Q21 Days Research Articles

LUX-Lung 3: A randomized, open-label, phase III study of afatinib versus pemetrexed and cisplatin as first-line treatment for patients with advanced adenocarcinoma of the lung harboring EGFR-activating mutations.

LBA7500 Background: Afatinib (A) is a selective, orally bioavailable, irreversible ErbB family blocker of EGFR (ErbB1), HER2 (ErbB2), and ErbB4. This global study investigated the efficacy and safety of A compared with pemetrexed/cisplatin (PC) in pts with EGFR mutation positive advanced lung adenocarcinoma. Methods: Following central testing for EGFR mutations (companion diagnostic TheraScreen EGFR RGQ PCR kit), 345 pts (stage IIIB/IV, PS 0–1, chemo-naive) were randomized 2:1 (A: 230; PC: 115) to daily A 40 mg or iv PC (500 mg/m2 + 75 mg/m2 q21 days up to 6 cycles). Primary endpoint was progression-free survival (PFS) by central independent review. Results: Baseline characteristics were balanced in both arms: median age, 61 y; female, 65%; Asian, 72%; never-smoker, 68%; Del19, 49%; L858R, 40%; other mutations, 11%. Treatment with A led to a significantly prolonged PFS vs PC (median 11.1 vs 6.9 mos; HR 0.58 [0.43–0.78]; p=0.0004). In 308 pts with common mutations (Del19/L858R), median PFS was 13.6 vs 6.9 mos, respectively (HR=0.47 [0.34–0.65]; p<0.0001). Objective response rate was significantly higher with A (56% vs 23%; p<0.0001). Significant delay in time to deterioration of cancer-related symptoms of cough (HR=0.60, p=0.0072) and dyspnea (HR=0.68, p=0.0145) was seen with A vs PC. Most common drug-related adverse events (AEs) were diarrhea (95%), rash (62%) and paronychia (57%) with A, and nausea (66%), decreased appetite (53%) and vomiting (42%) with PC. Drug-related AEs led to discontinuation in 8% (A; 1% due to diarrhea) and 12% of pts (PC). Conclusions: LUX-Lung 3 is the largest prospective trial in EGFR mutation positive lung cancer and the first study using pemetrexed/cisplatin as a comparator. Treatment with afatinib significantly prolonged PFS compared to PC, with significant improvements in secondary endpoints. AEs with afatinib were manageable, with a low discontinuation rate. With 4.2 mos PFS improvement in the overall population and 6.7 mos in pts with common mutations, afatinib is a clinically relevant first-line treatment option.

Phase II trials of cetuximab (CX) plus cisplatin (CDDP), 5-fluorouracil (5-FU) and radiation (RT) in immunocompetent (ECOG 3205) and HIV-positive (AMC045) patients with squamous cell carcinoma of the anal canal (SCAC): Safety and preliminary efficacy results.

4030 Background: Epidermal growth factor receptor (EGFR) expression and HPV infection are common in SCAC. We therefore initiated 2 phase II studies to evaluate the safety and efficacy of the EGFR inhibitor CX given concurrently with CDDP/5-FU/RT in HIV-positive (AMC045) and immunocompetent (E3205) patients with SCAC. Methods: All patients received CX (400 mg/m2 loading, then 250 mg/m2/wk IV x 6-8 wks) plus CDDP (75 mg/m2 IV q28 days x 2) and 5-FU (1000 mg/m2/day IV infusion days 1-4 q 28 days x 2) concurrently with RT (45-54 Gy) beginning with CX dose 2. Patients in E3205 also received 2 cycles of CDDP/5-FU alone prior to CX/CDDP/5-FU/RT; this was discontinued on recommendation of the NCI Anorectal Task Force after 28 patients. Both trials were powered to detect a reduction in 3-year local-regional failure (LRF) rate from 35% to 17.5% (alpha=0.10, beta=0.10), the primary end point. Other endpoints included progression free survival (PFS) and overall survival (OS). The results below include complete toxicity and preliminary efficacy data (including only the first 28 patients from E3205). Results: Expedited reporting was required for type I (any grade 5, grade 4 cardiac) or II (grade 4 RT skin, diarrhea) adverse events, with prespecified rates of >5% or >20%, respectively defined as unacceptable. Early stopping rules were not invoked for either trial. LRF rates data will be presented after more detailed case review is completed. Conclusions: CX plus CDDP/5-FU/RT is feasible in patients with SCAC, including patients with HIV infection. Preliminary safety and efficacy data appear encouraging, but accrual without neoadjuvant CDDP/5-FU continues in E3205, and additional followup of both study cohorts is required in order to determine whether pre-specified efficacy endpoints were met. [Table: see text]

Gemcitabine with nab-paclitaxel in neoadjuvant treatment of pancreatic adenocarcinoma: GAIN-1 study.

TPS4136 Background: Pancreatic adenocarcinoma remains a deadly disease with a dismal prognosis. Only 15% of patients present with resectable disease with 5-year survival only 20% despite adjuvant therapy. Neoadjuvant treatment may improve R0 resection rates, allows more patients curative surgery, is cost effective, and may improve overall survival by incorporating earlier systemic therapy. Methods: This is a prospective single arm open-label phase II trial using gemcitabine (G) and nab-paclitaxel (A) in the neoadjuvant treatment of resectable and borderline-resectable pancreatic cancer. Patients are stratified by risk group as defined by a predictive model published by Bao et al and the NCCN expert consensus statement (Table): low-risk resectable (Group 1) and high-risk resectable or borderline-resectable (Group 2). Group 1 receives 3 cycles of G+A then surgical resection. 1 cycle = G 1000mg/m2 +A 100mg/m2 IV on Days 1, 8, 15 Q28 days. Group 2 receives 2 cycles of G+A followed by 2 weeks of hypofractionated IMRT (50.4Gy in 10 fx) with G 400mg/m2 IV weekly, then surgical resection. The primary endpoints are R0 resection rate and overall response rates. Secondary endpoints are PFS, OS, 30-day post-op mortality, toxicity, QOL and molecular analysis including DPC4 and SPARC levels in tumor and stroma. Enrollment has just begun with a total accrual goal of 60 patients. This platform will allow targeted systemic therapy and tailored treatment stratification to optimize outcomes in curable pancreatic cancer. This study is registered with Clinicaltrials.gov (NCT01470417). [Table: see text]

Everolimus with paclitaxel plus bevacizumab as first-line therapy for HER2-negative metastatic breast cancer (MBC): A randomized, double-blind, placebo-controlled phase II trial of the Sarah Cannon Research Institute (SCRI).

