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4081 Background: Perifosine (Peri), a synthetic alkylphospholipid, inhibits or modifies a number of different signal transduction pathways (AKT, MAPK and JNK). Peri as a single agent or in combination with other cytotoxic agents, has shown clinical benefit with a manageable safety profile. In a phase I solid tumor trial, Peri was safely combined with capecitabine (Cap) and demonstrated interesting activity in patients (pts) with metastatic colorectal cancer (mCRC), with one patient progression-free for 49 weeks (wks). To assess the true effect of Peri, a phase II was initiated as an exploratory randomized double-blind, placebo controlled study where mCRC pts received Cap in combination with Peri or placebo. Methods: Pts with 2nd or 3rd line mCRC, not previously treated with single agent Cap. ECOG PS 0–1, normal organ/marrow function required. Dose for Cap was 825 mg/m2 BID d 1–14 q 3 weeks. Dose for Peri or placebo was 50 mg qd. Primary outcome analyses included median time to progression (TTP) and response rate (CR+PR). Results: 37 pts have been randomized. Median age 68 (range 32–83) and 57% were male. Median prior Rx was 2 (range 1 - 5). For the analyses, 25 pts were unblinded (12 too early) with 22/25 pts evaluable for response (2 pts off for toxicity at d 14, 46 and 1 patient off at d 4 for other disease; all 3 pts were on Cap + placebo). Results in table below. The log-rank p-value comparing active to placebo for TTP is 0.01. As of 12/08, all unblinded pts are off treatment and 11/12 that were too early remain on treatment with enrollment ongoing. Most frequent (>5%) grade 3 /4 adverse events for Cap + Peri was hand/foot syndrome (16%) and anemia (8%); for Cap + placebo was fatigue (8%). Conclusions: Perifosine in combination with capecitabine was well tolerated, clinically active and more than doubled median TTP over capecitabine alone in pts with advanced, metastatic CRC. [Table: see text] [Table: see text]

7006 Background: GCS-100 is a polysaccharide antagonist of galectin-3, a protein whose overexpression on certain tumor cells is associated with poor prognosis in cancer patients. GCS-100 has been shown to induce apoptosis of patient CLL cells ex vivo. In addition, GCS-100 potentiates the in vitro activity of other agents commonly used to treat CLL, including rituximab. This phase II clinical trial evaluated the potential of GCS-100 as a novel single-agent therapeutic for relapsed CLL. Methods: Patients with Rai Stage II or higher CLL who had relapsed after one or two prior therapies were eligible. Prior therapies included a range of chemotherapy combinations including FCR, cyclophosphamide/vincristine/rituximab, and chlorambucil/prednisone. Patients received GCS-100 i.v. at 160 mg/m2 for 5 days every 21 days until disease progression. Peripheral blood was collected on study days 1, 4, and 8 of each cycle to assess peripheral leukocyte counts and apoptosis. CD38 and Zap70 expression were assessed where possible. Results: 24 pts were enrolled;16 men and 8 women (median age 67 years, range 40–86 years, 15/24 pts were over 65 years). GCS-100 was well-tolerated. There were no cases of drug-related grade 3 or 4 hematological toxicity or other serious AE. Two patients discontinued treatment due to rash, which resolved with cessation of treatment and which has been shown to be responsive to steroids. Six (25%) patients experienced PR, including 4 patients with >50% shrinkage of lymph node lesions. Currently 6 patients remain on study with a median duration of 5 months (range 4.5–9 months). In addition, apoptosis of peripheral leukocytes was confirmed by caspase activation and by DNA fragmentation. Conclusions: GCS-100 has significant single-agent activity in relapsed CLL. Its lack of myelosuppression and potential synergy with other agents makes GCS-100 a strong candidate for further development in CLL, particularly for elderly patients for whom there is a major need for less toxic agents. [Table: see text]

Calretinin and calbindin-D28k are two calcium-binding proteins that are present in largely different sets of nerve cells in the central nervous system. Their appearance during development of the chick retina was studied by immunohistochemistry and Western blots. The patterns are mature one day before hatching. Each cell type acquires its characteristic calcium-binding protein several days after its differentiation has started, but in most cases before morphological maturation is complete. There is also an early phase of calbindin immunoreactivity in many immature amacrine cells, and of calretinin immunoreactivity in the presumptive photoreceptor layer, suggesting that these proteins may have distinct functions in differentiating cells.

Purine analog-based regimens have emerged as highly active regimens in the treatment of chronic lymphocytic lymphoma (CLL). Promising results have been reported with the combination of fludarabine (F), cyclophosphamide (C), and rituximab (R) (FCR) by Keating and colleagues at the University of Texas M.D. Anderson. A previous USOR trial, as well as a Mayo clinic trial, evaluated the combination of pentostatin (P), cyclophosphamide (C), and rituximab (R) (PCR); results suggested similar efficacy with less infectious complications than that seen with FCR. The current multicenter, randomized, community-based trial was conducted to compare FCR and PCR in previously untreated or minimally treated B cell CLL. The primary endpoint was infectious complications with efficacy and safety as secondary endpoints. Correlative studies of immune function were conducted by Kay and colleagues at the Mayo Clinic and will be reported separately. Patients (pts) were assigned to either PCR (P 4 mg/m2 Day 1, C 600 mg/m2 Day 1, R 375 mg/m2 Day 1) (2 1-day cycles) or FCR (F 20 mg/m2 Day 1–5, C 600 mg/m2 Day 1, R 375 mg/m2 Day 1) (28-day cycles). In both regimens the first dose of R 100 mg/m2 was given on Day 8 Cycle 1 and the remainder of the 375 mg/m2 dose was given on Day 9; in subsequent cycles the entire 375 mg/m2 dose was given on Day 1. 92 pts were randomized to each group (N=184). Groups were well balanced for sex, race, and age. Stage II/III/IV were 41%/22%30% for FCR vs 55%/17%/22% for PCR and ECOG PS 0/1/2 were 74%/22%/1% for FCR vs 62%/34%/2% for PCR; ~20% of pts in both groups had received prior chemotherapy; 80% were previously untreated. The infection rate (temperature □101 requiring antibiotics) in FCR was 30.7% vs 33.7% in PCR (p=0.67) while infective events (temperature □101°F w/o symptoms or

