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429 Background: Patients (pts) with advanced UTC who fail first-line therapy have poor prognoses. Durvalumab (D; anti-PD-L1) 10 mg/kg every 2 weeks is approved for treatment of metastatic urothelial carcinoma (mUC) after progression on platinum-based chemotherapy (CT). Further understanding of long-term safety and efficacy of D in platinum and non-platinum pretreated pts, using a fixed dose every 4 weeks (Q4W), is of value. Methods: Module A of the phase IIIb STRONG study (NCT03084471) investigated the safety of fixed-dose D (1500 mg, Q4W) in pts with urothelial and nonurothelial UTC who progressed on or after platinum/non-platinum CT. The primary endpoint was the number of pts with adverse events of special interest (AESIs) – events with an inflammatory or immune-mediated mechanism that may require interventions (eg, steroids/immunosuppressants), including immune-mediated adverse events (imAE). AEs with onset date on or after the date of first dose and up to 90 days after study discontinuation were included. Secondary endpoints included serious AEs and overall survival (OS). Exploratory endpoints included objective response rate (ORR) and disease control rate (DCR) (investigator assessed per RECIST 1.1). Results: A total of 867 pts received D monotherapy. Median age was 68.1 yr and 80.0% were male; 87.1% had an ECOG PS 0-1 and 12.7% had ECOG PS 2. Most (96.3%) had urothelial UTC, including urothelial variants. Tumor PD-L1 expression was high (≥25%) in 239/577 (41.4%) pts with available data. Median treatment and follow-up duration were 12.1 wk (range 1-128) and 13.8 mo (range 0.0-28.8), respectively. Safety data are reported in the table. Deaths related to study treatment occurred in 9 pts (1.0%). At data cutoff (March 31, 2020), 30.8% of pts were in survival follow-up. Median OS was 7.0 mo (95% CI: 6.4-8.2); OS rate at 1 and 2 yr was 35.8% (95% CI: 32.5-39.2) and 20.2% (95% CI: 16.5-24.1), respectively. ORR was 17.7% with complete responses in 5.1% of pts. DCR at 6 mo was 33.0%. Median OS of subgroups: PD-L1 high or low: 9.3 mo (95% CI: 6.7-12.7) and 6.5 mo (95% CI: 5.8-8.1); ECOG PS 0-1 or 2: 8.4 mo (95% CI: 7.2–9.8) and 3 mo (95% CI: 2.0-4.1); urothelial and nonurothelial UTC: 7.0 mo (95% CI: 6.4-8.2) and 7.0 mo (95% CI: 2.7-10.2), respectively. Conclusions: Fixed-dose D monotherapy Q4W is convenient with an acceptable safety profile in previously treated pts for UTC. Long-term safety and efficacy data reported are consistent with published studies of D and other IO agents in this setting. Clinical trial information: NCT03084471 . [Table: see text]

6032 Background: GLS-010 is a novel fully human anti-PD-1 mAb. Previous Phase I study exhibited favorable result of tolerance, preliminary efficacy and 240mg fixed dose q2w was selected as Recommended Phase II Dose (RP2D). This Phase II clinical trial is aimed to further evaluate the safety and anti-tumor activity of GLS-010 in patients with recurrent or metastatic cervical cancer. Methods: PD-L1 positive (combined positive score (CPS) ≥1) patients with recurrent or metastatic cervical cancer who had received one or more lines of chemotherapy were enrolled and received GLS-010 240mg every 2 weeks. Primary endpoint was the objective response rate (ORR) per RECIST 1.1, secondary endpoints included duration of response (DoR) and safety. Results: From May 16th 2019 to December 24th 2019, 44 pts were enrolled and treated in the study. As of December 24th 2019,the median line of prior systemic chemotherapy was 2(range: 1~4), and 59% (26/44) of pts had received ≥2 previous lines of chemotherapy. The median number of GLS-010 doses was 1.5(range: 1~4). 25 pts received response evaluation per investigator review. With a median follow-up of 2.9 months, 7 of 25 evaluable pts achieved a partial response (PR). The ORR was 28% (95% CI, 12.07-49.39), with 7 pts achieving a PR ( 3 of 7 confirmed), 3 pts achieving stable disease (SD) and 15 pts with progressive disease (PD), 1 of which was assessed as dissociated response with treatment ongoing. Median duration of response had not been reached yet. 33 of 44 patients (75%) experienced one or more treatment-related adverse events (TRAEs) per NCI CTCAE v4.03, most of which were grade 1 or 2. The most common TRAEs were Anaemia (15/44), and 73.3% of them were grade 1 or 2. The most common ≥grade 3 TRAE included Anaemia (4/44). As data cut off, only 1 pt discontinued treatment due to adverse event. Conclusions: GLS-010 showed impressive therapeutic activity and manageable safety profile in Chinese recurrent or metastatic cervical cancer patients. Current evidence support further development of GLS-010 in this and more indications. This trial is still ongoing, and we are looking forward to further results. Clinical trial information: NCT03972722.

484 Background: Patients (pts) with advanced UTC who fail first-line therapy have a poor prognosis and limited treatment options, with only modest benefit from chemotherapy. D (anti-PD-L1 antibody) is approved for the treatment of metastatic urothelial carcinoma after progression on platinum-based chemotherapy. Methods: Module A of the phase IIIb STRONG study (NCT03084471) will determine the short- and long-term safety of a fixed dose of D monotherapy (1500 mg, every 4 weeks) in pts with urothelial and non-urothelial carcinoma of the UT who progressed on or after prior chemotherapy. The primary endpoint is to determine the number of pts with adverse events of special interest (AESIs). This analysis included AEs with onset date on or after the date of first dose and up to 90 days after discontinuation of study treatment. Interim results from module A are reported. Results: A total of 700 pts received D monotherapy. Median age was 68.2 yr and 79.6% were male; 88.6% had an ECOG PS 0 or 1 and 11.3% an ECOG PS 2. Most (88.4%) had urothelial (transitional cell) carcinoma. Tumor PD-L1 expression was high (tumor or immune cell membrane positivity ≥25%) in 183/436 (42%) pts with PD-L1 data. Median treatment duration was 11.7 weeks (range, 1-73). AEs of any grade were reported in 86.9% of pts (Table), and in 89.0%, 86.9%, and 78.5% of pts with ECOG PS 0, 1, or 2, respectively. The most common grade ≥3 AESI was increased lipase (1.4%). Deaths related to study treatment occurred in 10 pts (1.4%). Conclusions: Fixed-dose D monotherapy has an acceptable safety profile as second-line therapy for UTC. Long-term safety data reported here are consistent with published studies of D monotherapy. Clinical trial information: NCT03084471.