1018 Background: Constitutive activation of mTOR and amplified PI3K/Akt/mTOR signaling are common in MBC, and increase as treatment-resistance is acquired. Everolimus (E), an mTOR inhibitor, has single agent activity, combines well with paclitaxel (P) and bevacizumab (B), and prolonged PFS when added to AI therapy in BOLERO-2. In this randomized phase II trial, E was added to P/B as first-line treatment of HER2-negative MBC. Methods: Women with untreated HER2-negative MBC were randomized (1:1) to P 90mg/m2 IV (days 1, 8, and 15) and B10mg/kg IV (days 1 and 15) q28 days with E 10mg PO (Arm 1) or placebo PO (Arm 2) daily. Response assessment was performed q8 weeks until progression or intolerable toxicity. Primary endpoint was PFS. Secondary endpoints: safety, overall response rate, response duration, overall survival. 110 pts allowed detection of improvement in median PFS from 11 to 16 months with 70% power. Results: Between 8/2009 and 6/2011, 112 pts were randomized (Arm 1=55; Arm 2=57). Median age: 58 years (range: 25-79). 88% were ER+ or PR+. Pts received a median 5 treatment cycles (range: <1- 26+); 18 (16%) pts remain on treatment (Arm1, 9; Arm 2, 9). Median PFS were 8.8 months (Arm 1) and 7.1 months (Arm 2) (95% CIs 7.4-9.6; 5.5-9.1 months, p=0.79, HR 0.94). Complete responses were observed in 5% [Arm1, 4 (7%); Arm 2, 2 (4%)] with partial responses in 49% [Arm1, 29 (53%); Arm 2, 26 (46%)]. Responses rates in taxane pretreated pts Arm 1 22%, Arm 2 12%. Hematologic toxicity was similar in both arms; grade 3 mucositis occurred in 13% of E pts. Dose reductions (47% vs 25%) and interruptions (42% vs 26%) were more frequent with E due to mucositis and rash. Treatment discontinuation rates were similar. Conclusions: The addition of E did not result in a significant improvement in the efficacy of weekly paclitaxel/bevacizumab in the first-line treatment of HER2-negative MBC although response rates and median PFS were better with E. Possible explanation for these results may include lower dose intensity in the E arm, treatment of less resistant pts, or intrinsic differences in E activity when added to antiestrogen vs chemotherapy.

Phase I trial of temsirolimus and lenalidomide in pts with rel/ref lymphomas.

8075 Background: The PI3K/Akt/mTOR axis is deregulated in lymphomas and is an emerging therapeutic target. We previously reported activity of temsirolimus (TEM) in DLBCL and FL (JCO 2010 28(31); however, the response duration was short. Lenalidomide (LEN) is an immunomodulatory agent with multiple anti-tumoral and microenvironmental effects, with activity across lymphoma subtypes. We are thus conducting a phase I/II study of TEM plus escalating doses of LEN. The phase I portion is completed. Methods: Patients (pts) had rel/ref lymphoma after >1 cytotoxic regimen. Other criteria: ANC > 1000/mL, platelets > 75,000/mL, nl renal and hepatic function, no VTE within 3 months, non-pregnant. A standard “3 + 3” design was used with dose levels (DL) listed (Table). TEM was given IV weekly and LEN was dosed orally on D1-D21, q28 days. Dose-limiting toxicity (DLT) was defined as cycle 1 grade 3 or 4 non-hematologic toxicity not responsive to standard supportive care, grade 4 thrombocytopenia > 7 days (or associated with bleeding or requiring more than 1 platelet transfusion), ANC < 500/mL > 7 days despite growth factors, or any thromboembolic event. Results: 18 pts (13M, 5F), med age 64 y (range, 42-80 y) were enrolled. 3 pts are ineval for DLT evaluation: one withdrew consent before starting treatment, 1 withdrew consent after a single dose, and 1 died of rapid disease progression after 1 dose. There was 1 DLT at DL1 and 2 DLTs at DL3 (Table). Adverse effects that did not meet DLT criteria: hypokalemia, hypertriglyceridemia, vomiting, urinary tract infection, skin infection, nausea, hypoxia, hyponatremia, diarrhea, and hyperglycemia (each occurring in one pt). There are 5 partial responses, 4 stable disease, 3 progressive disease, 2 not adequately assessed, and 4 still on active treatment. Conclusions: The combination of weekly intravenous TEM plus oral LEN is well-tolerated in a heavily pretreated group of pts with rel/ref lymphomas. The recommended phase II doses are TEM 25mg weekly plus LEN 20mg (D1-D21, q28d). [Table: see text]

A phase I study of MDM2 antagonist RG7112 in patients (pts) with relapsed/refractory solid tumors.

