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e18557 Background: Chronic hepatitis C virus (HCV) infection has been associated with hematologic malignancies such as B-cell non-Hodgkin lymphoma. In contrast, there is very little known about the relationship between HCV and myeloid malignancies such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). To determine the effect of HCV on MDS/AML clinical outcomes we conducted a retrospective analysis in a large inner city cohort of patients (pts) Methods: 478 pts with MDS and MDS-transformed AML were identified between 1997 and 2016; 13 pts were HCV-positive (HCV+/MDS) and 465 were HCV-negative (HCV-/MDS). Demographics, hematologic parameters, cytogenetics, IPSS-R scores and molecular profiles were compared for both groups (grp). Survival (surv) analysis was done using the Kaplan-Meier method Results: HCV+/MDS had significantly worse surv than HCV-/MDS pts on univariate analysis (UA) (median surv 16 vs 52 months, HR 2.8, 95% CI 1.4-5.5, p < 0.01). Difference remained strongly significant after exclusion of HIV-coinfected pts (HR 2.7, p = 0.02) and pts w/ AML on presentation (HR 3.1, p < 0.01). Cytopenias were worse in HCV+/MDS (mean Hgb level 8.2 vs 9.4 g/dl, p = 0.04; mean plt count 64 vs 139 103/µL, p = 0.03). Average IPSS-R score was higher in HCV+/MDS pts (5.5 vs 3.8, p = 0.02). IDH1 mutation was more prevalent in HCV+/MDS (25% vs 2%, p < 0.01). Differences in age between HCV+/MDS and HCV-/MDS were non-significant (mean 64 vs 69 respectively, p = 0.2). Male-to-female ratio was higher in HCV+/MDS but difference was non-significant (2.3 vs 0.9, p = 0.2). Interestingly, high HCV viral load and cirrhosis did not correlate with poor surv in the HCV+/MDS grp, suggesting deleterious effect occurs even in early stages of HCV infection. Conclusions: Our analysis suggests that chronic HCV infection strongly correlates with worse surv in UA and is associated with lower blood counts and higher IPSS-R scores at the time of diagnosis of MDS. We observed a high rate of MDS refractory to standard therapies and speculate that HCV may affect biology of the disease. Larger studies are warranted to determine the effect of HCV on surv in this population and to provide a rationale for trials of anti-HCV drugs concomitantly with MDS Tx.

e18077 Background: Even though HIV is associated with worse prognosis in many malignancies, the clinical course of MDS and AML in HIV+ pts has not been well studied. Determining the clinical presen...

3072 Background: Temsirolimus (T) is a first in class mTOR inhibitor FDA approved for advanced renal cell cancer. It is a water soluble rapamycin ester given IV weekly, rapidly metabolized to sirol...

e14083 Background: Designing individualized therapy in colorectal cancer is critical for disease management and necessitates fast and accurate identification of mutations and SNPs. Analyzing multip...

e13584 Background: ON 01910.Na is a novel multitargeted inhibitor of several regulatory pathways including polo-like kinase 1 (Plk1) and PI-3 kinases, with synergistic nonclinical activity when com...

2589 Background: Eribulin mesylate (E7389), a nontaxane microtubule dynamics inhibitor with a novel mechanism of action, has clinical activity as monotherapy in breast cancer and other solid tumors. This phase I, open-label, dose-finding study determined the maximum tolerated dose (MTD) for eribulin in combination with carboplatin. Methods: Patients with advanced solid tumors whose prior standard therapy failed were enrolled. Carboplatin was administered by 30-min IV infusion and eribulin by 2- to 5-min IV bolus, separated by 1 h. In stage 1, eribulin mesylate (0.7, 0.9, 1.1, and 1.4 mg/m2) was dose escalated with carboplatin AUC5 in a 3+3 design in two schedules differing by the order of administration. In stage 2, eribulin mesylate (1.1 and 1.4 mg/m2) was dose escalated with carboplatin AUC6 using the preferred schedule from stage 1. In both stages, the MTD was defined as the highest dose where

