Q3 Wks Research Articles

684 RADIUM-223 CHLORIDE (ALPHARADIN) IMPACT ON OVERALL SURVIVAL AND SKELETAL-RELATED EVENTS IN PATIENTS WITH CASTRATION-RESISTANT PROSTATE CANCER WITH BONE METASTASES A PHASE III RANDOMIZED TRIAL (ALSYMPCA)

684 RADIUM-223 CHLORIDE (ALPHARADIN) IMPACT ON OVERALL SURVIVAL AND SKELETAL-RELATED EVENTS IN PATIENTS WITH CASTRATION-RESISTANT PROSTATE CANCER WITH BONE METASTASES A PHASE III RANDOMIZED TRIAL (ALSYMPCA)

Overall survival benefit and safety profile of radium-223 chloride, a first-in-class alpha-pharmaceutical: Results from a phase III randomized trial (ALSYMPCA) in patients with castration-resistant prostate cancer (CRPC) with bone metastases.

8 Background: Radium-223 chloride (Ra-223) is a first-in-class alpha-pharmaceutical targeting bone metastases (mets) with high-energy alpha-particles of extremely short range (<100 μm). ALSYMPCA, a phase III, double-blind, randomized, multinational study, compared efficacy, in terms of overall survival (OS), and safety of Ra-223 plus best standard of care (BSC) vs placebo plus BSC in patients (pts) with bone mets in CRPC. Methods: Eligible pts had progressive, symptomatic CRPC with ≥ 2 bone mets on scintigraphy and no known visceral mets; were receiving BSC; and either previously received docetaxel, were docetaxel ineligible, or refused docetaxel. Pts were randomized 2:1 to receive 6 injections of Ra‐223 (50 kBq/kg IV) q4 wks or matching placebo and stratified by prior docetaxel use, baseline alkaline phosphatase level, and current bisphosphonate use. A planned interim analysis (IA) was conducted to assess the effect of Ra-223 on the primary endpoint (OS) using a predefined threshold. Survival data were compared using a stratified log-rank test. Results: 922 pts (Ra-223, n = 615; placebo, n = 307) were randomized from 6/2008-2/2011. 445 (58%) of 809 pts in the IA data set received prior treatment with docetaxel. Ra-223 significantly improved OS in pts with CRPC with bone mets vs placebo (two-sided P = 0.00185; HR = 0.695; 95% CI, 0.552-0.875; median OS 14.0 mo vs 11.2 mo, respectively). Safety and tolerability of Ra-223 were highly favorable and showed low incidence of myelosuppression (eg, grades 3/4 neutropenia in 1.8% and 0.8% and thrombocytopenia in 4% and 2% of the Ra-223 and placebo groups, respectively). Conclusions: Ra-223 is an effective therapy that improved OS with a highly favorable safety profile, and may provide a new standard of care for the treatment of CRPC pts with bone mets. [Table: see text]

Radium-223 chloride impact on skeletal-related events in patients with castration-resistant prostate cancer (CRPC) with bone metastases: A phase III randomized trial (ALSYMPCA).

9 Background: Radium-223 chloride (Ra-223) is a 1st-in-class alpha-pharmaceutical targeting bone metastases (mets) with high-energy alpha-particles of short range (<100 μm). ALSYMPCA, a phase III, double-blind, randomized, multinational study, compared Ra-223 plus best standard of care (BSC) vs placebo (pbo) plus BSC in patients (pts) with bone mets in CRPC. The primary endpoint was OS; secondary endpoints included skeletal-related events (SREs). Methods: Eligible pts had progressive, symptomatic CRPC with ≥ 2 bone mets on scintigraphy and no known visceral mets; were receiving BSC; and either previously received docetaxel, were docetaxel ineligible, or refused docetaxel. Pts were randomized 2:1 to receive 6 injections of Ra‐223 (50 kBq/kg IV) q4 wks or matching pbo and stratified by prior docetaxel use, baseline alkaline phosphatase level, and current bisphosphonate use. Results: 922 pts (Ra-223, n = 615; pbo, n = 307) were randomized from 6/2008-2/2011. Based on data from a planned interim analysis (n = 809), unblinded June 2011, Ra-223 significantly improved OS in pts with CRPC with bone mets vs pbo (median OS 14.0 vs 11.2 mo, respectively; two-sided P = 0.00185; HR = 0.695; 95% CI, 0.552-0.875). SREs were lower in the Ra-223 vs pbo group, and time to 1st SRE was significantly delayed (median time to SRE 13.6 mo vs 8.4 mo, respectively; P = .00046; HR = .610; 95% CI, .461-.807). Conclusions: Ra-223 significantly delayed time to 1st SRE and SRE components, except surgical intervention. These reductions in SREs, particularly SCC, are noteworthy. Ra-223 is an effective therapy with a highly favorable safety profile and may provide a new standard of care for treatment of CRPC pts with bone mets. [Table: see text]

Evaluation of paclitaxel/carboplatin in a dose dense or weekly regimen in 66 patients with recurrent or primary metastatic cervical cancer

Background and aimsTo evaluate paclitaxel/carboplatin in a dose dense (TCdd) and weekly (TCw) regimen in recurrent or primary metastatic cervical cancer. MethodsSix courses of paclitaxel (90mg/m2) and carboplatin (area under the curve (AUC) 4) were administered on d1, d8 q3 wks in TCdd. Eighteen courses of paclitaxel (60mg/m2) and carboplatin (AUC 2.7) were administered weekly in TCw. Response rates were determined using Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 criteria. Toxicity was evaluated according to the National Cancer Institute-Common Toxicity Criteria (NCI-CTC) Criteria. ResultsSixty-six patients were included (44 TCdd and 22 TCw). TCdd and TCw were administered as first-line chemotherapy in 48% and 41%, second-line in 43% and 18%, and third/fourth-line in 9% and 41%, respectively. Response (confirmed or unconfirmed) was observed in 58% and 36% for TCdd and TCw, respectively. As first-line, the response rates for TCdd and TCw were the same (55%). As second or more line, the response rates for TCdd and TCw were 61% and 29%, respectively. In patients, receiving TCdd as first-line systemic treatment, median overall survival (OS) and progression-free survival (PFS) was 10 and 5months. As first-line, the median OS for TCw also was 10months (median PFS not reached). There was no statistical difference in PFS or OS between patients treated with TCw or TCdd. Grade 3–4 toxicity was mostly bone-marrow related and was more common with TCdd. Febrile neutropenia was observed in 0% and 12% of the patients treated with TCw and TCdd, respectively. ConclusionsCombination of paclitaxel and carboplatin in a dose dense regimen or weekly regimen resulted in favourable response rate and toxicity profile compared with cisplatin-based combination regimens. TCdd appears to be more toxic than TCw, but resulted in higher response rates than TCw in patients with recurrent metastatic cervical cancer who received prior chemotherapy.