e13600^ Background: RG7112 is a small molecule MDM2 antagonist, designed to non-genotoxically activate p53. A phase I dose escalation (DE) was performed, followed by a sarcoma biomarker extension (EXT) in pts with wild type TP53. Methods: 106 pts (58M, 48 F), median age 57.9 yrs (range 22-84) participated; 76 in 9 cohorts (DE) from 20 to 1800 mg/m2, orally QD x 10 q28 days. 30 pts with sarcoma were treated at MTD (2500 mg) (EXT) with pre-and on dose (d5+/-2) biopsies. Analyses included TP53 mutation (AmpliChip), MDM2 amplification (ISH), p53 and p21 IHC, MDM2 RT-PCR, Ki-67, TUNEL and [18F]-FLT-PET. Blood was obtained for PK and MIC-1, a PD marker of p53 activation. Results: DE: MTD was1440 mg/m2/d (2500 mg flat dose). PK was ~dose linear (t½ 1-1.5 d) with high variability (CV~70%) in AUC and Cmax . Adverse events included nausea/GI and exposure-related neutropenia/thrombocytopenia. 3 DLTs: diarrhea, pancytopenia, hyponatremia occurred (at ≥ 640 mg/m2). Evidence of activity included: 1) concentration dependent increase in plasma MIC-1 (% baseline), 2) decrease in [18F]-FLT PET and PR each in liposarcoma pts at 1800 mg/m2 and 1440 mg/m2, respectively. EXT: Grade3/ 4 cytopenias at MTD precluded subsequent cycles in 6/8 pts (10 day schedule). Dosing was changed to 5 days, and only 3 patients had Gr3/4 cytopenias. 8/22 pts remained on study for >4 cycles, including 2 pts with SD for 7 and 9 cycles respectively. 3 of 4 EXT pts had decreased [18F]-FLT-PET activity. Biopsies (pre- and on treatment) demonstrated: 1) increase in p53 (median 1.5 fold change (X) by IHC, n=15); 2) increase in p21 (median 2.7X by IHC, n=14); 3) increase in MDM2 (median 2.5X by RT-PCR, n = 27); 4) decrease in % Ki-67(+) cells (median % change from baseline -65.4%, range -91% to +275%, n=17 ); 5) increase in TUNEL(+) cells of 9.0 (density of + cells/mm2, range -26.2 to +45.5, n=22). These results were seen both in tumors with and without MDM2 gene amplification, and in multiple sarcoma subtypes. Conclusions: RG7112 has manageable AEs (GI ) and cytopenias correlating with AUC. Single agent disease control, and biomarker activity was seen in both MDM2 amplified and non-amplified, heavily pretreated soft tissue sarcoma pts, with changes reflecting activation of p53-related pathways.

Phase I pharmacokinetic study of dasatinib (BMS-354825) in patients with advanced malignancies and varying levels of liver dysfunction: S0711, a SWOG early therapeutics committee study.

3078 Background: Dasatinib (D) is a first in class Src kinase inhibitor, and inhibits BCR-Abl, c-Kit, PDGFR-beta, EPHA2 and Src family kinases including Src, Lck, Yes, Fyn at nanomolar concentrations. Initially FDA approved for use in imatinib resistant CML. It is a small molecule targeted therapy hepatically metabolized primarily by CYP3A4. We conducted a phase I study to determine maximum tolerated dose (MTD) and pharmacokinetics (PK) of D in patients (pts) with liver dysfunction (LD). Methods: Pts with advanced solid tumors or lymphoma, Zubrod ≤2, no baseline ascites or pleural effusions, adequate renal and bone marrow function, received PO D daily. Cycles q28 days. Pts stratified into 4 LD groups: normal, mild, moderate, severe, using Child-Pugh classification (CPC). Data also collected for NCI ODWG Organ Dysfunction Working GroupCriteria. D dose was escalated in sequential cohorts of pts within each LD category. Blood analysis for D concentrations were determined during cycle 1 using a validated LC-MC/MS assay. Study objectives included characterizing safety, tolerability, PK, identifying the MTD and obtaining preliminary evidence of efficacy. Results: 54 registered pts, 51 pts received 51 cycles of D at doses starting at 100 mg in mild LD (50-140 mg). Median age 60, male 55%, Zubrod 1 70%. CRC 27%. Groups: normal-17, mild-20, moderate-13, severe-1 pt(s). Related AEs include fatigue 35%, diarrhea 27%, anemia 27%, nausea 25%, vomiting 21%, lymphopenia 13%, rash 13%, pleural effusion 8%. 1 DLT of increased CK in a pt in moderate LD with past history of similar episode with previous sorafenib. Previous linear PK disposition, and no accumulation. No apparent PK differences between normal and mild groups. Cycle 1 Day 1 D 140 mg Normal Group: Cmax 129 ng/mL. Mild Group 140mg: Cmax 157 ng/mL. Prolonged disease stabilization (≥4 cycles) in 6 pts, 3 CRC (4,5,8); 1 Pancreas, HCC, Bladder (4,5,6). Conclusions: Recommended dose for Dasatinib given PO QD for pts with mild, moderate, or severe LD using clinical criteria with CPC and no baseline ascites, are 140 mg, 70 mg, insufficient pts, respectively. Dose adjustment not necessary in pts with mild LD.

Safety and efficacy of eltrombopag (epag) versus placebo (pbo) for the treatment (tx) of chemotherapy-induced thrombocytopenia (CIT) in patients with solid tumors receiving gemcitabine (gem)-based chemotherapy (ctx): A phase I study.

9117 Background: There are limited tx options for CIT. Epag, an oral, small molecule, thrombopoietin-receptor agonist that increases platelet (plt) production, is being explored for tx of CIT. Methods: This was the Ph I portion of a Ph I/II, blinded, pbo-controlled multicenter study in adults with solid tumors and baseline plts ≤300,000µL, who received up to 6 cycles of gem (1000-1250 mg/m2 IV) as monotherapy on Days 1, 8, and 15 Q28 days or Days 1 and 8 Q21 days in combination with cisplatin (50-80 mg/m2 IV Day 1 or divided 1 and 8) or carboplatin (AUC 4-7 IV Day 1). Patients received ctx alone for Cycle 1 and ctx plus epag or matching pbo (randomized 3:1) daily on Days -5 to -1 and 2 to 6 for subsequent cycles. Epag or pbo was interrupted for plts ≥400,000/µL. Results: 33 patients were randomized; 26 received epag or pbo (Table). Data review with an external, independent physician found no safety concerns, and there were sufficient plt increases with a dose of 100 mg epag vs pbo. No dose-limiting toxicities were reported for epag but 1 for pbo. Most AEs were grade 1 or 2. The most common AE in combined epag- and combined pbo-treated groups was neutropenia. Conclusions: Epag was well-tolerated and improved plt counts. Based on these encouraging Ph I results, Ph II using 100 mg epag in thrombocytopenic patients is planned. [Table: see text]

A phase IB study of erlotinib in combination with gemcitabine and nab-paclitaxel in patients with previously untreated advanced pancreatic cancer: An Academic GI Cancer Consortium (AGICC) study.

