Introduction. For patients with non-small cell lung cancer (NSCLC) tobenefitfromALKinhibitors,sensitiveandspecificdetectionofALK genomic rearrangements is needed. ALK break-apart fluorescence in situ hybridization (FISH) is the U.S. Food and Drug Administration approved and standard-of-care diagnostic assay, but identification of ALK rearrangements by other methods reported in NSCLC cases that tested negative for ALK rearrangements by FISH suggests a significant false-negative rate. We report here a large series of NSCLC cases assayed by hybrid-capture-based comprehensive genomic profiling (CGP) in the course of clinical care. Materials and Methods. Hybrid-capture-based CGP using nextgenerationsequencingwasperformedinthe course ofclinicalcare of 1,070 patients with advanced lung cancer. Each tumor sample was evaluated for all classes of genomic alterations, including base-pair substitutions, insertions/deletions, copy number alterations and rearrangements, as well as fusions/rearrangements.

Low-molecular-weight heparins are widely employed in prophylactic and therapeutic antithrombotic regimens for venous thromboembolic events. Excessive anticoagulation with lowmolecular-weight heparins rarely can precipitate catastrophic bleeding complications. Currently, there is no specific or reliable antidote that can reverse the anticoagulant effects of low-molecular-weight heparins efficiently and safely. This report describes three individuals with underlying hypercoagulable states, who developed clinically significant bleeding complications while receiving therapeutic anticoagulation with enoxaparin. All of the hemorrhagic events subsequently were safely and effectively reversed with a single intravenous bolus infusion of recombinant activated factor VIIa (RFVIIa) concentrate. Hemoglobins, prothrombin times, and clinical overt bleeding were monitored before and after the administration of RFVIIa. In all three cases, bleeding was controlled without an increase in thrombotic events. Our findings demonstrate that RFVIIa can rapidly and safely reverse the hemorrhagic adverse effects associated with excessive levels of low-molecular-weight heparin in patients with pre-existing hypercoagulable conditions and/or acute venous thromboembolism. Am. J. Hematol. 81:582-589, 2006. V V C 2006 Wiley-Liss, Inc.

Purpose Pre-clinical data suggest that combining imatinib with traditional cytotoxic chemotherapy may improve imatinib efficacy. We conducted a Phase I study of imatinib in combination with paclitaxel in patients with advanced or metastatic solid tumors. Methods Patients were accrued to the study in a standard 3 + 3 design. Patients were restaged every two cycles, and those with stable disease (SD), or better, continued study treatment without interruption. Maximally tolerated doses (MTDs) and pharmacokinetic profiles of combination imatinib and paclitaxel were assessed. Results Fifty-eight patients were enrolled, including 40 in the Phase I dose escalation portion. Alternating dose escalation of imatinib and paclitaxel on a 28-day cycle resulted in MTDs of 800 mg imatinib daily, on days 1–4, 8–11, 15–18, and 22–25, and 100 mg/m2 paclitaxel weekly, on days 3, 10, and 17. Two expansion cohorts, comprising 10 breast cancer patients and 8 patients with soft-tissue sarcomas, were enrolled at the MTDs. The most common adverse events were flu-like symptoms (64 %) and nausea/vomiting (71 %). The most common Grade 3/4 toxicities were neutropenia (26 %), flu-like symptoms (12 %), and pain (12 %). There were no relevant differences in the pharmacokinetic profiles of either drug when given in combination compared with alone. Thirty-eight subjects were evaluable for response, 18 (47.4 %) of whom experienced clinical benefit. Five patients (13.2 %) had a partial response (PR) and 13 patients (34.2 %) had SD; the average time to progression in those with clinical benefit was 17 weeks (range: 7–28 weeks). Conclusions This combination of imatinib and paclitaxel was reasonably safe and tolerable, and demonstrated evidence of anti-tumor activity. Further exploration in disease-specific Phase II trials is warranted.

