Hr Infusion Research Articles

The Efficacy of Rasburicase and Rituximab Combined with FAB Chemotherapy in Children and Adolescents with Newly Diagnosed Stage III/IV, BM+ and CNS+ Mature B-NHL: A Children's Oncology Group Report

Abstract 2702 Introduction/BackgroundTumor Lysis Syndrome (TLS) is a potentially life-threatening metabolic syndrome that frequently complicates the management of newly diagnosed mature B-NHL in children and adults (Cairo et al., BJH 2010). We have demonstrated rasburicase to be superior to allopurinol in the rapid reduction of uric acid (UA). (Goldman/Cairo et al, Blood 2001) In the previous FAB/LMB/96 international mature B-NHL trial, variables associated with a significant inferior EFS included advanced stage, elevated LDH, primary mediastinal involvement (PMBL) and combined BM/CNS disease (Cairo et al, JCO, 2011). We have previously reported the pharmacokinetics and safety of the addition of rituximab to a modified FAB/LMB/96 backbone in children and adolescents with advanced stage mature de-novo B-NHL. (Cairo et al., ASCO, 2010) Here we focus on outcome in those specific high-risk sub-categories of advanced childhood mature B-NHL following the incorporation of a recombinant urate oxidase (Rasburicase) and targeted immunotherapy (Rituximab) to the FAB/LMB/96 chemotherapy backbones. Material and MethodsChildren with newly diagnosed stage III/IV or high-risk (BM+±CNS+) de-novo mature B-NHL were prospectively treated with cyclophosphamide, vincristine, and prednisone (COP) reduction therapy preceded by 4–24 hours of non-alkaline hydration and rasburicase (0.2mg/kg) (generously supplied by Sanofi-Aventis). Laboratory and clinical TLS (LTLS and CTLS) was prospectively monitored as previously defined (Cairo & Bishop, BJH, 2004). Immunochemotherapy consisted of FAB B4 or C1 therapy (adriamycin 1 hr infusion) as we have previously described (Patte et al and Cairo et al, Blood, 2007) with the addition of rituximab 375 mg/m2/dose (generously supplied by Genentech) with 2 doses administered in each induction cycle and 1 dose in each consolidation cycle. ResultsWith respect to LTLS and CTLS, 78 patients were evaluable: group B (stage III/IV) with NL-LDH (<2X ULN, n=23), Group B with HI-LDH (≥ 2X ULN, n=18), and Group C (n=37). The mean initial UA levels (mg/dl +/− SD) were 4.7±2, 8.7±4.6, and 7.1±4.6, respectively. At presentation, 31% of patients (all groups) had an elevated (> 8mg/dl) UA, and 47% received elective doses of rasburicase in the days prior to the first day of chemotherapy. The incidence of LTLS prior to rasburicase in Group B NL-LDH, Group B HI-LDH, and Group C, was 4.3%, 5.5%, and 16.6%, respectively. The incidence of CTLS prior to rasburicase was 0%, 11%, and 8.6%, respectively. Following the administration of rasburicase, the incidence of new onset LTLS and CTLS for the entire cohort was 13% (2.6% with hyperuricemia) and 4% (1% with hyperuricemia), respectively. Furthermore, there was a significant improvement in the estimated GFR in those with renal impairment from day -1 prior to rasbursicase to day+7 post R-COP (55 ± 29 ml/min1.73 m2 to 136 ± 29 respectively; p<0.0007; Figure 1). Following combined FAB 96 chemotherapy (with 1 hour Adriamycin) and rituximab, the 3- year EFS (95% CI) for pilot patients (6 doses of rituximab) with Stage III/IV and Group C BM/CNS patients were 95% (80–99%) (Figure 2) and 89% (73–98%), respectively. Interestingly, two of four patients with centrally reviewed mediastinal primaries developed recurrent disease, while none of the 19 stage III/IV patients with LDH < 2X ULN developed recurrent disease or toxic deaths. [Display omitted] ConclusionsRasburicase and non-alkaline hydration largely prevented (94% of the time) new onset TLS with hyperuricemia safely during COP reduction therapy in children with advanced stages of de-novo mature B-NHL. For patients with mediastinal primaries, the high failure rate with group B4 therapy + rituximab suggests it would be appropriate to investigate new treatment strategies. Excluding this histology, combined modified FAB/LMB 96 chemotherapy and rituximab resulted in only 5 deaths (2 toxic deaths, 3 disease related deaths) among our cohort of 62 with advanced mature B-NHL. In comparing these current results from the previous FAB/LMB 96 trial without rituximab, the stage III/IV patients had a 95% vs. 84% and patients with CNS+ disease a 93% vs. 72% 3 year EFS. (Patte et al., Cairo et al. Blood, 2007) Future efforts to intensify chemotherapy in patients with CNS involvement should proceed only with careful toxicity monitoring, as preliminarily these patients seem to have excellent outcome with this immunochemotherapy approach. Disclosures:Gross:Pfizer Oncology: Consultancy; Roche/Genentech: Consultancy; Eli Lilly: Consultancy.

Abstract B191: Phase 1 pharmacokinetic (PK) assessments of ATI-1123, a novel human serum albumin-stabilized nanoparticle docetaxel liposomal formulation, in patients with advanced solid malignancies.