4052 Background: The combination of gemcitabine (gem) and nab-paclitaxel (nab) has demonstrated promising activity in advanced pancreatic cancer. Erlotinib (erl) adds modest benefit to gemcitabine. We initiated this phase IB study to evaluate the safety of the three drug combination and obtain preliminary evidence of efficacy. Methods: Patients (pts) with previously untreated locally advanced (la) or metastatic (met) pancreatic cancer with ECOG PS 0-1 were treated with gem and nab IV days 1,8,15 and once daily erl days 1-28 Q28 days. Standard 3+3 design was used with dose levels (DL) (gem,nab,erl): 1(1,000, 125, 100), -1 (1,000, 100, 100), -2 (1,000, 75, 100), -3 (1,000,75,75). CT scans were obtained Q 2 cycles. DLT was defined as ≥grade (gr) 3 non-hematologic, febrile neutropenia, ≥gr 3 thrombocytopenia, or missing ≥2 doses gem, nab or >5 doses erl within first cycle (C). Results: Nineteen pts were enrolled and completed a total of 62 cycles (range 0-11). Pt characteristics: M/F (9/10), White/Hispanic/AA (15/2/2), median age 63 (range 54-78), ECOG PS 1=11, met/la (12/7). In DL1, 1/3 pts had gr3 dehydration in C 2 and 1/3 had gr 4 neutropenia/sepsis in C 4. Although not formally DLT, 3 more pts were enrolled. Of the next 3 pts, 1 DLT of gr 3 diarrhea/gr 4 neutropenia in C 1 was noted and 1 other pt DC’d therapy for neutropenia after 2 cycles. Of 3 pts in DL -1, 2 DLTs (gr 3 optic neuropathy, too many missed doses) were observed. Of 3 pts in DL -2, 2/3 had DLT (gr 3 esophagitis/fatigue and gr 3 transaminitis). Of 6 evaluable pts in DL -3, no DLTs were observed. Most common gr 3/4 toxicities were neutropenia (9), dehydration, thrombocytopenia (3 each), and hypotension (2). Of 13 pts evaluable for response, 6 had partial response (46%), 5 stable disease (38%), and 2 progressive disease (15%) as best response. Median PFS and OS of entire cohort were 5.3 and 9.3 months respectively. Conclusions: The combination of erlotinib with gemcitabine and nab-paclitaxel is not tolerable at standard single agent dosing of all drugs. However, significant clinical activity was noted, even at DL -3. Further study of the combination will need to incorporate reduced dosing.

Randomized phase II trial of gemcitabine/cisplatin (GC) with or without cetuximab (CET) in patients (pts) with advanced urothelial carcinoma (UC).

4506 Background: In UCpts EGFR over-expression correlates with high grade, stage, progression, short survival. Preclinical data show enhanced anti-tumor effect with CET + chemotherapy (CT). In several solid tumors CET added to CT improved survival. CET is hypothesized to improve UC response to CT. Methods: Pts with ECOG PS 0-2, adequate organ function, unresectable, locally recurrent or metastatic UC were stratified by disease state and randomized (1:2) to C 70mg/m2 d1, G 1000mg/m2 d1, d8, d15 (Arm A) or same CT + CET 500mg/m2 d1, d15 (Arm B) q28 days. Due to high thromboembolic events rate in Arm B, G dose was reduced to 800 mg/m2. 6 GC cycles were planned. Arm A pts progressing after 2 GC cycles had CET added. Arm B pts were to continue on CET monotherapy after 4-6 CT cycles. Imaging was q8 weeks. Primary endpoint: RECIST response rate (RR); secondary: safety, PFS, survival. Since E-cadherin impacts UC response to CET in vitro, serum level (sE-cad) was assessed at baseline, after 2 cycles, end of CT and at progression. With 1-stage design, assuming RR 50% (Arm A) and at least 65% (Arm B), planned sample size was 27/54 pts. RR improvement of 5% has 81% probability if true difference is 15%. Results: 88 pts were eligible and randomized, Arm A/B: median age 66/61 years; bladder primary 71.4%/77.2%; metastatic disease 92.9%/89.5%, median CT cycles number 6/5. 28 Arm B pts continued CET (median 3 cycles, range 1-29); 1 Arm A pt had CET added. Most common G3/4 adverse events (AEs) (Arm A, B): neutropenia (34.5%, 33.9%), anemia (10.3%, 5.1%), thrombocytopenia (27.6%, 22%), thromboembolism (6.9%, 18.6%), hyponatremia (3.5%, 10.2%); Arm B only: rash 28.8%, fatigue 11.9%, hypomagnesemia 11.9% and 2 deaths. 84 pts were response evaluable (see table below). sE-cad did not correlate with outcome. sE-cad increased in Arm A, but decreased in Arm B over time. Conclusions: GC/CET was feasible with no outcome improvement but higher AEs. sE-cad did not correlate with outcome. Decreased sE-cad in Arm B suggests potential EGFR-mediated E-cad proteolysis. [Table: see text]

Substitution of cisplatin for etoposide in 2 of 3 induction cycles of CAV/IE with subsequent irinotecan and vincristine for relapse in adults with Ewing sarcoma (ES) and primitive neuroectodermal tumor (PNET).

