6-month Progression Research Articles

Phase II trial evaluating imatinib (I) in patients (pts) with anaplastic thyroid carcinoma (ATC)

6057 Background: There is no standard treatment for ATC. Response to doxorubicin ranges between 5–22%; median survival ranges between 3–6 months. Affymetrix gene chip showed PDGFR overexpression in ATC. In p53 mutated/deficient ATC cell lines, c-Abl is overexpressed, and selective inhibition of c-Abl resulted in cytostatic effect. (I) inhibits tyrosine kinase activity of Bcr-Abl and PDGF. We hypothesize that ATC that overexpress PDGFR or Abl will respond to (I). Methods: Pts ≥ 18 years old with histologically confirmed ATC, overexpressing PDGFR or c-Abl by immunohistochemistry who had measurable disease were eligible. Pts must have Zubrod performance status ≤ 1, and adequate hepatic and renal function. Prior chemotherapy, chemoradiation, radiation therapy, or surgery must have been completed at least 28 days prior to registration. (I) was administered at 400mg orally twice daily without drug holiday. Response to treatment was assessed after every 8 weeks. Pts with complete response (CR)/partial responses (PR)/stable disease (SD) were treated until disease progression. The study was terminated early due to poor accrual. Results: From February 2004 to May 2007, eleven pts from our institution were enrolled and were started on (I) (6 men; 5 women) with a median age of 63 years (ranges 53–80). At baseline, 4/11 pts (36%) had locoregional disease, 5/11 pts (45%) had distant metastases, and 2/11 pts (18%) had both. Nine pts had prior chemoradiation, and 7 pts had thyroidectomy. Out of 11 pts, 8 were evaluable for response; 3 were excluded for lack of follow up radiological evaluation. The overall responses at 8 weeks were CR 0/8; PR 2/8 (25%); SD 4/8 (50%); and PD 2/8 (25%). The median time to follow up was 26 months (ranges 23–30 months). The estimate of 6-month progression free survival was 27% (95% CI, 7–54%). The estimate of 6-month overall survival was 46% (95% CI, 17–71%). The most common G3 toxicity was lymphopenia in 45%; other G3 toxicities included edema (27%), anemia (18%), and hyponatremia (18%). There was no G4 or higher or treatment related death. Conclusions: (I) appears to have activity in advanced ATC and is well tolerated. Due to difficulty of accruing pts with a rare malignancy at a single institution, investigation of (I) in ATC may be warranted in a multi-institution setting. No significant financial relationships to disclose.

A phase II trial of gefitinib and pegylated interferon alfa 2b (PEG-IFN) in previously-treated renal cell carcinoma (RCC)

e16115 Background: Modulation of the epidermal growth factor receptor (EGFR) pathway is relevant to IFN activity in RCC. Cell lines sensitive to IFN's antiproliferative effects downregulate EGFR, while IFN treatment of resistant cells precludes such an effect. (Eisenkraft et al, Cancer Res. 1991) Lack of EGFR down-regulation may thus be responsible in part for IFN resistance. To explore this hypothesis, we conducted a trial of the EGFR tyrosine kinase inhibitor gefitinib plus PEG-IFN in RCC patients (pts). Methods: Unresectable or metastatic RCC pts (no limit on prior therapies; performance status 0–2, and adequate end-organ function) were eligible. Prior IFN was allowed. Dose schedule: PEG-IFN SQ weekly (6μg/kg/week or 4 μg/kg/week) × 12 weeks and gefitinib 250 mg po daily until progression. A 6-month progression free survival (PFS) rate of 50% was considered promising (vs. 30%) in a two-stage design incorporating the Green-Dahlberg rule. We accrued 21 patients in the first-stage of accrual. Results: Pt characteristics: Males -16; median age - 56 years; Prior nephrectomy - 12. All had > 1 prior systemic therapy . Accrual slowed with increased use of small molecule kinase inhibitors, bevacizumab, and temsirolimus for RCC. At 6 months, PFS was 26% (95% CI: 9%, 49%); 20% (4 pts) had died. Best responses by RECIST: complete (1), partial (4), stable (8); progression (4). Response duration: CR (35+ months) and PR (3, 5, 5, 38+ months). Median time to treatment failure was 18.4 weeks (95%CI: 7.4, 24.9). Median PFS and overall survival were 23 and 53 weeks, respectively. Most common treatment-related toxicities were leucopenia, thrombocytopenia, rash, nausea, diarrhea, and hyperglycemia. Conclusions: Although gefitinib plus PEG-IFN did not meet the pre-specified 6-month PFS of 50%, it appears to have activity similar to other first-line therapies even in this previously-treated setting. (Supported by Astra Zeneca) [Table: see text]

Temozolomide for recurrent intracranial supratentorial platinum-refractory ependymoma