e14089 Background: Fixed dose schemes, regardless of body weight, have been accepted by the regulatory agencies for the PD-1 targeting antibodies. Zaho X. and Ratain M. have elucidated that the mean steady state concentrations of nivolumab (N) at flat-doses of 240 mg Q2W or 480 mg Q4W were 57 µg/mL and 47 µg/mL, respectively. These levels are very similar to those observed at the dosage of 3 mg/kg Q2W. Considering the long half-life of N, its mechanism of action and the absence of correlation between exposure and response or toxicity at clinically tested doses, other schemes can be explored. Moreover, therapeutic drug monitoring (TDM) can contribute to individualize and optimize dosage. We determined serum N levels in patients with solid tumors. Methods: The PK profile of N was analyzed in 15 patients with solid tumors who received 3 mg/kg Q2W from May 2017 through January 2019. Eligible patients had non-small-cell lung cancer (n = 7), urothelial cancer (n = 1), gastric cancer (n = 1), breast cancer (n = 1), renal cell cancer (n = 1), colorectal cancer (n = 1), prostate cancer (n = 1), melanoma (n = 1) and sarcoma (n = 1). Free N serum concentrations were determined with a quantitative ELISA capable of detecting ≥ 0.3 µg/mL (Shikari Q-Nivo, Matriks Biotek, Ankara, Turkey). A total of 28 TDM were done after steady state (6th and 26th cycle). Results: For different reasons, 9 patients received N at 3, 4, 5, 6 or 7 week intervals once the steady state was reached. In these patients, a median reduction of 20.8% (6.7% - 43.0%) of the received doses was observed. Mean plasma concentrations of N observed after administration every 2 weeks was 73.5±32.5 µg/mL (n = 9). Once the steady state was reached, mean plasma concentrations at 3, 4, 5, 6 or 7 weeks, were 54.0±1.3 µg/mL (n = 2), 45.1±25.3 µg/mL (n = 7), 42.9±29.5 µg/mL (n = 5) and 24.4±11.7 µg/mL (n = 5), respectively. No statistically significant differences were observed in the serum levels of N between the dosing intervals of 3, 4 and 5 weeks and the standard regimen (Q2W) (p > 0.05). These data are similar to those described by Long G.V. et al. that compared N pharmacokinetic exposure for the 480 mg Q4W schedule simulated in 3817 patients across multiple tumor types with those for the 3 mg/kg Q2W and 240 mg Q2W schedules. Conclusions: The incorporation of the TDM of N in routine clinical practice could help to maintain a therapeutic drug plasma concentration with lower or less frequent doses, adding a financial benefit, without decreasing clinical efficacy. Further randomized trials to explore alternative dosing schemes of N, including personalization through TDM, are warranted

6504 Background: Pembrolizumab (P) and nivolumab (N) were initially investigated and FDA-approved with weight-based dosing strategies, but later the approval label was amended to a fixed dose administration. Given increasing concerns about financial toxicity of cancer therapies, we hypothesize that weight-based dosing of P and N and allowing vial sharing among patients will result in substantial cost savings. Methods: We obtained IRB approval to retrospectively examine all outpatient doses of P and N given at three Stanford Medicine infusion centers between July 1, 2018 and Oct 31, 2018 using the Stanford Medicine Research Data Repository (STARR) database. We performed cost-minimization analysis modeling the impact of dosing strategies based upon patient weight versus fixed dosing (2 mg/kg vs 200 mg q3wks for P; 3 mg/kg vs 240 mg q2wks or 6 mg/kg vs 480 q4wks for N). “Dose-minimization” (DM) was defined as whichever dose was lower (weight-based or fixed dose). The impact of allowing vial sharing (considering commercially available vial sizes) between patients treated at the same site and on the same date was assessed. Average sales price (ASP) from Center for Medicare and Medicaid Services for Part B drugs was used for cost estimates. Results: A total of 1,029 doses of P or N were administered across a variety of cancer types. For most doses (N = 789, 77%), the calculated weight-based dose was less than the fixed dose. DM resulted in decreased usage and expenditures of both P and N, and a further decrease was observed with vial sharing. Total savings estimated with DM and vial sharing strategy were > $1.4 million (Table). This amounted to savings of > 22,000 mg of P (112 fixed doses) and > 11000 mg of N (47 fixed doses). Savings were greatest at the highest volume infusion center. Conclusions: Alternative dosing strategies of P and N would result in significantly less drug utilization and pharmaceutical expenditure without anticipated impact on efficacy. Potential barriers to this approach include existing policies regarding vial sharing and drug vial sizes. [Table: see text]

e12593 Background: Capecitabine (C) is the only oral chemotherapy agent for metastatic breast cancer (MBC), and compared to IV agents, can be continued indefinitely if toxicities can be managed. The optimal dose and schedule of C are not known. FDA approved dose of 2500 mg/m2 daily is associated with median PFS (progression free survival) of 4-5 months and dose reduction and discontinuation rates from toxicity of 35% and 16% respectively. According to Norton-Simon mathematical model of tumor growth in which dosing schedules are determined based on efficacy, a 7 day on and 7 days off (7-7) schedule of C was predicted as optimal. We report efficacy and toxicity of fixed dose C (1500 mg BID) on a 7-7 schedule in MBC. Methods: Retrospective chart review of patients with MBC treated at our institution between June 2013 and December 2018 and received fixed dose C (1500 mg BID) on a 7-7 dosing schedule were included. Results: 39 patients with MBC were identified; 14 (35%) had de novo MBC and 25 (62.5%) had recurrent disease. 31 (77.5%) had ER+ disease, 6 (15%) were HER2+, and8 (20.5%) had triple negative breast cancer (TNBC). 10 (25%) had received no prior chemotherapy, 15 (37.5%) had received 1 line of chemotherapy, and 14 (35%) had received ≥2 lines of chemotherapy. Median PFS was 13 months. PFS was 17 months in ER+ patients and 8 months in patients with TNBC. Palmar plantar erythrodysesthesia (PPE) was the most frequent toxicity with 11 (27.5%) having mild PPE, 2 (5%) with moderate PPE, and 5 (12.5%) with severe PPE. Mild diarrhea was experienced by 14 (35%) and one patient experienced severe diarrhea. One patient experienced grade 3 neutropenia. No patients discontinued C due to toxicity. 11 (27.5%) required a dose reduction. Conclusions: Fixed dose capecitabine (1500 mg oral BID) on a 7 day on and 7 day off schedule is associated with encouraging PFS and has limited toxicity and a low rate of dose reduction and therapy discontinuation. Randomized trial comparing this dose and schedule of capecitabine to standard dose and schedule of capecitabine is ongoing.

125 Background: GLS-010 is a novel fully human anti-PD-1 mAb. Phase Ia exhibited good result of tolerance and 240mg fixed dose was selected. Phase Ib is to explore efficacy and biomarkers in different types of advanced cancer. Here we report the preliminary result in Chinese gastrointestinal (GI) tumor patients (pts) from the phase Ib. Methods: All pts enrolled received GLS-010 240mg every 2 weeks. Tumor response was assessed by RECIST 1.1 every 8 weeks. Adverse events (AEs) were graded by NCI CTCAE v4.03. Several biomarkers were evaluated, including PD-L1 by IHC, tissue tumor mutation burden (tTMB) by whole exome sequencing (WES) from FFPE tissue, blood TMB (bTMB) by the multi-gene panel based next-generation sequencing (NGS) from blood ctDNA. Results: Until September 2018, 23 pts (including 10 gastric cancer or GC, 10 esophagus cancer or EC, and 3 biliary tract cancer or BTC) were enrolled in the phase 1b. The median dosing number was 4 (range: 1~16). The most common treatment related AEs included haemoglobin decreased (16/23, G1-2), leukopenia (6/23, G1-2), fever (4/23, G1), blood bilirubin increased (4/23, G1-3), ALT increased (3/23, G1), etc. Treatment–related grade 3-5 AEs include 1 multiple organ dysfunction syndrome, 1 interstitial lung disease and 1 blood bilirubin increased. 21 pts received response evaluation. Four patients achieved partial response (PR), including 1 GC (1/9), 2 EC (2/10), and 1 BTC (1/2). 2 subjects had stable disease (SD) at Week 8, and were still in treatment. No apparent correlation was observed between treatment response and PD-L1 expression. However, both tTMB and bTMB data obtained from 18 patients support positive correlation to tumor response. The tTMB level of 3 PR pts with valid data is significantly higher than that of 9 PD pts (P = 0.036). The bTMB level of 4 PR pts with valid data is significantly higher than that of 10 PD pts (P = 0.049). Conclusions: GLS-010 showed promising efficacy and acceptable safety in Chinese patients. For Chinese GI tumor TMB may be a useful biomarker to predict the treatment response to PD-1 inhibitor. Comparing to tTMB, bTMB may be of more future value due to its applicability in clinical practice.