Abstract Purpose: ATI-1123, a novel nanoparticle docetaxel liposomal formulation, is being investigated in patients (pts) with advanced solid malignancies. ATI-1123 is expected to reduce hypersensitivity reactions, have a broader therapeutic index and to enhance systemic exposure docetaxel. The objective of this study was to investigate the safety, tolerability, pharmacokinetics and tumor response of ATI-1123 in pts with advanced solid tumors following escalating doses of intravenously administered ATI-1123. Methods: This phase I study enrolled 29 pts. The dosing (1 hr infusion q 3 weeks) began at 15 mg/m2 using an accelerated titration design, followed by a modified Fibonacci schema to MTD. ATI-1123 doses ranged from 15 to 110 mg mg/m2. Plasma samples were obtained at baseline, 0.25, 0.5, 1, 2, 4, 8–10, 24, 48 hrs, day 8, and analyzed for encapsulated and non-encapsulated docetaxel using a validated HPLC MS/MS (BQL &amp;lt; 0.405 and 0.595 ng/mL, respectively). PK parameters were determined for encapsulated, the non-encapsulated and total docetaxel in each subject by standard model independent methods (Gibaldi and Perrier, 1982) using WinNonlin Professional 5.2.1 (Pharsight Corp., Mountain View, CA). Dose proportionality for the three analytes was assessed using a power-law model, linear-regression model and ANOVA model. Results: Total docetaxel Cmax, AUC(0-inf), T1/2, CL, and Vss mean values ranged from 2060 × 643 to 16200 × 2310 ng/mL, 5710 × 1550 to 40400 × 6160 ng·h/mL, 6.57 × 0.555 to 7.32 × 0.958 h, 2.63 × 0.741 to 3.43 × 1.50 L/h/m2 and 13.3 × 2.06 to 17.1 × 10.4 L/m2, respectively. Corresponding values for encapsulated docetaxel were 1560 × 460 to 9890 × 2170 ng/mL, 4480 × 1380 to 28500 × 7040 ng·h/mL, 5.08 × 1.08 to 6.23 × 0.732 h, 3.51 × 1.08 to 4.42 × 1.09 L/h/m2 and 15.0 × 3.11 to 21.3 × 3.68 L/m2. Encapsulated docetaxel Cmax and AUC were up to 4-fold higher while clearance were up to 4-fold lower than the corresponding values for non-encapsulated docetaxel (free portion). T1/2 values were ∼2–3-fold lower. The PK parameters for free docetaxel are in reasonable agreements with the values reported in the literature for standard docetaxel (Stephen et al., 1999, Bruno et al., 1998, Bruno et al., 1997). The PK exposure of encapsulated, non-encapsulated and total docetaxel was dose proportional as determined by the power-law model where the slope of Ln Cmax or Ln AUC vs. Ln dose has value of ∼1 and 90% confidence intervals for the slope include 1. In addition, p values determined by regressions models and ANOVA for slope and intercepts of Cmax or AUC (or normalized Cmax and AUC) vs. dose supported dose proportionality. Conclusions: ATI-1123 exhibited favorable PK in humans and the presence of the encapsulated docetaxel lead to the enhanced exposure of docetaxel. The PK exposure of encapsulated, non-encapsulated and total docetaxel was dose proportional. The estimated PK parameters for non-encapsulated docetaxel (free portion) are in reasonable agreements with the corresponding values reported in the literature for standard docetaxel. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B191.

Abstract A113: ATI-1123, a novel human albumin-stabilized docetaxel liposomal formulation: Final results of a phase I study in patients with advanced solid malignancies.

Abstract Background: ATI-1123 is a novel liposomal docetaxel (D) formulation utilizing human serum albumin that facilitates tumor targeting. It was hypothesized that liposomal D formulations may reduce hypersensitivity reactions, eliminate premedication requirements, have a broader therapeutic index, and enhance systemic D exposure. This study assessed the safety, tolerability, pharmacokinetics (PK) and antitumor activity of ATI-1123 in patients (pts) with advanced solid tumors. Methods: Eligible pts had progressive disease after standard therapy, measurable disease (RECIST), ECOG ≤ 2, and adequate organ function. Dosing (1 hr infusion) began at 15 mg/m2 using an accelerated titration design, followed by a modified Fibonacci schema to MTD. Dosing was continued until disease progression or unacceptable toxicities. Plasma was analyzed for encapsulated/non-encapsulated D using a validated assay. PK was determined by model independent methods. Results: 29 pts were enrolled, median age 60 yr, (range 35–81); 48% male; 6 (20.7%) NSCLC; 6 (20.7%) pancreas; 5 (17.2%) prostate; 3 (10.4%) ovary; cervix 2 (6.8%); 7 (24.2%) other. Nine out of 29 pts (31%) received prior D. Doses studied (mg/m2) were 15 (2 pts), 30 (1 pt), 60 (2 pts), 75 (8 pts), 90 (10 pts) and 110 (6 pts). MTD was 90 mg/m2. At 110 mg/m2, 2 pts experienced DLTs (Gr 3 mucositis; Gr 3 neutropenic fever) and the 90 mg/m2 cohort was expanded to 10 pts. Since 3 patients at 90 mg/m2 developed reversible, uncomplicated grade 4 neutropenia, an intermediate dose level of 75 mg/m2 was explored (8 pts) with no DLT. Five (26%) pts had hypersensitivity reactions in cycle 1, all Gr 2, managed with prolonged infusion time and/or premedication. One reaction required ATI-1123 discontinuation. No unexpected toxicities were noted compared to standard D. PR was seen in 1 NSCLC pt, and SD was noted in 22 of 29 pts (75.9%; pancreatic, 6; NSCLC, 5; prostate, 5; other, 6). Two prostate cancer pts had robust PSA response (&amp;gt;95% reduction) following multiple treatment cycles. PK results demonstrated linear and dose proportional PK. ATI-1123 appears to enhance the drug exposure compared to standard D, as demonstrated by Cmax and AUC0–24 ratios which were 1.60–3.32 and 1.80–4.11 fold higher, respectively, and by D clearance which was 1.68–4.10 fold lower with ATI-1123. Conclusions: ATI-1123 is a novel albumin-stabilized liposomal D formulation which demonstrated acceptable tolerability, a favorable PK profile and antitumor activity that warrant exploration in larger Phase 2 trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A113.

Abstract A86: A phase 1 study of LY2523355, an Eg5 inhibitor, administered on Days 1, 2, and 3 with or without pegfilgrastim in patients with advanced malignancy (NCT01214629).

Abstract Background: LY2523355 is a potent allosteric inhibitor of the motor protein Eg5 which selectively inhibits bipolar mitotic spindle formation. The objective of this Phase 1 study was to determine a Phase 2 dose and schedule of LY2523355 that may be safely administered to patients with advanced malignancy. Methods: Study I1Y-MC-JFBA is an open-label, multicenter, dose-escalation study in patients with advanced malignancy. A modified 3+3 dose-escalation scheme was used, followed by a dose confirmation phase with pre- and post-treatment tumor biopsies. Patients received LY2523355 as a 1hr infusion on days 1, 2 and 3 of a 21-day cycle with determination of the MTD with and without pegfilgrastim administration on day 4. Patients were assessed every other cycle by RECIST. Treatment related PD changes in phosphohistone H3 (pHH3) and Eg5 expression were assessed in skin and tumor biopsies by immunohistochemistry. Results: 46 patients were enrolled in the study as of October 2010. The most frequent related AEs reported (&amp;gt;10%) include leukopenia, neutropenia, fatigue, nausea, stomatitis, vomiting, alopecia, anemia, diarrhea, lymphopenia, pruritis/itching and rash. Dose-limiting toxicities include increased INR, leukopenia, diarrhea, rash (palmar plantar erythrodysesthesia), febrile neutropenia, and mucositis. The single and multiple dose pharmacokinetics of LY2523355 and metabolite were characterized. Dose dependent increase in LY2523355 plasma exposure and a minor degree of intra- and inter-cycle accumulation were observed. An exposure-dependent increase in pHH3 and Eg5 expression and increase in apoptotic cells in tumor and skin biopsies has been demonstrated. One patient with ovarian cancer had a confirmed partial response. Nine other patients had stable disease for at least 2 cycles. Conclusions: The MTD of LY2523355 for this schedule has been established with and without pegfilgrastim at 6mg/m2/d and 4 mg/m2/d, respectively. These doses have shown a quantifiable PD response in skin and tumor biopsies confirming the importance of maximizing exposure intensity for maximum PD response. Dose confirmation is on-going. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A86.