2061 Background: There is no standard therapy for platinum-resistant ependymoma and hence a need exists for new therapies. Objective: A retrospective evaluation of temozolomide (TMZ) in adults with recurrent supratentorial platinum-refractory WHO grade 2 ependymoma with an objective of determining 6-month progression free survival (PFS). Methods: 25 patients, ages 28–63 years, with recurrent ependymoma were treated. All patients had previously been treated with surgery, radiotherapy, and platinum-based chemotherapy (cisplatin: 15; carboplatin 10). Nine patients underwent repeat surgery. Patients were treated at second recurrence with TMZ (5 consecutive days), once every 4 weeks, defined as a single cycle. Neurological evaluation was performed every 4 weeks and neuroradiographic assessment every 8 weeks. Results: A total of 68 cycles of TMZ (median 2 cycles; range 1–6) was administered. TMZ-related toxicity included leukopenia (7 patients; 1 grade 3), constipation (6 patients; 0 grade 3), fatigue (5 patients; 0 grade 3), anemia (2; 0 grade 3), thrombocytopenia (2; 0 grade 3), and deep vein thrombosis (2; 0 grade 3). One patient (4%) demonstrated a partial radiographic response, nine (36%) stable disease, and 15 (60%) progressive disease following two cycles of temozolomide. Time to tumor progression ranged from 1–7 months (median: 2 months). Survival ranged from 2–8 months (median: 3 months). 6-month and 12-month PFS were 2% and 0% respectively. Conclusions: Temozolomide in this dose schedule demonstrated little efficacy in a cohort of adults with recurrent intracranial platinum-refractory ependymoma. No significant financial relationships to disclose.

A phase II randomized study of oral seliciclib in patients with previously treated nasopharyngeal carcinoma

6026 Background: Seliciclib is a selective inhibitor of cyclin dependent kinases (CDKs) 2, 7 and 9. In a phase I study of 2 weeks of oral administration, clinical antitumor activity was observed in patients with treatment-naive nasopharyngeal carcinoma (NPC) and biological effects consistent with CDK inhibition were detected in tumor biopsy samples. We are conducting a multicenter, randomized phase 2 study to evaluate the safety and efficacy of prolonged administration of seliciclib in patients with previously treated NPC. The study has a lead-in phase where the safety and tolerability of 2 dosing schedules of seliciclib are to be confirmed in patients with advanced solid tumors (including NPC) before being used in the randomized phase of the study where only NPC patients are eligible to participate. The primary efficacy endpoint is 6-month progression free survival. Here we report interim findings from the lead-in phase. Methods: Eligible patients must be ≥18 years with previously treated NPC or other incurable solid tumors; must have measurable disease according to RECIST, ECOG 0–1, and adequate bone marrow, hepatic and renal function. The planned sample size is 6 to 12 patients per dosing schedule. A dosing schedule is considered tolerable for proceeding to the randomized phase if <33% patients experienced dose-limiting toxicities (DLT) during the first treatment cycle. Results: Twenty-three patients (age 38 - 74) were enrolled and treated. DLTs were observed in 4 patients: grade 3 increase in ALT or AST (n=3), and treatment delay > 2 weeks for grade 1 creatinine (n=1). Common adverse events (all grades, regardless of causality) included fatigue, nausea/vomiting, constipation, cough, fever, hypokalemia, hyponatremia, and elevation in ALT/AST, most of which were mild to moderate in intensity. Conclusions: These interim data confirm that both dosing schedules are tolerable for proceeding to the randomized phase. Majority of stable disease occurred in NPC patients. Updated data will be presented at the meeting. [Table: see text] No significant financial relationships to disclose.

A North American brain tumor consortium phase II study of poly-ICLC for adult patients with recurrent anaplastic gliomas

This phase II study was designed to determine the objective response rate and 6-month progression free survival of adult patients with recurrent supratentorial anaplastic glioma when treated with the immune modulator, polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose (poly-ICLC). This was an open-labeled, single arm phase II study. Patients were treated with poly-ICLC alone. Patients may have had treatment for no more than two prior relapses. Treatment with poly-ICLC continued until tumor progression. Fifty five patients were enrolled in the study. Ten were ineligible after central review of pathology. Eleven percent of patients (5 of 45) had a radiographic response. Time to progression was known for 39 patients and 6 remain on treatment. The estimated 6-month progression free survival was 24%. The median survival time was 43 weeks. Poly-ICLC was well tolerated, but there was no improvement in 6-month progression free survival compared to historical database nor was there an encouraging objective radiographic response rate. Based on this study, poly-ICLC does not improve 6moPFS in patients with recurrent anaplastic gliomas but may be worth further study in combination with agents such as temozolomide.