1075 Background: In a clinical trial of 722 patients (pts) with locally recurrent metastatic breast cancer (MBC) solvent-based paclitaxel 90 mg/m2 was administered intravenously (IV) over 1 hr weekly for 3 weeks followed by a week of rest (q3/4w) alone or in combination with bevacizumab 10 mg/kg every 2 weeks (q2w) (Miller et al, ASCO 2005). As compared with single agent, the combination had a greater median progression-free survival (PFS; 11.4 vs. 6.11, p < 0.0001) and overall response rate (ORR; 30% vs. 14%, p < 0.0001). The purpose of the current study is to evaluate safety and tolerability and PFS, and secondarily ORR, of a solvent-free, 130- nanometer albumin bound (nab-) paclitaxel in combination with bevacizumab in MBC. Methods: In this multicenter, open-label study in the US Oncology Research Network, HER2-negative pts with MBC, receiving first line chemotherapy were given weekly nab- paclitaxel 125 mg/m2 IV infused over 30 minutes on days 1, 8, and 15, and bevacizumab 10 mg/kg on days 1 and 15 of...

15072 Background: P is a novel oral alkylphosphocholine with effects on multiple signal transduction pathways including Akt, MAPK and JNK. Unresectable HCC has a dismal prognosis. In the only large randomized trial, the response rate to single agent chemotherapy was 6 months. This included 2 with 2 and 3 prior regimens. Conclusions: This study demonstrated that perifosine has very little toxicity when administered at a dose of 50 mg daily and is active in HCC as well as other cancers [Table: see text] No significant financial relationships to disclose.

7533 Background: The optimal treatment of patients with advanced NSCLC and PS2 has not been resolved. A retrospective analysis of 99 pts with PS2 in CALGB 9730 (Lilenbaum, JCO 2005) demonstrated improved survival associated with combination carboplatin- paclitaxel versus paclitaxel alone (median overall survival=4.7 vs. 2.4 mos., p=.019). Gemcitabine-carboplatin (GC) is an active doublet in advanced NSCLC and is at least as active as paclitaxel-carboplatin (PC) in PS2 pts (ECOG 1599, Tester ASCO 2004). A prospective validation of the activity of GC is needed, which is addressed by comparing GC versus gemcitabine (G) alone in this setting. Methods: 161 chemonaïve pts with advanced NSCLC and PS2 were randomly assigned to G 1250 mg/m2 alone on Days 1,8 or GC (G 1000mg/m2 Days 1,8 followed by C AUC 5 on Day 1). Cycles were repeated every 21 days for 6 cycles or until disease progression or intolerable toxicity. Primary endpoint was median survival. Conclusions: GC resulted in an improved response rate among NSCLC pts with PS2 over G alone. As expected, G3–4 toxicities were greater with GC. Overall survival data will be reported at the time of the meeting. [Table: see text] [Table: see text]

7726 Background: Clinical studies of P have shown less overall toxicity and reductions in Grades 3–4 hematologic and nonhematologic toxicities when pts are pretreated with folic acid and vitamin B12. Current recommendations are to give folic acid 350 μg - 1,000 μg by mouth for at least 5 of 7 days prior to the 1st dose of P, and 1 injection of vitamin B12 1000 μg during the week preceding the 1st P dose. Treatment delay to allow this supplementation may be clinically undesirable, particularly in pts with aggressive malignancies. A trial evaluating single-agent P for the treatment of relapsed SCLC gave us opportunity to observe the effects of a shortened lead-in time for vitamin supplementation. Methods: We reviewed data from a U.S. trial designed to assess the safety and efficacy of single-agent P in chemosensitive and chemorefractory relapsed SCLC pts. Eligible pts had limited or extensive-stage SCLC, PS 0 to 2, and 1 prior chemo regimen. Pts received P doses of 500 mg/m2 or 900 mg/m2 q 21 d. The protocol required the administration of folic acid for at least 5 of 7 days prior to the 1st P dose, and vitamin B12 administration on Day 1, Cycle 1, or up to 14 days prior to the 1st P dose. Included in the analysis were pts who received at least 1 dose of folic acid prior to 1st P dose. We then analyzed preliminary toxicity results for pts receiving vitamin B12 for 0–3, 4–6 and =7 days prior to 1st P dose. Results: From 7/2004 to 3/2006, 116 pts were treated with P. At baseline M/F 57%/59%; median age 64.5 years (range 35–85); PS 0/1/2 was 39%/57%/20%. Cycle 1 vitamin administration timing data is available for 109 pts. Data for all 116 pts will be reported at time of meeting. Because toxicities observed between the 2 P doses were not significantly different, the combined toxicities for both dosing groups are reported here. Conclusions: Based on this data, Vitamin B12 given less than 7 days prior to P does not appear to be associated with increased serious toxicities. No significant financial relationships to disclose. [Table: see text]

4082 Background: Panitumumab, a fully human monoclonal antibody against EGFr, is approved for EGFr-expressing mCRC pts with disease progression (PD) on or after fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy. However, the predictive value of EGFr tumor-membrane staining as measured by immunohistochemistry (IHC) is undetermined. Methods: This multicenter, single arm, phase 2 study enrolled pts with documented PD during or after fluoropyrimidine and adequate doses of irinotecan and oxaliplatin, and within 6 months after the most recent chemotherapy regimen (determined by an independent eligibility review committee [IERC]), 2–3 prior regimens, and low (1%-9%) or negative ( [Table: see text] No significant financial relationships to disclose.