P5-19-11: Tesetaxel, an Oral Taxane, as First-Line Therapy for Women with Metastatic Breast Cancer.

Abstract Background Parenteral taxanes (docetaxel, paclitaxel) are among the most active agents in treating metastatic breast cancer (MBC). However, their use is limited by inherent or acquired multidrug resistance, hypersensitivity, and neurotoxicity. Tesetaxel is an advanced-generation, orally available taxane that is formulated as a capsule for oral administration and has a long terminal half-life in plasma (∼180 hrs). Unlike standard taxanes, tesetaxel is not a substrate for P-glycoprotein (P-gp), a major cause of taxane resistance. The drug is highly concentrated in cells that overexpress P-gp. In taxane-resistant breast cancer xenografts (DU4475), tesetaxel induced a 94% reduction in tumor size, substantially exceeding the activity of docetaxel and paclitaxel (46% and 26%, respectively). Neurotoxicity was also substantially lower with tesetaxel compared with equi-myelotoxic doses of docetaxel. Among more than 350 patients (pts), there have been no occurrences of hypersensitivity reactions. An initial phase 2 study as 2nd-line therapy for pts with MBC who progressed after multidrug anthracycline-containing regimens showed a 38% partial response (PR) rate using tesetaxel Q3 wks at a dose of 27–35 mg/m2. We conducted a Phase 2, open-label, multicenter study of the efficacy and safety of tesetaxel as first-line therapy in women with MBC. Methods: Eligible pts have Stage IV, HER2−negative MBC; ECOG PS 0–1; and adequate organ function. No prior chemotherapy is allowed (other than 1 regimen in the adjuvant setting). Tesetaxel was administered orally Q3 wks at a starting dose of 27 mg/m2 with escalation to 35 mg/m2 as tolerated. No premedication for potential hypersensitivity was used. RECIST response rate was the primary endpoint. A Simon min-max two-stage design was used with a target response rate of 30% in 25 pts. Results: To date, 20 women have been enrolled and treated. The median age was 62 years (range, 45–78). Time from diagnosis was > 4 years in 5 pts and ≤ 4 years in 6; MBC was newly diagnosed in the remaining 9. Hormone receptor status was triple negative in 5 pts at diagnosis and 10 at the time of metastasis. The most common sites of metastasis were lung (13 pts) and bone (9). Prior treatment included hormonal therapy in 13 pts, adjuvant chemotherapy in 16 (most commonly, ACT), and radiotherapy in 9. Of 11 pts currently evaluable for response, PR was achieved in 6 (55%), with confirmation of response in 4 and an ongoing PR in 1 of the 2 pts with an unconfirmed PR. SD was observed in 2 and disease progression in 3. Neutropenia was the most common adverse event, affecting 50% of pts; Grade 3–4 occurrences were observed most often after escalation of the tesetaxel dose to 35 mg/m2. Single occurrences (Grade 1) of neuropathy and nail changes were reported. There were no occurrences of hypersensitivity. Conclusions: Tesetaxel overcomes multiple disadvantages of standard parenteral taxanes and is highly active in 1st- and 2nd-line MBC. To date, overall response rates in these settings are 55% and 38%, respectively. In view of this, we have amended the trial to expand the initial cohort. Potential schedule-dependency will be examined in a future cohort with a newly developed weekly-times-3 schedule. Updated results in both cohorts will be presented. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-19-11.

Eculizumab Is An Effective Long-Term Treatment In Patients with Atypical Hemolytic Uremic Syndrome (aHUS) Previously Receiving Chronic Plasma Exchange/Infusion (PE/PI): Extension Study Results,