e13133 Background: ON 01910.Na is a new multikinase inhibitor, which induces mitotic catastrophe and apoptosis in cancer but not in normal cells. Multiple pathways are involved including polo-like kinase. Cell killing effects are exposure time-dependent in vitro. In addition, a combination of ON 01910.Na with oxaliplatin produced significant synergy in effect, prompting phase I evaluation in humans. Methods: Patients with advanced cancer received a starting dose of ON 01910.Na 250mg/m2 as a 24hr continuous infusion (CI) repeated weekly. Oxaliplatin was administered biweekly as 85mg/m2, 2 hr infusion. The ON 01910.Na dose cohorts ranged from 250-1350 mg/m2 based on a modified Fibonacci escalation algorithm using the accelerated titration scheme (NCI). Intrapatient dose escalation was allowed. Pharmacokinetic (PK) sampling is to be performed at the maximum tolerated dose (MTD) level. Results: 13 patients (pts) (all females; ages: 38-71 yrs) have received combination therapy. At the highest dose (1350 mg/m2)...

3567 Background: EGFR directed therapy is limited by mutations in KRAS or BRAF; however, the search for other predictive biomarkers is critical (Clin Cancer Res, 2008; 68: 1953). In our study, we e...

e20709 Background: Quality of life (QoL) assessment in clinical trials has been gaining more attention. FACT-G surveys have been validated to assess QoL in clinical trials involving oncology patient (Cella DF et al, J Clin Oncol 11:570–579, 1993). However, there is paucity of evaluation of QoL in patients with advanced cancer participating in Phase I clinical trials. Methods: FACT-G surveys were conducted within the context of a Phase I trial to identify a safe dose and potential drug-drug interations of capecitabine and irinotecan combination (Goel, S et al, Invest New Drugs 25:237–245, 2007). The FACT-G survey consists of 28 questions in 5 sections, namely, physical well-being, social/family well-being, emotional well-being, relationship with doctor, and functional well-being). Patients were requested to complete the FACT-G surveys at baseline and every two cycles thereafter (each cycle of 3 weeks duration). Results: Forty-one of 47 patients with advanced solid tumors who participated in the clinical trial completed FACT-G surveys. Mean scores were calculated for each time point. The mean QoL scores at baseline and post cycle 2 were 53 and 58, respectively (p = 0.1). Post cycle 4, the mean QoL score was 62 [p = 0.01, (vs. baseline)]. Following cycle 4, the number of respondents decreased to the extent where we were unable to ascertain any further changes in the QoL scores. Conclusions: It is feasible to use FACT-G survey as a tool to assess QoL in patients participating in an oncology phase I clinical trial. Although the sample size of the patient population was not powered for any statistical significance, there was a trend toward improving QoL based on FACT-G survey scores. This suggests that phase I clinical trials may provide improvement of QoL for some patients. FACT-G is a useful tool in assessing QoL in oncology phase I trial study population. No significant financial relationships to disclose.

3583 Background: Reolysin is reovirus serotype 3 - Dearing strain, a double-stranded replication- competent RNA non-enveloped icosahedral virus. It induces cytopathic and anti-cancer effects in cells with an activating mutation in the ras proto-oncogene. Methods: This was a single center dose escalation trial of Reolysin administered intravenously every four weeks in doses ranging from 1X108 to 3X1010 tissue culture infective dose (TCID)50. Serum for neutralizing antibody, and serum, stool, saliva, and urine for viral shedding were collected. Tumor samples were analyzed for activating mutations in the ras and braf oncogenes. Results: Eighteen patients received 27 doses of Reolysin in 6 dose cohorts accomplishing a 300 fold dose escalation without a protocol-defined dose limiting toxicity. Drug related grade 2 toxicities included fatigue and fever (1 patient each). All patients developed neutralizing antibody during the course of the study. Viral shedding was observed in 6 patients [urine (5), serum (4), saliva (3), and stool (2)]. One patient with anthracycline and taxane refractory breast cancer experienced a partial response (PR) and her tumor had a mutation in the ras oncogene. Biopsy from a chest wall mass showed evidence of necrosis and viral replication by electron microscopy. The overall clinical benefit rate was 45% and appeared higher in patients with viral shedding (67%) than those without (33%). Conclusions: Reolysin administered as a one hour infusion on a monthly schedule is safe and well-tolerated even in multiple doses. Reolysin has anti-tumor activity as a single agent warranting further evaluation, including in combination with chemotherapy. Viral shedding may suggest intrapatient replication yielding a benefit and should be studied carefully in future studies. [Table: see text]