21134 Background: Clofarabine (CLOLAR®) is a next-generation nucleoside analog designed as a hybrid molecule to improve the efficacy and minimize the extramedullary toxicity of other nucleoside analogs. Such analogs are known to have a variety of effects on both humoral and T-cell immune function. Fludarabine, the drug most closely related to clofarabine, causes major alterations in the CD4:CD8 lymphocyte ratios, associated with marked increases in the rate of opportunistic infections. In contrast, gemcitabine has a selective detrimental effect on the B-lymphocyte subset. Therefore, while conducting a phase I dose-finding trial of clofarabine in patients with solid tumors, we investigated its effects on lymphocyte sub-populations. Methods: A phase I dose-finding study is ongoing in patients with solid tumors who receive clofarabine once a week for 3 weeks every 28 days. Blood samples were collected from patients in the highest dose levels before, during, and after clofarabine administration for lymphocyte quantitation and phenotyping using flow cytometry. Results: Of the 11 patients who had samples collected, 5 currently have both baseline and postbaseline values available (1 at the 129 mg/m2 dose level and 4 at the 103 mg/m2 dose level). Overall, the percentage of T cells and CD8 suppressor cells did not decrease significantly with clofarabine administration. In 1 patient where data from 2 cycles were available, CD4 cells decreased slightly after the first cycle, suggesting a possible cumulative effect. However, in all 5 patients CD19 cells decreased significantly after the first infusion of clofarabine and remained suppressed for the duration of the study period. Conclusions: Although clofarabine is a purine analog (as is fludarabine), its effects on lymphocyte subsets more closely resemble gemcitabine, a pyrimidine analog. If substantiated, these findings should have bearing on future decisions about appropriate drug combinations involving clofarabine. No significant financial relationships to disclose.

7716 Background: Pts with relapsed SCLC have a poor prognosis and few effective treatment options. P is a novel multitargeted antifolate that is active and well-tolerated as a single agent in lung cancer. We undertook a trial to assess the efficacy and safety of single- agent P in both chemosensitive (S) and chemorefractory (R) relapsed SCLC pts. Methods: Eligible pts had limited or extensive- stage SCLC, PS 0 to 2, and only 1 prior chemo regimen. S pts were defined as having had a prior response with disease progression >2 mos from end of 1st-line chemo. R pts were those who progressed while on 1st-line therapy, or had any response but progression 2 q 21 d. Planned sample sizes were 36 S pts in a 2-stage sequential fashion with potential early stopping for lack of efficacy or unacceptable toxicity, and 25 R pts in a single-stage design with no stopping rule. The stopping rule was invoked when 2 in additional cohorts of 40 S and 40 R pts. Pts were to receive folic acid and Vitamin B12 prior to treatment with P. The primary outcome measure was response rate. Results: From 7/04 to 3/06, 121 pts were enrolled, with 116 pts treated. S and R pts were analyzed separately at both dose levels. S pts (n=56): M/F, 29/27; median age 65 (range 43–82); PS 0/1/2, 25/23/8. R pts (n=65): M/F, 31/34; median age 64 (range, 35–85); PS 0/1/2, 16/37/12. *3 S pts treated with P 900 mg/m2 remain with disease control after a minimum of 11 mos of follow-up. Conclusions: Preliminary clinical benefit rates (CR+PR+SD) of 20% and 17.4% achieved respectively in S and R pts treated with P 500 mg/m2 suggest modest activity of single-agent P in relapsed SCLC. P can be given at a dose of 900 mg/m2 without a significant increase in Grades 3–4 toxicities, although this does not appear to increase efficacy. [Table: see text] [Table: see text]

4076 Background: BICC-C was a multicenter, randomized study that assessed efficacy & safety of irinotecan/fluoropyrimidines combinations in previously untreated mCRC patients. This study showed that FOLFIRI or FOLFIRI+bev were superior to their comparators (Proc ASCO 2006). We conducted a secondary analysis of efficacy & safety among all patients >65 years compared with those =65. Methods: Pts were randomized to: infusional FOLFIRI, modified bolus IFL (mIFL), or CapeIri; and concurrent celecoxib or placebo in a double-blind fashion. The protocol was amended in April 2004 and bevacizumab (bev) was added to the FOLFIRI and mIFL arms whereas CapeIri was discontinued. Period 1 (P1) and Period 2 (P2) designate subjects enrolled before or after the amendment. Results: Of 430 pts enrolled in P1, 150 were age >65 (median 71; range, 66–87) and 280 were = 65 (median, 56; 20–65). Of 117 pts in P2, 75 were >65 (median, 73; 66–84) and 42 were = 65 (median, 54; 32–65). No significant differences in efficacy or safety were observed between the two age groups. Results for P1: median progression free survival (PFS) was 6.5 and 6.7 mos; and median overall survival (OS) was 18.8 and 19.2 for >65 and =65, respectively. For the FOLFIRI regimen specifically median PFS was 7.5 and 7.6 mos, and median OS was 20.1 and 24.3 mos for >65 and =65, respectively. Results for P2: median PFS was 10.3 and 10.6 mos; and median OS was 19.8 and 23 mos for >65 and =65, respectively. For the FOLFIRI+bev regimen specifically median PFS was 11.1 and 11.2 mos for >65 and =65 respectively, and median OS has not yet been reached for either subgroup at time of analysis. Common grade = 3 AEs are listed below. Conclusions: Efficacy and safety for first line irinotecan/fluoropyrimidine regimens and for FOLFIRI & FOLFIRI+bev, specifically, did not differ for older and younger mCRC patients. [Table: see text] [Table: see text]