Abstract 3303▪▪This icon denotes a clinically relevant abstract INTRODUCTION:Chronic uncontrolled complement activation drives systemic thrombotic microangiopathy (TMA) and life-threatening complications in aHUS. In the initial 26-wk, phase II trial of eculizumab, (ECU) a terminal complement inhibitor, in pts with aHUS requiring chronic PE/PI for an extended period of time, a statistically significant and sustained suppression of TMA was observed. In addition, no pt required PE/PI, no new dialysis was required and all pts either maintained/improved renal function in the absence of PE/PI (Licht ASN 2011). We report longer follow-up data from this trial. METHODS:Pts ≥12 yrs with aHUS, receiving chronic PE/PI on an unchanged regimen were enrolled in a controlled, open-label, single-arm, phase II trial. After an 8-week observation period, pts discontinued PE/PI and started ECU (900mg/week for 4 wks, 1200mg at wk 5, then 1200mg q2 wks). Pts received a meningococcal vaccine. Primary endpoint: TMA event-free status defined as ≥12 consecutive wks of stable platelet count, no PE/PI and no new dialysis. Secondary endpoints included TMA intervention rate (no. of PE/PI and new dialysis events/pt/day), renal function, and safety. Pts continued into an extension trial. RESULTS:Of 20 pts (median age=28 yrs) who received ECU through Wk 26 of the initial trial, 19 pts continued ECU treatment into the extension trial. Mean (SD) duration of ECU treatment was 60 (12) wks at data cut-off. Median time from diagnosis to screening=48 mo (0.66–286). Median time from overt clinical symptoms of aHUS to screening=8.6 mo (1.2–45). Median no. of PE/PI sessions per pt during current clinical presentation=62 (20–230). Median duration of eGFR ≤60 mL/min/1.73m2=180 days (23–485). Six pts had no complement regulatory factor mutation (CRFM) identified. Ongoing treatment with long-term ECU was associated with continued improvements in TMA intervention rate and TMA event-free status and further improvement in renal function (Table). Long-term ECU treatment showed a highly significant time-dependent improvement in eGFR (p<0.0001) with a significant improvement from baseline of 8 mL/min/1.73m2 at 1 yr (p<0.0001). PE/PI or new dialysis was not required with chronic ECU treatment in any pt through Wk 26 or during ongoing long-term ECU therapy (through data cut-off). ECU was similarly effective in pts with/without identified CRFMs. ECU was well tolerated; only 7 pts had adverse events deemed possibly or probably related to drug (mild to moderate in severity). The extension trial continues. CONCLUSIONS:Despite PE/PI, >50% of pts with aHUS are expected to die, require dialysis or have permanent renal damage within the first year of diagnosis. In this trial, all pts treated with ECU for a mean duration of >1 year are still alive and none progressed to ESRD or required new dialysis with sustained ECU treatment. Importantly, compared with historical outcomes with chronic PE/PI, initiation of sustained, long-term ECU therapy, without PE/PI, was associated with a highly significant time-dependent improvement in eGFR. Switching to chronic ECU therapy significantly changed the course of the disease in severe and prolonged renal insufficiency pts, resulting in sustained suppression of TMA. These data further demonstrate ECU to be the new standard of care for aHUS.ParameterWk 26 ECU Treatment (N=20)Data cut-off (mean* duration of ECU=60 wks] (N=20)TMA event-free status, n†1617Median TMA intervention rate0 (p<0.0001)0 (p<0.0001)Improvement in ≥ 1 CKD from BL, n†79≥25% reduction in serum creatinine from BL, n†37Change in eGFR from BL, mL/min/1.73m26 (p=0.0003)8‡ (p<0.0001)Significance was tested with two sided signed rank test or repeated measures analyses.BL=baseline.*Median (range) duration=62 wks (26–74);†n=number of pts;‡At1 yr. Disclosures:Licht:Alexion: Honoraria, Research Funding. Off Label Use: Eculizumab but as part of clinical controlled trials. Muus:Alexion: Membership on an entity's Board of Directors or advisory committees, Research Funding. Legendre:Alexion: Research Funding. Douglas:Alexion: Genzyme, but not relevant to current submission, Research Funding. Hourmant:Alexion: Research Funding. Delmas:Alexion: Research Funding. Herthelius:Alexion: Research Funding. Trivelli:Alexion: Research Funding. Goodship:Alexion: Honoraria, Research Funding. Bedrosian:Alexion: Employment. Loirat:Alexion: Honoraria, Research Funding.

Eculizumab Is An Effective Long-Term Treatment In Patients with Atypical Hemolytic Uremic Syndrome (aHUS) Resistant to Plasma Exchange/Infusion (PE/PI): Results of An Extension Study

Abstract 193▪FN2▪This icon denotes a clinically relevant abstract INTRODUCTION:aHUS is a genetic, systemic disease with a devastating prognosis caused by chronic uncontrolled complement activation leading to thrombotic microangiopathy (TMA), progressive organ damage and premature mortality. In a 26-wk phase II trial, pts receiving ECU, a terminal complement inhibitor, had a highly significant increase in platelet count (a measure of TMA improvement) (primary endpoint: 73×109/L increase; p=0.0001). 13/15 pts with low platelet count at baseline (BL) (ITT) had platelet normalization at Wk 26. 15/17 pts (88%) achieved TMA event-free status (≥12 wks of stable platelet count, no PE/PI and no new dialysis). 13/13 pts treated with ECU for 26 wks had platelet normalization at Wk 26 and 15/15 treated with ECU for 26 wks achieved TMA event-free status. Median TMA intervention rate was 0 (no. of PE/PI and new dialysis events/pt/day). Importantly, 4/5 pts on dialysis with PE/PI discontinued dialysis with ECU. ECU was well tolerated (Legendre. ASN 2010). We report longer follow-up data from the extension phase of this ongoing trial. METHODS:Pts ≥12 yrs with aHUS and persistent TMA despite ≥4 PE/PI sessions 1 wk before screening were enrolled in a 26-wk, controlled, open-label, single-arm phase II trial and continued into an extension trial. ECU dosage: 900mg/wk for 4 wks, 1200mg at Wk 5, 1200mg q2 wks. All pts received a meningococcal vaccine and prophylactic antibiotics ≥14 days after vaccination. Efficacy analyses were based on ITT population. RESULTS:17 pts enrolled (2 discontinued at Wks 1 and 6; systemic lupus erythematosus [protocol violation] and an adverse event unrelated to ECU, respectively). Median time from diagnosis to screening=10mo (0.3–236). Median duration from overt clinical manifestations of aHUS to screening=0.75mo (0.2–4). Median number of PE/PI sessions per pt during aHUS current clinical presentation=17 (2–37). 5 patients (29%) required dialysis at baseline. Median age=28 yrs. 4 pts (24%) had no identified complement regulatory factor mutations (CRFM). ECU mean (SD) duration=58 (29) wks at data cut-off. Mean change (SD) in platelet count from BL was maintained (97×109/L [81] at Wk 26 vs 98×109/L [60] at 1 yr). All 13 pts who had platelet normalization at Wk 26 continued to maintain normal levels at data cut-off. The same 15/17 (88%) pts achieved TMA event-free status at data cut-off. All pts receiving sustained ECU treatment throughout the study achieved TMA event-free status at data cut-off. Renal function was maintained and continued to further improve in pts with ongoing ECU: improvement ≥1 CKD stage from BL: from 10 (59%) pts at Wk 26 to 11 (65%) pts at data cut-off and ≥25% decrease in creatinine from BL: from 11 (65%) pts at Wk 26 to 13 (77%) pts at data cut-off. With sustained ECU therapy, only 1 of the 5 pts at baseline continued on to require dialysis and no patient newly required dialysis (as of data cut off). Long-term chronic ECU was similarly effective in pts with/without identified CRFM. ECU was generally well tolerated; adverse events deemed related to ECU were reported in 12 pts (mostly mild to moderate, 1 severe). The extension trial continues. CONCLUSIONS:In aHUS, despite PE/PI, >50% of pts either die, require dialysis, or have permanent renal damage within the first year of diagnosis. In contrast, all pts treated with ECU for a mean duration of >1 yr remain alive, 4 out of 5 pts became dialysis free, and no pt newly required dialysis. This demonstrates that continued ECU treatment significantly transformed the clinical course of aHUS in this pt population. In addition, long-term ECU therapy suppressed TMA and dramatically improved renal function. These long-term follow-up data further strengthen the evidence for ECU as the new standard of care for aHUS. Disclosures:Greenbaum:Alexion: Consultancy, Honoraria, Research Funding, Speakers Bureau. Off Label Use: Eculizumab for the treatment of atypical hemolytic syndrome as part of clinical trials. Babu:Alexion: Research Funding. Furman:Alexion: Research Funding. Sheerin:Alexion: Research Funding. Cohen:Alexion: Research Funding. Gaber:Alexion: Research Funding. Delmas:Alexion: Research Funding. Loirat:Alexion: Research Funding. Bedrosian:Alexion: Employment. Legendre:Alexion: Research Funding.