16529 Background: Our previous phase I study (Mani et al. Annals of Oncology 2007) determined a dose of 40 mg/m2 as the recommended phase II dose of ixabepilone. We expanded this cohort to examine ...

6572 Background: The majority of published series of phase I oncology trials has reported response rates between 4 to 6 percent. A recent meta-analysis of phase I studies showed a higher response r...

2515 Background: ON 01910.Na induces G2/M cell cycle arrest, apoptosis, and cell death in a broad spectrum of cancer cells, but not in non-neoplastic cells. In vitro, cell killing is dependent on d...

3584 Background: Tetra-o-methyl nordihydroguaiaretic acid (terameprocol-also EM-1421 or M4N) is a semi-synthetic derivative of a naturally occurring plant lignan. Terameprocol blocks cell cycle progression by inhibiting expression of the Sp1-dependent cdk1 gene and promotes apoptosis by inhibiting survivin. Methods: A dose escalation, open-label study enrolled patients (pt) with malignancies refractory to surgery, radiation therapy, and/or chemotherapy. Terameprocol was administered daily by intravenous infusion for 5 days (d) every 28 d over 30 minutes, with dose escalation (100, 200, 375, 750, 1,500, 2,200, and 3,300 mg) in cohorts of 3–6 pt. Tumor measurement (CT and PET scans) was performed at baseline and every 2 to 4 cycles. Pt at the 2,200mg and 3,300mg doses had circulating tumor cells (CTC) measured prior to dosing. Pharmacokinetics (PK) was evaluated for the first 2 cycles. Results: Twenty nine pt (17 male), median age 61 years, with gynecological (21%), lung (17%), colorectal (17%), or other cancer (45%) were enrolled. All pt were evaluable for toxicity and 21 pt for efficacy. At the highest dose (3,300 mg/d), dose limiting toxicity (DLT) of metabolic acidosis/respiratory failure considered drug related was observed in 1 of 3 pt, and no additional pt was enrolled at this dose. The next lower dose cohort (2,200 mg/d) was expanded (11 pt) and no DLT has been observed. Best response by RECIST criteria included a partial response in 1 pt and stable disease in 6 pt. Three pt discontinued for reason other than progression, and 11 had progressive disease. Pharmacokinetics demonstrated dose linearity. The volume of distribution was 300–1,000 liters, and the half-life ∼ 20–30 hours. No obvious trend was seen in CTCs. Across all doses, 108 adverse events, with 10 severe events, were observed. Conclusions: Terameprocol is well tolerated up to a dose of 2,200 mg and warrants further evaluation. Expansion continues at this dose level. There is clinical benefit in this refractory population that warrants further investigation. No significant financial relationships to disclose.