2524Background: Seribantumab (MM-121) is an anti-ErbB3 human monoclonal antibody being tested as an anti-cancer therapy for patients with high expression of heregulin mRNA in NSCLC (SHERLOC study, ...

10020Background: This multi-site, double blind, parallel arm, fixed dose phase III study compared megestrol acetate 480 mg/day, dexamethasone 4 mg/day and placebo for their net short-term effect on...

172 Background: In-situ forming polymer-delivered, subcutaneous leuprolide acetate (SC-LA) has previously been shown to suppress serum T levels to ≤20ng/dL in advanced PCa patients. Currently, luteinizing hormone releasing hormone agonists are dosed independently of body weight (BW) or age. Reaching nadir T90% of patients in all age groups (including 100% of those 90 kg) and youngest age (

TPS538 Background: Despite initial high response rates to current SoC first-line chemotherapy, most patients with locally advanced or metastatic urothelial carcinoma (UC) eventually experience disease progression. With no defined SoC second-line therapies, prognosis remains poor. Durvalumab is a selective, high affinity, engineered human IgG1 mAb that blocks programmed cell death ligand-1 binding to programmed cell death-1 and CD80. Most current Phase 3 trials of durvalumab were initiated using weight-based dosing (mg/kg) regimens. STRONG (NCT03084471), a Phase 3b safety study of durvalumab alone or in combination with the anti-CTLA-4 agent tremelimumab is being conducted to expand understanding of the safety of fixed dosing in patients with advanced solid tumors. Module A of the study is enrolling patients with UC and non-urothelial carcinoma of the urinary tract (any histology) for treatment with durvalumab in the second-line setting post-chemotherapy. Other study modules will include durvalumab + tremelimumab combination arms. Methods: This is an open-label, multicenter study. Module A will enroll approximately 1200 patients to receive durvalumab monotherapy 1,500 mg i.v. q4w until disease progression or unacceptable toxicity. The study opened for enrolment on 17 April 2017 and is expected to be completed within 5 years. Patients must have histologically or cytologically confirmed disease that has progressed during or after nonplatinum or platinum-based chemotherapy either for metastatic disease or progressive disease less than 12 months after adjuvant or neo-adjuvant chemotherapy, and ECOG performance status 0–2. The primary objective is to assess the safety of durvalumab in terms of incidence, severity, nature, seriousness, intervention, outcome and causality (including immune-relatedness) of adverse events of special interest (AESIs). Secondary objectives include additional assessment of safety and tolerability, the frequency of treatment interruption and discontinuation, and overall survival. Clinical trial information: NCT03084471.

TPS111 Background: Bacille Calmette-Guerin (BCG) is the most effective agent in the treatment of high grade superficial bladder cancer (HGSBC); however, not all patients respond to BCG, and recurrent disease is associated with a poor prognosis. The blockade of immune checkpoints of the pathway involving programmed death 1 (PD1) has been shown recently to be effective in cancer therapy. We started the first trial in the United States to combine an anti-PD1 drug (pembrolizumab) with BCG therapy in patients with HGSBC. Methods: The primary objective of the study was to determine the safety of administering a 200 mg fixed dose of pembrolizumab in conjunction with intravesical BCG treatment in HGSBC patients who have failed two courses of induction therapy or one course of BCG induction therapy followed by maintenance therapy. Patients included had to have pathologically documented HGSBC (Ta, T1) at time of restaging, or have pathologically documented high grade CIS of the bladder at time of initial resection for recurrent/persistent bladder cancer. Subjects were treated with six cycles (21 day cycle) of pembrolizumab treatment combined with six consecutive weeks of concurrent BCG installation beginning with cycle 3 of pembrolizumab. The first three subjects were to be treated at a dose of 100 mg pembrolizumab to ensure safety for the combination. If no safety issues were to happen, dosing was to be escalated to 200 mg every three weeks. Our secondary objective was to determine the 19 week and the three, twelve, and twenty-four month post-treatment completion complete response rate. The first patient received cycle 1 of pembrolizumab treatment in July of 2015. As of the date of writing this letter, five patients have completed treatment on this trial. The trial is soon to open a second site at Henry Ford Health System in addition to Southern Illinois University with the goal of full enrollment to be achieved in the next 6 months. Clinical trial information: NCT02324582.

Purpose The majority of cytotoxic drugs for adults are dosed based on body surface area (BSA), aiming to reduce interpatient variability in drug exposure. We prospectively studied the usefulness of BSA-based dosing of cisplatin in patients at extremes of BSA values. Patients and Methods Patients were randomly assigned to receive a fixed dose of cisplatin in course 1, and a BSA-adjusted dose in course 2, or vice versa. The fixed dose was based on the average BSA for males and females, while extremes were set at BSA values exceeding the average ± 1 standard deviation. Subsequently, we retrospectively analyzed data from a normal population. Results In 25 patients assessable for both courses, the use of a fixed dose of cisplatin resulted in reduced exposure to unbound platinum in patients at the upper extremes of BSA (P = .003) and higher exposures in patients at the lower extremes (P = .009), as compared with exposures following the BSA-adjusted dose. Although clearance was related to BSA (R2 = 0.44; P < .001), only a small reduction in interpatient variability in clearance after correction for BSA was achieved (20.8% v 17.1%). In the retrospective analysis, compared with the average patient, the clearance of unbound platinum in patients with a BSA value ≤ 1.65 m2 was 16% slower (P < .001), while an 18% faster clearance (P < .001) was observed in patients with a BSA value ≥ 2.05 m2. Conclusion Unless better predictors for platinum clearance are identified, fixed-dose regimens per BSA cluster (≤ 1.65 m2; 1.66 m2 to 2.04 m2; ≥ 2.05 m2) are recommended.