Use of a novel technique, solid phase microextraction, to measure tranexamic acid in patients undergoing cardiac surgery

Solid phase microextraction (SPME) is a technique widely used and accepted in the field of food technology and in environmental and biological analyses. Despite its numerous advantages over older analytical methods, it has not been studied extensively in the medical sciences. Tranexamic acid (TXA) is currently the sole antifibrinolytic agent used during cardiac surgery involving the use of cardiopulmonary bypass (CPB). The current standard method of measuring TXA in plasma is based on plasma protein precipitation (PPP), but this analytical approach is time-consuming and not practical for routine use. The aim of the current study was to compare plasma TXA levels measured with the PPP method vs those acquired with the novel, highly efficient SPME technique. We also investigated the use of automated SPME with the aim of improving the technique so it could be used efficiently for measuring plasma TXA levels. With Research Ethics Board approval, we undertook a prospective, investigator-blinded study in ten patients undergoing cardiac surgery with CPB. An initial TXA bolus of 30mg·kg(-1) was infused over 15min followed by a 16mg·kg(-1)·hr(-1) infusion until chest closure with a 2mg·kg(-1) load in the pump prime. Each blood sample was divided into two portions and assigned a random number to blind the analyzing laboratory. The blood TXA concentration was measured using both PPP and SPME. Agreement between the two tests was analyzed using the Bland-Altman plot. Comparisons of plasma TXA concentrations measured with the two methods (PPP and SPME) showed good agreement. Absolute recovery of TXA for PPP was 64.9-78.2%; its precision, as a percentage of the relative standard deviation (RSD) was < 10% [with the exception of the lower limit of quantification (LLOQ), where the RSD was 18%]; and its accuracy, as the bias against the nominal concentration, was < 7% (for LLOQ it was 15%). Thus, extraction with SPME compared favourably with the PPP technique. Solid phase microextraction is a relatively simple, rapid extraction technique that can facilitate future pharmacokinetic studies analyzing TXA drug concentrations and drug dosing in various clinical settings.

The role of neuromuscular blocking drugs in early severe acute respiratory distress syndrome

Acute respiratory distress syndrome (ARDS) is defined as severe hypoxemic respiratory failure resulting from diffuse lung injury and secondary to direct and indirect insults. Despite advances, mortality remains as high as 40-60%. Neuromuscular blocking agents (NMBAs) are used to facilitate mechanical ventilation in patients with ARDS and have been shown to improve arterial partial pressure of oxygen. However, the association between NMBAs and mortality is unclear. Furthermore, morbidity concerns exist, particularly regarding a putative role in intensive care unit (ICU)-acquired weakness. The purpose of this study was to compare survival in adult patients with early ARDS who were randomized to receive either a 48-hr infusion of the NMBA, cisatracurium, or a placebo. This study was a multicentre double-blinded randomized controlled trial involving 20 ICUs in France from March 2006 to March 2008. Eligible patients were > 18 yr with an intubated trachea and ventilated lungs for acute hypoxemic respiratory failure. Their PaO(2)/F(i)O(2) ratio was < 150 at a tidal volume of 6-8 mL·kg(-1) ideal body weight and a positive end-expiratory pressure (PEEP) ≥ 5 cm H(2)O for < 48 hr. Additional inclusion criteria were radiographic evidence of bilateral pulmonary infiltrates and the absence of left atrial hypertension. Exclusion criteria included patients already receiving NMBA at enrolment; those who had increased intracranial pressure, severe chronic respiratory disease, or severe chronic liver disease; those who had received a bone marrow transplant or had chemotherapy-induced neutropenia; those who had a pneumothorax; and those who were expected to require mechanical ventilation for < 48 hr or were enrolled in another trial within 30 days. Three hundred twenty-six patients were screened, and 340 of these underwent randomization in blocks of four and received either a 48-hr infusion of cisatracurium (15 mg bolus followed by 37.5 mg·hr(-1)) or a volume equivalent placebo. One hundred and seventy-eight patients received a cisatracurium infusion, and one patient withdrew leaving 177 patients included in the analysis. One hundred and sixty-two patients received the placebo infusion. Prior to either infusion, patients were sedated to a Ramsay sedation score of 6. Patients' lungs were ventilated by a volume assist-controlled mode according to the ARDS Clinical Network Mechanical Ventilation Protocol (http://www.ardsnet.org/) with the goal SpO(2) of 88-95% (or PaO(2) 55-80 mmHg) and goal plateau pressure ≤ 35 cm H(2)O. Open-label boluses of cisatracurium 20 mg (maximum of two per 24-hr period) were allowed if plateau pressures remained > 32 cm H(2)O despite increased sedation and despite decreased PEEP and decreased tidal volumes. Monitoring of paralysis via peripheral nerve stimulation was not permitted. The primary outcome was death before hospital discharge and within 90 days of study enrolment. It was determined a priori that this would be adjusted for imbalance in key risk factors at baseline, as derived from Cox regression. Secondary outcomes included 28-day mortality, number of ventilator-free days, number of days outside of ICU, number of days without organ system failure, rate of barotrauma, and rate of ICU-acquired paresis (as defined by a Medical Research Council [MRC] score < 48) on day 28 and at ICU discharge. With regard to the primary outcome, crude 90-day mortality was 31.6% in the cisatracurium group vs 40.7% in the placebo group. This outcome did not reach statistical significance (P = 0.08). However, post hoc analysis found a reduction in 90-day mortality in the cisatracurium group compared with placebo (95% confidence interval 0.48 to 0.98; P = 0.04). Results suggest that the reduction in 90-day mortality in the cisatracurium group was confined to those patients with a PaO(2)/F(i)O(2) ratio < 120. Additionally, 28-day mortality was significantly lower in the cisatracurium group (absolute difference -9.6%; P = 0.05). The cisatracurium group also had significantly more ventilator-free days, more days outside of the ICU, and more days free of organ-failure. Similarly, pneumothorax developed more often and earlier in the placebo group than in the cisatracurium group. The rate of ICU-acquired weakness at day 28 or at ICU discharge did not differ significantly between the two groups. Treatment in early severe ARDS with the NMBA, cisatracurium, for 48 hr was associated with lower adjusted 90-day mortality. It was also associated with decreased morbidity, which included increased ventilator-free days, increased ICU-free days, and increased organ failure-free days. These benefits occurred without increasing the incidence of ICU-acquired weakness.