2005 Background: Ixabepilone (Ixa) is the first analog in a new class of antineoplastic agents, the epothilones, which stabilizes microtubules and induces apoptosis. Ixa has shown clinical activity in a broad range of tumors. Oxidative metabolism by CYP3A4/5 appears to be a prominent route of Ixa biotransformation in vitro. As a single agent, the recommended dose is 40 mg/m2 over 3 hours once every three weeks. Methods: This was an open-label, sequential study to assess the effect of CYP3A4/5 inhibition on the pharmacokinetics (PK) and pharmacodynamics (PD) of Ixa. Ketoconazole (K) was used as a model inhibitor of CYP3A4/5. Patients were administered a single 10 (n=4), 20 (n=12), 25 (n=7) or 30 (n=4) mg/m2 intravenous (iv) infusion of Ixa with K (400 mg/d orally x 6 days) during cycle 1, and a single 40 mg/m2 iv infusion of Ixa during Cycle 2. Cycles were repeated every 21 days. Detailed PK and PD analysis was performed in cycles 1 and 2. Results: The observed adjusted geometric mean of Ixa AUC for subjects with K was 2892 vs. 1628 ng/mL*hr in subjects without K. The ratio of the geometric means of normalized Ixa AUC and Cmax in Cycle 1/Cycle 2 were 1.78 and 1.07, respectively. The percent of peripheral blood mononuclear cells with tubulin bundle formation after administration of 20 mg/m2 Ixa with K was similar to that observed with single agent Ixa at a dose of 40 mg/ m2. The maximum tolerated dose of Ixa with K was 20 mg/m2. Dose limiting toxicities of Ixa with K were similar to those observed in previous Phase 1 studies of single agent Ixa and included prolonged neutropenia, febrile neutropenia, mucositis, elevated liver function enzymes, and fatigue. Conclusions: Oxidative metabolism by CYP3A4/5 appears to be a clinically important route of Ixa biotransformation. Inhibition of CYP3A4/5 by K affects the Ixa tolerable dose, increases the AUC and results in similar PD effects at half the recommended dose. [Table: see text]

2003 Background: KOS-1584 (9,10-didehydroepothilone D) was discovered as part of a screening program to develop a new generation of epothilones with higher potency and an improved pharmacologic/pharmacokinetic (PK) profile. Epothilones stabilize microtubule polymerization, inducing rapid G2/M arrest and apoptosis. Antitumor activity of KOS-1584 (Chou et al 2003) is approximately 3–12 fold more potent when compared to the structurally related Epothilone D. KOS-1584 demonstrates enhanced tumor tissue penetration and reduced exposure to selected tissues (including CNS). We report the results of the initial dose-escalation trial in which KOS-1584 was administered to pts with advanced solid malignancies. Methods: Define the MTD, toxicity profile and PK of KOS-1584 when administered via 3-hour infusion every 3 weeks. PK was determined after the 1st and 2nd infusion. Pharmacodynamics were assessed by serial sampling of PBMCs for microtubule bundle formation. Results: 27 pts (17 F; median age 60; median ECOG PS 1; median prior regimens 3, range 0–7) enrolled in 8 dose levels (between 0.8 - 11.3 mg/m2). To date, no Cycle 1 DLT has been seen. Toxicities (n=24) did not show obvious dose dependency; common toxicity (Grade 1–2) included gastrointestinal (diarrhea, constipation, nausea), fatigue, and ↑AST. Drug-related Grade 3 toxicity: constipation, fatigue and ↑AST (1 each). Drug-related neurotoxicity was not notable. PK/parent (n=25): t½ 17.7 ± 4.6h, Vz 741±330 L and CL 30.2± 16.5 L/h. At 8.5 mg/m2 Cmax 78 ± 29 ng/mL; AUCtot 631 ± 337 ng*h/mL. Cmax and AUCtot increased linearly with dose over the range tested. Vz is ∼5-fold and t½ 2-fold higher than that of Epothilone D. Dose dependent increases in microtubule bundle formation were observed (8.5 mg/m2: 40–50% at end of infusion, compared to 60–65% for ixabepilone and 50–60% for Epothilone D using the same assay at their phase 2 dose). A sigmoidal Emax model described the relationship between plasma concentration and microtubule bundle formation. Activity consisted of 4 pts with extended stable disease (6 cycles leiomyosarcoma and ovarian cancer; 5 cycles colon cancer; a 2nd patient with ovarian cancer is active at 5 cycles). Of these, 3 had document progressive disease prior to study. Conclusions: Accrual is continuing in order to define the optimal dose on the 3-week regimen. [Table: see text]

3090 Background: E7389 is a synthetic analog of halichondrin B, which was isolated from the marine sponge Halichondria okadai.It has a unique profile of tubulin interactions and exhibits broad anti...