9571 Background: Treatment for adults with cyclophosphamide, doxorubicin and vincristine alternating with ifosfamide and etoposide (CAV/IE) for ES/PNET is based on the success reported in children however the same treatment in adults is less effective. 50% of relapsed disease is expected to occur in the lungs with median survival of 12.5 months (mo) after relapse. Since Cisplatin is used for relapse, we initially substituted cisplatin for etoposide in courses # 2 and # 3 of IE for 2 patients (pts) who were not responding to IE as determined by serial CT scanning and then used it for all pts. Relapsed pts were treated with irinotecan + vincristine (IRI-V) for at least 2 cycles as salvage therapy. We report the effect of cisplatin on influencing the relapse pattern and the effect of IRI-V on survival for pts after relapse Methods: A retrospective chart review of 19 consecutive adult pts (July 2004 to June 2011), with newly diagnosed ES /PNET were treated with CAV/IE as per H. Grier NEJM 2003 and modified as a 14 day cycle. Cisplatin 20 mg/m2 I.V. q d X4 was substituted for etoposide for courses # 2 and 3 of IE and combined with ifosfamide as above (IC) followed by surgery or RT. For pts with relapse Irinotecan was given I.V. 20mg/m2 days 1-5 & 8-12 + vcr I.V. 2mg days 1 & 8 q21 days for 2 or more cycles. Repeat treatment with CAV, IE or IC was also utilized for relapse. We evaluated the toxicities, the pattern of relapse and the survival after relapse with these treatments Results: Grade IV hematologic toxicity occurred in 11 of 19 pts treated with CAV vs. 7of 19 pts treated with IE vs. 7 of 19 pts treated with IC and 1 of 11 pts treated with IRI-V but 3 of those 11 pts had Grade IV diarrhea. Median survival was 44.8+ mo for 10 pts with non- metastatic and 23 mo for 9 pts with metastatic disease respectively. More importantly median survival from the time of relapse was 22.5+ mo, (range 12.7 to 31+ mo). 11 pts relapsed: 2 pts only in bone, 9 pts Local only, 0 pts had distant lung recurrence Conclusions: Cisplatin appears to markedly alter the relapse pattern in adults with ES/PNET and Irinotecan +vcr appears to prolong survival in relapsed pts previously treated with cisplatin.

Weekly ixabepilone with or without concurrent bevacizumab in the treatment of recurrent endometrial cancer.

e15526 Background: Ixabepilone for endometrial cancer has only been evaluated in phase II studies administered at 30-40 mg/m2 q21 days (GOG 129P, GOG 86P). The objective of this study is to describe the institutional experience using a weekly dosing strategy of ixabepilone ± bevacizumab in the treatment of paclitaxel/platinum-resistant recurrent endometrial cancer. Methods: Patients who received weekly ixabepilone (16-20 mg/m2 on days 1, 8, 15 of a 28-day cycle) ± bevacizumab (10 mg/kg on days 1, 15 of a 28-day cycle) off-protocol were identified retrospectively. Results: Thirteen patients were included. Demographic/disease characteristics are provided in Table 1. Median time to first recurrence was 15.9 months (IQR: 9.5-21.66). Patients received a mean of 4.8 ± 1.9 cycles of ixabepilone; treatment is ongoing in 4 patients. A total of 46% of patients demonstrated either a partial response (PR, 8%) or disease stabilization (SD, 38%). PR/SD was associated with a mean decline in CA-125 of 56%. Approximately 50% of patients received concurrent bevacizumab. Of patients who did not receive concurrent bevacizumab, 83% experienced progression and 17% demonstrated SD. Median survival after ixabepilone initiation was 12.7 and 6.9 months in patients treated with and without concurrent bevacizumab, respectively (HR 0.42 [0.09-1.98]). Grade 1/2 hematologic (thrombocytopenia, 15.4%) and gastrointestinal toxicities (emesis/constipation, 7.7%) were observed infrequently. Median overall survival of this cohort was 2.88 years. Conclusions: Ixabepilone shows encouraging activity and promising durability in patients with heavily pre-treated paclitaxel/platinum-resistant recurrent endometrial cancer. Weekly dosing at 16-20mg/m2 on days 1, 8, and 15 ± bevacizumab is well-tolerated. Additional investigation of this regimen and long-term follow-up is warranted. [Table: see text]

SWOG S0635 and S0636: Phase II trials in advanced-stage NSCLC of erlotinib (OSI-774) and bevacizumab in bronchioloalveolar carcinoma (BAC) and adenocarcinoma with BAC features (adenoBAC), and in never-smokers with primary NSCLC adenocarcinoma (adenoCa).

7517 Background: Despite recent changes to lung adenoCa pathologic classification, adv stage BAC remains a definable and clinically applicable entity. Patients (pts) with BAC, as well as never-smoking (NS) pts with adv lung adenoCa, have emerged as relevant clinical subpopulations with a high probability of clinical benefit from epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), likely related to the high proportion of activating mutations in the EGFR gene in such pts. Based on these results and the potential for increased clinical activity conferred by addition of B to E, SWOG initiated a pair of phase II trials of this combination in pts with adv BAC (S0635) or NS pts with adv lung adenoCa (S0636). Methods: NS pts with BAC or adenoBAC were preferentially enrolled on S0636. A total of 78 and 85 eligible pts were enrolled and treated on the S0635 and S0636 trials, respectively. Patients received E 150 mg PO daily and B 15 mg/kg IV q21 days until progression or prohibitive toxicity. Tumor tissue submission for pathologic review and assessment of molecular markers was mandated. Results: Pt demographics of the two trials are as shown in the table below. RECIST response rate among 61 BAC pts on S0635 with measurable disease was 18%, and among 53 NS pts on S0636, it was 47%. Median progression-free survival is 5 and 8 months (mo) on S0635 and S0636, respectively; median overall survival (OS) is 17 and 26 mo on S0635 and S0636, respectively. Toxicity consisted primarily of rash, diarrhea, and hypertension; no treatment-related deaths were reported. Molecular marker studies will be presented separately. Conclusions: In populations selected by clinical parameters, E withB is associated with modest toxicity and encouraging clinical efficacy that exceeded the prespecified OS threshold of 16 mo in studies of both adv BAC and NS pts, exceeding two years in NS pts. [Table: see text]

Use of early 18f-fluorodeoxyglucose-positron emission tomography to predict clinical outcome of patients with advanced non-small cell lung cancer on gefitinib treatment versus carboplatin plus paclitaxel.