3081 Background: GX15–070 is an antagonist of the BH3-binding groove of the bcl-2 family of anti apoptotic proteins. GX15–070 activates apoptosis in vitro and exhibits clinical activity in chronic lymphocytic leukemia (O’Brien et al, ASH 2005) with a recommended phase II dose of 28 mg/m2 every 3 weeks with DLT of grade 3 infusional CNS toxicities. Methods: In a standard titration design, 4 cohorts of 3 patients (pt) were treated with 5mg/m2 - 14 mg/m2 IV infused over 3 hours, weekly. Each cycle of therapy consisted of 4 weekly infusions. Pharmacokinetics (PK) and pharmacodynamic (PD) response based on plasma oligonucleosomal DNA levels were evaluated. Results: N=15 pts were treated. Median age was 58 (range 24–71). Median number of prior regimens was 4 (range 1–11). A total of 105 infusions (26 cycles) was administered. GX15–070 underwent first order elimination kinetics with a short initial distribution phase (α t1/2=0.6 h), followed by a longer elimination γphase (t1/2=43.8 h). At the 14 mg/m2 dose level, median C max and AUC values were 98 ng/ml and 276 ng.hr/ml, respectively. The coefficient of variation was low at 38%. Adverse events have mostly been observed during or shortly after the infusion and have been transient. The most common pertain to the central nervous and gastro-intestinal system (drowsiness, euphoria, ataxia, and abdominal pain). Most toxicities were mild to moderate, with the exception of grade 3 pain experienced by 2/2 pts with Hodgkin’s disease, that resolved rapidly but resulted in treatment discontinuation in 1 patient. One episode of Grade 3 infusional CNS toxicity was reported at 14 mg/m2 requiring the inclusion of 6 patients with no further DLT. No neutropenia, thrombocytopenia or lymphopenia have been reported. The MTD has not been reached. Mean increase in plasma oligonucleosomal DNA was 36 fold (range 0–182 fold) over baseline. Best response to treatment to date : SD ≥ 8 weeks (4); PD (5); too early (6). Conclusion: Weekly GX15–070 as been well tolerated at doses showing biological activity. Dose escalation will be pursued up to 28 mg/m2 weekly. No significant financial relationships to disclose.

Introduction: rFVIIa has been touted as a pancoagulant to reverse untoward hemorrhage in various clinical situations. We describe 3 hypercoagulable patients with enox-induced bleeding treated successfully and safely with rFVIIa. Case Summaries: Patient 1, a 58 year old female, received enox 60mg SQ q12 h for a left femoral DVT. On day 2, a bleeding right femoral pseudoaneurysm was detected. On day 3, the patient’s hematocrit fell from 37.5% to 22%, as swelling and pain ensued in the right thigh 4h after receiving her AM dose of enox. The concurrent PT, INR and aPTT were 18.1, 1.72 and 34.2 sec respectively. rFVIIa (20μg/kg) was administered intravenously with rapid cessation of bleeding. Patient 2, a 42 year old male, with a history of SLE, antiphospholipid antibody syndrome, and a distant history of a distal DVT was admitted for acute renal failure (creatinine of 4.2) secondary to lupus nephritis. One day after a kidney biopsy, the patient was placed on coumadin 5mg and continuous infusion of unfractionated heparin which was then changed to enox 70 mg SQ q 12. Both coumadin and enox were held after 4 d, once his PT, INR and aPTT reached 30, 3.97 and 56.2 sec respectively. The next day, a CT scan to evaluate a new abdominal pain revealed a large bleed at the kidney biopsy site. Despite transfusions of 6 bags of red blood cells, 4 bags of fresh frozen plasma, and 10mg of SQ vitamin K1, his hematocrit dropped to 19% and his PT, INR, and aPTT remained elevated at 28, 3.49, and 60.8 sec respectively. Thromboembolization was achieved to terminate bleeding from 2 of his 3 renal biopsy sites, the last of which was technically inaccessible. rFVIIa (30μg/kg) was administered as an intravenous bolus with immediate cessation of active bleeding. The next day, the antifactor Xa level was 0.12 anti-Xa U/ml and the PT, INR, and aPTT were 13.7, 1.09 and 45.1 sec, respectively and remained at these levels for the next 4 days. Patient 3, a 56 year old female with a prior history of multiple PEs and proximal DVTs due to protein S deficiency, was admitted for total knee arthroplasty. Admission labs were all within normal limits. Enox 80mg sq was initiated 24 h post-operatively for DVT prophylaxis. Four h later, brisk bleeding developed acutely from the surgical site. The simultaneous antifactor Xa level was 0.49 anti-Xa U/ml. rFVIIa (20μg/kg) was administered as an intravenous bolus and bleeding from the JP drain ceased instantly. All 3 patients stabilized within hours following administration of rFVIIa for their acute bleeding events; all required multiple transfusions of FFP and packed RBCs before rFVIIa; and all resumed anticoagulation without further bleeding. Discussion: Many clinicians fear that the rare untoward hemorrhage associated with any low molecular weight heparin (LMWH) preparation cannot be efficiently or rapidly reversed as there is no specific or reliable antidote. rFVIIa concentrate has reversed the anti-Xa properties of LMWH in ex vivo plasma-spiking experimental models but experience with use of rFVIIa to reverse LMWH-induced bleeding in vivo is lacking. Conclusion: This report suggests that rFVIIa administered in low doses (20–30μg/kg) reverses clinically significant LMWH-induced bleeding complications effectively, rapidly, and safely and should be considered as an adjunct in the treatment of LMWH-induced bleeding in patients with either hypercoagulable conditions or acute VTE. Clinical trials are needed to confirm the effectiveness of rFVIIa in this clinical scenario.