4027 Background: This multicenter, randomized study assessed efficacy & safety for irinotecan/fluoropyrimidines combinations in previously untreated mCRC. Methods: Pts were randomized to: infusional FOLFIRI, modified bolus IFL (mIFL), or CapeIri; and concurrent celecoxib or placebo in a double-blind fashion. The protocol was amended in April 2004: bevacizumab (bev) was added to the FOLFIRI and mIFL arms, whereas CapeIri was discontinued. Period 1 (P1) and Period 2 (P2) designate subjects enrolled before or after the amendment. Initial efficacy & safety analyses were reported at ASCO ’06. We now report follow-up of 46 months for P1 and 31 months for P2. Results: 430 pts were treated in P1 and 117 pts in P2. Baseline characteristics and post-study treatment were balanced. P1 results: Median progression free survival (PFS) was 7.6 mos for FOLFIRI; 5.9 mos for mIFL (p=0.004); and 5.8 mos for CapeIri (p=0.015). Median overall survival (OS) was 23.1 mos for FOLFIRI; 17.6 mos for mIFL (p=0.087); and 18.9 mos for CapeIri (p=0.27). One-year survival rate favored FOLFIRI (75%) compared to either mIFL (65%) or CapeIri (66%). Overall Response Rate (ORR) was 47% in FOLFIRI, 43% in mIFL, 39% in CapeIri (not significantly different). P2 results: Median PFS was 11.2 mos for FOLFIRI+bev and 8.3 mos for mIFL+bev (p=0.28). Median OS was not reached for FOLFIRI+bev but was 19.2 mos for mIFL+bev (p=0.007). One-year survival rate favored FOLFIRI+bev (87%) when compared to mIFL+bev (61%). ORR was 58% for FOLFIRI+bev and 54% for mIFL+bev (p=0.73). Common grade = 3 AEs are listed below. Celecoxib did not impact safety or efficacy. Conclusions: First line FOLFIRI or FOLFIRI+bev were superior to their comparators and show favorable results in survival and tolerability in untreated mCRC. Median survival for FOLFIRI+bev has not been reached. [Table: see text] No significant financial relationships to disclose.

4071 Background: The treatment of adenocarcinoma of the gastroesophageal junction /stomach (AGEJ/S) remains a therapeutic challenge. This study was conducted to explore the efficacy and safety profile of the combination of docetaxel+oxaliplatin in patients with previously untreated advanced AGEJ/S. Docetaxel has shown significant single-agent activity and has recently been shown to increase response rates and overall survival when combined with cisplatin plus 5-FU. Oxaliplatin is associated with a more favorable safety profile compared to other platinum-based drugs (ie, cisplatin). Methods: Patients with metastatic (Stage IV) AGEJ/S were eligible. Treatment consisted of docetaxel 60 mg/m2 over 1 hour IV followed by oxaliplatin 130 mg/m2 over 2 hours on Day 1 of each 21-day cycle. Patients were treated until disease progression or unacceptable toxicity; primary endpoints are response rate, toxicity, and progression free and overall survival. Results: We have enrolled all planned eligible patients (N = 71). Baseline characteristics include a median age of 59.5 years, 72% male patients, 76% white, and ECOG PS scores 0/1/2 of 45%/49%/6%, respectively. 32.8% of patients had distal gastric cancer (fundus or pylorus). The median number of cycles delivered to date is 6 (range, 1–14). Twenty patients (31%) have required dose reductions primarily due to neutropenia. Grade 3–4 toxicities include neutropenia (69%); vomiting (17%); nausea (16%); dehydration, fatigue, and diarrhea (13%, each), and thrombocytopenia and febrile neutropenia (7%, each). Sixty-six patients have completed ≥2 cycles. The best overall confirmed response rate, by RECIST, was 24 PR (35.6%) for an overall response rate of 35.6%. Median time to response was 2.4 months and median duration of response was 4.1 months. Median survival was 9.2 months and median PFS was 4.4 months. Conclusions: The combination of docetaxel and oxaliplatin is associated with manageable toxicity in this group of patients with AGEJ/S. The best overall response rate of 35% and median survival of 9.2 months is encouraging and comparable to other standard front-line regimens. This research was supported, in part, from a research grant from sanofi-aventis. [Table: see text]

3547 Background: Panitumumab is a fully human monoclonal antibody directed against EGFr. We investigated the antitumor activity of panitumumab in pts with mCRC who failed prior therapy and had low or negative EGFr tumor expression. Methods: In this multicenter, phase 2 study of 150 planned pts, pts had documentation of disease progression (PD) during or after adequate doses of fluoropyrimidine, irinotecan, and oxaliplatin (centrally confirmed refractory disease [CCRD]), 2–3 prior regimens, ECOG score 0–2, and low or negative EGFr staining (by IHC) in evaluable tumor cells. Pts received panitumumab at 6 mg/kg Q2W until PD or drug intolerability. Tumor assessments (modified WHO, blinded central review) were taken periodically from wk 8 until PD. Endpoints were objective response (OR) through wk 16 (+ ≥ 4 wk confirmation; primary) and OR throughout study, response duration, progression-free survival (PFS) time, survival time, and safety (secondary). Results: In this interim analysis (6/05), 88 pts were enrolled and had ≥ 1 dose of panitumumab (safety set); 23 pts had ≥ 20 wks before the cutoff and CCRD (efficacy set). The efficacy set consisted of 16M/7W, median age of 65 (range: 46, 85) yrs, 83% white, 100% with ECOG ≤ 1, 74% colon cancer and 26% rectal cancer; all received ≥ 2 prior regimens (equivalent characteristics for safety set). 2/11 (18%) pts with EGFr-negative tumors and 1/12 (8%) with low EGFr staining had a partial response. Duration was up to 16 wks. 7/23 (30%) of all pts had SD. Median (95% CI) PFS was 7.9 (7.0, 23.0) wks. In the safety set, all pts had a treatment-related adverse event; 19% grade (gr) 3; 2% gr 4. Integument and eye toxicities were: 92% skin, 17% eye, 28% nail, 8% hair, and 2% chelitis. 20 (23%) had diarrhea (1 gr 3); 7 (8%) had hypomagnesemia (2 gr 3/4). Three pts had an infusion reaction-1 gr 3 (led to panitumumab discontinuation) and 2 gr 1/2. In 65 pts with both a baseline and post-baseline sample, no human anti-human antibodies to panitumumab were detected. Updated data will be presented. Conclusions: Responses to panitumumab were seen in pts with mCRC with both low and negative EGFr levels. Efficacy appears similar to that in other studies with panitumumab in pts with higher EGFr tumor levels. [Table: see text]

