Treatment modification with sunitinib in first-line (1L) metastatic renal cell carcinoma (mRCC): An analysis of the STAR-TOR registry.

602 Background: The standard dosing schedule for administration of Sunitinib is 50mg once daily for a 4-week period followed by 2 weeks off. However, in clinical practice, many patients require schedule or dose reductions to mitigate toxicity. We aimed to assess if these treatment modifications result in improved outcomes in mRCC patients. Methods: Data were drawn from STAR-TOR, a German, multi-centre, real-world, prospective registry to report outcomes of mRCC patients who received Sunitinib in 1L. Patients were categorised into 2 treatment groups: 1) Sunitinib initiated at standard schedule/dose with subsequent schedule/dose modification (SM), 2) Sunitinib as per standard schedule/dosage (SS). Kaplan-Meier survival analysis was used to determine time on treatment (TT) of Sunitinib and progression-free survival (PFS). Differences between groups were assessed using log-rank tests. Results: In total 297 patients were identified initiating 1L Sunitinib. Schedule or dose reductions occurred in 33% of patients. Significant differences between groups at baseline are noted in Table 1. Median TT was greater in SM vs. SS (15.1 vs. 3.9 months (m), p < 0.0001). Median PFS was improved in SM vs. SS (15.1 vs. 6.0 m, p < 0.0001). Fatigue (31/14%), hand-foot syndrome (HFS) (28/10%), diarrhea (35/19%) and stomatitis (20/6%) were more frequently reported in SM vs. SS since initiation of Sunitinib. Incidence of adverse events, (excluding diarrhea) was reduced following schedule/ dose modification of sunitinib; fatigue (before SM/ after SM) (18/7%), HFS (21/8%) and stomatitis (8/4%). Conclusions: Modifying Sunitinib schedule or individualizing the dose represent therapy management strategies that are associated with improved tolerability, prolonged treatment duration and significant improvement in PFS in a real life setting. These data suggest that effective management of toxicity of Sunitinib can optimize patient outcomes. [Table: see text]

Nanoceria biodistribution and retention in the rat after its intravenous administration are not greatly influenced by dosing schedule, dose, or particle shape

Nanoceria distribution and retention in the rat is not greatly affected by its dose, size, shape, or dosing schedule.

Current patterns of chemotherapy and supportive care for early-stage breast cancer (ESBC).

1062 Background: ESBC is commonly treated with myelosuppressive chemotherapy, and high relative dose intensity (RDI) correlates with improved overall survival. A retrospective analysis of patients with ESBC treated from 1997–2000 showed that 56% received an RDI < 85% (Lyman et al. JCO. 2003;21:4524-4531). To determine current practice, we evaluated ESBC treatment patterns at 24 US community- and hospital-based oncology practices. Methods: Data were abstracted from medical records of 532 patients with ESBC treated from January 2007–December 2009. Inclusion criteria included surgically resected ESBC (stage I-IIIA); ≥ 18 years old; and completion of at least 1 standard chemotherapy cycle on an every 2 or 3 week schedule. The primary endpoint was RDI over planned cycles. Other endpoints were incidence of dose delays ≥ 7 days, dose reductions ≥ 15% from standard, grade 3/4 neutropenia (SN), febrile neutropenia (FN), FN-related hospitalization, granulocyte-colony stimulating factor (G-CSF) use, and antimicrobial therapy. Descriptive statistics were generated for all endpoints. Results: In this study, mean (range) age was 55 (29–85) years. Relative to previously published results, chemotherapy regimens have shifted from mainly doxorubicin + cyclophosphamide (AC) (previously 35%) to docetaxel + cyclophosphamide (TC; n = 221; 42%) and AC followed by paclitaxel (AC-T; n = 163; 31%). Mean RDI is now higher (93% for both TC and the most common AC-T schedule [dose dense AC-T; n = 84] vs 79% previously); the incidence of dose delays (16% vs 25% previously) and dose reductions (21% vs 37% previously) have decreased; and primary prophylactic use of G-CSF has increased (76% vs 3% previously). In this study, 40% of patients had SN, 3% had FN, 2% had an FN-related hospitalization, and 30% received antimicrobial therapy. These measures were not available in the previously published results. Conclusions: The observed changes between the two studies are noteworthy though inferential comparisons are limited by changes in treatments and other factors. RDI has improved over time, but 16% of patients in this study received an RDI < 85%. Further evaluation is needed to identify factors associated with lower RDI and determine outcomes for these patients.