Bevacizumab and Irinotecan in the Treatment of Recurrent Malignant Gliomas

Rapidly dividing glioma cells maintain adequate oxygen and nutrient delivery through co-opting existing host blood vessels or promoting the formation of new vessels, a process called angiogenesis. Vascular endothelial growth factor is a mediator of hypoxia-induced endothelial cell proliferation and migration and is highly expressed in gliomas, where it acts as a potent regulator of angiogenesis. The use of vascular endothelial growth factor receptor antagonists and vascular endothelial growth factor scavenging antibodies has generated excitement in neuro-oncology because of the rapid but reversible decrease in vascular permeability. This decrease in vascular permeability is marked by a decrease in cerebral edema and a decrease in contrast enhancement visualized on magnetic resonance imaging. These effects on the tumor vasculature are mistakenly referred to as tumor responses because the historical method of measuring tumor response and progression was based on tumor size assessed by contrast permeability through a leaky blood brain barrier. Despite the difficulties in accurately measuring the effect of antivascular endothelial growth factor therapy on tumor viability, several studies confirm that the antivascular endothelial growth factor human monoclonal antibody bevacizumab combined with irinotecan can significantly improve 6-month progression free survival of patients with malignant gliomas compared with historical controls. The impact of cytotoxic chemotherapy on the efficacy of bevacizumab and the effect of this therapy on overall survival are important questions that remain to be answered.

A phase II study evaluating systemic sagopilone (ZK-EPO) treatment in patients with recurrent malignant gliomas

2083 Background: Sagopilone (ZK-EPO) is a fully synthetic epothilone that exhibits activity in MDR tumors, and has demonstrated antitumor activity in orthotopic human glioma models in vivo. This 2-arm, phase II study aims to evaluate the safety and efficacy of sagopilone in patients (pts) with pretreated, recurrent malignant glioma who have received 2 or ≥3 prior lines of therapy, respectively. Methods: Sagopilone (16 mg/m2) was administered iv for 3 h every 21 d. The primary end point was 6-month progression- free survival (PFS-6), and secondary end points were safety, toxicity, and response rate. MRI evaluations (McDonald criteria) were performed every 2 cycles and toxicity was evaluated using CTCAE 3.0. Clinical and electrophysiological tests were undertaken before the 1st and at the 3rd and 6th cycle. Data are presented from a protocoled independent analysis of ≥3-line arm. Results: A total of 15 pts with recurrent malignant gliomas (glioblastoma multiforme [n=11] or anaplastic astrocytoma [n=4]) who had received prior surgery, radiotherapy, and ≥3 lines of chemotherapy (temozolomide/BCNU) were recruited. A median of 4 (1–6) cycles was administered and 3 pts are still receiving treatment. No objective responses were observed but stable disease of >6 wks was reported in 9 pts. Median TTP was 13 wks (1.3 to 38 wks) and 5/15 pts (target 3 pts) reached PFS-6, excluding a lower rate of 12%, although in the absence of a control arm this may be a self- selecting group and requires confirmation. The most frequent AE was neuropathy, which improved after treatment cessation. Grade 3/4 peripheral neuropathy occurred in 4 pts, with 1 requiring morphine treatment for neuropathy affecting their activities. Neuropathy presented as a mixture of paresthesia and dysesthesia, typically in a stocking distribution. Electromyography assessments showed axonal sensorimotor polyneuropathy with slight reductions of sensory action potential consistent with a primarily sensory defect. Only 1 pt had grade 4 toxicity (prolonged neutropenia) during the 1st cycle. Conclusions: Sagopilone demonstrated an acceptable safety profile and clinically relevant activity in pts with pretreated, recurrent malignant gliomas. The study continues in the 2nd-line arm and mature data will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bayer Schering

A phase II, randomized, non-comparative clinical trial of the effect of bevacizumab (BV) alone or in combination with irinotecan (CPT) on 6-month progression free survival (PFS6) in recurrent, treatment-refractory glioblastoma (GBM)