10577 Background: Early prediction of clinical efficacy is of great value in cancer patients in avoiding unnecessary toxicities and giving them another chance for different treatments. This study aimed to assess the 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) at 3 days on treatment as an early predictor of clinical outcome in patients with advanced non-small cell lung cancer (NSCLC) treated with gefitinib and in those treated with cytotoxic chemotherapy. Methods: This study comprised two groups: patients with stage IIIB or IV NSCLC were treated with gefitinib (250mg) once daily (gefitinib group) or with carboplatin (AUC 6, day 1) plus paclitaxel (200mg/m2, day 1) q21 days (CP group) according to the physicians’ choice. FDG-PET was performed before, 3 days on and 28 days on each treatment. Reduction of tumor FDG uptake was assessed by using standardized uptake value (SUV). Metabolic response was defined as reduction of FDG uptake in the tumor ≥ 25% according to the criteria of the European Organization for Research and Treatment of Cancer. Metabolic response was correlated with clinical outcomes. Results: This study included 38 patients: 19 in gefitinib group and 19 in CP group. Reduction of SUV at 3days on treatment preceded tumor shrinkage more closely in gefitinib group. Metabolic response was significantly correlated with longer progression-free survival (PFS) in gefitinib cohort (median PFS 15.8 months [95% CI 13.2-18.4] vs. 3.7 months [95% CI 0.1-8.0], p < 0.001), but not in CP group (median PFS 5.7 months vs. 2.9 months, p = 0.054). Furthermore, metabolic response was significantly correlated with longer overall survival (OS) in gefitinib group (median OS 28.7 months [95%CI 23.5-33.9] vs. 9.8 months [95% CI 2.1-17.5], p = 0.009), but not in CP group (median OS 13.9 months vs. 10.5 months, p = 0.56). In multivariate analysis using Cox hazards models, metabolic response was a significant predictive factor of PFS and OS. Conclusions: Reduction of SUV levels on FDG-PET at 3 days on treatment may predict response and survival in gefitinib-treated patients with advanced NSCLC.

Prospective analysis of prostate cancer (PC) circulating tumor cells (CTCs) to predict response to docetaxel (DOC) chemotherapy.

100 Background: Taxane chemotherapy induces cellular microtubule stabilization (bundling) leading to mitotic arrest and apoptotic cell death. We recently reported that in castration-resistant PC, stabilizing of microtubules by taxanes inhibits ligand-induced androgen receptor (AR) nuclear translocation and activation of ARE-gene transcription (Cancer Res 2011;71:6019). This suggests the clinical activity of DOC results from inhibition of AR signaling. A pilot analysis of CTCs from 14 CRPC pts receiving taxanes revealed that predominant cytoplasmic AR and decreased total AR intensity each was associated with increased odds of response (P<0.001). We initiated a prospective trial to determine if CTC analysis could predict DOC response. Methods: Eligibility: Patients (pts) receiving DOC q21 days for CRPC with >5 CTCs determined by CellSearch. On cycle 1 d1 + d8, CTCs are isolated by ficoll tube separation and by CellSearch enrichment. Cells are stained for expression of prostate specific membrane antigen (PSMA), CD45, AR and acetylated tubulin (AcTub) as a marker of microtubule stabilization. AR localization and total fluorescence intensity, and AcTub intensity are quantitated by confocal microscopy and correlated with response to DOC using PCWG2 criteria. 72 pts are planned to provide 80% power to detect an association. Results: 28 of 72 pts have been prospectively enrolled to assess AR and AcTub as a biomarker of response. 20 pts have discontinued DOC. Day 1 samples were obtained from 27 pts and day 8 on 22 (5 pts on days 9 to 21). Immunofluorescence staining and evaluation of PSMA, CD45, and acetylated tubulin was performed successfully in 8 pts analyzed to date. CTCs can be identified in all pts. Cells are scored for AR and AcTub intensity (scale 1- 4) and AR nuclear vs cytoplasmic localization. Conclusions: Our results to date indicate that PC CTCs can be readily isolated from men receiving DOC chemotherapy in a multicenter fashion and assayed for AR localization and AcTub. Preliminary results suggest that monitoring AR subcellular localization and microtubule bundling in CTCs may predict clinical responses to DOC chemotherapy, warranting further study, including our prospective trial.

Long-term survival outcome of E1201: An Eastern Cooperative Oncology Group (ECOG) randomized phase II trial of neoadjuvant preoperative paclitaxel/cisplatin/radiotherapy (RT) or irinotecan/cisplatin/RT in endoscopy with ultrasound (EUS) staged esophageal adenocarcinoma.

69 Background: E1201 included operable esophageal adenocarcinoma, staged II-IVa by EUS and accrual ended Oct 2004. The primary endpoint was pathologic complete response (pCR), a surrogate endpoint generally associated with survival which did not meet criteria for further study of either arm. Long term survival results are now available. Stratification included clinical/EUS stage and ECOG performance status (PS). Methods: 81 eligible patients (pts) began treatment. Arm A was cisplatin (C) 30mg/m2 and irinotecan (I) 50 mg/m2 on days (d) 1, 8, 22, 29 of 45 Gy RT/5 weeks. Post-op therapy was C 30 mg/m2 and I 65 mg/m2 d 1, 8 q21 days x 3. Arm B therapy was C 30 mg/m2 and paclitaxel (P) 50 mg/m2 1 hour infusion d 1, 8, 15, 22, 29 with RT. Postoperative therapy was C 75 mg/m2 and P 175 mg/m2 day 1 q21 days x 3. Results: In Arm A, 26/39 have died. Median survival (S) is 35 m (months) and the 5, 6, and 7 year S was 46%, 39%, and 35%. In Arm B, 31/42 pts have died (one pt refused follow-up). Median S in arm B is 21 m. The 5, 6, and 7 year S was 27%, 27%, and 23%. Survival by EUS stage strata: For strata 1 (Stages T2N0M0 or T3N0M0), 14/20 have died. Median S is 37 m and 5 year S is 44%. In stage stratum 2 (Stages T1-3N1M0 or T1-3N0-1M1a), 43/61 have died. Median S is 24 m and 5 year S is 34%. For PS Strata: Patients with PS 0, had median S 35 m and 5 year S of 37% whereas for those with PS 1, the outcomes were 20m and 35%. Survival differences for the treatments and for these strata were not statistically significant. Conclusions: Long term survival is similar for both treatment arms and does not appear superior to results achieved with 5FU based regimens. The prognostic importance of the pretreatment strata was not confirmed. These data, along with the reported pCR (15% arm A; 17% arm B) and toxicity data (> =grade 3 during chemo/RT 68% arm A; 65% arm B), may have importance in aiding in the design and interpretation of ongoing and planned phase II trials adding novel agents or treatment approaches to backbones built on variations of these two regimens.