Phase III randomized study of ipilimumab (IPI) plus dacarbazine (DTIC) versus DTIC alone as first-line treatment in patients with unresectable stage III or IV melanoma.

LBA5 Background: IPI monotherapy (3mg/kg) improved overall survival (OS) in a phase III study of previously treated, unresectable or metastatic melanoma. Current study in 1st line metastatic melanoma evaluates combination of DTIC (a global standard of care) plus IPI. Methods: In this double-blind phase 3 study, patients (pts) with metastatic melanoma, ECOG PS 0/1, and no prior therapy for advanced disease, were randomized 1:1 to IPI (10 mg/kg) + DTIC (850 mg/m2) or placebo + DTIC (850 mg/m2) at Wks 1, 4, 7, 10 followed by DTIC q3 wks through Wk 22 (induction). Eligible pts received IPI or placebo q12 wks as maintenance. Primary endpoint was OS; 2-sided log-rank test was performed, stratified by baseline M stage and ECOG PS. Results: Of 502 pts, 56% had M1c disease, 40% elevated LDH, and 26% adjuvant therapy. 37% in IPI + DTIC and 65% in DTIC alone arms received 4 induction doses. A significant improvement in OS (HR=0.72; P=0.0009) and higher estimated 1, 2 and 3 yr survival rates were seen with IPI + DTIC (Table). 56% in IPI +DTIC (n=247) and 27% in DTIC alone (n=251) arms had grade 3/4 adverse events (AEs, regardless of attribution), including: elevated ALT (22% vs 1%); diarrhea (4% vs 0%); rash (1% vs 0%). No intestinal perforations or hypophysitis were noted. There were no drug-related deaths in IPI + DTIC and one in DTIC alone arm [gastrointestinal (GI) hemorrhage]. Conclusions: IPI (10mg/kg) + DTIC significantly improved OS in 1st line metastatic melanoma vs DTIC alone; durable survival and objective responses were noted in some pts after follow-up for up to 4yrs. Type of AEs was consistent with prior IPI studies; however, frequencies of some AEs differed with a higher transaminitis and lower diarrhea/colitis/ GI perforation rates than expected. No drug-related deaths were noted in IPI arm. OS benefit of IPI is confirmed in treatment-naive metastatic melanoma. [Table: see text]

Phase III, randomized, open-label study of triweekly versus biweekly docetaxel (T) as a treatment for advanced hormone-refractory prostate cancer (HRPC): Final analysis of the Finnish Uro-oncological Group Study 1-2003.

4527 Background: T administered at 3-week intervals is standard treatment for advanced HRPC. We compared 2-weekly to 3-weekly T as first-line chemotherapy of advanced HRPC (prior estramustine phosphate allowed). Methods: 361 pts were entered in this prospective, randomized multicenter trial from March 2004 to May 2009. 346 pts were eligible and received at least one T cycle. The pts were centrally randomly assigned to receive T i.v. either 75 mg/m² d1 q3 wks (tT) or 50 mg/m² d1 and d 14, q4 wks (bT). Prednisolon 10 mg/d was administered orally in both groups. The groups were well balanced with the WHO performance status, mean age (69.3 yrs, range 45-87 yrs vs. 68 yrs, range, 46-85 yrs), and the median serum PSA content at study entry (108.5 µg/L, range 11-1230 vs. 116 µg/L, range 12-1870, respectively). The primary end point was time to treatment failure (TTTF). The planned sample size was 348 pts (α 0.05, 1-ß 0.80, 2-sided log-rank test). Study identifier: NCT00255606. Results: The 346 eligible pts who received at least one dose of docetaxel (tT, 176; bT, 170) are included in the analysis. 1249 and 1051 T cycles were administered in the tT and bT groups, respectively. Serious adverse events were reported more often with the 3-weekly schedule (5.9 vs. 9.4 % of cycles, p=0.002). The median TTTF was longer in the bT group compared to tT (5.6 vs. 4.9 mos, respectively; p=0.016). PSA response was equally frequent in both groups (CR+PR 23%; SD 46%). Overall survival did not differ significantly between the 2 groups (median, 11.2 vs. 11.8 mos, respectively, p=0.164). Conclusions: T administered every 2 weeks was better tolerated than 3-weekly administration and resulted in a longer TTTF, but did not improve survival.