2010b Background: Effective 2nd-line therapies are absent in GBM leading to poor survival. VEGF upregulation is implicated in GBM tumorigenesis. In a single-arm PhII trial of BV + CPT in recurrent GBM, activity was demonstrated, warranting further investigation of clinical benefit of BV alone, and in combination with CPT (Vredenburgh J, JCO 2007). Methods: From June 2006 to Feb 2007, 167 patients (pts) with recurrent GBM were randomized 1:1 to BV (10 mg/kg q 2 wks) (Arm 1, n=85) or BV + CPT (340 mg/m2 if enzyme-inducing anti- epileptic drugs (AEDs) and 125 mg/m2 for non-AEDs) (Arm 2, n=82), stratified by KPS: 70–80, 90–100, and relapse (1st or 2nd). The co- primary endpoints were PFS6 (defined at 24-weeks) and objective response rate (ORR) determined by an independent radiology facility (IRF), with secondary endpoints of safety, PFS, and duration of response determined by IRF, and overall survival. The trial provided approximately 80% power to detect 13% improvement in PFS6 from an assumed rate of 15%, and 90% power to detect 13% improvement in ORR from assumed rates of 5% (Arm 1) and 10% (Arm 2) (2-sided significance level of 0.025). Results: Clinical outcomes are shown in Table 1. Median OS was based on 61.2% of deaths for BV alone and 67.1% of deaths for BV+CPT. One intracranial hemorrhage occurred in Arm 1 (Gr 1; 1.2%) and one in Arm 2 (Gr 4; 1.3%) during planned treatment period. The dose of corticosteroid required diminished from baseline to cycle 4 (Table 1). Benchmarking OS to that in a national GBM database is ongoing. Ä in KPS and neurocognitive function from baseline, and post-progression response will be presented. Conclusions: Both the PFS6 and OS of >9 months with BV alone or with CPT provides encouraging evidence of significant activity in this poor prognosis population. In addition, the reduction in corticosteroid use has the potential to provide benefit to patients. Randomized Subjects BV (n=85) BV + CPT (n=82) Median OS months (95% CI) 9.7 (8.2–11.8) 8.9 (7.8–11.9) PFS6 % (97.5% CI) 35.1 (23.2–47.0) 50.2 (36.6–63.8) ORR % (97.5% CI) 20 (12.7–29.5) 32.9 (23.4–43.5) Treated Subjects BV (n=84) BV + CPT (n=79) Grade >3 toxicities, % 47.6 67.1 Grade 5 AEs, % 2.4 1.3 BV discontinuation due to AEs, % 3.5 13.9 Corticosteroid dose (mg/kg) BV (n=84) BV + CPT (n=79) N, Mean (SD) Day 1 44, 7.3 (7.37) 46, 8.0 (4.96) Day 42 41, 5.0 (5.59) 44, 7.5 (5.71) Day 84 34, 3.1 (2.80) 34, 4.7 (3.68) Day 126 21, 2.7 (3.13) 21, 3.9 (2.60) Day 168 12, 1.1 (1.04) 15, 4.4 (4.13) No significant financial relationships to disclose.

Phase II single arm trial of aflibercept in patients with recurrent temozolomide-resistant glioblastoma: NABTC 0601

2020 Background: Anti-vascular endothelial growth factor (VEGF) therapy is a promising treatment approach for patients with recurrent glioblastoma. Aflibercept (VEGF Trap) is a recombinantly-produced fusion protein which scavenges both VEGF and placental growth factor (PlGF) removing important ligands for the VEGF family receptors expressed on tumor endothelium. Methods: We report the results of a phase II trial of aflibercept monotherapy for patients with temozolomide-resistant recurrent glioblastoma and anaplastic glioma at first relapse. Patients received 4 mg/kg aflibercept IV every 2 weeks. The primary endpoint was 6-month progression free survival (PFS) and secondary endpoints include radiographic response rate (RR), PFS, overall survival and toxicity. Response was assessed using Macdonald's criteria. At this time, we provide preliminary response and toxicity data but complete information will be available at the time of presentation. Results: A total of 48 patients have been enrolled; 32 patients with glioblastoma and 16 patients with anaplastic glioma (median age 54; median KPS 90%). Investigator assessment of RR demonstrated a 50% response rate for the anaplastic glioma cohort (4 SD, 5 PR, 2 CR of 14 evaluable patients) and a 30% response rate for patients with glioblastoma (14 SD, 8 PR of 27 evaluable patients). The primary endpoint assessment of 6-month PFS will be presented. The main treatment-related NCI CTC grade 3 adverse events (18 total) included fatigue, hypertension, hand-foot syndrome, lymphopenia, thrombosis and proteinuria. One CNS ischemia and one systemic hemorrhage grade 4 toxicities were reported. A total of 12 patients (25%) discontinued therapy due to toxicity, on average less than 2 months into treatment. In conjunction with a decrease in permeability on DCE-MRI, aflibercept therapy induced a rapid and prolonged decrease in free levels of VEGF and PlGF confirming sequestration of target growth factors. Analysis of growth factors mediating angiogenic escape is ongoing. Conclusions: Aflibercept was moderately well tolerated and has evidence of single agent activity in patients with recurrent glioblastoma and anaplastic glioma. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis, Schering-Plough, Semafore Johnson and Johnson, Pfizer Genentech, Novartis, Schering-Plough Genentech, Novartis, Regeneron

CPT-11 for recurrent temozolomide-refractory 1p19q co-deleted anaplastic oligodendroglioma