PD07-01: Sequential Treatment with Epirubicin/Cyclophosphamide, Followed by Docetaxel vs. FEC120 in the Adjuvant Treatment of Breast Cancer Patients with Extensive Lymph Node Involvement: Final Survival Analysis of the German ADEBAR Phase III Study.

Abstract Background: Based on meta-analytic evidence, taxane containing adjuvant chemotherapy has been established as standard treatment in node-positive breast cancer. However, in the MA-21 study, adriamycin-cyclophosphamide, followed by paclitaxel (AC-P) was significantly inferior to the gold standard of anthracycline treatment, FEC120 (Burnell, SABCS 2006). We prospectively compared a sequential epirubicin-docetaxel chemotherapy regimen to FEC120. Patients and Methods: The ADEBAR study was a multicenter phase III trial (n=1502) to evaluate whether breast cancer (BC) pts with > 3 axillary lymph node metastases benefit from a sequential anthracycline-docetaxel regimen (E90C-D: 4 cycles epirubicin [E] 90 mg/m2 plus cyclophosphamide [C] 600 mg/m2 q21 days followed by 4 cycles docetaxel [D] 100mg/m2 q21 days) compared to dose-intensive anthracycline-containing polychemotherapy (FE120C: 6 cycles E 60 mg/m2 d 1+8, 5-FU 500mg/m2 d 1+8 and C 75 mg/m2 d 1–14, q4 weeks). The median follow-up time will be 60 months. Results: Treatment was stopped prematurely in 3.7% of the pts in the E90C-D arm and in 8.0% in the FE120C arm due to toxicity (p=0.0009). Antibiotic treatment was given in 10.4% (E90C-D) vs. 19.7% (FE120C), G-CSF support in 39.2% vs 61.4% and erythropoietin stimulation in 8.7% vs. 20.0%, respectively (p<0.0001). Haematological toxicity (leucopenia, neutropenic fever, thrombocytopenia, anemia) was significantly higher in the FE120C-arm. Mature final 5-year-survival data will be presented at the SABCS meeting 2011. Conclusion: Different toxicity profiles given, hematological toxicity in the FE120C group was more severe than in the E90C-D. Mature survival data will be discussed in this context. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD07-01.

P5-13-09: Correlation of Oncotype DX Recurrence Scores with Pathologic Response Following Neoadjuvant Ixabepilone and Cyclophosphamide in Patients with HER2−Negative Breast Cancer: A Sarah Cannon Research Institute Phase II Trial.

Abstract Background: Ixabepilone (Ixa) is active in anthracycline and taxane-refractory metastatic breast cancer as well as in the neoadjuvant setting where Ixa yielded a pathologic complete response (pCR) rate of 11%. In this study, we evaluated Ixa in combination with cyclophosphamide (C) as neoadjuvant treatment for ER+/ER- HER2−negative breast cancer. The primary endpoint was pathologic complete response (pCR) rate, defined as no residual invasive cancer in breast or lymph nodes. The Oncotype DX Breast Cancer Assay, that uses reverse transcriptase-polymerase chain reaction (RT-PCR) to assess a panel of 21 tumor genes to calculate a score predictive of the likelihood of the magnitude of adjuvant chemotherapy benefit, was applied to pretreatment and residual disease tumor samples obtained at the time of definitive surgery. The likelihood of whether neoadjuvant clinical or pathological responses may be predicted by Oncotype DX recurrence scores (RS®) was assessed. An interim analysis of the first 81 patients (pts) was reported at ASCO 2011. The final analysis will be presented on all 168 pts. Methods: Eligible women had locally advanced breast cancer that was HER2−negative (IHC 0–1+ or FISH negative), T >2 cm or lymph node positive. Pts with inflammatory breast cancer or T1N0 tumors were excluded. Pts received Ixa 40mg/m2 with C 600mg/m2 day 1 q21 days x6 cycles. Following 6 cycles, had definitive surgery. Postoperative locoregional radiation therapy and/or hormonal treatments were at discretion of the treating MD per institutional guidelines. Breast core biopsy tumor samples were obtained pretreatment and at the time of surgery in those pts demonstrating residual disease at surgery. Tumor specimens were analyzed using the Oncotype DX RT-PCR assay. An interim pretreatment RS assessment in the first 38 pts and paired samples in 21 pts was conducted and correlated with clinical and pathologic responses. Results: 168 women enrolled. Baseline characteristics and toxicity for the first 118 pts are reported (median age 52 years; 90% invasive ductal carcinoma; T2/T3 52%/31%; 42% triple negative). 81 pts have undergone surgery. 25 pts discontinued treatment early (toxicity — 12; disease progression — 8; pt/MD request — 3; pt non-compliance — 2).Grade 3/4 toxicity included: neutropenia (65%), leukopenia (47%), neuropathy (10%), and febrile neutropenia (7%). Preliminary toxicity results with this neoadjuvant treatment have been previously reported (Peacock et al, ASCO 2011 Abstract #1066). Oncotype DX pretreatment evaluations for the initial 38 pts demonstrated a significant logistic regression of pretreatment recurrence score with pCR (p = 0.025). Conclusions: Neoadjuvant therapy with Ixa and cyclophosphamide yielded a preliminary pCR rate of 19% (in 81 pts), similar to results with other 2-drug combination chemotherapy regimens. Preliminary Oncotype DX assessments at baseline indicated that baseline recurrence scores may predict pCR rates. These exploratory Oncotype DX recurrence scores at baseline and paired with scores obtained at the surgery and correlations with pCR will be presented for the entire cohort. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-13-09.