Tesetaxel, an advanced-generation oral taxane, as first-line treatment in women with metastatic breast cancer.

TPS123 Background: Taxanes such as docetaxel and paclitaxel are among the most active agents in metastatic breast cancer (MBC). Tesetaxel is an active novel taxoid that overcomes disadvantages of these standard agents. Among other features, the drug is taken by mouth as an oral capsule. Tesetaxel is not a substrate for P-glycoprotein, a major cause of taxane resistance. The drug is not associated with hypersensitivity reactions, thus obviating the need for both premedications and extended medical/nursing observation. Preclinical studies in human tumor xenografts show activity in taxane-resistant BC as well as reduced peripheral neuropathy. In dose-ranging studies, 8 of 13 evaluable patients (pts) (62%) with MBC achieved prolonged stable disease (SD) (i.e., up to 24 cycles) when the drug was administered once every 3 weeks (wks). A phase II trial of tesetaxel (27-35 mg/m2 p.o. Q3 wks) showed a 38% partial response (PR) rate among 34 pts who had progressed after an anthracycline-containing regimen. Based on these favorable data, we have initiated a multicenter study to assess the efficacy and safety of tesetaxel as 1st-line therapy in MBC. Methods: Eligible patients have: Stage IV, HER2-negative MBC; ECOG PS 0-1; adequate organ function; no prior chemotherapy for MBC, although 1 adjuvant regimen is allowed. Tesetaxel is administered Q3 wks at a starting dose of 27 mg/m2 p.o., which can be increased to 35 mg/m2 depending on tolerability. A Simon mini-max two-stage design is being used. Target accrual is 25 pts. Response rate, per RECIST 1.1 criteria, is the primary endpoint. Other objectives include progression-free survival and safety. Assuming initial results are favorable, we will examine a weekly dosing schedule in a second pt cohort.

A phase Ib dose-escalation study of the safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of the humanized monoclonal antibody (huMAb) anti-EGFL7 (MEGF0444A) in combination with bevacizumab with or without paclitaxel in patients with advanced solid tumors.

2514 Background: Epidermal growth factor-like domain 7 (EGFL7), is a vascular-restricted, tumor selective, extracellular matrix protein that forms perivascular tracks and promotes endothelial cell adhesion and survival, especially under stress. Anti-EGFL7 (MEGF0444A) is a huMAb that inhibits these activities of EGFL7. In combination with an anti-VEGF antibody, anti-EGFL7 significantly enhances the anti-tumor activity of anti-VEGF in multiple murine tumor models. Methods: A standard 3+3 dose escalation design was used to study safety, PK, PD and anti-tumor activity in 40 patients (pts) with advanced solid tumors. In Arm A, MEGF0444A was given IV at doses of 2, 5 or 10 mg/kg followed by bevacizumab IV at 10 mg/kg on Days 1 and 15 of each 28-day cycle. Pts in Arm B also received paclitaxel (90 mg/m2) on Days 1, 8 and 15 of each 28 day cycle. PD biomarkers including circulating progenitor cells (CPC) and dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) were assessed. Results: The combination of MEGF0444A and bevacizumab, with or without paclitaxel, was well tolerated without exacerbation of bevacizumab-related adverse events. MEGF0444A demonstrated linear PK typical of IgG1 monoclonal antibodies. Responses were observed in multiple tumor types in both arms of the on-going Phase Ib. Maximal changes in CPC and DCE-MRI measurements occurred at the 5 mg/kg dose level, consistent with anti-angiogenic effects. Conclusions: MEGF0444A has demonstrated favorable PK properties and is well tolerated in combination with bevacizumab and bevacizumab/paclitaxel. Activity of the combinations has been observed based upon clinical responses, changes in CPCs and DCE-MRI. Study data supports a Phase II dose of 5 mg/kg q2 wks (flat dose equivalent, 400mg q2 or 600mg q3 wks). Further studies of MEGF0444A in combination with chemotherapy and bevacizumab are planned.

Dose-ranging study of tesetaxel, a novel oral taxane, administered as second-line therapy at a flat dose to patients with advanced gastric cancer.

4110 Background: Tesetaxel, a novel oral taxane, yielded a 20% major objective response rate in pretreated patients (pts) with advanced gastric cancer when administered at a dose of 27 mg/m2 Q3 wks...

Population pharmacokinetic (PK) analysis supports fixed dosing for the humanized monoclonal antibody (huMAb) anti-EGFL7 (MEGF0444A) administered intravenously in patients with advanced solid tumors.

2586 Background: Monoclonal antibody therapeutics in oncology are most frequently dosed using body weight (BW)-based dosing, which may be due to the perception that BW-based dosing may be more precise. MEGF0444A is a huMAb that targets and inhibits the epidermal growth factor-like domain 7 (EGFL7) and has anti-vascular, and anti-re-growth effects on tumor vasculature and anti-tumor activity, particularly in combination with anti-VEGF. The objective of this analysis was to characterize MEGF0444A PK from two Phase I studies in patients (pts) with solid tumors and to evaluate the potential for using fixed dosing in Phase II studies. Methods: Noncompartment and population analyses were performed using pt data from the Phase Ia (0.3, 1, 3, 7.5, and 15 mg/kg q3wk) and Ib (2, 5, and 10 mg/kg q2wk) studies. Pt demographic data and other clinical relevant covariates were incorporated in the population analysis. PK simulation of 1000 subjects with a BW distribution was performed to compare the inter-individual variability of MEGF0444A exposure following fixed or BW-based dosing. Results: MEGF0444A was characterized by linear PK in the dose range tested. The clearance (CL) and volume of distribution (Vd) values were consistent with those of a typical huMAb. The elimination half-life was approximately 2 weeks. BW effect on CL and Vd was found to be minor to moderate, which appeared to be smaller when compared with other oncology MAbs. PK simulations suggest that fixed dosing may result in less inter-individual variability in MEGF0444A exposure compared with BW-based dosing. In addition, under- and over-exposure in extreme BW pts tended to be reduced with fixed dosing. Conclusions: PK characteristics support dosing of MEGF0444A every 2 or 3 weeks to maintain desired drug exposure. Population PK analysis results support fixed dosing of MEGF0444A at the equivalent 5 mg/kg q2 wk doses (400mg q2 or 600mg q3 wks) in future studies. The current analysis provides valuable insights on fixed dosing for oncology MAbs.