A Phase II study of CPT-11 in adults with recurrent, temozolomide (TMZ)-refractory, 1p19q co-deleted, anaplastic oligodendroglioma (AO) with a primary objective of determining 6-month progression free survival (PFS). There is no standard therapy for alkylator-resistant AO. Twenty-two patients (11 men; 11 women) ages 26-65 (median 40), with radiographically recurrent AO were enrolled. All patients had previously been treated with surgery, involved-field radiotherapy, and adjuvant chemotherapy (TMZ in 15; BCNU in 6). Fifteen patients were treated at first recurrence with an alternative chemotherapy. 13 patients underwent repeat surgery. All patients were treated at either first or second recurrence with CPT-11 administered intravenously once every 3 weeks. Neurological and neuroradiographic evaluations were performed every 8-9 weeks. All patients were evaluable for toxicity and response. A total of 141 cycles of CPT-11 (median 3 cycles; range 3-18) were administered. CPT-11 related toxicity included diarrhea (14 patients; 4 grade 3), neutropenia (8; 4 grade 3), fatigue (12; 3 grade 3), and delayed nausea/vomiting (12; 3 grade 3). 5 patients (23%) demonstrated a partial radiographic response, 8 (36%) demonstrated stable disease and 9 (41%) had progressive disease following three cycles of CPT-11. Time to tumor progression ranged from 2 to 13.5 months (median: 4.5 months). Survival ranged from 3 to 21 months (median: 5.5 months). Six-month and 12-month PFS were 33% and 4.5% respectively. CPT-11 demonstrated modest efficacy (similar to other salvage glioma regimens) with acceptable toxicity in this cohort of adults with recurrent, 1p19q co-deleted AO all of whom had failed prior TMZ chemotherapy.

Efficacy and Safety of Weekly Low Dose Paclitaxel and Cisplatin as First Line Therapy in Advanced NSCLC of Elderly Patients

Purpose: Anti-cancer chemotherapeutic agents act by inhibiting tumor cell proliferation through cytotoxic action, therefore the generally tolerated maximum dose is administered to patients. However, this often results in the production of undesirable toxicities, such as bone marrow suppression, and a long interruption of treatment is necessary for recovery to occur before additional cycles of treatment are administered. Paclitaxel and cisplatin are well known effective chemotherapeutic agents used for the treatment of Non-Small Cell Lung Cancer (NCSLC), however, they have substantial toxicities. To evaluate efficacy and safety of a therapy consisting of a weekly low dose of paclitaxel and therapy in elderly patients with advanced NSCLC. Materials and Methods: Thirteen treatment-naive, elderly patients over 65 years old who were diagnosed with stage IV NSCLC at Konyang University from April 2005 to October 2006 were enrolled in the present study. Paclitaxel at a dose of 55 mg/m2 in combination with cisplatin at a dose of 20 mg/m 2 was administered intravenously on day 1, 8, and 15 with 1 week of interruption for a total of six cycles of chemotherapy. Results: The mean age of the ten patients included in this study was 69.5 years. Following treatment, 50 % of the patients exhibited a partial response to treatment, whereas the disease remained stable in 40% of the patients, and progressed in 10% of the patients. The median survival time (Kaplan-Meier method) was 15 months (4 ∼24 months), and the 6-month, 1-year, and 2-year survival rates were 80%, 50%, and 10%, respectively. The median progression survival time was 8 months (2 ∼14 months) and the 6- and 12-month progression free survival rates were 60% and 10%, respectively. Grade 3 neutropenia occurred in only 1 case (10%). Conclusion: The results of this study indicated that chemotherapy consisting of a weekly low dose of paclitaxel and cisplatin could be more effective and have lesser toxicity when administered to elderly patients with advanced NSCLC. In addition, this treatment regimen showed a promising response rate. (J Lung Cancer 2007;6(2):85�� 90)

Phase II study of POLY-ICLC in recurrent anaplastic glioma–A North American Brain Tumor Consortium study

1550 Background: The goals of this study were to determine the 6-month progression free survival (PFS) for patients with recurrent anaplastic glioma (AG) treated with the immune-modulatory agent POLY-ICLC, and to evaluate toxicity. Low dose Poly-ICLC has a direct immune enhancing action which includes an increased antibody response to antigen and activation of NK-cells, T-cells, macrophages and cytokines. Previously documented side effects include transient flu-like symptoms, which responds to acetaminophen and pain related to the intramuscular administration. Methods: Eligibility included age >18 years, recurrent AG, no more than 2 prior relapses, normal laboratory parameters and informed consent. Poly-ICLC was administered at 20mcg/kg 3x/week by intramuscular injection in 4 week cycles continuously. Dose reductions were allowed for toxicities. Patients were assessed for tumor response every 2 months. Treatment continued until tumor progression, unacceptable toxicity or patient withdrawal. The study had a 2 stage design with the initial assessment of 6 month PFS for the first 22 patients with possible expansion to a total of 46 patients, if more than 7 patients of the 22 had a 6 month PFS. Results: As of 12/05, 46 patients were treated (49% males). Median age was 42 years (range 21–70 years) and median KPS was 90. The agent was well tolerated and the toxicity profile was as previously reported. The response rate and 6 month PFS of the 22 patients in the first stage of the study was 9% and 23% respectively. Based on these findings the cohort was expanded to 46 patients. Of the 15 patients in the second cohort with at least 1 post treatment response assessment available, there is 1PR and 7 SD (47%). Conclusions: 6 month PFS for the entire cohort continues to be assessed but preliminary results suggest antitumor activity of this agent in recurrent anaplastic glioma. No significant financial relationships to disclose.