13063 Background: Perifosine (P) is known to modulate signal transduction pathways, including Akt which is frequently constitutively activated in NSCLC. The half life of P is ∼100 hours and GI toxicities are dose limiting. Studies of a single dose weekly regimen found that the maximum tolerated dose (MTD) was 800 mg. This study was undertaken to see if a higher MTD could be reached using divided doses in NSCLC patients. Methods: Twenty NSCLC patients (pts) were given P, 300 mg, at intervals of 4–6 hours with no more than 4 doses in a 24 hour period. The starting dose was 900 mg and this was escalated by 300 mg/week in subsequent pts to an MTD of 1800 mg. Results: The median age of pts was 62 (range 39–79); 9 were male and median ECOG performance status was 1 (range 0–1). Nineteen pts had received prior chemotherapy (median 2 regimens) and 18 prior radiotherapy. Three pts were entered at each dose and the cohort expanded to 6 pts if 1 or more experienced a grade 3/4 non-hematologic toxicity (DLT) during the first week of therapy. A dose level was toxic if 2 or more pts experienced a DLT. The median time on study was 8 weeks (range 2–28). Seventy-seven percent of pts had no dose reduction (85% of those on 900 mg, 95% on 1200, 72% on 1500, and 78% on 1800 mg). In cohort 1, one pt died within a week without toxicity from P and 1 pt experienced grade 3 nausea, so this cohort was expanded. The other pts in the cohort had no toxicity. In cohort 4 one pt. took 300 mg daily for 6 days and was considered inevaluable. In cohort 3, grade 3/4 toxicity was not observed until after day 28 in 3 pts. Fifteen pts were evaluable for response; 1 had an unconfirmed partial response and 2 had stable disease. Conclusions: This study demonstrated that higher doses of P can be administered on a weekly schedule with divided doses. Weekly doses of 900 and 1200 mg lead to almost no toxicity in most pts. This study has been expanded to a phase 2 trial with direct comparison of weekly and daily doses. The grade 3/4 toxicities for each cohort are given in the table below. [Table: see text] [Table: see text]

3506 Background: This multicenter, randomized study assessed efficacy & safety for 3 irinotecan/fluoropyrimidines combinations in previously untreated mCRC. In a 3 × 2 factorial design, we also assessed whether celecoxib added to chemotherapy (CT) improved CT efficacy and/or reduced toxicity. Methods: Pts were randomized to: FOLFIRI - irinotecan (I) 180 mg/m2, leucovorin (LV) 400 mg/m2, 5-FU bolus 400 mg/m2, & infusional 5-FU 2400 mg/m2 over 46 hours q 2 wks; modified IFL (m-IFL) - I 125 mg/m2, LV 20 mg/m2, & bolus 5-FU 500 mg/m2 wkly × 2, q 3 wks; or CapeIri - I 250 mg/m2 day 1 & capecitabine 1000 mg/m2 po BID × 14 days, q 3 wks. Pts were also randomized to concurrent celecoxib (400 mg po BID) or placebo in a double-blind fashion. Time to progression (TTP) was the primary endpoint. Results: 430 pts were enrolled from 2/03 to 4/04, prior to an amendment that added bevacizumab to CT arms. Baseline characteristics were balanced. TTP for FOLFIRI (median = 8.2 mos) was significantly better than for either m-IFL (6.0 mos; p = 0.01) or CapeIri (5.7 mos; p = 0.01). Overall survival (OS) also favored FOLFIRI (median = 23.1 mos) compared to either m-IFL (17.6 mos; p=0.10) or CapeIri (18.8 mos; p = 0.19). Common grade ≥ 3 toxicities are listed below. CapeIri had the highest rates of nausea, vomiting, diarrhea, dehydration & hand-foot syndrome, whereas FOLFIRI had lower rates. Among all 430 pts, median TTP did not differ for pts randomized to celecoxib compared to placebo (6.9 vs 6.9 mos; p=0.71). Median OS was also similar for celecoxib vs placebo (19.5 vs 18.8 mos; p=0.63). CT toxicities did not differ for celecoxib vs placebo. Rates for MI/stroke were 1.5% for celecoxib and 1.9% for placebo. Conclusions: First-line FOLFIRI offers a superior TTP when compared to m-IFL or CapeIri; OS & toxicity analyses also favored FOLFIRI. Celecoxib neither improved CT efficacy nor reduced CT toxicity. Updated survival data & data on pts enrolled after the addition of bevacuzimab will be presented. [Table: see text] [Table: see text]