2526 Background: Gemcitabine (gem) with nab-paclitaxel (nab-p) is known to have antitumor activity and a favorable toxicity profile. The addition of bevacizumab (bev) to nab-paclitaxel has also been found to enhance nab-paclitaxel cytotoxicity. Methods: We therefore performed a modified 3+3 dose escalation study with 15 dose levels of fixed dose gem 1000 mg/m2IV (day 1, 8, 15) and escalating doses of nab-p IV (day 1,8, 15) and bev IV (day 1,15) every 28 days. The study design allowed for the possibility of multiple MTDs. Correlative studies on VEGF polymorphism and response were planned. (NCT01113476). Results: 103 patients (45 male) with advanced cancers were enrolled (19 ovarian, 18 pancreatic, and 18 gastroesophageal (GE) cancers among the most common). All patients were ECOG PS 0-2, median age was 60 years (range 17-85), and 51 patients (50%) were gem refractory with a median of 3 prior lines of therapy. 3 DLTs were observed during dose escalation - one with nab-p 50 mg/m2 and bev 10 mg/m2 (grade 3 dysphagia, dehydration), one with nab-p 75 mg/m2 and bev 10 mg/m2 (grade 3 cellulitis) and one with nab-p 150 mg/m2 and bev 5 mg/m2 (grade 3 bacteremia, hypotension). 2 DLTs were observed among the 13 patients in the nab-p 100 mg/m2 and bev 5 mg/m2 expansion cohort (one grade 3 diarrhea, one grade 3 fatigue) and 1 DLT among the 12 patients in the nab-p 75 mg/m2 and bev 10 mg/m2 expansion cohort (grade 3 rectal bleed). Dose escalation up to nab-p 125 mg/m2 and bev 15 mg/m2was well tolerated with no MTD. One patient with gem refractory peritoneal papillary carcinoma achieved a complete response, 13 patients (13%) had partial responses (PR), and 54 patients (52%) had prolonged stable disease (pSD) ≥ 12 weeks. 4 patients achieving PR and 26 patients with pSD were previously gem refractory. 3/6 (50%) small cell cancers achieved PR and all 6 of these patients had tumor shrinkage of at least 25%. 4/19 (21%) ovarian cancers achieved PR, 3/18 (17%) GE cancers achieved PR, and 1/18 (6%) pancreatic cancers achieved PR. Conclusions: The combination of gem 1000 mg/m2, nab-p 125 mg/m2 and bev 15 mg/m2 is safe, well-tolerated, and has activity even at lower doses in advanced malignancies, including gem refractory tumors. Correlative VEGF polymorphism studies are ongoing. Clinical trial information: NCT01113476.

e14015 Background: OMC, as continuous administration of low doses of chemotherapy acts as direct cytotoxic as well as antiangiogenetic agent. wP also induces antiangiogenic effects in mouse models. The aims of this trial were to determine the recommended Phase 2 dose (RP2D) of wP given in combination with OMC, and estimate activity and safety of the combination. Methods: Methods This is a single-center, phase 1 trial. Patients (pts) > 18 years with refractory metastatic cancers were eligible if no standard curative measures existed. Paclitaxel was administered IV weekly (D1, D8, D15; D1 = D28) in combination with a fixed dose of OMC (50mg x2/day). A 3+3 design was used for Dose-Escalation of wP (40 mg/m² to 75 mg/m²), followed by an expansion cohort at RP2D. The primary endpoint was the dose-limiting toxicity (DLT), defined as grade > 3 non-hematological or grade 4 hematological toxicity (NCI-CTCAE v4.0) occurring in the first 28 days, or any toxicity leading to a dose reduction. Results: 28 pts (18 in dose-escalation phase and 10 in expansion cohort) were included between May 2011 and December 2013. The sex ratio was 2:1, the median age was 54.5 (range, 26-67); the most common primary tumors were colorectal cancers (n = 9), sarcomas (n = 4), Head & Neck (n = 3). 16/18 pts enrolled in the dose-escalation phase were evaluable for DLT. DLT occurred in 0/3, 1/6 (neuropathy), 0/3 and 2/4 pts (hematological toxicity) at dose 40, 60, 70 and 75 mg/m² of wP, respectively. The RP2D of wP was 70 mg/m2; 1/10 pts in the expansion phase had an hematological DLT. At RP2D (n = 14), the maximal grade of adverse events (AE), regardless of causality, was Gr2 in 3 pts, Gr3 in 7 pts, Gr4 in 3 pts and Gr5 in 1 pt; the maximal grade of treatment-related AE was Gr1 in 1 pt, Gr2 in 8 pts, Gr3 in 3 pts and Gr4 in 1 pt (no AE in 1 pt). At RP2D, the median PFS was 2.8 mo and Growth Modulation index was ≥1.33 in 4/14 pts (29%). There was 1 objective response (1/14; 7%): 1 pt with lung adenocarcinoma achieved a partial response. Conclusions: The combination of OMC and wP resulted in an acceptable safety profile. Further evaluation of this combination with wP at 70mg/m² could be warranted in a phase 2 trial. Clinical trial information: NCT01374620.

PURPOSE Based on in vitro studies that have shown synergistic effects of sequential administration of methotrexate (MTX) and thioguanine (6-TG), we conducted a pharmacologically guided trial of sequential MTX and 6-TG to determine the following: (1) the maximum-tolerated dose (MTD) of 6-TG; (2) the nature of the dose-limiting toxicity; and (3) the modulation effect of MTX on 6-TG given by this sequence and schedule. PATIENTS AND METHODS Thirty-one children with advanced malignancies (acute leukemia, n = 10; lymphoma n = 10; and solid tumors, n = 11) were treated weekly for 3 weeks with a 2-week rest; treatment consisted of a fixed dose of MTX (30 mg/m2 over 24 hours) followed by a 2-hour infusion of 6-TG in escalating doses. RESULTS Measurement of plasma MTX, 6-TG, and mononuclear 5-phosphoribosyl-1-pyrophosphate (PRPP) levels indicates that the desired biochemical modulation and serum levels were achieved. Nonhematologic toxicities were mild and the dose-limiting toxicity was bone marrow depression. A 300-mg/m2 dose of 6-TG with MTX is considered the MTD. Responses were noted in patients with lymphoma. CONCLUSION Encouraging antitumor effects were produced with this regimen in heavily pretreated patients with lymphoma, particularly Hodgkin's disease (HD). The durations of responses were 17, 13+, 12, 9, and 7+ months. A phase II trial of the MTX/6-TG combination is warranted for the treatment of relapsed lymphoma.

7505 Background: Classic dosing of chemotherapy does not account for pts’ variability and some pts could be underdosed. We tested whether toxicity-adjusted dosing of chemotherapy was more active th...

e16062 Background: Growing evidence (eg, Klotz et al, EAU Congress 2014) suggest that prostate cancer patients undergoing androgen deprivation therapy who attained castrate levels of testosterone (...

e17028 Background: In pre-clinical models of HNSCC, VEGFR, PDGFR, and c-kit are frequently overexpressed. Upregulation of angiogenesis by VEGFR activation is a mechanism of resistance to EGFR inhib...

