3512 Background: The combination of S and T is hypothesized to maximize pathway inhibition by concurrently targeting parallel signaling mechanisms and will abrogate potential resistance mechanisms directed towards the MAPK pathway through increased signaling via the survival pathway involving PI3K/Akt. Methods: Eligible patients (pts) were treated with escalating continuous oral doses of S (200 and 400 mg BID) and weekly T IV (15 mg, 25 mg). S began on day 8 of course 1 to permit PK evaluations of T. PD studies in PBMCs were performed serially in pts. Results: To date, 24 evaluable pts have received 85 courses [median 3;range1–12] in the following S/T dose cohorts; cohort 1: 200 mg/15 mg (n=6), cohort 2: 400 mg/15 mg (n=11), cohort 3: 400 mg/25 mg (n=6), and cohort 4: 200 mg/25 mg (n=1). Patients demographics were males/female 11/13, median age 54.5 [range 27–71] and PS of 0/1/2 : n=9/13/2. Dose limiting toxicities (DLT) were grade 3 typhlitis in 1/6 pts in cohort 1, and mucositis in 1/6 pts in cohort 2. Expansion of cohort 2 to 11 patients resulted in 4 additional DLTs (hand foot syndrome (HFS) x 2 pts, thrombycytopenia/rash x 1 pt, creatinine elevation x 1 pt). 3 of 6 pts in cohort 3 experienced DLT (HFS x 2 pts, thrombocytopenia x 1 pt). PK analyses show no evidence of S effect on T kinetics while Css,min values of S are consistent with those reported in single-agent studies (S 200mg BID median Css,min 4.42 μg/mL [SD 3.05], S 400 mg BID median Css,min 5.11 μg/mL [SD 4.35]). Apparent downregulation of 4E-BP1 and activated forms of p70S6 kinase and ERK was observed in some patients following treatment. Partial responses have occurred in NHL (1 pt) and papillary thyroid cancer (1 pt) and prolonged SD (> 12 mo) has been observed in RCC (1 pt). Conclusions: The combination of S and T demonstrate significant mucocutaneous toxicity at full doses of S, however preliminary PK analyses show no evidence of drug-drug interactions. Characterization of an intermediate dose of S 200 mg BID/T 25 mg IV is ongoing. [Table: see text]

No abstract

3585 Background: CX-3543 inhibits over-expressed ribosomal RNA synthesis in cancer cells by disrupting an essential protein-rDNA quadruplex complex, thereby inducing selective apoptosis. A phase I clinical trial for CX-3543 was undertaken to determine the dose limiting toxicities (DLTs), maximum tolerated dose (MTD), and pharmacokinetics (PK) of this agent. Methods: Eligible patients with advanced solid tumors received CX-3543 in successive dose cohorts at: 10, 20, 40, 80, 160, 240, 360 and 480 mg/m2. Drug is administered by daily intravenous infusion on the first five consecutive days of a three week cycle, and the infusion duration has varied from one hour to six hours. Response by RECIST is determined after every 2 cycles. Results: Thirty-three patients (M/F:19/14; median age 69, range 44–83) with advanced solid tumors were treated with intravenous CX-3543. No drug related serious adverse events (SAEs) were encountered. DLTs of infusion-related cough and headache were identified at 480 mg/m2 (The MTD was 360 mg/m2). These adverse events were fully and rapidly reversible upon slowing or interrupting the infusion. Other drug-related adverse events were of mild to moderate intensity. Four patients had stable disease for longer than 4 months and one patient, with stable disease for over one year, currently continues on study. CX-3543 demonstrated an increasing plasma terminal half life at the higher dose levels due to a ‘reservoir‘ effect from CX-3543 reversibly binding to blood cells. Conclusions: CX-3543 administered as a 6 hour infusion for five consecutive days of a three week cycle is well tolerated and has stabilized disease in a number of patients enrolled in this phase I study. This trial is now in an expanded enrollment phase at 360 mg/m2 and pharmacodynamic measures, specifically FDG-PET scans and circulating tumor cells, have been included to detect biological activity at this dose level. No significant financial relationships to disclose.

14025 Background: We demonstrated in mouse xenografts that the combination of docetaxel chemotherapy with 2DG is feasible and increases responses against tumors (CancerRes; 2004 64:31–4). Methods: To determine the maximum tolerated dose (MTD) of daily oral doses of 2DG given alone and in combination with weekly docetaxel (DC) in patients (pts) with advanced malignancies who had relapsed after chemotherapy, and to evaluate the pharmacokinetics (PK) of 2DG alone and in combination with weekly DC. 2DG was initially administered orally once daily for 7 days every other week starting at a dose of 2 mg/kg, and DC was administered at 30mg/m2 for 3 of every 4 weeks. A modified accelerated titration design was used. Following completion of the every other week (EOW) 2DG dosing regimen, 3 weeks on and 1 week off (3–1W) dosing; and then continuous (CW) 2DG dosing were investigated. Results: 21 pts were enrolled in the EOW dosing at 2DG doses up to 88 mg/kg/day; another 10 pts were enrolled in the other dosing regimens. 5 pts had lung cancer (4 NSCLC + 1 SCLC); and another 6 pts had H/N cancers. One pt discontinued for DC-related sensory neuropathy. Single cases of DLT occurred - asymptomatic (64mg/kg) and symptomatic (88 mg/kg) Grade 3 hyperglycemia. The MTD was not reached with the EOW regimen. 2DG is rapidly absorbed (Tmax 0.5–1h) with a half-life of 5–10h. 2DG exhibits linear PK following single and multiple doses with minimal accumulation after multiple doses at 63 and 88 mg/kg. 2DG PK and DC PK do not alter each other. One of 18 evaluable pts in the EOW dosing with breast cancer had a partial response (PR). Another 8 pts achieved disease stabilization (SD) among them: 2 of 4 pts with NSCLC, 2 of 6 pts with H/N cancers, 1 pt with thyroid cancer, and 1 of 3 pts with adenoidcystic carcinoma. The others were unknown primary and a breast lymphoma. Also the MTD was not reached at 63mg/kg (3–1W) dosing where one patient with H/N cancer achieved stabilization of his disease. Enrollment of pts in the CW regimen is ongoing now. Conclusions: The combination of 2DG and DC appears to be feasible and safe with no evidence of PK interactions. Evidence of anti-tumor activity was observed in patients with NSCLC and H/N cancers. No significant financial relationships to disclose.