We have previously demonstrated activity with immunotherapy composed of autologous tumor cells genetically modified to secrete GM-CSF (GVAX|[reg]|) in advanced stage NSCLC1. In an effort to remove the requirement and variability associated with genetic transduction of individual tumors we developed a |[ldquo]|bystander|[rdquo]| GVAX|[reg]| platform composed of autologous tumor cells mixed with an allogeneic GM- CSF secreting cell line. We conducted a phase I/II trial of this immunotherapy (3 to 12 biweekly injections) in advanced stage NSCLC. Tumors were harvested from 86 patients, tumor cell processing was successful in 76, and 49 received study treatment. The most common toxicity was local injection site reactions. Serum GM-CSF pharmacokinetics were consistent with secretion of GM- CSF from the injected cells for up to 4 days with associated transient leukocytosis confirming GM-CSF bioactivity. Evidence of treatment-induced immune activation was demonstrated; however, objective tumor responses were not seen. Compared with autologous GVAX|[reg]| immunotherapy for lung cancer prepared by transduction of individual tumors with an adenoviral GM-CSF vector, GM-CSF secretion was approximately 25-fold higher with the bystander GVAX|[reg]| product used in this trial. However, the frequency of injection site reactions, tumor response, time to disease progression, and survival were all less favorable in the current study in comparison to prior results. Follow-up results will be presented.

685 Background: Indisulam (E7070) is a sulfonamide that inhibits cell cycle progression at multiple checkpoints by inducing expression of p53, p21 and suppressing expression of phosphorylated Rb, c...

7120 Background: Talabostat (T) is an oral inhibitor of dipeptidyl peptidases such as fibroblast activation protein found on the stroma of tumors. Administration of T stimulates cytokine and chemok...

7563 Background: Talabostat (T) is an oral inhibitor of dipeptidyl peptidases including fibroblast activation protein found on the stroma of tumors and in melanomas. T stimulates cytokine and chemo...

3115 Background: Clofarabine, a next-generation nucleoside analogue that inhibits DNA synthesis, has demonstrated activity in acute leukemia in Phase I and II trials. The agent has also shown poten...

3652 Background: This ongoing randomized, multicenter study (BICC-C) aims to determine the optimal regimen for the treatment of metastatic CRC by comparing 3 regimens: irinotecan + either infusiona...

7530 Background: SYN-D is a pentapeptide with a unique mechanism of action that potentially differs from microtubule stabilizers (taxanes and epothilones) and tubulin inhibitors (vinca alkaloids and other dolastatins) as it is postulated to inhibit microtubule nucleation. SYN-D has been chemically modified to improve pharmacological properties and is orally bioavailable with a therapeutic window potentially enhanced over previous generations of dolastatins. The substantial cardiovascular toxicity observed with previous dolastatins was not observed in the SYN-D phase I studies. Due to activity in melanoma observed both in xenograft models and in the phase I setting (Ebbinghaus, ASCO 2003), SYN-D is being evaluated in pts with locally advanced or metastatic melanoma. Methods: In this multi-institutional phase II study, SYN-D was administered at 28 mg/m2 IV for 30 mins qdx5q3w with response rate as the primary endpoint. The study was designed: to assess the feasibility of increasing SYN-D dose if

The melanoma differentiation-associated gene-7 (mda-7) is a tumor suppressor gene whose expression causes apoptotic cell death in cells from a wide variety of solid tumor types, but has little effect in non-malignant cell cultures. To begin to characterize the safety and biologic activity of mda-7 gene transfer in a clinical setting, we conducted a phase I trial using intratumoral injections of an adenovirus containing the mda-7 construct (Ad-mda7; INGN 241) in patients with resectable solid tumor lesions. Sequential cohorts of patients received escalating doses of INGN 241 from 2 × 1010 to 2 × 1012 viral particles (vp) injected into the center of the accessible target tumor lesion. In the first 5 cohorts, the injected lesions were resected at 24 to 96 hours post injection, serially sectioned, then analyzed to determine the distribution and concentration of the viral agent, mRNA and protein expression, and assess the resultant biologic effects on the tumor cells. The last two cohorts had incisional biopsies performed pre-treatment and 30 days post treatment with the final cohort receiving 2 × 1012 vp injected twice weekly for 3 weeks of a 28 day cycle. All injected lesions demonstrated INGN 241 vector DNA and mRNA copies with the highest level near the injection site, then decreasing inversely with distance. Protein expression of MDA-7 determined by immunostaining paralleled the geographic and temporal pattern of expression of DNA and mRNA. Apoptosis staining by TUNEL reactivity also closely correlated with the expression pattern of the MDA-7 protein. Toxicity attributable to the injections consisted of transient low grade fever and mild injection site pain and erythema. Evidence of activity in two patients was seen with the repeat injections. One was a patient with metastatic melanoma who achieved a complete response in two separately injected lesions. In summary, INGN 241 delivered through intratumoral injection is well tolerated, induces apoptosis in a large percentage of tumor cells where protein expression is seen, and, with repeat injections, demonstrates evidence of clinically significant activity.

Calcium transients in single rat cardiomyocytes were inhibited by arachidonic acid (AA) exposure in a concentration-dependent (25–100 μM) and reversible manner.

Bioactive gibberellins (GAs) are essential endogenous regulators of plant growth. GA signaling is mediated via GAI, a nuclear member of the GRAS family of plant transcription factors. Previous experiments have suggested that GAI is a GA-derepressible repressor of plant growth. Here we test this hypothesis by examining the effects of the expression of Arabidopsis GAI in transgenic Basmati rice. High-level expression of GAI caused dwarfism and reduced GA responses, and the strength of this effect was correlated with the level of transgene expression. In particular, the expression of GAI abolished the GA-mediated induction of rice aleurone alpha-amylase activity, thus implicating GAI orthologs in the well-characterized cereal aleurone GA response. The GA derepressible repressor model predicts that high-level expression of GAI should confer dwarfism, and these observations are consistent with this prediction.