2575 Background: Preclinical data indicate that abexinostat enhances sensitivity to DNA-damaging agents, such as doxorubicin, particularly when administered 48h before infusion. A phase I dose-esca...

e15016 Background: Thougha triplet chemotherapy with D plus CF (DCF) has shown promising activity, high incidence of adverse events (AEs) especially in febrile neutropenia (FN) was observed in previous studies for head and neck cancer (TAX323, 324) and gastric cancer (TAX325). To reduce its AEs with keeping activity, we conducted a multicenter open-label phase I/II study of biweekly D plus CF for AEC. Methods: Eligibility criteria included histologically proven AEC with measurable disease, age 20 to 75, non-resectable or recurrent disease, performance status (PS) 0 to 1. Pts received escalating doses of D (dose level (DL) 1: 30 mg/m2, DL 2: 40 mg/m2, on days 1, 15) in combination with fixed dose of CF (cisplatin 80 mg/m2 on day 1, fluorouracil 800 mg/m2on days 1-5) repeated every 4 weeks with 3+3 design in phase I part (P-I). The primary endpoint of P-I was dose limiting toxicity (DLT) and that of phase II part (P-II) was response rate (RR) defined by central peer review. Based on a SWOG two stage design (p0=35%, p1=50%; one-sided a=0.1, β =0.2) at least 22 responders among 50 eligible pts should be observed to satisfy the primary endpoint. Results: Between Feb 2009 and Mar 2010, 62 pts were enrolled for P-I and P-II. In P-I, 10 pts were enrolled with DLT of 0/3 in DL1 and 2/7 in DL2. Considering DLT and treatment compliance, the recommended dose for P-II was determined as DL1. Thus, 3 (P-I) and additional 52 pts (P-II) were analyzed: 53 for efficacy (excluded 2 ineligible pts) and 55 for safety. Pts characteristics were as follows: male/female 49/6, age median 61 (range 44 to 75), PS 0/1 39/16. The RR was 62% (95% confidence interval, 48-75%, p2) combined with CF showed promising activity and tolerability. A phase III study comparing CF with DCF is warranted. Clinical trial information: UMIN000001737.

e19570 Background: In comparative trials of P and F, bone and joint pain are evident and with similar incidences. Also, muscle pain is clinically noted. Pain severity may differ between P and F, especially when a short fixed-dose regimen of F is used. Methods: This is a prospective observational and ethics-approved study. It compares the incidence & severity of muscle and/or joint pain (MJP) in patients (pts) receiving P (6mg SC for 1 day) or fixed-dose F (300mcg SC for 7-8 days) initiated 24 hours after chemotherapy. Eligible were women with breast cancer receiving neo- or adjuvant chemotherapy, and P or F. Choice of P or F were at the oncologist’s discretion based on patient preference & insurance coverage. Pts were ineligible if they could not complete the pain diary, or had received P or F in the past 6 months. Efficacy of P and F was evaluated by comparing febrile neutropenia (FN) and neutropenia (N) requiring delay of the second cycle of chemotherapy. Patient & treatment characteristics were captured to assess for risk factors for developing MJP. A pain diary assessed MJP severity, its management and impact on everyday activities. It was completed starting the evening of chemotherapy for 14 consecutive days. Statistical analysis was performed with Stata 12, including multi-level longitudinal mixed models for MJP scores. Results: 140 pts were enrolled with mean age 52 yr and 58% receiving docetaxel-based chemotherapy. One-third received F and two-thirds received P. Both diary muscle and joint pain peaked in prevalence and severity on days 3 to 6. Over 50% of pts reported MJP at the peak. Pain that increased ≥3 points from baseline was reported by 48% of pts. Daily activities were affected in 48% of 1,960 reporting-days, with 26% reporting moderate or severe impairment. Despite similar incidences of pain, P was associated with lower mean muscle (p=0.0049) and joint (p=0.014) pain scores by regression analyses. FN and N were not different. Use of docetaxel was the sole baseline risk factor for developing MJP. Conclusions: Patients experience substantial MJP with impairment of daily activities but pts receiving pegfilgrastim experience less pain and less burden relating to pain.

10037 Background: Local tumor control and preservation of limb function are major goals of treatment of STS. With current standard of combining limb-sparing surgery and 5-6 weeks of neoadjuvant or adjuvant 50-65 Gy radiation, reducing local recurrence has been a challenge with rates of 15-30%. Eilber et al. (Cancer Treatment Symposia 1985; 3:49-57) used a fixed daily dose of doxorubicin for three days with radiation of 35Gy. This yielded a 5% local recurrence, while wound complication rate was 35 %. We reduced the radiation dose to lower the wound complications rate. We report a cohort of patients treated in this manner at our institution. Methods: After a baseline echocardiogram, patients received a radiosensitizing dose of intravenous doxorubicin (30mg/day) for 3 consecutive days, then radiation with 2.7 Gy in 10 fractions, followed by limb sparing surgery. After IRB approval, we retrospectively analyzed records of 191 patients during the treatment period from 1991 to 2010. Data extracted included local tumor recurrences and wound complications defined as non-healed wound at 1 month, number of limb salvage surgeries and involvement of surgical margins. Results: Of the 191 patients, median age was 53 (range, 13-89). Stages at presentation included I, II, III and IV, with 2%, 33%, 61%, 4% respectively. The median follow up was 5 years. Of the 24 types of sarcomas treated, pleomorphic sarcoma was the most common at 21%. The local recurrence rate was 5% (95% CI, 2.7-8.6%) and local wound complications were 21% (95% CI, 15-28%). Most (172 or 90%) of patients were able to undergo limb salvage surgery while 19 (10%) required amputation. Of the 172 patients that had limb salvage, 97% (95% CI, 93-98%) had wide surgical margins, three had < 2 cm margins and two had involved margins. Conclusions: To our knowledge, this is the largest study showing that this short two week course of chemoradiation is effective in achieving high rate of local control, acceptable wound complication rate, wide surgical margins and limb salvage in the treatment of STS. Randomized trials are warranted to confirm results.

1067 Background: The pro-drug capecitabine is approved in anthracycline- and paclitaxel-resistant MBC. However, GI/skin toxicity and wide interpatient PK variability occur despite body surface area...

TPS239 Background: Cancer cachexia impacts physical functioning, appetite, tolerability and success of anticancer treatments of patients with advanced cancer. Currently, there is no standard treatm...

9028 Background: The rate of neuropathic pain (NP) control with single agents is low. Oxycodone and pregabalin alone have proven activity in NP, but controlled data on their rational combination is...

e14560 Background: Concurrent chemo-radiotherapy is the standard treatment of non-surgery care for patients with locally advanced esophageal cancer. Nimotuzumab (h-R3) is a genetically engineered h...

2058 Background: Temozolomide (TMZ) a DNA alkylating agent crosses the blood brain barrier reaching therapeutic levels in brain; concurrent with whole-brain radiotherapy (WBRT) has been a treatment of brain metastases (BM). TMZ alone has been administered in advanced neoplasms at oral fixed-dose for 5 of every 7 days, at a maximum tolerated dose of 360 mg/d. Methods: This open label, randomized phase II trial, was designed with a type I error of 0.05 and power of 0.80. The primary aim was to find a difference in objective response rate (ORR) of 0.29 favorable to experimental arm (A). Patients (Pts) received TMZ at a fixed oral dose of 200 mg on Monday, Wednesday, Friday; 300 mg on Tuesday, and Thursday, before each one of 10 WBRT sessions, 30 Gy/2 weeks total dose, in arm A (without extra cycles of TMZ). In control arm (B) the same WBRT schedule only. Secondary aims were to compare BM progression-free survival (BMPFS), overall survival (OS), and systemic toxicity (AE) development. Eligibility criteria: bo...

e14655 Background: This phase I dose-escalation study was conducted to determine the recommended dose of oral S-1 in combination with a fixed dose of sorafenib in patients with advanced HCC. Second...