Phase I study of bevacizumab, sorafenib, and low-dose cyclophosphamide (CYC) in children and young adults with refractory solid tumors.

9500 Background: Angiogenesis is necessary for tumor growth, metastasis, and survival. Endothelial cells and pericytes, key cellular components of blood vessels, are primarily regulated by VEGF and PDGF signaling. We therefore performed a phase I trial to determine the feasibility and toxicity profile of agents combined to inhibit angiogenesis by targeting PDGFR-β and VEGFR2 with sorafenib, VEGF with bevacizumab, and endothelial cells with continuous low-dose CYC. Methods: Cohorts of 3-6 eligible patients with recurrent solid tumors received CYC and escalating dosages of sorafenib and then of bevacizumab (see table). Each course of therapy was 21 days. We used standard physical exams and laboratory tests to assess toxicities. Results: 19 patients (11 males; median age, 9.2 years) received a median of 4 courses (range, 1-23). The table summarizes dose levels explored and dose-limiting toxicities (DLTs) in course 1. With additional 71 courses of therapy, the most common nonhematologic toxicities ≥ grade 3 included rashes (5) and febrile neutropenia (2). Predominant hematologic toxicities were neutropenia and lymphopenia. Five of 17 evaluable patients had partial tumor responses (2 rhabdoid, 1 rhabdomyosarcoma, 1 medulloblastoma, 1 synovial sarcoma), and 9 had disease stabilization. First-dose pharmacokinetics results from 14 patients follow. The median (range) apparent CYC clearance was 2.03 L/hr/m2 (1.8-2.1 L/hr/m2), and the absorption rate constant was 0.12 hr-1 (0.08-0.23 hr-1). Sorafenib at 90 and 110 mg/m2yielded the following respective median (range) values: Cmax, 1.1 (0.37-2.4) and 1.6 (0.91-2.4) mg/L; Tmax, 8.5 (3.9-17.5) and 10.7 (8.2-14.1) h; AUC (0-12h), 10.4 (2.6-23.0) and 13.6 (8.0-20.4) mg*h/L. Conclusions: The recommended phase II doses are sorafenib, 90 mg/m2/dose BID; bevacizumab, 15 mg/kg q3 weeks; and CYC, 50 mg/m2 once daily. This regimen is feasible with promising evidence of anti-tumor activity that warrants further investigation. No. pts* Sorafenib (mg/m2) PO BID Bevacizumab (mg/kg) IV q3 wks No. DLT DLT course 1 3 90 5 0 None 4 110 5 2 Grd 3 rash, ↑lipase 6 90 10 1 Grd 3 thrombus 6 90 15 1 Grd 3 rash, anorexia *All received CYC (50 mg/m2) PO once daily.

Phase I dose-escalation study of ALN-VSP02, a novel RNAi therapeutic for solid tumors with liver involvement.

3025 Background: ALN-VSP02 is a RNA interference (RNAi) therapeutic comprised of lipid nanoparticle-formulated small interfering RNAs (siRNAs) targeting the expression of vascular endothelial growth factor (VEGF)-A and kinesin spindle protein (KSP). Methods: A multi-center, open label, phase I dose-escalation trial of ALN-VSP02 administered as a 15-minute iv infusion q2 wks was initiated in patients (pts) with advanced solid tumors and at least one measurable liver lesion. Main objectives included evaluation of safety/tolerability and assessment of PK/PD. Results: Thirty-one pts were enrolled across 7 dose levels (0.1-1.5 mg/kg); median age 57 yrs, all with multiple prior therapies. A total of 140 doses were administered, mean of 4.5 (range 1-17). Treatment was generally well-tolerated, with no dose-dependent trends in clinical or laboratory adverse events. One on-study death (liver failure in a pt with near complete replacement of the liver by tumor) deemed possibly related to treatment occurred at 0.7 mg/kg. Low-grade acute infusion reactions occurred in 10% of pts and were managed with slowing of infusion. Dose-limiting toxicities at doses >0.7 mg/kg included 1 episode each of reversible grade 3 thrombocytopenia (1.25 mg/kg) and hypokalemia (1.5 mg/kg). Plasma PK showed dose-proportional AUC and Cmax. Post-treatment biopsies from 10 pts (7 liver and 3 extrahepatic tumors) showed pharmacologically relevant concentrations (0.3-142 ng/g tissue) of both siRNAs. Molecular evidence of RNAi-mediated VEGF mRNA cleavage was shown in liver (n=2 at 0.4 mg/kg) and in an extrahepatic tumor (ovarian cancer at 1.25 mg/kg) through use of the 5’ RACE assay on tumor biopsies. Additional evidence for an anti-VEGF effect with ALN-VSP02 included a decrease in Ktrans of at least 40% by DCE-MRI in 56% of evaluable pts. Among 27 pts evaluable for response, 8.3% (1 of 12) at doses ≤ 0.4 mg/kg had stable disease (SD) for at least 2 mo compared to 46.6% (7/15) with SD (n=6) or PR (n=1, endometrial cancer with liver metastases) at doses ≥ 0.7 mg/kg. Conclusions: ALN-VSP02 is well-tolerated and has antitumor activity. Pharmacodynamic data are consistent with an anti-VEGF effect, and 1.25 mg/kg q2wks is the recommended phase II dose.

Phase III, randomized, open-label study of triweekly docetaxel versus biweekly docetaxel as treatments for advanced hormone-refractory prostate cancer: Findings from an interim safety analysis of the Finnish Uro-oncological Group Study 1-2003.