2072 Background: We have previously demonstrated that Cp may be administered safely as a daily “flat” total dose with Ir given every 3 weeks [Am J Clin Oncol 2002 25: 528–34]. Since the usual North American schedule of Ir is a weekly dosing scheme, we designed a study using a weekly combined drug regimen. Methods: This is an open label standard phase I dose escalation trial. Ir was given as a 30-minute infusion on days 1 and 8, without prophylactic atropine, and Cp on days 1–14 of a 21day cycle. Results: Forty seven patients (pt) -median age 60 (range 32–83) years; performance status 0–1 (96%); diagnoses- ovarian (10), breast (5), cervical (5), colorectal (10) and others (17) have received 202 (1–18) cycles in 6 dose cohorts-Ir (mg/m2)/Cp (mg/m2/day in 2 divided doses) 75/1500, 85/1500, 85/1750, 100/1750, 100/2000, 115/2000. There was no cycle 1 dose limiting toxicity (DLT) in the first four dose cohorts tested. At the highest dose level (Ir/Cp 115/2000), 1 of 3 pt developed grade 4 neutropenia with fatal...

2558 Background: ING-1 is a high-affinity, human-engineered monoclonal antibody that recognizes a 40 kD Epithelial Cell Adhesion Molecule (EpCAM) glycoprotein. EpCAM is expressed in high levels on ...

4223 Background: Bryo, a macrocyclic lactone, modulates protein kinase C and enhances P's ability to induce apoptosis. Enhanced apoptosis induction is only seen when P precedes bryo (Koutcher, Clin Cancer Res. 6: 1498). In the phase I study of sequential P followed by bryo, activity in pancreas cancer was seen; myalgias were dose limiting (Kaubisch, Proc ASCO, 2000, Abstr. 900). Methods: Patients (pts) with pathologically confirmed, locally advanced or metastatic adenocarcinoma of the pancreas were eligible. Prior treatment was permitted, prior taxane exposure was not. P was given at 90 mg/m2 over 1 hour day 1, followed by bryo 25 mcg/m2 over 1 hour on day 2, weekly x 3, followed by one week rest (28 day cycles). CT's were performed every 2 cycles. Results: 20 pts (mean age 58, 21–82) received an average of 2.6 cycles (0–10, median 2). Five pts are not evaluable for response (2 early deaths: (fungal sepsis, liver abscess); one pt withdrew, one was never treated, one ineligible). One pt (6%) achieved a min...

2113 Background: In vitro studies demonstrate synergy between fluoropyrimidines and IRI. We conducted a phase I study to evaluate the safety and tolerability of a convenient dosing schedule for the combination of IRI with an oral fluoropyrimidine, CAP. Methods: Thirty-one patients (pt), median age 60 years, performance status 0–1 (97%), prior chemotherapy 30 pt (97%), primary cancer: ovarian (7), breast (5), colorectal (4), others (15) have received 111 cycles (range 1–11) in 6 dose cohorts. IRI 75–115 mg/m2 was administered on days 1 and 8, as a 30-minute intravenous infusion, without prophylactic atropine, every 21 days (1 cycle). CAP 1500–2000 mg/m2/day was administered in 2 divided doses on days 1–14. Results: There was no cycle-1 dose limiting toxicity (DLT) observed at the first 4 dose cohorts. At dose level 5 (IRI 100 mg/m2 / CAP 2000 mg/m2), among the 12 pts entered, one pt developed cycle-1 DLT - grade 3 diarrhea and vomiting. At the next higher dose level (IRI 115 mg/m2 / CAP 2000 mg/m2) 1 of 3 ...