7.7 months, respectively. 2 pts with deleterious mutations in BRCA2 were included: Pt 6 had a PR and remains on study after 17 months; Pt 14 had a CR and a normalization of CA 19-9, and is still on treatment after 10 months. Conclusions: The combination of ABT-888, 5-FU, and Ox is safe and well tolerated. The combination has demonstrated promising efficacy in MPC, particularly in pts with BRCA2 gene mutations. Clinical trial information: NCT01489865.

Clinical Activity and Tolerability of a 14-Day Infusional Ifosfamide Schedule in Soft-Tissue Sarcoma

Background. Soft-tissue sarcomas (STS) are a heterogeneous group of diseases with lack of effective treatments in most cases. Previous data suggest that continuous infusional ifosfamide regimens might improve cytotoxicity and tolerability compared to standard schedules. Methods. We retrospectively report the outcome of 35 patients affected by STS treated with a 14-day infusional ifosfamide regimen (1000 mg/m2/day) in our institution. Predictive factors for toxicity were also explored. Results. Median age was 53 years. There were 16 males and 19 females. Classification by histology was dedifferentiated liposarcoma (DDLPS): 22 (62.8%), synovial sarcoma: 7 (20%), myxoid/round-cell liposarcoma: 3 (8.5%), and others: 3 (8.5%). Overall, 7 patients (20%) achieved partial response (PR) and 10 patients (29%) achieved stable disease (SD). DDLPS showed special sensitivity: 5 patients (22.7%) had PR, 7 patients (31.8%) had SD, and disease control rate was 54.5%. Median progression-free survival and overall survival were 4.2 and 11.2 months, respectively. The most common toxicities were fatigue, nausea, and vomiting (all grades: 85.7%, 83%, and 54.3%, resp.). Neither hypoalbuminaemia nor gender was found to predict toxicity, although encephalopathy predominantly affected females. Conclusion. Ifosfamide administered as a 14-day continuous infusion is a safe regimen in STS with notable activity in DDLPS.

Neoadjuvant-intensified treatment for rectal cancer: Time to change?

To investigate whether neoadjuvant-intensified radiochemotherapy improved overall and disease-free survival in patients with locally advanced rectal cancer. Between January 2007 and December 2011, 80 patients with histologically confirmed rectal adenocarcinoma were enrolled. Tumors were clinically classified as either T3 or T4 and by the N stage based on the presence or absence of positive regional lymph nodes. Patients received intensified combined modality treatment, consisting of neoadjuvant radiation therapy (50.4-54.0 Gy) and infusional chemotherapy (oxaliplatin 50 mg/m(2)) on the first day of each week, plus five daily continuous infusions of fluorouracil (200 mg/m(2) per die) from the first day of radiation therapy until radiotherapy completion. Patients received five or six cycles of oxaliplatin based on performance status, clinical lymph node involvement, and potential risk of a non-sphincter-conserving surgical procedure. Surgery was planned 7 to 9 wk after the end of radiochemotherapy treatment; adjuvant chemotherapy treatment was left to the oncologist's discretion and was recommended in patients with positive lymph nodes. After treatment, all patients were monitored every three months for the first year and every six months for the subsequent years. Of the 80 patients enrolled, 75 patients completed the programmed neoadjuvant radiochemotherapy treatment. All patients received the radiotherapy prescribed total dose; five patients suspended chemotherapy indefinitely because of chemotherapy-related toxicity. At least five cycles of oxaliplatin were administered to 73 patients. Treatment was well tolerated with high compliance and a good level of toxicity. Most of the acute toxic effects observed were classified as grades 1-2. Proctitis grade 2 was the most common symptom (63.75%) and the earliest manifestation of acute toxicity. Acute toxicity grades 3-4 was reported in 30% of patients and grade 3 or 4 diarrhoea reported in just three patients (3.75%). Seventy-seven patients underwent surgery; low anterior resection was performed in 52 patients, Miles' surgery in 11 patients and total mesorectal excision in nine patients. Fifty patients showed tumor downsizing ≥ 50% pathological downstaging in 88.00% of tumors. Out of 75 patients surviving surgery, 67 patients (89.33%) had some form of downstaging after preoperative treatment. A pathological complete response was achieved in 23.75% of patients and a nearly pathologic complete response (stage ypT1ypN0) in six patients. An involvement of the radial margin was never present. During surgery, intra-abdominal metastases were found in only one patient (1.25%). Initially, 45 patients required an abdominoperineal resection due to a tumor distal margin ≤ 5 cm from the anal verge. Of these patients, only seven of them underwent Miles' surgery and sphincter preservation was guaranteed in 84.50% of patients in this subgroup. Fourteen patients received postoperative chemotherapy. In the full analysis of enrolled cohort, eight of the 80 patients died, with seven deaths related to rectal cancer and one to unrelated causes. Local recurrences were observed in seven patients (8.75%) and distant metastases in 17 cases (21.25%). The five-year rate of overall survival rate was 90.91%. Using a median follow-up time of 28.5 mo, the cumulative incidence of local recurrences was 8.75%, and the overall survival and disease-free survival rates were 90.00% and 70.00%, respectively. The results of this study suggest oxaliplatin chemotherapy has a beneficial effect on overall survival, likely due to an increase in local tumor control.