Levosimendan reduces heart failure after cardiac surgery: A prospective, randomized, placebo-controlled trial*

To investigate whether levosimendan diminishes the incidence of heart failure after cardiac surgery. Prospective, randomized, placebo-controlled clinical study. Cardiac surgery operating room and postanesthesia care unit in a university hospital. Two hundred patients assigned to undergo heart valve or combined heart valve and coronary artery bypass grafting surgery. Patients were randomized to receive a 24-hr infusion of placebo or levosimendan administered as a 24 μg/kg bolus over 30-mins and thereafter at a dose of 0.2 μg/kg/min. Heart failure was defined as cardiac index<2.0 L/min/m or failure to wean from cardiopulmonary bypass necessitating inotrope administration for at least 2 hrs postoperatively. Heart failure was less frequent in the levosimendan compared to the placebo group: 15 patients (15%) in the levosimendan and 59 patients (58%) in the placebo group experienced heart failure postoperatively (risk ratio 0.26; 95% confidence interval 0.16-0.43; p<.001). Accordingly, a rescue inotrope (adrenaline) was needed less frequently in the levosimendan compared to the placebo group (risk ratio 0.11; 95% confidence interval 0.01-0.89), p=.005. Intra-aortic balloon pump was utilized in one patient (1%) in the levosimendan and in nine patients (9%) in the placebo group (risk ratio 0.11; 95% confidence interval 0.01-0.87), p=.018. The hospital and the 6-month mortality were comparable between groups. There were no significant differences in major organ failures postoperatively. Eighty-three patients were hypotensive and needed noradrenaline in the levosimendan compared to 52 patients in the placebo group, p<.001. The cardiac enzymes (creatine kinase MB isoenzyme mass) indicating myocardial damage were lower in the levosimendan group on the first postoperative day, p=.011. In the present study, levosimendan infusion reduced the incidence of heart failure in cardiac surgery patients but was associated with arterial hypotension and increased requirement of vasopressor agents postoperatively. Improved mortality or morbidity was not demonstrated.

Delayed treatment with W1-mAb, a chimpanzee-derived monoclonal antibody against protective antigen, reduces mortality from challenges with anthrax edema or lethal toxin in rats and with anthrax spores in mice

W1-mAb is a chimpanzee-derived monoclonal antibody to protective antigen that improved survival when administered before anthrax lethal toxin challenge in rats. To better define W1-mAb's efficacy for anthrax, we administered it after initiation of 24-hr infusions of edema toxin and lethal toxin either alone or together in rats or following anthrax spore challenge in mice. W1-mAb or placebo treatment. In toxin-challenged rats treated with placebo, survival rates were lower with edema toxin (500 μg/kg) compared to lethal toxin either alone (175 μg/kg) or with edema toxin (175 μg/kg each) (8%, 33%, and 32%, respectively), but the median time to death was longer (36, 11, and 9 hrs, respectively) (p ≤ .01 for all comparisons). W1-mAb administered up to 12 hrs after edema toxin and 6 hrs after lethal toxin increased survival and reduced hypotension (p ≤ .01). However, only administration of W1-mAb at 0 hrs improved these variables with lethal toxin and edema toxin together (p ≤ .0002). In C57BL/6J mice challenged with anthrax spores subcutaneously, compared to placebo treatment (0 of 15 animals survived), W1-mAb administered beginning 24 hrs after challenge increased survival (13 of 15 survived) (p ≤ .0001). While rapidity of lethality may influence the effectiveness of delayed W1-mAb treatment, these rat and mouse studies provide a basis for further exploring this agent's usefulness for anthrax.

A phase I study of the CDK inhibitor dinaciclib (SCH 727965) administered every 3 weeks in patients (pts) with advanced malignancies: Final results.

3080 Background: Dinaciclib is a potent and selective inhibitor of CDKs 1, 2, 5, and 9 with anti-tumor activity in multiple tumor cell lines and xenograft models. Methods: Dinaciclib is administered every 3 weeks in pts with advanced malignancies. Part 1: accelerated titration design to establish the RP2D of a 2-hr IV infusion. Part 2: 8 and 24-hr continuous IV infusions. Part 3: determined effect of the CYP3A4 inhibitor aprepitant on PK. PD assessments: ex vivo lymphocyte proliferation assay; FDG-PET/CT scans; and skin and/or tumor biopsies for IHC of cdk targets. Results: 81 pts treated. Part 1: Doses 1.85 to 58 mg/m2. RP2D 50 mg/m2. DLTs: non-neutropenic sepsis (1), neutropenic fever (2), neutropenia with pneumonia (1), hypotension (1), and rise in transaminases (3). Part 2: 7.4 and 10.4 mg/m2 well tolerated as 8- and 24-hr infusions, respectively. DLTs seen at lower doses with 8-hr and 24-hr vs 2-hr infusions. 8-hr DLTs: neutropenia with or without fever (5), hypotension (1), syncope (1), and elevated transaminases (2). 24-hr DLTs: rise in bilirubin (1) and delirium (1). Part 3: pts received dinaciclib 29.6 mg/m2 by 2-hr infusion +/- aprepitant. Among all pts, the most common treatment-related adverse events were nausea, vomiting, diarrhea, neutropenia, and fatigue. Dinaciclib was rapidly eliminated with a t1/2 of 1.4-3.3 hrs. Coadministration of aprepitant had no significant effect on PK. PD: Dose and infusion time correlated with degree and durability of suppression of lymphocyte proliferation. Tumor metabolic changes occurred in some pts by FDG-PET at day 8 but were not predictive of response. No objective responses by RECIST; SD ≥6 cycles (range 6-30) achieved in 10 pts. Pre/post tumor biopsies from 2 pts with melanoma show reduced phospho-Rb [pT356] post-treatment; total Rb was preserved. In 1 pt, p27 and p53 increased post-treatment, consistent with cdk2 and cdk9 inhibition. Analysis of skin biopsies ongoing. Conclusions: Dinaciclib has an acceptable safety profile at 50, 7.4 and 10.4 mg/m2 for 2-, 8- and 24-hr infusions, respectively, without PK interaction with aprepitant. Prolonged SD was achieved in some pts. Trials are ongoing in hematologic malignancies and melanoma.

A randomized phase II study of carboplatin (C) and etoposide (E) with or without pan-BCL-2 antagonist obatoclax (Ob) in extensive-stage small cell lung cancer (ES-SCLC).