In this paper recent experimental work on the collisional quenching reactions of O2(a 1Δg) and O2(b 1Σg+) at high temperatures is reviewed. The results were obtained with a combined discharge flow—shock tube technique in which singlet oxygen is generated in a microwave discharge, mixed with a quencher and raised to a high temperature in a shock tube. The factors which contribute to the reliability of the technique are discussed. Results from previous studies for both O2(a 1Δg) and O2(b 1Σg+) are presented, together with some preliminary results for quenching of both species by SO2 and HCl. Taken together, the results present a complex picture of quenching efficiencies and temperature dependences which cannot be correlated with any single physical property. The present theoretical approaches do not appear to be capable of explaining the results in a quantitative way.

Using a discharge flow/shock tube measurements have been made of the quenching of O2(a 1Δg) and O2(b 1Σ+g) by H2 and D2 at 292 K and between 500 and 1000 K. Results are also reported for the quenching of O2(b 1Σ+g) by HCl over a similar temperature range and by HBr at 292 K. No measurements were possible for HBr at high temperatures. The two excited states differ in the temperature dependence of their quenching rate constants: the results for O2(a 1Δg) can be fitted approximately to the Arrhenius equation, while those for O2(b 1Σ+g) change only slightly with temperature. The results are considered in terms of current models for electronic energy transfer.

The place of the encounter group within the framework of humanistic psychology is examined and an assessment of the moral significance of the humanistic psychology movement and the encounter group technique is attempted. Some contemporary moral objections to the technique, and to its implied moral dangers, are outlined and answered.

The metabolism of the reproductive toxicant bis(2-methoxyethyl) ether was studied in male Sprague-Dawley rats, and the principal metabolite (2-methoxyethoxy)acetic acid and its metabolic precursor 2-(2-methoxyethoxy)ethanol were evaluated separately as testicular toxicants. For the metabolism study, rats were given single po doses of (1,2-ethylene-/sup 14/C)bis(2-methoxyethyl) ether at 5.1 or 0.051 mmol/kg body wt. Within 96 hr, approximately 86 to 90% of the radioactivity was excreted in the urine. Urinary metabolites were separated by high-performance liquid chromatography and isolated for characterization by gas chromatography-mass spectrometry. The principal urinary metabolite, accounting for 67.9 +/- 3.3% of the administered high dose and 70.3 +/- 1.3% of the low dose, was identified as (2-methoxyethoxy)acetic acid. A second metabolite, representing 6.2 +/- 0.8% of the high dose and 5.8 +/- 0.8% of the low dose, was identified as methoxyacetic acid, a previously recognized testicular toxicant. In the toxicity study, (2-methoxyethoxy)acetic acid and 2-(2-methoxyethoxy)ethanol were administered to rats at 5.1 mmol/kg body wt by gavage as single daily doses for as many as 20 consecutive days. The testes of rats killed 24 hr after the administration of even numbered doses showed no gross or microscopic abnormalities. These results are in contrast to the previously reported testicular atrophymore » evoked after as few as 8 daily doses of the parent compound, bis(2-methoxyethyl) ether, tested under the same experimental conditions. Thus, the testicular toxicity reported for bis(2-methoxyethyl) ether could be explained by the presence of a minor metabolite, methoxyacetic acid.« less

The mechanism of biologic response from exposure to a 12% subtilisin Carlsberg preparation is shown to be one of histamine release in the guinea pig. Three groups of guinea pigs were pretreated by intradermal injections withsaline solution of (1) the commercial proteolytic enzyme preparation containing 12% subtilisin Carlsberg, (2) an alkaline protease preparation obtain from Aspergillus oryzae that was isolated from cotton dust, or (3) a nonproteolytic mixture of proteins and lipases obtained from cotton seeds. The histamine content of the ling, liver, and ear tissues of guinea pigs that were pretreated with any one of the three preparations showed an in untreated animals. Following challenge by intratracheal injection of a saline solution containing the subtilisin preparation, the guinea pigs pretreated with the same preparation showed a markedly reduced liver histamine level. Challenge by inhalation exposure to the subtilisin preparation of guinea pigs that were pretreated with any one of the above preparations resulted in a lower histamine concentration in the lungs and livers.

The onset of testicular pathology in the rat and possible recovery over an 8-week period were evaluated after the administration of up to 20 daily oral doses of bis(2-methoxyethyl) ether (diglyme) at 5.1 mmol/kg bw (684 mg/kg bw). Primary and secondary spermatocyte degeneration and spermatidic giant cells were observed after six to eight treatments. In addition, the testes-to-body weight ratio was significantly reduced by the tenth day of treatment and continued to be depressed eight weeks after discontinuation of the treatment. Testicular LDH-X activity, a pachytene spermatocyte marker enzyme, was significantly decreased in animals by the eighteenth day of treatment with diglyme.

Maps are an important source of data for planning and land use analysis of flood-prone areas. Map users with inadequate training are not aware that map errors can lead to ineffective decisions. Although inherent errors introduced by transformation, map construction, and symbolization are never identified on maps, they limit the effectiveness of maps as sources of data. Additional vertical and horizontal errors can be introduced during map use. Knowledge of the sources and amounts of such errors should result in more effective decisions regarding flood hazards.

(1976). ‘Finny’—Portrait of a Self-Actualizing Teenager? Self & Society: Vol. 4, No. 11, pp. 1-9.

