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7071Background: Allogeneic stem cell transplant (SCT) is the only potentially curative treatment for intermediate and high-risk myelofibrosis (MF). The use of Ruxolitinib (Rux) in the pre-SCT setti...

Purpose We investigated dose and pharmacokinetics of erlotinib in patients with hepatic dysfunction or renal dysfunction. Patients and Methods Patients were assigned to one of three cohorts: cohort 1, AST ≥ 3× upper limit of normal; cohort 2, direct bilirubin of 1 to 7 mg/dL; and cohort 3, creatinine of 1.6 to 5.0 mg/dL. Cohort 1a was amended for albumin less than 2.5 g/dL. Erlotinib was administered orally daily to groups of at least three assessable patients in escalating doses of 50, 75, 100, and 150 mg, starting with 50 mg in hepatic dysfunction patients and 75 mg in renal dysfunction patients. Results Between December 2001 and May 2005, 55 patients were accrued. The distribution of assessable patients was: two of three in cohort 1, three of three in cohort 1a, 16 of 30 in cohort 2, and 18 of 18 in cohort 3. Dose-limiting toxicity (DLT) consisted of elevation of both total and direct bilirubin ≥ 1.5× baseline in three patients (cohort 1: one of five patients at 50 mg; cohort 2: two of six patients at 100 mg). In cohort 2, one of seven patients had DLT at 75 mg. No DLT was encountered in cohort 3 with 12 patients at 150 mg. Apparent oral clearance (mean ± standard deviation) was cohort dependent as follows: 1.9 ± 0.2 L/h in cohort 1; 3.7 ± 4.7 L/h in cohort 1a; 2.4 ± 1.1 L/h in cohort 2; and 4.5 ± 2.7 L/h in cohort 3 (Kruskal-Wallis, P < .017). Conclusion Patients with renal dysfunction tolerate 150 mg of erlotinib daily and seem to have an erlotinib clearance similar to patients without organ dysfunction. Patients with hepatic dysfunction should be treated at a reduced dose (ie, 75 mg daily) consistent with their reduced clearance.

PURPOSE To characterize the maximum-tolerated dose, dose-limiting toxicities (DLTs), and pharmacokinetics of paclitaxel in patients with abnormal liver function. PATIENTS AND METHODS Adults with tumors appropriate for paclitaxel therapy who had abnormal liver function tests were eligible. Patients were assigned to one of three treatment cohorts: I, AST level twofold normal and bilirubin level less than 1.5 mg/dL; II, bilirubin level 1.6 to 3.0 mg/dL; and III, bilirubin level greater than 3.0 mg/dL. Doses were explored in at least three patients within each cohort. Although designed to assess a 24-hour infusion schedule, the trial was extended to also assess a 3-hour regimen. Pharmacokinetics were to be studied in all patients. RESULTS Eighty-one patients were assessable for toxicity. Patients with bilirubin levels greater than 1.5 mg/dL had substantial toxicity at all doses explored, whereas the toxicity for patients with elevated AST levels occurred at doses that ranged from 50 to 175 mg/m2 administered over 24 hours. In most patients, the DLT was myelosuppression. The pharmacokinetic data were insufficient to adequately evaluate the relationship between pharmacokinetics and toxicity in patients who received 24-hour infusions but provided evidence of a longer exposure to paclitaxel than anticipated for the doses used in this study in the 3-hour infusion group. CONCLUSION If paclitaxel is used for patients with elevated levels of AST or bilirubin, dose reductions are necessary, and an increase in toxicity can be anticipated. The increased myelosuppression observed is at least partially because of altered paclitaxel pharmacokinetics in such patients.

2056Background: GBM patients (pts.) aged 70 yrs or older have a poorer prognosis than younger pts. IDH1/2 mutations are more prevalent in younger GBM pts. and confer a more favorable prognosis. We compared molecular alterations between younger pts. (YP; 18 = 70), with additional stratification for wild type IDH1/2 status. Methods: GBM tumors submitted for tumor profiling between 2009 and Jan 2016 were tested with NextGen sequencing (SEQ), immunohistochemistry (IHC), fluorescent in-situ hybridization (FISH), fragment analysis (FA) and promoter methylation (Me). Retrospective analysis was performed on 375 GBM’s (YP = 197, OP = 178). Pediatric tumors were excluded. Chi-square was used for exploratory analyses and significance was defined as p < 0.05. Results: Alterations including overexpression of ALK (29% vs. 4.2%), RRM1 (47% vs. 32%) and mutations of ATRX (73% vs. 11%), BRAF (9.3% vs. 1.7%), IDH1 (24% vs. 3%), PDGFRA (7% vs. 0), PTPN11 (6.6% vs. 1%) and TP53 (58% vs....