7001 Background: Ob is a pan-BCL-2 antagonist that is synergistic in vitro with cisplatin and E. A phase I study concluded that a 3-hr Ob infusion in combination with C and E was favored over a 24-hr infusion (ASCO 2010, Ab e13531). Methods: Patients (pts) with chemotherapy-naive ES-SCLC, measurable disease, and PS 0-2 were randomized to receive six 21-day cycles of CE (C AUC 5 D1, and E 100 mg/m2 D1-3) or CEOb (CE plus Ob [30 mg as a 3-hr infusion D1-3]). 73 evaluable pts were planned for each arm. 1° endpoint was ORR (confirmed CR & PR); 2° endpoints included PFS and OS. After completing 6 cycles, responders received prophylactic cranial irradiation; pts on CEOb continued Ob as maintenance therapy. Results: 165 pts were randomized; 155 pts (77 CEOb; 78 CE) received treatment. The arms were well balanced for gender, PS, and metastatic sites; 21% in each arm had brain mets. CNS adverse events (AEs) (such as somnolence [46% all grades] and euphoric mood [31% all grades]) occurred during and shortly after the Ob infusion. The only Grade 3/4 non-heme AE with ≥ 5% increase in absolute frequency in the Ob arm was somnolence (8 vs 0%). Grade 3/4 febrile neutropenia was rare (5% both arms). Grade 3/4 hematologic lab data were similar for each arm (CEOb vs CE): anemia (8 vs 15%), neutropenia (61 vs 58%), and thrombocytopenia (17 vs 10%). 74% of the pts on the CEOb arm alive without progression after 6 cycles started maintenance therapy. Efficacy data, including death or progression during initial 6 cycles of chemotherapy (refractory rate) are summarized in the table below. Conclusions: The CEOb arm demonstrated a trend for improved ORR, PFS, 12 mo and overall survival (OS). Most importantly, consistent with its in vitro synergy, Ob markedly decreased the rate of refractoriness to the initial 6 cycles of chemotherapy by 36.5%. Pts with screening PS of 2 did poorly in either arm; OS in PS 0-1 pts will be evaluated in a phase III trial comparing CE to CEOb. Study arm ORR PFS 12-month survival OS OS (PS 0-1) Refractory rate (PS 0-1) CEOb 64.9% 6.0 mos* 45.5% 10.6 mos* 11.9 mos* 25.4% CE 53.8% 5.4 mos* 37.2% 9.9 mos* 10.1 mos* 40.0% One-sided p value 0.11 0.08 0.19 0.0506 0.052 0.05 Hazard ratio - 0.79 - 0.72 0.71 - * Median

Efficacy endpoints of RTOG 0247: A randomized phase II study of neoadjuvant capecitabine (C) and irinotecan (I) or C and oxaliplatin (O) with concurrent radiation therapy (RT) for locally advanced rectal cancer.

3517 Background: The primary endpoint analysis of RTOG 0247 showed that preoperative pelvic RT plus C + O achieved a pathologic complete response rate (pCR) pre-specified threshold (21%) to merit further study, whereas the RT+ C + I arm did not (10%) (ASCO 2008). This current analysis reports on the secondary efficacy endpoints. Methods: A randomized phase II trial evaluated preoperative RT (50.4 Gy in 1.8 Gy fractions) with (1) concurrent C (1,200 mg/m2/d orally M-F during RT) and I (50 mg/m2 IV weekly x 4 doses) (Arm 1), and with (2) concurrent C (1,650 mg/m2/d orally M-F during RT) and O (50 mg/m2 IV weekly x 5 doses) (Arm 2) in patients with clinical stage T3 or T4 rectal cancer ² 12 cm from the anal verge. Surgery was performed 4-8 weeks following completion of chemoradiation. Four to 6 weeks after surgery, adjuvant chemotherapy (O 85 mg/m2; leucovorin 400 mg/m2 IV over 2 hours; 5FU 400 mg/m2 IV bolus; 5FU 2400 mg/m2/46 hr infusion) was administered every 2 weeks x 9 cycles. Disease-free (DFS) and ov...

Final results of a phase I dose-escalation study of ON 01910.Na in combination with oxaliplatin in patients with advanced solid tumors.

e13584 Background: ON 01910.Na is a novel multitargeted inhibitor of several regulatory pathways including polo-like kinase 1 (Plk1) and PI-3 kinases, with synergistic nonclinical activity when combined with oxaliplatin, prompting phase I clinical evaluation. Methods: Patients with advanced cancer received escalating doses of ON 01910.Na as 24hr weekly continuous infusions. Oxaliplatin was administered biweekly as a 85mg/m2, 2 hr infusion. The ON 01910.Na dose cohorts ranged from 250-1,350 mg/m2 based on a modified Fibonacci escalation algorithm using the accelerated titration scheme (NCI). Intrapatient dose escalation was allowed. Results: Thirty patients (pts) (22 females; ages: 29-80 yrs received an overall mean 9.4 (range=1-30) number of weeks of combination therapy: ON 01910.Na mg/m2: 250 n=10; 650 n=9; 1,050 n=8; 1,350 n=3. No dose-limiting toxicity was observed in any patient. Grade 3+ toxicities included pain (3 pts), lethargy and weakness (1 pt), pneumonia (1 pt), hyponatremia (1pt), anemia (1pt), transient ischemic attack (1pt), vomiting (1pt), urinary tract infection (1pt), shortness of breath and myocardial infarction (1pt). Confirmed partial response was observed in 1 pt with chemotherapy- refractory ovarian cancer (duration = 11 wks) and in another pt with metastatic breast cancer (duration = 13 wks). Stable disease was observed in 4 pts with colon cancer (42 wks and 12 wks), ovarian and renal cancer (12 wks). Conclusions: ON 01910.Na administered as a 24hr infusion in combination with oxaliplatin was well tolerated and resulted in objective tumor responses in advanced ovarian, breast, colon and renal cancer.

A phase I dose-escalation study of the Hsp90 inhibitor ganetespib (STA-9090) administered twice weekly in patients with solid tumors: Updated report.

3051 Background: Ganetespib is a potent, next-generation Hsp90 inhibitor that is structurally unrelated to the first-generation ansamycin class of Hsp90 inhibitors and has shown superior activity to these agents in preclinical studies. It has been well tolerated and shown promising antitumor activity in early trials in multiple cancers. Preclinical data indicate that different client proteins show disparate expression kinetics upon Hsp90 inhibition. Therefore, twice-weekly dosing may be needed in some tumor types. Methods: Patients (pts) with solid tumors who have exhausted standard treatment options received ganetespib as a 1 hr infusion twice weekly for 3 weeks (wks) of a 28 day cycle until disease progression. Serial PK and pharmacodynamic samples were obtained during cycle 1. Safety assessments included frequency and grade of AEs, laboratory parameters and ECG changes. Results: Data are presented for 49 pts (22 M, 27 F; median age 55 yrs, range 32-81; ECOG status range 0-2) treated at doses from 2-144 mg/m2. Pts received a median of 2 (range 1-12) cycles of ganetespib. AEs reported in ≥20% of pts treated at doses from 2-120 mg/m2 are fatigue, diarrhea, nausea, anemia, abdominal pain, constipation, anorexia, vomiting, and headache; the majority of events were mild to moderate in severity with absence of severe liver, ocular, cardiac and renal toxicity. Two DLTs (elevated transaminases) have been reported in the 10 and 144 mg/m2 cohorts; expansion of the latter cohort is ongoing. Ganetespib shows linear PK, rapid distribution, a mean terminal half-life of 10-14 hours, a volume of distribution greater than total body water and no accumulation in plasma. HSP70 plasma protein levels will be presented. A confirmed durable PR by RECIST has been seen in a pt with metastatic melanoma. Additionally, 2 NSCLC pts who received 6 months of treatment had durable SD, with tumor shrinkage. Conclusions: Ganetespib has been well tolerated at dose levels up to 120 mg/m2 administered twice weekly. Preliminary safety profile, activity signals and differences in client protein kinetics warrant continued evaluation of ganetespib using a twice-weekly dosing regimen. Dose escalation continues.