SWOG 0338: A phase II trial of imatinib mesylate in combination with capecitabine in metastatic breast cancer

10529 Background: Imatinib mesylate targets c-kit and platelet derived growth factor receptor (PDGFR) tyrosine kinases, and both are variably expressed in breast cancer. Inhibition of PDGFR by imatinib mesylate may decrease tumor interstitial pressure and improve delivery of chemotherapy. Based on preclinical synergy, SWOG conducted a phase II trial in metastatic breast cancer. Methods: Patients were eligible if they had adenocarcinoma of the breast that had progressed on at least 1 but ≤ 2 prior chemotherapy regimens for metastatic disease. No prior 5-FU or capecitabine for metastatic disease was allowed. Patients had to be > 18 years with a Zubrod performance status ≤ 2 and have adequate organ function. Patients with brain metastases were ineligible. Patients received imatinib mesylate 400 mg orally daily and capecitabine 1000 mg/m2 orally twice daily on days 1–14 of a 21-day cycle. If tolerated, the imatinib mesylate was increased to 600 mg daily in subsequent cycles. This was a 2-stage design with 25 patients with measurable disease accrued in the first stage. A total of 70 patients was planned, including those with nonmeasurable disease, if accrual proceeded to the second stage. The primary endpoint was to determine the confirmed response rate (RR) to the combination therapy. Secondary endpoints were to estimate the 6-month progression free survival, to determine the toxicities, and to explore c-kit and PDGFR in this population. Results: 27 patients were accrued; 6 were ineligible. 19 patients received therapy and were evaluable for toxicity. The median age was 59 years (36–78). Four responses were seen: 1 complete, 1 confirmed partial, and 2 unconfirmed partial (RR 21%). The 6-month progression free survival was 16%. There were no grade 4 toxicities. The most common grade 3 toxicities, seen in 7 patients, were diarrhea, fatigue, and hand-foot syndrome. As 2 of the 4 responses were unconfirmed, accrual did not proceed to the second stage. Conclusions: The combination of imatinib mesylate and capecitabine was well tolerated in patients with metastatic breast cancer, but the RR was not better than was seen in a prior study of single agent capecitabine. Correlative studies to explore c-kit, PDGFR, and estrogen receptor expression and response are in progress. No significant financial relationships to disclose.

Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial

5-Aminolevulinic acid is a non-fluorescent prodrug that leads to intracellular accumulation of fluorescent porphyrins in malignant gliomas-a finding that is under investigation for intraoperative identification and resection of these tumours. We aimed to assess the effect of fluorescence-guided resection with 5-aminolevulinic acid on surgical radicality, progression-free survival, overall survival, and morbidity. 322 patients aged 23-73 years with suspected malignant glioma amenable to complete resection of contrast-enhancing tumour were randomly assigned to 20 mg/kg bodyweight 5-aminolevulinic acid for fluorescence-guided resection (n=161) or to conventional microsurgery with white light (n=161). The primary endpoints were the number of patients without contrast-enhancing tumour on early MRI (ie, that obtained within 72 h after surgery) and 6-month progression-free survival as assessed by MRI. Secondary endpoints were volume of residual tumour on postoperative MRI, overall survival, neurological deficit, and toxic effects. We report the results of an interim analysis with 270 patients in the full-analysis population (139 assigned 5-aminolevulinic acid, 131 assigned white light), which excluded patients with ineligible histological and radiological findings as assessed by central reviewers who were masked as to treatment allocation; the interim analysis resulted in termination of the study as defined by the protocol. Primary and secondary endpoints were analysed by intention to treat in the full-analysis population. The study is registered at http://www.clinicaltrials.gov as NCT00241670. Median follow-up was 35.4 months (95% CI 1.0-56.7). Contrast-enhancing tumour was resected completely in 90 (65%) of 139 patients assigned 5-aminolevulinic acid compared with 47 (36%) of 131 assigned white light (difference between groups 29% [95% CI 17-40], p<0.0001). Patients allocated 5-aminolevulinic acid had higher 6-month progression free survival than did those allocated white light (41.0% [32.8-49.2] vs 21.1% [14.0-28.2]; difference between groups 19.9% [9.1-30.7], p=0.0003, Z test). Groups did not differ in the frequency of severe adverse events or adverse events in any organ system class reported within 7 days after surgery. Tumour fluorescence derived from 5-aminolevulinic acid enables more complete resections of contrast-enhancing tumour, leading to improved progression-free survival in patients with malignant glioma.