Final results of a phase I/II study in patients with pancreatic cancer, malignant melanoma, and colorectal carcinoma with trabedersen.

4034 Background: TGF-β2 overexpression in solid tumors triggers key cancer pathomechanisms, i.e. suppression of antitumor immune responses system and metastasis. Trabedersen specifically inhibits TGF-β2 expression. In the clinical Phase I/II study we evaluate MTD, safety, pharmakokinetics (PK), and efficacy of i.v. trabedersen in patients with advanced tumors. Methods: A total of 61 patients with pancreatic cancer (PancCa, n=37), malignant melanoma (MM, n=19), or colorectal carcinoma (n=5) were treated with i.v. trabedersen as 2nd to 4th-line therapy with escalating doses in 2 treatment schedules. (1st schedule: 7d on, 7d off; 2nd schedule: 4d on, 10d off; up to 10 cycles). Within the 1st schedule, the MTD was established at 160 mg/m2/d. In the 2nd schedule dose-escalation was stopped before reaching MTD. In the Phase II-part of the study further PancCa and MM patients were treated with 140 mg/m2/d. For assessment of PK parameters, plasma time profiles were analyzed for trabedersen and its n-1 to n-5 metabolites by non-compartimental analysis. Results: Trabedersen was safe and well-tolerated. The only expected adverse reaction identified is non-serious and transient thrombocytopenia. Only 2 SAEs (gastrointestinal hemorrhage und pyrexia) were considered as possibly related to study medication. Further clinical development will focus on PancCa patients receiving 140 mg/m2/d trabedersen as 2nd-line treatment. Survival analysis of these patients revealed a mOS of 13.4 months (n=9; 95% CI: 2.2, 39.7). One PanCa patient had a complete response of liver metastases and is still alive after 75 months. Promising efficacy data were also seen in MM patients enrolled into the last cohort (140 mg/m2/day) with a current mOS of 9.3 months (n=14; 95% CI: 6.5, 12.2). PK analyses showed for both treatment schedules that exposure to trabedersen was in the expected range for all doses and half-life of trabedersen (1.12 to 2.08 hrs) as well as clearance (2.22-4.37 L/h*m2) were independent of dose. Conclusions: Trabedersen showed excellent safety and encouraging survival results in the Phase I/II clinical study. A randomized, active-controlled study in 2nd line stage IV PanCa patients is in preparation.

A Phase 1 Dose-Escalation Study of the Novel KSP Inhibitor ARRY-520 in Advanced Leukemias.