2554 Background: The risk of severe toxicity of CPT-11 can be in part explained by polymorphism of UGT1A1. The most common polymorphism in Whites is UGT1A1*28. UGT1A1*6 is another common polymorphism in Asians. We designed a phase I study to investigate UGT1A1 genotype-directed maximum tolerated dose (MTD) of CPT-11 plus fixed dose of capecitabine in patients (pts) with Korean mCRC. Methods: Pts with mCRC screened UGT1A1 genotyping (*28 and *6) and were stratified into one of 3 groups according to the number of defective allele (DA): 0 (none of *28 or *6 allele), 1(only one of *28 or *6 allele), and 2 (*28/*28, *6/*6, or double heterozygous for *28 and *6). The dose of CPT-11 was escalated as following: Level -I:200, I:240, II:280, III:320, IV: 350, V: 380 mg/m2 (IV, once every 3 weeks). Capecitabine (1,000 mg/m2 PO BID) was administered on days 2–15 every 3 weeks. Dose limiting toxicity (DLT) and pharmacokinetic analyses was determined at cycle 1. Results: Forty-two pts, median age 50 years, EOOG performance ≤1 were recruited: 0 DA group (18 pts), 1 DA (18), and 2 DA (6). In 0 DA group, two of six pts experienced DLT at 380 mg/m2 with grade III asthenia (1 pts) and febrile neutropenia (1). In 1 DA group, all of two pts experienced DLT at 380 mg/m2 with grade III asthenia. In 2 DA group, two of three pts experienced DLT at 240 mg/m2 with febrile neutropenia (1) and grade IV neutropenia (1). The MTD was defined as CPT-11 350 mg/m2 for pts with 0 and 1 DA group and CPT-11 200 mg/m2 for pts with 2 DA group, with capecitabine. Median SN-38G/SN-38 AUC was 10.45, 8.78, and 1.66 in pts with 0, 1, and 2 DA group, respectively. Conclusions: CPT-11 dosing by UGT1A1*28 and *6 genotypes is feasible in Korean pts with mCRC. A dose of CPT-11 350 mg/m2 IV for pts with 0 and 1 DA group and CPT-11 200 mg/m2 for pts with 2 DA group, with capecitabine every 3 weeks, is recommended for further study. [Table: see text] No significant financial relationships to disclose.

e14600 Background: We report our initial experience with fixed dose bevacizumab at 200mg (approximately 3mg/kg). Phase I studies suggested that an optimal dose for phase II studies with bevacizumab is 3mg/kg and that circulating VEGF was undetectable at 0.3mg/kg. (Gordon et al. JCO 2001) We proposed a fixed-dose regimen of bevacizumab which we hypothesized would yield equivalent response rates with reduced toxicities and cost versus higher-dose regimens. Patients with advanced malignancies for whom bevacizumab would be indicated were analyzed. Methods: 15 patients were treated with 200mg bevacizumab in combination with antineoplastic therapy. 6 patients had NSCLCa, 8 patients had Colorectal cancer, and 1 patient had BRCA. Results: 15 patients are evaulable for response and have completed a total of 234 doses of bevacizumab (median number of doses =13) with no grade III/IV toxicity, or bevacizumab associated toxicities seen. No grade III or greater hypertension was observed. Proteinuria was not formally assessed, but no grade 3 or greater proteinuria was reported. All patients are evaluable for response with overall response rate of 33% (5/15). With a median follow-up (from the start of bevacizumab) of 452 days (222–1,699 days), median survival has not been reached with only 2 deaths. Conclusions: Fixed dose bevacizumab appears to be effective, less toxic, significantly less expensive and supported by biologic rationale and prior phase I studies and warrants further investigation. Additional patients will be accrued in a prospective phase II trial. [Table: see text]

10023 Background: LEN, which has immunomodulatory, antiangiogenic, and antiproliferative effects, is indicated for the treatment of adults with MDS and multiple myeloma. We report the final results of a phase 1 and PK study of LEN in children with recurrent or refractory solid tumors (ST) or MDS. Methods: LEN was administered by mouth once daily for 21 of 28 days. Cohorts of 3 to 12 children with ST were enrolled at 15, 25, 40, 55 and 70 mg/m2/d dose levels. Children with MDS received a fixed dose of 5 mg/m2/d. PK and correlative biology studies were performed in cycle 1. Results: 49 patients (23 female), median age 16 years (range, 1–21) were enrolled and received a median of 1 cycle (range 1–11). 39/46 ST patients and 3/3 MDS patients were fully evaluable for toxicity. 0/3 patients with MDS had DLT. At 15 mg/m2/d, 1/6 ST patients developed DLT (Gr 3 hypercalcemia). At 25 mg/m2/d 1 patient had a cerebrovascular ischemic event of uncertain relationship to LEN; future subjects were screened for thromboembolic risk factors prior to enrollment. At 40 mg/m2/d 3/12 patients developed DLTs (Gr 3 hypophosphatemia/hypokalemia; Gr 4 neutropenia delaying the start of the next cycle for > 7 days; Gr 3 somnolence); at 55 mg/m2/d 1/6 patients developed DLT (Gr 3 urticaria). At 70 mg/m2/d 0/6 patients had DLT. No further dose escalation was attempted. No objective responses were observed. LEN enhanced IL-2 and IL-15 concentrations; NK expansion and activation; and NK and LAK cytotoxicity (Ayello, ASH, 2008). The median apparent LEN clearance and half-life were 135 ± 45 ml/min/m2 and 2.3 ± 1.1 hr. Conclusions: LEN is well tolerated at doses up to 70 mg/m2/d x 21d of 28 days in children with recurrent or refractory ST. Enhancement of immune function is significant. PK parameters in children are similar to those in adults. No significant financial relationships to disclose.

e14522 Background: To determine the optimal time for the assessment of the perfusion in patients receiving AVE8062 (Vascular Disrupting Agent) at different doses combined with a fixed dose of cisplatin and then to correlate these results with the tumor response. Methods: Patients (pts) with advanced solid tumors, treated with AVE8062 (from 11.5 to 30 mg/m2) in combination with 75 mg/m2 cisplatin given every 3 weeks, were prospectively followed by DCE-US. DCE-US was performed before treatment, at 3 time points (0, 6 and 24 hours (h)) on Day 1 of the first (C1) and second cycle (C2), then every 2 cycles thereafter. Contrast uptake was acquired using VRI perfusion software after SonoVue bolus injection. Time-Intensity Curves (TIC) were determined using linear raw- data from CHI-Q (Toshiba) software. Peak Intensity (PI) representing the blood volume was calculated from automatic modeling of TIC. CT-scans performed before treatment and every 2 cycles were reviewed and tumor response assessed (RECIST). Results: A total of 96 DCE-US were performed in 13 pts, 11 of whom had data for both cycle 1 and cycle 2. Among these 11 patients, 8 presented with a dramatic decrease of PI and 3 with an increase of PI. At cycle 1, mean change from baseline in PI was -36% at 6h and -47% at 24h after AVE8062 infusion. Greater decreases were observed at cycle 2, -70% at 6 h and 78% at 24 h. No pt had a clinical response, but by cycle 2, the 8 pts with a decrease in PI at 24h went on to have stable disease as best response; 3 pts with increased PI 24h after their second treatment all had disease progression as best response. Conclusions: The best timing to observe the effect of AVE8062 on the PI seems to be 24 hours after drug administration at cycle 2. These preliminary results suggest that 24 hr PI at cycle 2 could be useful for determining pts who are more likely to have disease progression as best response to AVE8062. If confirmed, the assessment of PI variation may predict the clinical response to AVE8062. Further studies are needed to assess the possible predictive value of DCE-US on duration of progression-free survival. No significant financial relationships to disclose.