(1) The hydrolysis of 32P- or myo-[2-3H]inositol-labelled rat liver microsomal phospholipids by rat liver lysosomal enzymes has been studied. (2) The relative rates of hydrolysis of phospholipids at pH4.5 are: sphingomyelin>phosphatidylethanolamine>phosphatidylcholine> phosphatidylinositol. (3) The predominant products of phosphatidylcholine and phosphatidylethanolamine hydrolysis are their corresponding lyso-compounds, indicating a slow rate of total deacylation. (4) Ca2+ inhibits the hydrolysis of all phospholipids, though only appreciably at high (>5mm) concentration. The hydrolysis of sphingomyelin is considerably less sensitive to Ca2+ than that of glycerophospholipids. (5) Analysis of the water-soluble products of phosphatidylinositol hydrolysis (by using myo-[3H]inositol-labelled microsomal fraction as a substrate) produced evidence that more than 95% of the product is phosphoinositol, which was derived by direct cleavage from phosphatidylinositol, rather than by hydrolysis of glycerophosphoinositol. (6) This production of phosphoinositol, allied with negligible lysophosphatidylinositol formation and a detectable accumulation of diacylglycerol, indicates that lysosomes hydrolyse membrane phosphatidylinositol almost exclusively in a phospholipase C-like manner. (7) Comparisons are drawn between the hydrolysis by lysosomal enzymes of membrane substrates and that of pure phospholipid substrates, and also the possible role of phosphatidylinositol-specific lysosomal phospholipase C in cellular phosphatidylinositol catabolism is discussed.

The problem of finding a minimum number of patterns to exercise the logic elements of a combinational switching net is investigated. Throughout, the word “testing” refers to exercising of this kind; or, equivalently, to fault diagnosis where each line of the net can be directly observed. Any set of permanent faults can be selected to test against, examples of which range from “stuck-at” faults (allowing the most economical test) to “any possible fault” (requiring the most complete test). The method used depends upon exact structural analysis rather than upon search algorithms or random pattern generation. The types of results presented appear to be fundamentally new. In particular, the maximum number of patterns required to test any one of an infinite class of nets is frequently found to be finite and extremely small. For example, any nontrivial connected tree of 2-input nand gates can be tested for “any possible fault” by exactly five patterns—no more and no less. The method in brief: Given a set F of switching functions and a set of required inputs for each (collectively denoted T ), a “testing” function is defined for each element of F for each positive integer r . If the lines of a net can be mapped to the domain of the testing functions P ( T, r ) so that the gates perform consistent with these functions, we say the net “accepts” P ( T, r )—and then r patterns are sufficient to test the net for T . Only nets in which each logic element is intended to realize the same switching function are discussed here. Trees (nets without fanout) are studied first, and the conditions under which a tree of identical gates “accepts” a partial function on an arbitrary domain is established. Then the common symmetric switching functions are separately investigated to find for each a minimum value of r such that all trees composed solely of the function accept P ( T, r ) (for various T ). In most cases, as in the example given, the number of patterns required to test any such tree is extremely low. The conditions under which all nets (nontrees included) accept a set of partial functions with arbitrary domain are then established. These conditions are rarely met in practice, even where F consists of a single function. However, many subclasses of nets can be identified which require only a few patterns at most (depending on the function and the class of faults selected). These subclasses often contain nets of arbitrary size and complexity, and frequently consist of exactly those nets for which a related graph can be “colored” (i.e., h -node colored for some particular h ) in the classical graph-theoretic sense. For example, any net of 2-input nand gates can be tested by five patterns if one of its related graphs is 2-colorable and another one is 3-colorable (!). The detailed results and methods used to obtain them are summarized, and in conclusion coloring problems and test construction are commented upon.

1. 1. An unusual and rare case of fetal monstrosity is reported. 2. 2. I have been unable to find a similar one in the literature at my disposal. 3. 3. An interesting comparison is shown between the pre- and postnatal roentgenologic studies of the case.

The work described in a previous paper, “Efficient Exercising of Switching Elements in Nets of Identical Gates,” is continued. Sections 1, 3, and 4 of the previous paper are prerequisites to the current work. Exercising, or “testing,” the gates of a net is equivalent to performing fault diagnosis in the case in which each fault is detectable. Where F is any set of switching functions, this paper establishes a necessary and sufficient condition on an arbitrary function set G such that all trees composed only of functions from F will accept G ; choosing G as the “testing” functions P ( T, r ) of the previous paper, this is the condition under which all such trees can be tested by r (or fewer) patterns. The case of “stuck-at” faults is then investigated at length. It is shown that: (a) all trees can be tested for stuck-at faults by three patterns, and nearly all by two patterns; (b) for some interesting classes of functions, all nets can be tested by two patterns—in general, many nets can; (c) for any set of functions which are functionally complete and suitably closed under constant inputs, there are nets which require arbitrarily many patterns. The latter result suggests that nets requiring arbitrarily many patterns exist for nearly all interesting choices of functions and of faults. For “input dependence” tests, a result is cited to show that economical testing of nets of nand (nor) gates of mixed sizes is possible. Finally, for the case of exhaustive testing, experience suggests that economical tests exist for most nets composed from functions of F wherever F is a bounded set—i.e. a set of functions for which there is a fixed upper bound on the number of patterns required to test any tree. The (individually) bounded functions are completely characterized; then the bounded sets of symmetric functions are completely characterized. The latter prove to be those sets for which: (a) each function is individually bounded (i.e. not “and,” “or,” or constant); and (b) F contains at most one of the following: (1) “not,” (2) a “nand” function, (3) a “nor” function. Thus bounded sets of functions are the rule, not the exception, and economical testing appears to be generally possible.

Given an associative system in which each word is assigned a cost and in which an equivalence relation obtains between elements, it is often of interest to ask the question: what is the least costly word equivalent to a given word? The case in which the equivalence relation is a two-sided congruence relation is studied here, one example being the problem of optimizing a type of computer program. Such optimizing processes may be formalized as Markov normal algorithms. A general results concerning order relations on finite alphabets is established first. Then, the properties of a class of Markov normal algorithms are investigated. It is shown that each such algorithm must always terminate, and that every class of mutually equivalent algorithms contains a unique minimal algorithm which can be obtained by applying any algorithm of the class to itself.