2575 Background: 5-imino-13-deoxydoxorubicin (DIDOX; GPX-150) is a doxorubicin (dox) analog modified in two locations to prevent formation of a) cardiotoxic metabolites and b) reactive oxygen species. In a rabbit model comparing the cardiotoxicity of dox vs. DIDOX, chronic doses of each caused similar myelosuppression, but only dox caused cardiotoxicity as assessed by echocardiography and histopathology scoring. In view of the non-cardiotoxic nature of DIDOX along with its anticancer efficacy in preclinical studies, DIDOX was entered into a Phase I, open-label, non-randomized dose-finding study in up to 30 patients with solid tumors. Methods: Inclusion criteria included progressing solid tumors and cardiac ejection fraction (CEF) 110% of lower limit of institutional normal (assessed by MUGA). There are 8 dose cohorts and up to 8 cycles/cohort, dosing (iv) once every 3 weeks with an accelerated titration dosing design at the three lowest cohorts. Cohort A =14, B=28, C=56, D=84, E=112, F=150, G=200, and H=265 mg/m2/cycle. Dose was escalated to next dose level if < 1 dose limiting toxicity (DLT) is reported. Maximum tolerated dose (MTD) will be exceeded when 2 or more patients in a cohort elicit DLT; the next lower dose is defined as the MTD. DLT occurs when a decrease in CEF is grade 2 or higher, or grade 4 neutropenia lasts > 5 days. Results: Cohorts A-G have been completed. Number of patients for the cohorts are: A=1, B=1, C=1, D=4 E=3 F=3 G=4, and H = 2 (with 4 more to be enrolled in H). No decrease in CEF occurred in any cohorts. There were no DLTs in cohorts A-G. One patient in H had neutropenia grade 4 for 11 days (a DLT). Another patient in H had neutropenia grade 4 for 4 days. There was no disease progression at the completion of dosing for 6 of the 12 patients in cohorts E-H. In contrast, all 7 patients had disease progression in cohorts A-D. Conclusions: No cardiotoxicity was observed in any patient. No DLT was observed in cohorts A-G. With one DLT in cohort H, one more DLT will define MTD for DIDOX at 200 mg/m2. At higher DIDOX doses (E-H), 6 of 12 patients showed no disease progression. (IND No. 77,051). Clinical trial information: NCT00710125.

3056 Background: Epigenetic gene regulation is likely a contributing mechanism of cancer initiation and progression. Emerging evidence indicates that epigenetics may also play a key role in the development of chemoresistance in melanoma. We proposed combining the histone deacetylase inhibitor panobinostat (PT) and the demethylator decitabine (D) to overcome the development of epigenetic mediated temozolomide (TMZ) resistance in metastatic melanoma. Methods: Eligible patients must be ≥18, stage IV melanoma, and naïve or previously treated, with good performance status (ECOG ≤ 2) and normal organ functions. Patients with previous exposure to TMZ were allowed on study. The study includes the dose escalation of D and PT followed by expansion cohorts. D (0.1mg/kg SQ, 0.2mg/kg SQ) on days 1, 3, 5, 8, 10,12, PT (10mg PO, 20mg PO, 30mg PO) Q96h starting day 8, and TMZ 150mg/m2 PO daily on days 9-13 of each 42 day cycle. TMZ was increased to 200mg/m2 in the absence of grade 2 thrombocytopenia. Primary endpoints of phase I study are to determine the toxicity, safety and maximum tolerated dose (MTD) of the D, PT and TMZ combination. Results: To date, the phase I portion of this trial is completed. We report on the safety data for this combination. 17 patients received treatment (1st cohort: 5; 2nd cohort: 4; 3rd cohort: 4; 4th cohort: 4 ). M:F 11:6. Median age: 56 (32-77); Median ECOG PS: 1; 82% of the patients received at least one cycle (n=14). Median number of cycles given: 2 (0-6). To date, no DLTs have occurred. The MTD was not reached. The only grade (G) 4 adverse event (AE) is neutropenia on a patient in cohort 3 and it resolved within 3 days. G3 AEs included lymphopenia (n=4, 23%), anemia (n=2, 12%), leukopenia (n=2, 12%) and fatigue (n=2, 12%). Common G2 toxicities were leukopenia (n=5, 30%), neutropenia (n=4, 23%), nausea (n=4, 23%) and lymphopenia (n=3, 18%). Conclusions: The combination of D, PT, and TMZ appears to be safe and well-tolerated. The recommended dose for the phase II study remains to be determined.