15639 Background: As single agent GEM is a standard therapy for APC. CDDP is the oldest platinum compound which appears to be active in the treatment of this cancer. GEM has demonstrated activity i...

13522 Background: This phase I/II study evaluated the safety of the combination of irinotecan, docetaxel and estramustine phosphate (EMP) for selected advanced solid tumors and also obtained initia...

2574 Background: SLM reduces Iri toxicity in xenograft models at associated selenium (Se) concentrations (Con) = 15μM. We conducted a phase I clinical trial of a fixed dose Iri with escalating doses of SLM in order to identify the highest safe dose of SLM that achieves and maintains Se Conc > 15μM. Methods: A standard 3–3 escalation was conducted. Iri was given at 125mg/m2/week x 4 weeks every 6 weeks. SLM was started 1 week prior to 1st dose of Iri. A loading BID dose of SLM was given for 1 week, followed by a daily maintenance dose. Selenium trough levels were obtained on days 8 and 29 of the study (days 1 and 22 irinotecan) and once every 6 week-cycle. Seven dose-levels of SLM were investigated (loading/maintenance, in mcg): 3,200/2,800, 3,200/3,200, 4,000/3,200, 4,000/4,000, 4,800/4,800, 5,600/5,600, and 7,200/7,200. Results: 31 patients enrolled on this study: age (median 57, range 21–80), Male/Female 21/10, ECOG 0/1 (15/16), 31 with prior chemotherapy, 12 with prior radiation, 22 colorectal and 9 mixed solids. Dose escalation was successful up to dose level 7 (7,200mcg SLM PO BID × 1 week followed by 7,200mcg SLM PO QD), which was declared the recommended dose. 2 Dose limiting toxicities occurred on study: one DLT of Grade (G) 3 febrile neutropenia, G3 sepsis, G3 dehydration occurred on dose-level 1; one DLT of G3 febrile neutropenia, dehydration occurred on dose-level 7. Both DLT occurred in a setting of partial small bowel obstruction related to peritoneal carcinomatosis. Non-DLT = G3 treatment-related toxicities included: 3 G3 neutropenia (< 1 week) at DL2, 3 & 7; 2 G3 diarrhea lasting < 48 hours on DL5 & 7. A lower incidence of G2+ toxicities was noted in patients with higher Se Conc (86% for Se < 15; 67% for Se 15–20; 57% for Se> 20 μM). Toxicities related to SLM were limited to garlic-like smell to breath, sweat, and urine in few patients. Responses included 7 confirmed stable diseases and 2 confirmed partial responses. A Se Con > 15 μM was achieved at all SLM dose levels of 4,800 mcg and above. Conclusions: Doses of SLM up to 7,200 mcg BID × 7 days followed by 7,200 mcg QD can be administered safely with standard doses of Iri. Formal phase II and III studies are needed to determine if SLM reduces Iri toxicity. No significant financial relationships to disclose.

18588 Background: CIA in cancer pts results in fatigue and reduction of QoL. DA is a unique erythropoiesis-stimulating agent (ESA) effective for the treatment of CIA when administered weekly (QW), every 2 weeks (wks, Q2W) or every 3 wks(Q3W).Fixed dosing of DA is routinely used in clinical practice, but little data are available on its patterns of use and effectiveness. Methods: Prospective, observational, multicenter study performed in 30 centres across Spain. Eligible pts: ≥18 yrs, anemic(Hb ≤11 g/dL), with non-myeloid malignancies, and scheduled to receive ≥12 wks of chemotherapy. Data were collected from pts starting treatment with DA 150mcgQW for a maximum of 16 wks (dose to be doubled if Hb increased [Table: see text]

12026 Background: Gemcitabine can be administered as a 30-minute infusion or a prolonged, fixed-dose infusion (FDR). FDR may have improved clinical activity. Gemcitabine and capecitabine have non-overlapping mechanism of activity. This phase I trial explored the combination of FDR gemcitabine plus capecitabine. Methods: Patients received gemcitabine (G) as a fixed dose on day (D) 1 and 8 and capecitabine orally D1–14 of a 21-day cycle. Capecitabine (C) dose was fixed at 500 mg/m2 twice daily (BID) with escalating doses of G, beginning at 400 mg/m2. The trial was a standard phase I trial with cohorts of three. Dose-limiting toxicity (DLT) was defined as febrile neutropenia, grade 3/4 neutropenia lasting > 7 days, grade 3/4 thrombocytopenia lasting > 7 days, grade ¾ nausea/vomiting despite maximal anti-emetic therapy, grade 3/4 diarrhea, or grade 3/4 hand-foot syndrome. Results: Nine patients have enrolled to date, receiving a total of 56 courses at dose level one (G 400 mg/m2, C 500 mg/m2 BID). Median age is 61 (range 47–61). Grade 3 neutropenia has been the predominate toxicity, occurring in 12.5% of courses. One patient with renal cell carcinoma had a partial response. Four additional patients had prolonged stable disease lasting 7–15 months. Prolonged stable disease was observed in two patients with cholangiocarcinoma, one patient with renal cell carcinoma and one patient with anal squamous cell carcinoma. Conclusions: This combination has manageable toxicity with some evidence of activity at G 400 mg/m2 and C 500 mg/m2 BID. Dose escalation continues. No significant financial relationships to disclose.

6072 Background: Sexual morbidity after chemotherapy and hormonal therapy for breast cancer can seriously affect patients’ quality of life. Bupropion is an antidepressant that has been reported to increase libido. Objective: To investigate the improvement of sexual function in female breast cancer patients using bupropion. Methods: We performed an eight week open trial using bupropion in women diagnosed with breast cancer who had received chemotherapy and were currently receiving adjunctive hormonal therapy. The Arizona Sexual Experience Scale (ASEX) was used. The ASEX scale includes five questions that evaluate sexual function in the following areas: libido, excitability and ability to reach orgasm. Women received oral Bupropion 150mg/ daily for eight weeks and were evaluated prior to the initiation of the study and again during Weeks 4 and 8. Results: Twenty patients were included in the study. At the beginning of the study, the mean ASEX score was 23.45 [21.67–25.24] 95% CI. After four weeks of treatment, we observed a reduction in the mean ASEX score that persisted until the end of the study, at eight weeks: 18.45 [16.59–20.31] 95% CI, p = 0.0003) and 18.95 (SD ± 5.02 [16.60–21.30] 95% CI, p = 0.0024), respectively. Conclusions: In this non-controlled open trial bupropion 150 mg/daily was associated with improved sexual function in women receiving adjuvant systemic treatment for breast cancer. No significant financial relationships to disclose.