Abstract 2047 Poster Board II-24 Introduction: The mitotic kinesin spindle protein (KSP) is required for the assembly of a normal bipolar spindle and cell cycle progression through mitosis. ARRY-520 is a potent, selective inhibitor of KSP that arrests cells in mitosis forming an abnormal monopolar spindle with subsequent onset of apoptosis. ARRY 520 has shown potent activity in preclinical models of hematological malignancies which support clinical investigation of this novel targeted antimitotic therapy in patients with leukemias. ARRY-520 was evaluated in a Phase 1 trial, administered as an intravenous (IV) infusion on Day 1 or on Days 1, 3 and 5 in patients with advanced/refractory leukemias. Objectives: The primary objectives of this study were to establish the safety and the maximum tolerated dose (MTD) of ARRY-520 when given as a 1-hour infusion in either a single dose or on a Days 1, 3 and 5 divided-dose schedule per cycle. Secondary objectives were to characterize the pharmacokinetics (PK) of ARRY-520 when given on these schedules, to assess evidence of preliminary clinical activity, and to explore potential biomarkers of KSP inhibition. Methods: ARRY-520 was administered as a 1-hour IV infusion as a single dose per cycle or on a divided dose schedule, in a “3 + 3” Phase 1 design. PK analyses for ARRY-520 were performed on plasma samples collected during Cycle 1 and Cycle 2. Results: A total of 33 patients with acute myelogenous leukemia (AML) and with a median age of 66 years (range 21-88 yrs) were enrolled: 15 in the single-dose schedule (dose levels 2.5, 3.75, 4.5 and 5.6 mg/m2) and 18 in the divided dose schedule (dose levels 0.8, 1.2, 1.5 and 1.8 mg/m2/day). All but one patient had disease refractory to and/or relapsed from prior therapy with a median of 4 prior regimens (range 0-7). The MTD was 4.5 mg/m2 for the single-dose schedule with the dose-limiting toxicity (DLT) of Grade 3 mucositis and was 1.5 mg/m2/day (cumulative dose per cycle of 4.5 mg/m2) for the divided dose schedule, with DLTs of Grade 3 mucositis, hand-foot syndrome and hyperbilirubinemia. ARRY-520 was well tolerated at the MTD and doses below. At the MTD, Grades 3 or 4 reversible drug-related leukopenia were observed in 4/8 evaluable patients (Grade 0 or 1 WBC at baseline) with a median nadir occurring on Day 7. In both schedules ARRY-520 showed promising signs of clinical activity as measured by significant decreases in leukemic blasts in both the peripheral blood and bone marrow. Four of 33 patients (12%) showed at least 50% reduction in bone marrow blasts and 12/33 patients (36%) showed > 1 log reduction in blasts in the peripheral blood. Preliminary plasma PK analyses revealed increasing ARRY-520 concentrations with increasing dose, a mean terminal t1/2 of ∼90 hours, with clearance values ranging from 1.6 to 8.0 L/hr. Conclusions: ARRY-520 showed promising signs of clinical activity and has been well tolerated in both schedules investigated in patients with AML. The most prominent DLTs were mucositis and hand-foot syndrome. The MTD was determined to be the same total dose per cycle for the single-dose and the divided-dose schedule. Data including the safety, PK, pharmacodynamics and preliminary activity of ARRY 520 from this study will be presented. Disclosures: Bethelmie-Bryan: Array BioPharma: Employment. Rush:Array BioPharma: Employment. Freeman:Array BioPharma: Employment. Simmons:Array BioPharma: Employment. Ptaszynski:Array BioPharma: Employment.

A dose and schedule optimizing evaluation of MG98 given as either a 2 hour IV infusion twice weekly or as a 7 day continuous infusion in combination with interferon alpha (INF) in nephrectomized patients (pts) with advanced renal cell carcinoma (RCC)

14557 Background: RCC is often associated with hypermethylated and silenced tumour suppressor genes. The enzyme DNMT1 is responsible for the majority of cellular DNA methylating capacity. MG98 is a second generation antisense inhibitor of DNMT1 which has been shown to reduce DNMT1 mRNA and protein. Methods: A trial of MG98 given as a 2 hour IV infusion twice weekly (Intermittent Schedule, IS) or as a 7 day continuous infusion (CI) in combination with INF has been conducted with nephrectomized pts with advanced RCC. Main endpoints: identification of the optimum regimen, safety, tolerability, pharmacokinetics (PK) and the degree of PBL DNMT1 mRNA suppression. Results: CI schedule: dose levels of 125mg of MG98 combined with 12 MIU of INF (125/12) and 125/9 have been evaluated (9 pts). The MTD has been reached; thrombocytopenia is dose limiting at 125/12. Pt demographics: M:F= 6:3, mean age of 63.2y (52–71). Most common Adverse Events (AEs): fever and chills (gr.1), fatigue (gr.1–2; 100% of pts), nausea and anorexia (gr.1–2), vomiting (gr.2; 66%). Best response: Stable Disease (SD) =3; Partial Response (PR) =1. Currently within the IS schedule, 3 dose levels (9 pts) have been evaluated: 160/12, 200/12 and 200/9, totaling 26 cycles. The MTD has been reached, with GI/constitutional symptoms being dose limiting at 200/12. Demographics: M:F= 7:2 median age 59.8y (40–76). Most common AEs in the first 3 pts are nausea and chills (100% of patients); fatigue (gr.1–2) and fever (66%; gr. 1–3). Best responses: 3 SD, 1 PR. PK evaluation on both schedules revealed no interaction between INF and MG98. DNMT1 inhibition data will be presented. Conclusions: Combination of INF and MG98 exhibits clinical activity and acceptable safety. [Table: see text]