Phase I study of ATI-1123, a novel human serum albumin-stabilized docetaxel liposomal formulation, in patients with advanced solid malignancies.

2609 Background: Liposomal (LIPO) docetaxel (DOCE) formulations may reduce hypersensitivity reactions, eliminate premedication requirements, have a broader therapeutic index, and enhance systemic DOCE exposure. ATI-1123 is a novel LIPO DOCE formulation utilizing human serum albumin that facilitates LIPO tumor targeting. We studied safety, tolerability, pharmacokinetics (PK) and tumor response of ATI-1123 in patients (pts) with advanced solid tumors. Methods: Pts enrolled had progressive disease after standard therapy, measurable disease (RECIST), ECOG ≤ 2, survival ≥ 3 mo. Dosing (1 hr infusion) began at 15 mg/m2 using an accelerated titration design, followed by a modified Fibonacci schema to MTD. Dosing was continued until pts had progressive disease or unacceptable toxicities. Plasma was analyzed for encapsulated / non-encapsulated DOCE using a validated assay. PK was determined by model independent methods. Results: To date, 19 pts were enrolled (median age 62 yr; range 40-80 yr; 58% male; 5 (26%) NSCLC; 5 (26%) pancreas; 4 (21%) prostate; 3 (16%) other and 2 (11%) ovary. Doses studied (mg/m2) were 15 (2 pts), 30 (1 pt), 60 (3 pts), 90 (7 pts) and 110 (5 pts). Two DLTs were noted at the 110 mg/m2 cohort (Gr 3 mucositis; Gr 3 neutropenic fever) and the 90 mg/m2 cohort expansion is ongoing. At Cycle 1, 5 (26%) pts had hypersensitivity reactions (all Gr 2). One reaction required ATI-1123 discontinuation; the remainder were managed with test dose, prolonged infusion time and/or premedication. No new toxicities were noted relative to standard DOCE. PR was seen in 1 NSCLC pt. SD was noted in 4 of 9 pts (44%) for which protocol-defined followup was available (prostate, 2; pancreatic, 1; cervix, 1). Two prostate ca pts had pronounced PSA (>95% reduction) response following multiple treatment cycles. PK results demonstrated linear and dose proportional PK. Compared with standard DOCE PK Cmax and AUC0-24 ratios were 1.60-3.32 and 1.80-4.11 fold higher, and DOCE clearance was 1.68-4.10 fold lower with ATI-1123. Conclusions: ATI-1123 exhibited acceptable tolerability, a favorable PK profile and antitumor activity that warrant exploration in larger Phase 2 trials.

The Royal Marsden Hospital experience of trabectedin in patients with advanced soft tissue sarcoma (STS): Toxicity and efficacy in a nonselected group.

e20507 Background: Trabectedin (T) is approved in Europe for advanced soft tissue sarcoma (STS). The Royal Marsden Hospital (RMH) has treated 133 STS pts with this agent, the majority outside of clinical trial. This affords the opportunity to determine the toxicity profile and clinical benefit of T in the largest, non-selected cohort published to date. Methods: Patients who started T as a 24 hr infusion for advanced STS between May 1999 and August 2010 were analysed for clinical outcome and toxicity. Results: 133 patients were identified: 60% female; median age 50yrs (18-77yrs) and median prior treatments =1 (0-4). The histological subtypes included leiomyosarcoma (43%), myxoid liposarcoma (13%) and synovial sarcoma (12%); metastatic sites: lung (57%), liver (27%), retroperitoneal (20%). Median number of cycles was 3 (1-24); 32% ≥6 cycles, and 19% only 1 cycle (65% due to PD). Median overall PFS and OS were 67 and 153 days respectively and 28% were progression-free at 6 months. Myxoid liposarcomas were associated with significantly better PFS (median 221 vs 52 days; p=0.003), with synovial sarcomas showing a trend towards an improved PFS. Clinical benefit (PR +SD) was seen in 52% (PR=10%). Dose reductions, delays and change to q4wk schedule due to toxicity were necessary in 25%, 28% and 11% respectively. 22% required hospitalisation and 9% died within 3 weeks of therapy (3.5% toxicity-related). Overall 55% of patients experienced grade 3/4 toxicity (predominantly myelotoxicity, transaminitis, and fatigue), toxicity-related dose modification (25%), and there were 5 toxicity related deaths. Elevations in creatinine kinase occurred in 18% of cycles. Conclusions: This analysis of this largely non-selected STS cohort confirms the clinical activity of trabectedin, particularly in myxoid liposarcomas and synovial sarcomas, with approximately a third of patients experiencing prolonged disease control. Whilst it is generally well tolerated, significant toxicity was observed, with 25% of cases requiring dose reduction. Further analysis of the data is ongoing to better define those factors that may better define those not likely to benefit from T.

A randomized two‐by‐two comparison of high‐dose bolus tirofiban versus abciximab and unfractionated heparin versus bivalirudin during percutaneous coronary revascularization and stent placement: The tirofiban evaluation of novel dosing versus abciximab with clopidogrel and inhibition of thrombin (TENACITY) study trial

In the absence of high-dose thienopyridines, placebo-controlled trials have demonstrated a reduction in ischemic events with intravenous glycoprotein IIb/IIIa antagonists during percutaneous coronary intervention (PCI). One head-to-head trial comparing abciximab and tirofiban among PCI patients found tirofiban to be inferior, and laboratory evidence confirmed that the bolus dose of tirofiban tested in that trial to be less effective than abciximab. Whether a higher bolus dose of tirofiban would be as efficacious as abciximab during PCI is uncertain. Patients undergoing PCI were randomized equally to abciximab or to tirofiban, given as high-dose bolus (25 μg/kg) plus 12-hr infusion (0.15 μg/kg/min). All patients received aspirin and clopidogrel and were additionally randomized to unfractionated heparin or bivalirudin. Approximately 8,000 patients were to be studied, but after 383 were enrolled, the study sponsor discontinued the trial for financial reasons. The primary endpoint of 30-day death, myocardial infarction, or urgent target vessel revascularization occurred in 8.8% of patients randomized to abciximab and 6.9% of those randomized to tirofiban. The respective rates of major bleeding were 1.5 and 1.6%. Additionally, the primary endpoint occurred in 8.1% of patients randomized to unfractionated heparin and 7.6% of those randomized to bivalirudin. The respective rates of major bleeding were 2.5% and 0.5%. With limited assessment, this direct comparison of high-dose bolus tirofiban versus abciximab produced encouraging results and suggests that further study of this tirofiban dose regimen is warranted. The limited assessments comparing heparin and bivalirudin are consistent with prior observations.