A Phase II Study of Sepantronium Bromide (YM155) Plus Rituximab in Previously Treated Subjects with Aggressive CD20-Positive B Cell Non-Hodgkin's Lymphoma Who Are Ineligible for or Have Previously Received an Autologous Stem Cell Transplant - Stage I Results.

AbstractAbstract 2731 Background:Survivin is responsible for preservation of cell viability and regulation of mitosis in tumor cells. Survivin is overexpressed in the majority of aggressive B-cell lymphomas and thus is an attractive target in subjects with relapsed lymphoma. YM155 is a survivin suppressant that in vitro, when combined with rituximab, synergistically enhances the induction of apoptosis in lymphoma cells. In human DLBCL xenograft models, this combination significantly inhibits tumor growth and prolongs survival. Based on these preclinical combination data and single agent clinical data, a Phase 2 study utilizing YM155 rituximab was initiated. Methods:The study employs a two-stage group sequential method, designed to enroll a total of 40 subjects with an interim futility assessment (Stage I). Eligible patients have histologically confirmed relapsed CD20-positive primary or transformed diffuse large B cell lymphoma (DLBCL) or grade 3 follicular lymphoma (FL) and are either not candidates or previously had an autologous stem cell transplant (ASCT). Subjects had received ≥ 1 prior anthracycline containing regimen with a documented response to the last regimen prior to study entry. Induction, ASCT and maintenance therapy were considered as one regimen. The dosing regimen was YM155 5 mg/m2/day as a 168 hour (7-day) continuous infusion in a 14 day cycle and rituximab 375 mg/m22 Days 1 and 8 cycles 1 – 4 and then repeated every 10 cycles. The primary endpoint of the study is objective response rate (ORR) per modified IWG 2007. Imaging studies are performed every 8 weeks (4 cycles) after initiation of therapy. In order to continue enrolling in the study, an overall response rate of 4/16 (25%) must be achieved. Results from the completed Stage I are reported here. Results:Sixteen subjects, the majority of whom were male 13/16 (81%), were enrolled in Stage I. The median age was 62.9 (range: 32 – 78) with a majority of subjects 15/16 (93.8%) with DLBCL. IPI/FLIPI scores were intermediate in 10 subjects (62.5%) and high in 3 subjects (18.8%). The median number of prior therapies was 2 (range: 1 – 5), 16/16 (100%) of patients received rituximab in 1st or subsequent lines of therapy. Seven patients (43.7%) had prior ASCT. The median number of cycles of YM155 administered was 11 (1–37). The overall response rate was 9/16 (56.3%) with 2/16 (12.5%) CR, 7/16 (43.8%) PR and 4/16 (25%) SD. The median time to response was 53 days (range: 52 – 109). Median duration of response and median PFS has not been achieved. Clinical benefit rate was 13/16 (81.3%). The most common adverse events reported, regardless of relationship, were pyrexia 8/16 (50%), cough 7/16 (43.8%), asthenia 5/16 (31%) and fatigue, back pain, vomiting, neutropenia and thrombocytopenia each 4/16 (25%). Five subjects (31.3%) experience Grade 4 adverse events and 2 (12.5%) had Grade 5 adverse events (disease progression and respiratory failure), neither of which was considered related to therapy. The most common Grade 4 event was neutropenia 4/16 (25%), with all other Grade 4 events occurring in only 1 subject (febrile neutropenia, thrombocytopenia, general physical health deterioration, infusion site extravasation, central line infection, infective thrombosis, mediastinitis, dyspnoea, pleural effusion). Conclusion:In subjects with relapsed aggressive NHL receiving combination YM155 and rituximab, the ORR for Stage I was 56.3%, which exceeds the requirement to continue to Stage II. Overall the combination regimen was well tolerated with limited hematologic toxicities. Stage II enrollment is ongoing. Disclosures:Papadopoulos:Astellas: Consultancy, Research Funding. Steinberg:Astellas Pharma: Employment. Papa:Astellas Pharma: Employment. Keating:Astellas Pharma: Employment.