Phase II Trial of Radiosurgery for One to Three Newly Diagnosed Brain Metastases From Renal Cell Carcinoma, Melanoma, and Sarcoma: An Eastern Cooperative Oncology Group Study (E 6397)

Long-term brain metastases survivors are at risk for neurologic morbidity after whole-brain radiotherapy (WBRT). Retrospective radiosurgery (RS) reports found no survival difference when compared with WBRT. Before RS alone was evaluated with delayed WBRT in a phase III trial, the feasibility of RS alone was tested prospectively. Patients with renal cell carcinoma, melanoma, or sarcoma; one to three brain metastases; and performance status of 0 to 2 were enrolled. Exclusion criteria were leptomeningeal disease; metastases in medulla, pons, or midbrain; or liver metastases. On the basis of tumor size, patients received 24, 18, or 15 Gy RS. At recurrence, management was discretionary. The primary end point was 3- and 6-month intracranial progression. Between July 1998 and August 2003, 36 patients were accrued; 31 were eligible. Median follow-up was 32.7 months and the median survival was 8.3 months (95% CI, 7.4 to 12.2). Three- and 6-month intracranial failure with RS alone was 25.8% and 48.3%. Failure within and outside the RS volume, when in-field and distant intracranial failures were scored independently, was 19.3% and 16.2% (3 months) and 32.2% and 32.2% (6 months), respectively. Approximately 38% of patients experienced death attributable to neurologic cause. There were three grade 3 toxicities related to RS. Intracranial failure rates without WBRT were 25.8% and 48.3% at 3 and 6 months, respectively. Delaying WBRT may be appropriate for some subgroups of patients with radioresistant tumors, but routine avoidance of WBRT should be approached judiciously.

Fludarabine-Based Regimens in the Treatment of Indolent Non-Hodgkin's Lymphoma Patients: A Clinical Study of the Fludarabine Cooperation Group in 16 Hospitals in Eastern China.

Objective: We performed this prospective, multi-center study to evaluate the efficacy and safety of fludarabine-based regimes in the treatment of previously untreated and refractory, or relapsed, indolent non-Hodgkin's lymphoma (NHL).Methods: Two fludarabine-based regimens were used in the clinical study. The FC regimen which consisted of fludarabine 50 mg/day, and cyclophosphamide 200 mg/day, intravenously, for 3 consecutive days, was given to the previously untreated patients. The FMD regimen which consisted of fludarabine 50 mg/day, intravenously, for 3 consecutive days, mitoxantrone 10 mg/m2, intravenously, on the first day, and dexamethasone 20 mg/m2/day, intravenously, for 5 consecutive days, was given to the relapsed and refractory patients.Results: Forty-seven indolent NHL patients (29 male and 18 female) were enrolled in this study from February 2003 to May 2005. The main disease subtypes were: chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL; n = 25), follicular lymphoma (FL; n = 18), lymphoplasmic lymphoma (LPL; n = 3), marginal zone lymphoma (MZL; n =1). Overall response (OR) rate was 93.62%, and 44 of 47 patients achieved a response. The complete response (CR) rate was 63.83%, and 30 of 47 patients achieved a response. In the 16 previously untreated patients, the CR rate was 75.0% (n =12); the OR rate was 93.8% (n = 15). In the 31 relapsed and refractory patients, the CR rate was 61.3% (n =19) and OR rate was 93.5% (n =29). Median patient follow-up was 12 months (range, 1–27 months). The 12-month progression free survival (PFS) rates of previously untreated patients and relapsed or refractory patients were 93.3±6.4% and 91.04±6.1%, respectively; and the 18-month overall survival (OS) rates were 90.9±8.67% and 90.32±6.90%, respectively. Both regimens were well tolerated and the major toxicities were bone marrow suppression and gastrointestinal response.Conclusion: The FC and FMD regimens are effective and safe for indolent NHL patients.

Radiation Dose Considerations in the Palliative Treatment of Locally Advanced Adenocarcinoma of the Pancreas

Treatment of locally advanced pancreatic cancer with high-dose radiotherapy has not been curative, and can be difficult to tolerate. We decided to compare retrospectively the outcomes of patients treated concurrently with 5-fluorouracil and either 30 Gy or more than 30 Gy of radiation. From December 1993 through May 2001, 107 patients with locally advanced adenocarcinoma of the pancreas had been treated with palliative chemoradiation. Eighty-six patients had received a prescribed dose of 30 Gy and 50.4 Gy had been prescribed in 18 patients. Two of these patients were unable to complete the full dose of radiotherapy due to toxicity, and 3 received intraoperative radiotherapy boost (20 Gy). Three additional patients received a prescribed dose of 33 Gy, 36 Gy, and 52.2 Gy, respectively. These patients were grouped together (n = 21, median 50.4 Gy). All patients had received concurrent protracted venous infusions of 5-fluorouracil (300 mg/m Monday through Friday). The median survival time was not affected significantly by a higher radiotherapy dose (8 months for the 30 Gy group versus 9 months for the group receiving higher doses; P = 0.64). The 6-month actuarial progression rates were 45% versus 50% (P = 0.90) for local disease progression, and 54% versus 50% (P = 0.94) for distant metastasis for the 30 Gy and the higher dose groups, respectively. Ten of the 86 patients (12%) who had received 30 Gy were hospitalized for treatment-related gastrointestinal toxicity (grade 3) versus 6 of the 21 (29%) patients given higher doses (P = 0.05). Compared with higher doses given over 5 to 6 weeks, chemoradiation (30 Gy in 10 fractions in 2 weeks with concurrent infusional 5-FU) results in a similar median survival, and local disease progression rates in patients with locally advanced pancreatic cancer apparently do not substantially improve local disease control or median survival time. Because higher doses of radiotherapy can lead to increased acute treatment-related morbidity, we recommend using 30 Gy in 10 fractions unless the patient is part of a prospective study evaluating novel biologic or cytotoxic radiosensitizers.