Flavopiridol Can Be Safely Administered Using a Pharmacologically Derived Schedule and Demonstrates Activity In Relapsed and Refractory Non-Hodgkin's Lymphoma.

AbstractAbstract 2834 Background:A phase 2 study of flavopiridol administered according to a pharmacokinetically- (PK-) derived schedule has demonstrated significant activity in CLL, irrespective of high-risk genomic features. In combination with fludarabine and rituximab, flavopiridol has further shown promising activity in mantle cell lymphoma (MCL) and indolent B-cell non-Hodgkin's lymphoma (NHL). However, the safety and efficacy of single-agent flavopiridol administered on this schedule has not yet been characterized in patients with relapsed/refractory NHL. Methods:We conducted a standard cohorts-of-3 phase 1 trial to determine the maximum tolerated dose (MTD) and safety of single-agent flavopiridol in each of 4 groups: indolent B-NHL, aggressive B-NHL, MCL, and T-NHL. Adult patients (age >18y) with previously-treated (T-NHL '1 prior; B-NHL ≥2 prior), preserved end-organ function, adequate hematologic parameters (unless attributable to disease), and preserved performance status (≤ECOG 2) were eligible. Further, pts were only eligible if they had exhausted all other therapeutic options. All pts signed informed consent. Flavopiridol was given as a 30 min loading dose followed by a 4 hr infusion weekly for 4 weeks of a 6 week cycle (max 6 cycles). Dose levels (DL) 1, 2, and 3 were 30 mg/m2 + 30 mg/m2, 30 mg/m2 + 50 mg/m2, and 50 mg/m2 + 50 mg/m2, respectively. The first infusion was administered in hospital, but treatment could continue outpatient thereafter. Pts received allopurinol, phosphate binders, and Kayexalate (if pre-treatment K+ >4.5) prophylaxis for tumor lysis syndrome (TLS). Steroid pre-medication and/or treatment for cytokine release syndrome (CRS) was given at the discretion of the treating clinician. Dose-limiting toxicity (DLT) was generally defined as any grade 3/4 non-hematologic toxicity not resolving to ≤grade 2 within 2 wks or any grade 4 hematologic toxicity (except leukopenia/neutropenia) resulting in >1 wk treatment delay. Results:28 pts evaluable for toxicity have thus far completed cycle 1, which was used to define DLT: median age 66 years (range 34–84), 13 female (46%), median prior therapies 3 (range 1–8). All B-NHL patients received prior rituximab. Subsequent dose evaluation continues in the MCL and T-NHL arms. Across all pt groups, there were 11 pts at DL 1, 11 pts at DL 2, and 6 pts at DL 3. No DLTs have been observed to date. Median number of cycles received was 2. Seven pts completed all 6 cycles: 4 pts 30+30, 2 pts 30+50, 1 pt 50+50. Although no DLTs were observed, grade 3/4 hematologic toxicity was seen in 26 pts: neutropenia (23 pts), thrombocytopenia (3 pts), and anemia (7 pts). Grade 3 neutropenic fever and infection, however, were only observed in 2 and 5 pts, respectively. Common grade 3 non-hematologic toxicities included diarrhea (15 pts), fatigue (8 pts) and elevated transaminases (3 pts). Grade 3 CRS and TLS occurred in only 2 pts, both during cycle 1. Only 2 grade 4 non-hematologic toxicities (elevated transaminases, elevated lipase) were observed, both of which resolved without sequelae. Among pts completing ≥1 cycle, the most common reason for discontinuing treatment was disease progression (17 pts). One pt withdrew after diagnosis of a second cancer, 2 pts proceeded to transplant, and 2 pts withdrew for toxicity (1 persistent fatigue, 1 persistently elevated transaminases/malaise). Four pts expired on study: 3 progression, 1 sudden cardiac death unrelated to flavopiridol. Of 26 pts evaluable for response, 6 pts (21%) had partial responses: 2 follicular (30+30, 30+50), 1 SLL (50+50), 2 MCL (30+30, 30+50), and 1 DLBCL (50+50). Seven pts had stable disease for ≥1 cycle: 1 follicular (30+50), 1 MCL (30+30), 1 Richter's CLL (30+30), 1 DLBCL (50+50), and 3 PTCL (2 pts 30+30, 1 pt 30+50). Conclusions:Administered according to a PK-derived schedule, single-agent flavopiridol can be successfully delivered to multiply relapsed and/or refractory NHL pts with acceptable hematologic and non-hematologic toxicity. Both the promising activity and relative safety observed in these heavily pre-treated NHL pts warrant further investigation of this agent earlier in the course of disease and/or in combination with other agents, particularly in indolent B-cell and mantle cell NHL. Disclosures:Blum:Celgene : Research Funding.

Randomized Phase II Study of Two Schedules of Flavopiridol (Alvocidib, F) Given as Timed Sequential Therapy (TST) Wtih Ara-C and Mitoxantrone (FLAM) for Adults with Newly Diagnosed, Poor-Risk Acute Myelogenous Leukemia (AML)

AbstractAbstract 186Acute Myeloid Leukemia - Therapy, excluding Transplantation: Pediatric and Adult AML TherapyF is a protein bound, cytotoxic, cyclin dependent kinase inhibitor. A prior Phase II trial of TST with FLAM, with F given by one hour bolus daily × 3 for adults with newly-diagnosed AML with poor-risk features demonstrated that the complete remission (CR) rate was 30/45 (67%) with median overall survival (OS) and disease-free survival (DFS) for CR patients being 12.6 and 13.3 months, respectively. We now compare FLAM using bolus F (50 mg/m2 daily × 3; Arm A) vs. FLAM using F given by pharmacologically-derived “hybrid” schedule (30 mg/m2 bolus over 30 min followed by 40 mg/m2 in a 4 hr infusion daily × 3; Arm B) in 70 newly-diagnosed AML patients (pts) with poor-risk features. Results: Pt demographics are presented below.Age# < 50Secondary AMLAdverse GeneticsMDS/MPDt-AMLSingleComplexFlt3ARM A (n = 36)59ü(24–78)31956133Total 24/36 = 67%Total 22/36 = 61%ARM B (n = 34)58ü(20–73)51698105Total 25/34 = 74%Total 23/34 = 68%Grade > 3 tumor lysis occurred in 4/70 (6%) with 1 death (A), 1 transient hemodialysis (A), 1 transient hyperkalemia (B), and 1 discontinuation of therapy (B). Four pts (6%) died from regimen toxicity before day 60 (1 A, 3 B). Median time for ANC >500/uL was Day 33 (range 22–71), and platelets > 50,000/uL Day 30 (21-80) for both arms. CR rate in Arm A is 23/36 (64%) including 16/24 (67%) with prior MDS and 13/19 (68%) with adverse cytogenetics and 3/3 (100%) with FLT3-ITD. CR rate in Arm B is 24/34 (71%) including 16/24 (67%) with prior MDS, 12/18 (67%) with adverse cytogenetics, and 4/5 (80%) with FLT3-ITD. As of 7/1/10, 20/23 Arm A CR pts have received chemotherapy and/or allogeneic hematopoietic stem cell transplantation (HCT) in CR: 15/23 (65%) of these pts remain alive and in continuous CR for up to 14+ months, 2 relapsed 4 months post-HCT, and 2 died (1 FLAM consolidation, 1 HCT). Similarly, 20/24 Arm B CR pts have received chemotherapy and/or HCT in CR: 12/20 (60%) remain alive and in continuous CR for up to 18+ months. Of Arm B pts receiving FLAM consolidation, 1 relapsed at 2 months, 1 died at 8 months of cardiac failure, and 2 died during therapy. Three were unable to receive a second cycle and 1 refused. Overall, 51/70 (73%) of all pts and 40/47 (85%) of CR pts are alive 2+ - 19+ months after FLAM. Conclusions: TST with FLAM induces CR in >60% of newly diagnosed, poor-risk AML pts, including those with prior MDS and adverse genetics. There does not appear to be major difference in toxicity or responses between the two F schedules (bolus vs. “hybrid” bolus-infusion). Thus far, allogeneic HCT has been successfully undertaken in 21/47 (45%) of first CR patients, median age 57 (20-64), with 2 early relapses and 1 death from GVHD. Bolus F may be easier to administer than hybrid F and is therefore recommended for further study in newly diagnosed AML pts. These salutary results of FLAM in poor-risk pts will now be evaluated broadly in adults with AML and compared to traditional cytotoxic chemotherapy induction regimens. Disclosures:No relevant conflicts of interest to declare.