Modified DCF (mDCF) regimen seems to be as effective as original DCF in advanced gastric cancer (AGC)

The aim of this retrospective study (from January 2007 to December 2011) was to investigate the efficacy and tolerability of mDCF schedule for chemotherapy-naïve AGC patients. Patients (n = 54) with locally inoperable or distant metastasis and performance status of 0-2 were eligible. The triplet combination chemotherapy consisting of docetaxel 60 mg/m(2) on day 1, cisplatin 60 mg/m(2) on day 1, and 5-fluorouracil 600 mg/m(2) for 5 days of continuous infusion were administered every 21 days, up to nine cycles. Prophylactic G-CSF was not allowed. In all, 36 (67 %) patients were male and 18 (33 %) were female; median age was 59 years. The majority of patients (n = 46, 85 %) had metastatic disease and 8 (15 %) of them had locally advanced disease. Liver metastasis and peritonitis carcinomatosa were found in 20 (43 %) and 18 (39 %) of the 46 cases, respectively. The median cycle of chemotherapy was 6. In assessing 50 patients for response evaluation, one had complete response. Partial response was achieved in 27 (54 %) patients. Seventeen patients (34 %) had stable disease and 5 (10 %) had progressive disease, while 4 % (n = 2) and 11 % (n = 6) of the patients developed severe (grade 3-4) neutropenia and anemia, respectively. During the median follow-up time (6.9 months, range 0.4-24), 28 (52 %) patients died. The overall and progression-free survival were 10.7 [95 % CI 8.9-12.4] and 6.8 [95 % CI 5.8-7.8] months, respectively. Although this was not a prospective comparative study, the mDCF regimen seems to be as effective as the original DCF in AGC with acceptable and manageable side effects.

Phase I study of the Aurora B kinase inhibitor barasertib (AZD1152) to assess the pharmacokinetics, metabolism and excretion in patients with acute myeloid leukemia

PurposeBarasertib (AZD1152) is a pro-drug that rapidly undergoes phosphatase-mediated cleavage in serum to release barasertib-hQPA, a selective Aurora B kinase inhibitor that has shown preliminary activity in clinical studies of patients with acute myeloid leukemia (AML). The pharmacokinetic (PK), metabolic and excretion profiles of barasertib and barasertib-hQPA were characterized in this open-label Phase I study.MethodsFive patients with poor prognosis AML (newly diagnosed, relapsed or refractory) received barasertib 1,200 mg as a 7-day continuous infusion every 28 days. On Day 2 of Cycle 1 only, patients also received a 2-hour infusion of [14C]-barasertib. Blood, urine and feces samples were collected at various time points during Cycle 1. Safety and preliminary efficacy were also assessed.ResultsBarasertib-hQPA was extensively distributed to tissues, with a slow rate of total clearance (CL = 31.4 L/h). Overall, 72–82 % of radioactivity was recovered, with approximately double the amount recovered in feces (mean = 51 %) compared with urine (mean = 27 %). The main metabolism pathways for barasertib were (1) cleavage of the phosphate group to form barasertib-hQPA, followed by oxidation and (2) loss of the fluoroaniline moiety to form barasertib-hQPA desfluoroaniline, followed by oxidation. One of the four patients evaluable for response entered complete remission. No new or unexpected safety findings were observed; the most common adverse events were nausea and stomatitis.ConclusionsThe PK profile of barasertib is similar to previous studies using the same dosing regimen in patients with AML. The majority of barasertib-hQPA clearance occurred via hepatic metabolic routes.

MK-0457, an Aurora kinase and BCR–ABL inhibitor, is active in patients with BCR–ABL T315I leukemia

MK-0457, an Aurora kinase and BCR-ABL inhibitor, was studied on a Phase I/II study in 77 patients with refractory hematologic malignancies. The average number of cycles per patient was 3 (range 1-21). Maximum tolerated doses for a 5-day short infusion and continuous infusion regimens were 40 mg/m(2)/h and 144 mg/m(2)/h, respectively. Drug-related adverse events (AEs) included transient mucositis and alopecia. Eight of 18 patients with BCR-ABL T315I-mutated chronic myelogenous leukemia (44%) had hematologic responses and one of three patients (33%) with Philadelphia chromosome-positive acute lymphoblastic leukemia obtained complete remission. MK-0457 has important activity in patients with leukemias expressing the highly resistant T315I BCR-ABL mutation.