8192 Background: Clinical studies have demonstrated that epoetin alfa is effective when administered once weekly (QW) at an initial fixed dose of 40,000 IU, increased to 60,000 IU for hemoglobin (H...

2080 Background: SLM, an organic selenium (Se) compound, potentiates IRI activity, protects against toxicity, and allows dose-escalation of IRI in pre-clinical models. IRI dose-escalation in mice models was possible only in association with serum Se concentrations > 1200ng/ml. We initiated a phase I study of daily SLM with weekly IRI to investigate: 1) the maximum tolerated dose (MTD) of IRI when combined with high dose SLM; 2) the pharmacokinetics (PK) of both compounds. Methods: IRI was escalated in a standard 3+3 design. SLM was administered at a fixed dose of 2200 μg/day starting 1 week before the 1st dose of IRI. IRI was administered intravenously weekly x 4 repeated every 6 weeks (1cycle). Dose level (DL) 1 and DL2 consisted of IRI 125mg/m2 and 160mg/m2 respectively. Blood for Se was drawn on days 1, 2, 8, 15, 29 and 50 (and later where possible). Results: 10 evaluable pts were treated on study (M/F: 6/4; median age: 59; ECOG 0/1: 3/7; prior chemo: 10). At DL2, 3 out of 4 pts had G3 diarrhea (DLT). ...

6691 Background:High dose chemotherapy and autologous transplant remains the goal for patients with chemo-responsive relapsed lymphoma. Microtubule agents (Paclitaxel and Vinorelbine) may synchroni...

8184 Background: Epoetin alfa for cancer-associated anemia is effective given as a weight-based dose (WBD; 150 IU/kg) or fixed dose (FD; 10,000 IU) 3-times weekly (TIW), or a FD (40,000 IU) once weekly (QW). Methods: To evaluate the effect of body weight on efficacy of FD vs WBD epoetin alfa, data from a FD trial (40,000 IU QW increased to 60,000 IU QW for insufficient response; N = 2964; Gabrilove 2004) and data from 8 WBD studies (150 IU/kg TIW increased to 300 IU/kg for insufficient response; N = 944) were analyzed and compared. Body weights were defined by quartiles (Q) derived from the European Cancer Anaemia Survey (Ludwig 2004). Efficacy endpoints were erythropoietic response (ER; hemoglobin [Hb] increase ≥2 g/dL) and Hb change from baseline. Safety was evaluated across weight categories in the FD trial. Results: Heavier patients (Q4; >79.5 kg) in the FD group had significantly (P=.0182) lower ER than lighter patients (Q1; ≤60.3 kg), 61% vs 66%, respectively. In the WBD group ER for heavier- vs lig...

1533 Background: RSR13 is an allosteric modifier of hemoglobin which has been shown to increase tumor oxygen delivery, with potential to improve cytotoxic therapy. Previous studies in glioblastoma have demonstrated that the agent is tolerable at 100 mg/kg when delivered daily prior to radiotherapy, and survival was reported in excess of one year. Preclinical studies have shown enhancement of the response to certain chemotherapeuticagents as well. This protocol is assessing the safety and tolerance of escalating doses of RSR13 when administered prior to BCNU in patients with recurrent high grade glioma, as well as maximum tolerated dose and pharmacokinetics of RSR13 when administered with BCNU. Methods: RSR13, in escalating doses of 25 mg/kg, to a maximum of 100 mg/ kg, in cohorts of six patients each, was administered over 30 minutes prior to infusion of BCNU 200 mg., every six weeks, for a maximum of six cycles. Only nonhematologic toxicities are assessed in determining the dose limiting toxicity (DLT) o...

2042 Background: Oral irinotecan has the potential to safely and conveniently achieve protracted exposure of cycling tumor cells to SN-38 (irinotecan's active metabolite). The maximum tolerated dose (MTD) of irinotecan SSM was 60 mg/m2/day x 5 (Proc ASCO 22:130, 2003 (#521). This study evaluates the MTD, dose-limiting toxicities (DLT), of oral irinotecan SSM capsules administered Day 1–5 followed by Day 6–14 oral capecitabine. Methods: Sequential groups of pts received oral irinotecan once daily for 5 consecutive days followed by capecitabine for 9 consecutive days Q3W. MTD is defined as the highest dose level at which less than 2/3 or 2/6 pts experience DLT. 11 additional pts were treated at the MTD. Results: 21 pts with solid tumors (median age=53.5, range 28–78; M/F=10/11; ECOG PS 0/1/2=5/12/3) received starting doses of irinotecan 40 (n=18), and 50 (n=3) mg/m2/d in combination with a fixed dose of capecitabine 800 mg/m2/bid. During dose escalation segment, DLTs were observed in 2/3 pts at 50 mg/m2 (G3...

7245 Background: In preclinical trials, Carboplatin (C) followed by Gemcitabine (G) after 24 hours demonstrates a supra-additive/synergistic effect in term of cell killing. To evaluate the clinical implications of this sequence, we performed a pilot study to explore the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of C and G administered respectively on days 1,2 every 15. Methods: Eligible criteria were a stage IIIb/IV NSCLC, age ≤ 80 years, ECOG Performance Status 1 or 2, adequate marrow, renal and hepatic functions. The starting-dose of C-day 1- (AUC = 2.5) was escalated, stepwise AUC =0.5, (three patients entered per dose level) in combination with a fixed dose of G -day 2- (1500 mg/m2) until achievement of DLT. A cycle (30 days) consisted of 4 administrations (days 1,2,15,16). DLT was considered any ≥ grade 2 myelotoxicity resulting into a treatment delay of >2 consecutive weeks or any grade >2 organ-specific toxicity. Results: Between March and August 2003, 18 chemo naive pts were en...

3755 Background: X (Xeloda) has superior activity and improved safety compared to bolus 5-FU/LV in 1st-line MCRC. Addition of irinotecan (CPT) to 5-FU/LV improves efficacy. In combination, X should preserve the safety advantages of protracted infusions of 5-FU while improving convenience for pts. Continuous X monotherapy (666 mg/m2 twice-daily) is safe and effective in MCRC (Van Cutsem, JCO 2000). Methods: X was given as a fixed dose of 1000 mg twice daily plus intravenous CPT 75 mg/m2 weekly, for the 1st 4 weeks of each 6-week cycle. Pts ≥65 years old received reduced doses (CPT 60 mg/m2; X 750 mg twice-daily). Study objectives were efficacy and safety. Results: Of 52 pts enrolled, all were evaluable for safety and 49 for response: 35 men (67%), 17 women (33%); median Karnofsky PS 90 (70–100), median age 65 (39–78). 36 pts (69%) had colon cancer, 11 rectal (21%) and 5 both (10%). Most common metastatic sites were liver (79%), nodes (58%), lung (33%), and soft tissue (13%). At diagnosis, 63% of pts had me...

2089 Background: Our group previously reported PAC significantly decreased the systemic clearance and volume of distribution of a fixed dose of GEM administered after PAC. Therefore, this study was...

7525 Background: To define the maximum tolerated dose (MTD) of treosulfan in combination with a fixed dose of gemcitabine and to estimate clinical efficacy in uveal melanoma patients. Preclinical s...