129 Background: Docetaxel (T) administered at every three weeks is standard treatment for advanced HRPC. We compared 2-weekly to 3-weekly T as first- or second-line chemotherapy of advanced HRPC in this prospective randomized multicenter trial. Methods: 360 pts were randomly allocated to receive T 75 mg/m2 i.v. d1 q3 wks (tT) or 50 mg/m2 i.v. d1 and d 14, q4 wks (bT) from March 2004 to May 2009. Prednisolon 10 mg/day was administered in both groups. The groups were well balanced according to the WHO performance status, mean age (70 vs. 68, range 45–87), and the median serum PSA level at study entry (109 vs. 98 μ g/L, range 11–1,490). The primary endpoint was TTF. Study identifier: NCT00255606 . Results: 158 pts (tT, 79; bT, 79) were included in this preplanned interim safety analysis. 567 and 487 cycles were administered in the tT and bT groups, respectively. The most common grade 3–4 adverse events (expressed as %/cycles) in tT /bT were neutropenia 20%/14%, infection with/without neutropenia 8%/3%, fatigue 3%/ 3%, febrile neutropenia 2%/1%, and bone pain 2%/1%. Serious adverse events occurred more frequently in tT (n=60, 10.6% of cycles) than in bT (n=29, 6.0%, p=0.012). One pt. died from coronary infarction and one was diagnosed with ALL (both in bT group). 30 pts (38%) in bT group and 22 pts (28%) in tT group were receiving treatment at 6 months. (p=0.176). Conclusions: Biweekly T has been better tolerated than the conventional triweekly T with fewer serious adverse events and may be associated with similar efficacy. [Table: see text]

A randomized cross-over trial comparing single-agents capecitabine (C) and UFT plus leucovorin (LV) in patients (Pts) with advanced colorectal cancer (CRC): Preliminary data of a patient preference study.

558 Background: Oral fluoropyrimidines such as C and UFT plus LV (U) are widely used pro-drugs dedicated to the care of CRC. Although their toxicity profile may slightly differ, no direct comparison between these treatments has been done as both molecules are converted into fluorouracil. To help the physicians to choose between C and U, we initiated this randomized cross-over trial aimed to assess patient's preference. Methods: Pts with advanced CRC received either a first cycle of C (1,250mg/m2 x 2/d for 14 days, q3 wks) or a first cycle of U (UFT 300mg/m2/d plus LV 75 mg/d in 3 divided doses every 8 hrs for 28 days, repeated at 35-day intervals). Patients were randomized to receive C at cycle 1 followed by U (arm A) or U at cycle 1 followed by C (arm B). After 2 cycles, pts were asked which treatment they preferred. Treatment was then continued with the chosen regimen. Preferences rates are presented with 95% confidence intervals and the two groups are compared with the chi-squared test. Results: 89 pts were enrolled from 10/2005 to 6/2010. Treatment arms were well balanced for baseline characteristics: male 57%; median age 66 years; PS 0-1 81%. Most of the pts were heavily pretreated (0/1/2/ and &gt;2 previous chemotherapy lines: 6/2/15/66). 64 (arm A: 35, arm B: 29)/89 pts received at least 2 cycles of chemotherapy and were evaluable for preference. At cycle 1, 21% and 43% of the pts presented at least 1 severe toxic event with C and U, respectively. Pts with U at cycle 1 presented more likely with severe fatigue and anorexia. There was 1 toxic death under C (gr. 3 diarrhea, gr.4 neutropenia) at cycle 1. Overall, 66% (95%CI: 52-77%) of evaluable pts expressed preference for C, and there was a statistically significant difference between arms A and B (p&lt;0.02) with more pts preferring C in arm A: 79% (95%CI: 61-91%), as compared to arm B: 50% (95%CI: 31-79%). Conclusions: Pts with advanced CRC preferred C over U, especially when given during the first cycle. No significant financial relationships to disclose.

First-line treatment (txt) with pemetrexed-cisplatin (PC), followed sequentially by gefitinib (G) or pemetrexed, in Asian, never-smoker (n/smkr) patients (pts) with advanced NSCLC: An open-label, randomized phase II trial.

7591 Background: Asian, n/smkr NSCLC pts show more favorable clinical course and improved outcomes when treated with EGFR-TKIs or chemo, particularly in presence of EGFR mutations (mut). In unknown EGFR mut status pts, optimal selection/integration of both modalities is unclear. This trial compared first-line sequential (seq) txt with PC followed by either G or P. Methods: Asian, n/smkr, chemonaive, stage IIIB/IV NSCLC and ECOG PS ≤1 pts, of unknown EGFR mut status, were randomized to Arm A (4 cycles: P[500 mg/m2] + C[75 mg/m2] q3 wks followed by G [250 mg/d]) or Arm B (induction chemo per Arm A followed by P [500 mg/m2] q3 wks [+C, max 2 additional cycles]). While progression-free survival (PFS) was calculated from randomization, the primary objective was a comparison during the seq phase only (ie, from cycle 5) by a time-dependent Cox model. Tissue collection for EGFR mut analysis was optional. Results: Primary endpoint analysis results are presented. Between (btwn) Feb-Nov 2007, 70 pts from China, Korea and Taiwan received induction PC. Baseline characteristics were balanced btwn arms. 49 pts (70.0%) received seq txt (n=25 G; n=24 P), while 21 pts (30.0%) discontinued during induction. The primary endpoint indicates pts on seq G have significantly lower risk of progression and PFS overall indicates a trend favoring Arm A. Response was not statistically different btwn txt arms, yet duration of response was improved in Arm A. Survival was consistently higher for Arm B pts. No significant difference was observed btwn txt arms for grade 3/4/5 toxicities. Conclusions: Pts receiving first-line PC followed by seq G showed prolonged PFS, in excess of 9 mths. OS, although immature, is encouraging regardless of seq txt choice. Evaluation of txt sequence according to EGFR mut status in NSCLC pts is warranted. Arm A Arm B Induction PC (N=39)Seq G (N=25) Induction PC (N=31)Seq P (N=24) HR (95% CI); p value PFS HR seq phase only 0.194 (0.075, 0.502); <0.001 PFS HR overall 0.533 (0.272, 1.044); 0.067 PFS median mths (95% CI) 9.95 (5.85, 16.49) 6.83 (5.78, 7.98) Overall survival (OS), % 12 mths 74.8 93.3 24 mths 59.6 71.1 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Lilly Lilly Lilly