A phase II study of docetaxel weekly in combination with carboplatin every three weeks as first line chemotherapy in stage IIB-IV epithelial ovarian cancer: Neurological toxicity and quality-of-life evaluation

The purpose of this study was to assess the response rate, toxicity, progression-free survival (PFS) and overall survival (OS) in a series of advanced stage ovarian carcinoma patients treated with a first-line weekly docetaxel and three weekly carboplatin regimens. All eligible patients were treated with intravenous docetaxel (30mg/m2) on Days 1, 8 and 15, and carboplatin (area under the curve, 5) on Day 1; Q21 days for at least 6 cycles. Neurological tests, questionnaires, and the EORTC QLQ-C30 and OV28 were used for quality-of-life assessments. One hundred and six patients received at least one cycle of primary chemotherapy (median 6.0; range, 1-9) and they were evaluable for toxicity assessment. Eighty-five patients had evaluable disease and received at least 3 courses of chemotherapy and were evaluable for clinical response rate. The overall response rate was 78.8% (95% CI 70.1-87.5%) and the biochemical response was 92.8% (95% CI 87.2-98.4%). The median PFS was 12.0 months and the median OS was 35.3 months. Thirty-six patients (34.0%) experienced grades 3 and 4 neutropenia, which resulted in the removal of 3 patients. Six patients (5.7%) experienced grades 3 or 4 thrombocytopenia. No patients experienced grade 3-4 sensory neuropathy. Epiphora, nail changes and fatigue were frequently recorded non-hematological side effects. The tolerable hematological toxicity (no need for colony-stimulating factors) and the low rate of severe neurotoxicity (only grade 1-2) and response rates in line with the standard 3-week paclitaxel-carboplatin regimen for advanced primary ovarian carcinoma after suboptimal cytoreductive surgery make this regimen an interesting alternative in selected patients.

A Phase I/II Trial of Combination Gemcitabine and Bortezomib (VELCADE®) for Relapsed/Refractory T-Cell Non-Hodgkin Lymphoma (NHL) and Aggressive B-Cell NHL

Abstract 1646 Background:NF-κB has been shown to be deregulated in B-NHL and T-NHL subtypes. The proteasome inhibitor, bortezomib, has the capacity to reverse the downstream consequences of NF-κB, while gemcitabine has documented single-agent activity in relapsed/refractory NHL. Further, in vitro and murine xenograft tumor models have demonstrated synergy between these two agents. Based on these data, and the continued unmet clinical need for patients with relapsed/refractory aggressive NHL either ineligible for or relapsed after stem cell transplant (SCT), we conducted a phase I/II trial utilizing this novel combination. Methods:This was a phase I/II investigator-initiated clinical trial conducted through two centers. The phase I design was a classic 3+3 with dose escalation of bortezomib (1.3 mg/m2 to 1.6 mg/m2 given day (D) 1 and D8) with static gemcitabine dosing (800 mg/m2 D1 and D8) given on q 21 day cycles. The definition of dose limiting toxicity (DLT) was: a) grade 3 or 4 non-hematologic toxicity (other than grade 3 nausea or vomiting); b) grade 4 vomiting despite maximal anti-emetic support; c) grade 4 neutropenia on D1 of a treatment cycle (despite growth factor support); and d) grade 4 thrombocytopenia on D1 of a treatment cycle. Following completion of bortezomib escalation, a planned phase II expansion of the study was planned. The null hypothesis was that the true success was less than or equal to 15% and the alternate hypothesis was that the true success was 40% or higher; type I error of 5% and a power of 80% was assumed. Results:From April 2006 to December 2010, we enrolled 32 relapsed/refractory NHL pts onto this phase I/II clinical trial. Sixteen pts had T-NHL (n=12 peripheral T-NHL NOS and n=1 each with angioimmunoblastic T-NHL, NK-/T-NHL, transformed large cell [from pre-existing cutaneous T-cell], and hepatosplenic) and 16 had B-NHL (all relapsed/refractory DLBCL). There were 16 women and 16 men with a median age of 61 years (range, 37–85 years). The median ECOG performance status was 1 (range, 0–2), median prior therapies were 2.5 (range, 1–5), while 35% had failed prior autologous SCT. During the initial phase I dose escalation, 2 DLTs were noted (grade 3 hypertension and grade 3 elevation of liver function tests), while a maximally tolerated dose was not identified. However, among the first 18 pts treated on the D1+D8 (q21 day) dosing schedule, 67% experienced grade 3/4 neutropenia and/or grade 3/4 thrombocytopenia, primarily on D8 of treatment cycles. These recurrent D8 cytopenias resulted in repeated treatment delay(s). The median number of cycles delivered for these 18 pts were 1.0 (due to hematotoxicity), which was associated with a low (59%) median normalized dose-intensity. Thus, in early 2009, the clinical trial was amended instituting a modified treatment schedule of gemcitabine 800 mg/m2 and bortezomib 1.6 mg/m2 to both be administered on D1 and D15 of a 28-day schedule for an additional 22 patients. Treatment-related toxicity was markedly reduced using this modified treatment schedule; only one grade 3 event each of anemia and thrombocytopenia were recorded. However, after 14 pts had accrued to the modified treatment schedule, efficacy data were analyzed by the Northwestern University Data Monitoring Committee (DMC). Among all 32 patients, the ORR was 16% (complete remission (CR) 13%). Further, the ORR for all B-NHL pts was 6% (no CR) and 25% for T-NHL (19% CR). On the modified D1+D15 treatment schedule, the ORR for B-NHL was 0% (0/8); while among T-NHL, the ORR was 50% (3/6) with each of these latter pts remaining in continued remission at 29+, 26+, and 19+ months. Nevertheless, an analysis performed by the DMC for the overall study conduct recommended premature study closure; thus the final planned 8 pts did not enroll. Conclusions:We determined in this phase I/II study for pts with relapsed/refractory, aggressive T-NHL and B-NHL that combined bortezomib/gemcitabine using a dosing schedule of D1+8 q21 days was not tolerated and is not recommended for further study. Modification of bortezomib/gemcitabine dosing to D1+15 q28 days was tolerated markedly better, allowing consistent treatment delivery. Altogether, clinical efficacy of gemcitabine plus bortezomib in aggressive B-NHL was low (with either schedule), while there was a potential signal of activity with durable responses in a small number of pts in the T-NHL population utilizing the modified treatment schedule. Disclosures:Evens:Millennium: Research Funding, advisory board. Off Label Use: Velcade in T-cell and aggressive (non-MCL) B-cell NHL. Winter:Millennium: Research Funding. Smith:Millennium: Research Funding.