8012 Background: LY2127399 (LY) is a human mAb that neutralizes membrane-bound and soluble B cell activating factor (BAFF). LY has activity in xenograft models of multiple myeloma (MM) and is being...

10525 Background: Trabectedin (ET-743, Yondelis), a marine-derived alkaloid has demonstrated significant activity in the treatment of soft tissue sarcomas (STS) in phase III trials, and has recently received EMEA approval in this indication. A subtype that accounts for 10% of STS, MRCL, displays the fusion FUS-CHOP in 95% of all cases. Preliminary results of neoadjuvant trabectedin (T) in advanced MRCL show reduction in the radiological density of the tumor, clinical improvement, and a pathological complete response (pCR) in the resected tumor mass. A phase II study to further determine the response to T in the MRCL population is presented. Methods: In this multicenter Phase II trial, patients (pts) with locally advanced (stage III) or locally recurrent MRCL were treated for 3 - 6 cycles with T (1.5 mg/m2 q3wk) in the neoadjuvant setting. Main endpoints were: pCR rate, objective response rate by RECIST, and correlation of molecular parameters from tissue samples with clinical outcomes. Results: Twenty-five pts with locally advanced MRCL have been recruited, of whom 20 are evaluable. All had the translocation (t12q13, 16p11) which causes the chimeric FUS-CHOP. Median age was 53 (23–75) and male:female ratio was 1. Thirteen pts completed therapy and underwent curative surgery. Pathological assessment was performed in 10 pts: 2 achieved pCR, 1 as per central pathology review and 1 by local pathology assessment. In addition, 1 pt had a very good pathological response. Ten patients remain to be histologically evaluated. Response rate by RECIST from pts who completed therapy was: 6 partial responses (46%) and 7 disease stabilizations. Remarkably, pathological response does not entirely correlate with response by RECIST since the pts with pCR still had radiological disease but no malignant component was found in the excised tumor mass (only connective and reactive tissue). Two serious adverse reactions of severe rhabdomyolysis, and asthenia, nausea and transaminase elevation were reported. Most common toxicities were liver enzyme elevation, neutropenia and thrombocytopenia. Conclusions: These preliminary results in terms of objective and complete pathologic responses, strongly suggest that T may have a role in the neoadjuvant setting in pts with MRCL. [Table: see text]

13003 Background: Improved survival of patients with newly diagnosed malignant glioma has been acheived with the addition of either intracavitary carmustine (BCNU) chemotherapy or oral temozolomide...

4582 Background: No standard 2nd-line chemotherapy exists for metastatic TCC. Response rates to 2nd-line chemotherapy for advanced TCC are low and response duration tends to be short. Bortezomib is a proteasome inhibitor with preclinical activity against TCC. Methods: Twenty-five patients with advanced TCC who had been previously treated with combination chemotherapy were enrolled in a multi-institutional single-arm trial from December 2003 through April 2005. Treatment consisted of bortezomib 1.3 mg/m2 intravenously twice weekly for two consecutive weeks, followed by a 1-week rest period. The primary endpoint was objective response rate by RECIST criteria. Secondary endpoints included safety, toxicity, progression-free survival, and overall survival. Results: The median age was 65.5 yrs (59–7-74.9) and the median number of years since diagnosis was 1.4 (0.9–3.6). 72% of patients were male. 65% of patients had visceral metastases, and 20% of patients had lymph node-only metastases. Prior chemotherapy regimens included gemcitabine/cisplatin (50%), gemcitabine/carboplatin (25%), paclitaxel/carboplatin (5%), single agent paclitaxel (5%), and other multi-agent regimens (15%). Median hemoglobin was 11.4 g/dL (inter-quartile range 10.6–12.3). No objective responses were observed. The median time to progression was 2.1 months (95% CI= 1.4–5.5). Median overall survival was 5.5 months (95% CI= 3.6–8.1). Toxicity was modest. Grade 3/4 drug-related toxicities included thrombocytopenia (6%), sensory neuropathy (6%), hyperglycemia (6%), neuropathic pain (6%), dehydration (6%) and vomiting (6%). There were no treatment-related deaths. Conclusions: Although bortezomib is well tolerated in patients with previously treated advanced TCC, it does not have anti-tumor activity as 2nd-line therapy in TCC. No significant financial relationships to disclose.

4597 Background: Metastatic renal cell cancer (RCC) is associated with a

6586 Background: For cell membrane association, small GTPases such as Ras, Rap1A, Rab, and Rho must undergo post-translational isoprenylation modification. Isoprenoid intermediates of the mevalonat...