Randomized phase II study of carboplatin plus either docetaxel (CbD) or paclitaxel (CbP) in Japanese patients with advanced non-small cell lung cancer (NSCLC): JMTO LC07-01.

e18069 Background: Platinum-based taxane chemotherapy has become a standard in the treatment of advanced NSCLC. However, no randomized data of CbD versus CbP have been available to date in Asian patients (pts). We report the analysis of a randomized phase II study comparing these two regimens. Methods: Chemotherapy-naive, ECOG PS 0-1, advanced NSCLC pts were enrolled. Carboplatin was administered at a fixed dose of AUC 6 on day1. Pts were randomized to either CbD (docetaxel 60 mg/m2 on day1, q3 wks) or CbP (paclitaxel 200 mg/m2 3h on day1, q3 wks) × 6 cycles in a ratio of 2 to 1, where the planned accrual was 90 pts (60/30 for CbD/CbP). Primary endpoint was PFS rate at 6 months (mo). Results: Ninety-one pts were enrolled and 90 pts were evaluable: median age 67 (range 37-82); M/F, 77/23%; cStage IIIB/IV/Relapse, 34/54/12%; Ad/Sq/Others, 59/26/16%; 6% had received prior RT. Demographics were well balanced between the two arms. Of the planned 360/180 cycles, 64/77% of those were administered in CbD/CbP. Median follow-up time was 15.8 mo. Data for survival, response rate, and toxicity in both arms are presented in the Table. PFS rate at 6 mo and median PFS were 41% and 4.8 mo in CbD and 37% and 5.1 mo in CbP. Although summary statistics for efficacy were similar in both arms, survival (OS and PFS) curves crossed each other. There was one treatment-related death due to pneumonitis in CbD. Conclusions: Two taxane drugs were tolerated and showed a similar activity in combination with carboplatin. Besides CbP, one of the current standard, CbD can be an alternative platform regimen in the first-line treatment of advanced NSCLC. Regimen CbD CbP N 60 30 Response rate, 90% CI 22% (13-32%) 33% (19-50%) PFS, % at 6 mo (90% CI) median (90% CI) 41% (30-52%) 4.8 mo (4.1-6.9 mo) 37% (22-51%) 5.1 mo (4.4-6.1 mo) OS, % at 12 mo (90% CI) median (90% CI) 60% (48-69%) 18 mo (12-23 mo) 60% (44- 73%) 15 mo (10-18 mo) Gr ≥3 neutropenia 75% 87% Gr ≥3 anemia 10% 10% Gr ≥3 thrombocytopenia 5% 3% Gr ≥3 febrile neutropenia 15% 17% Gr ≥3 nausea 5% 3% Gr ≥3 vomiting 5% 0% Gr ≥2 sensory neuropathy 17% 13% Gr ≥2 myalgias 7% 0% Treatment-related death 1 case 0 case No significant financial relationships to disclose.

Randomized phase II study of weekly versus every 3 week ixabepilone plus bevacizumab (ixa/bev) versus paclitaxel plus bev (pac/bev) as first-line therapy for metastatic breast cancer (MBC): Final results.

1040 Background: Pac/bev is superior to pac alone as first-line therapy for MBC. Ixa/bev has greater preclinical activity than pac/bev in human tumor models. The primary objective of this trial was to evaluate objective response rates (ORR) of ixa/bev given weekly or every 3 weeks relative to pac/bev as first-line therapy for women with advanced breast cancer. Methods: Women with measurable HER2-negative tumors and no prior chemotherapy for advanced breast cancer were randomized in a 3:3:2 ratio to Arm A (ixa 16 mg/m2 IV on days 1, 8, and 15 q28 days/ bev 10 mg/kg IV q 2 wks), Arm B (ixa 40 mg/m2 IV q3 wks /bev 15 mg/kg IV q 3 wks) or Arm C (pac 90 mg/m2 IV, schedule/bev as in Arm A). Treatment was continued until disease progression or unacceptable toxicity. Results: Final efficacy and safety results of all randomized/treated subjects are presented here. Baseline characteristics were balanced between arms except for hormone receptor status, liver metastasis, and time from diagnosis to randomization, which favored arm C. Exposure to chemotherapy in each arm was comparable; median cycles for bev received was 6.0 for Arm A and 10.5 for arms B and C. Conclusions: Ixa/bev given weekly or q 3 wks demonstrated encouraging clinical activity relative to pac/bev, although observed efficacy was better in the q 3 wks arm. Safety profile was manageable and similar to pac/bev in first-line treatment of MBC. These results support ongoing clinical trials of ixa in first-line MBC, and in combination with bev. Ixa (weekly)+ bev Ixa (q3wks) + bev Pac + bev Arm A (N=46)* Arm B (N=45) Arm C (N=32) Baseline characteristics (%) ER+/PR+ 70 58 75 ER+/PR- 9 20 9 Triple-negative 17 20 16 Liver metastasis 48 47 28 Median time from initial diagnosis to randomization (wks) 39 38 55 Efficacy ORR, % (95% CI) 48 (32.9- 63.1) 71 (55.7-83.6) 63 (43.7-78.9) Median PFS (mo) (95% CI) 9.6 (6.1-11.7) 11.9 (8.7-14.7) 13.5 (10.0- 18.2) Safety, % Grade 3 peripheral neuropathy 18 24 25 Grade 3/4 neutropenia 16 60 22 Febrile neutropenia 0 2 0 * N > 45 treated subjects. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb, GlaxoSmithKline, Novartis, Roche, sanofi-aventis Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb, Genentech