Optimizing obatoclax administration schedule: Safety and efficacy of 3-hour versus 24-hour infusion in combination with carboplatin and etoposide for patients with extensive-stage small cell lung cancer (ES-SCLC).

e13531 Background: Previous studies with obatoclax (Ob), a pan-BCL-2 antagonist, identified infusional CNS effects as dose- limiting adverse events (AEs) that occur with greater frequency and intensity with 3-hr versus 24-hr infusions of Ob. This phase I study of Ob used both infusion schedules to compare the safety and efficacy when used in combination with carboplatin (Carb) and etoposide (Et). Methods: As previously reported (ASCO, 2009, Ab 3576) this phase I study evaluated Ob given on a 21-day (D) cycle together with Carb (AUC 5 D1) and Et (100 mg/m2 D1-3), in separate fixed dose escalations using Ob as a 3-hr infusion D1-3 (15 mg, 30 mg and 45 mg) and as a 24-hr infusion D1-3 (30 mg, 45 mg and 60 mg). Eligible patients (pts) had ES-SCLC, measurable disease, ≤1 prior therapy, ECOG PS ≤1, and adequate organ function. 3-6 pts were enrolled into ascending dose cohorts with standard DLT rules. Results: 25 pts were enrolled (14 males; median age 66). 18 pts were previously untreated (12 in 3-hr group; 6 in 24-hour group). Since only chemotherapy-naive pts were to be enrolled in phase II, safety and efficacy data from those pts are presented here. Preliminary safety data indicate that AEs of all grades with >33% difference between the arms were somnolence (83% in 3-hr vs. 0% in 24-hr), euphoric mood (58 vs. 0%), dysguesia (50 vs. 0%), hyponatremia (8 vs. 50%), and chest pain (42 vs. 0%). CNS AEs were generally transient and without sequelae. The RR, PDs during the planned 6 cycles of combination therapy, median PFS, and median OS all demonstrated a trend in favor of the 3-hr infusion arm. Minimum follow-up for all 18 pts is 10.4 months. Conclusions: Although associated with a higher incidence of some (particularly CNS) AEs, Ob 3-hr infusion in combination with Carb and Et showed a trend toward higher RR, PFS, and OS than 24-hour infusion. 3-hr infusions with Carb and Et have been studied further in a randomized, phase II trial in pts with chemotherapy-naïve ES-SCLC which has now completed enrollment. RR % Progression during 6 cycles Median PFS (days) Median OS (days) 3-hr 100 1/12 197 (126-390) 312+* (175-516+) 24-hr 66 2/6 185 (43-224) 198 (80-315+) * Median not reached No significant financial relationships to disclose.

Phase I dose-escalation study of ON 01910.Na in combination with oxaliplatin in patients with advanced solid tumors.

e13133 Background: ON 01910.Na is a new multikinase inhibitor, which induces mitotic catastrophe and apoptosis in cancer but not in normal cells. Multiple pathways are involved including polo-like kinase. Cell killing effects are exposure time-dependent in vitro. In addition, a combination of ON 01910.Na with oxaliplatin produced significant synergy in effect, prompting phase I evaluation in humans. Methods: Patients with advanced cancer received a starting dose of ON 01910.Na 250mg/m2 as a 24hr continuous infusion (CI) repeated weekly. Oxaliplatin was administered biweekly as 85mg/m2, 2 hr infusion. The ON 01910.Na dose cohorts ranged from 250-1350 mg/m2 based on a modified Fibonacci escalation algorithm using the accelerated titration scheme (NCI). Intrapatient dose escalation was allowed. Pharmacokinetic (PK) sampling is to be performed at the maximum tolerated dose (MTD) level. Results: 13 patients (pts) (all females; ages: 38-71 yrs) have received combination therapy. At the highest dose (1350 mg/m2), 2 pts have received 6 weeks of continuous therapy. The overall mean (range) number of weeks of continuous therapy delivered was 11.1 (3-42). Grade 2 toxicities (2-grade increase in toxicity) include anorexia (1 pt), nausea (2 pt), fatigue (1 pt), peripheral sensory neuropathy (1 pt), abdominal cramps (1 pt), neutropenia (1 pt) and vomiting (2 pt). Partial response was observed in 1 pt with chemotherapy- refractory ovarian cancer (26 wk, prior progressions on paclitaxel+carboplatin [carbo], topotecan+docetaxel, carbo+gemcitabine, doxorubicin hydrochloride liposome, paclitaxel+bevacizumab, and etoposide). Stable disease was observed in a pt with colon cancer (42 wk, prior progressions on FOLFOX-4 and FOLFIRI+bevacizumab), and in a pt with ovarian cancer (19 wk, prior progressions on carbo+paclitaxel, doxorubicin hydrochloride liposome, gemcitabine+carbo, topotecan, vinorelbine, and bevacizumab+paclitaxel). Conclusions: It is feasible to administer ON 01910.Na as a 24hr infusion in combination with oxaliplatin. Tumor response was seen in chemotherapy-refractory ovarian cancer. The toxicities are tolerable and dose escalation continues. Further analysis of response and toxicity as well as PK at the MTD dose level is planned as this study continues to enroll patients. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Onconova Therapeutics, Inc. Onconova Therapeutics, Inc. Onconova Therapeutics, Inc.