RTOG 0131: Phase II trial of pre-irradiation and concurrent temozolomide in patients with newly diagnosed anaplastic oligodendrogliomas and mixed anaplastic oligodendrogliomas

1520 Background: RTOG 9402 showed that a dose-intense pre-radiation chemotherapy regimen consisting of procarbazine, lomustine and vincristine (PCV) for anaplastic oligodendrogliomas (AOs) and mixed anaplastic oligoastrocytomas (MAOs) produced improved progression free survival at the expense of increased toxicity, but no improvement in overall survival. A less toxic chemotherapy, temozolomide (TMZ), has also shown efficacy in several glial tumors, and it can be given concurrently with radiation therapy (RT) with acceptable toxicity. Methods: A phase II study was performed to evaluate the efficacy of pre-RT TMZ and the toxicity of concurrent RT and TMZ in patients with newly diagnosed AO or MAO. The primary endpoint was to determine the pre-RT TMZ six-month progression rate. Results: 40 eligible patients were entered into the trial; 55% were male, median age was 45, 50% had an AO. Twenty-seven patients completed 6 months of pre-RT TMZ and have undergone central review, and three are too early to evaluate. Of the remaining ten patients, two withdrew early due to tumor progression (not reviewed) and 4 withdrew due to toxicity. Four other patients withdrew from study without evidence of toxicity or progression. Pre-RT TMZ responses in centrally-reviewed patients (N = 27) were as follows: 1 CR (3.7%), 8 PR (29.6%), 15 SD (55.6%) and 1 PD (3.7%). CR required resolution of both T1 and T2 changes. Two patients (7.4%) had no evaluable disease. If the 2 patients who withdrew due to reported progression are included, the 6-month progression rate is 3/29 (10.3%). During concurrent RT and TMZ treatment there were two (5%) grade 3 and zero grade 4 non-hematologic toxicities. Conclusions: Pre-RT TMZ appears to be feasible, without an inordinately high rate of early progression (10.3%). In comparison, the overall 6-month progression rate observed in the pre-RT PCV arm of RTOG 9402 was 20%. Toxicity of the concurrent RT and TMZ regimen was acceptable. Analysis of tumor 1p/19q status is ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Schering Oncology

Fluorouracil, leucovorin and oxaliplatin (FLO) versus fluorouracil, leucovorin and cisplatin (FLP) as a first line therapy for patients with advanced gastric cancer; first interim analysis of a randomised multicenter phase II study

4015 Background: To evaluate the potential role of oxaliplatin in the treatment of patients (pts) with advanced gastric cancer. Methods: Eligible patients had ECOG performance status (PS) 0–2, adequate liver, renal, and haematological function. Pts were randomised to receive FLO: F 2600mg/m2 24h infusion, L 200mg/m2, and oxaliplatin 85mg/m2 every two weeks or FLP: F 2000mg/m2 24h infusion, L 200mg/m2, weekly, and cisplatin 50mg/m2 every two weeks. The primary end point was the 6-month progression free survival rate. A protocol planned interim analysis to evaluate response and safety was performed when 80 patients had been randomized and completed at least one treatment cycle. Results: 105 pts have been randomised. Data on 80 pts were available for toxicity and response (see table). Conclusions: The overall toxicity was low in both arms. The activity of FLO appears promising. Since grade 3/4 non-haematological toxicity affected less than 10% of patients in both arms, no dose adjustments were performed and accrual will continue to the target of 180 patients. No significant financial relationships to disclose.

A phase I evaluation of the safety of escalating doses of atrasentan in adults with recurrent malignant glioma (MG)

1526 Background: Atrasentan is a highly potent and selective endothelin (ET) receptor antagonist that may inhibit cell proliferation by blocking the ET receptor that regulates angiogenesis of glioma growth. This dose-finding study evaluates the safety and toxicity, and seeks preliminary evidence of efficacy, of Atrasentan in the treatment of MG. Methods: Patients (pts) with MG with prior radiation and < 1 chemotherapy were eligible. Planned dose levels were: 10 and 20 mg/day (cohorts of size 2), then 30 and incrementing by 20 mg/day up to a dose of 150 (cohorts of size 3), until a dose-limiting toxicity (DLT) is observed. The maximum tolerated dose (MTD) is defined as the maximum dose that causes no DLT in an expanded cohort of 10 pts. The cycle length was 28 days and intra-pt dose escalation was not allowed. Patients remained on study until progression. Results: Twenty-five pts, 16 (64%) males, median age = 53 years (range: 25–70); median KPS = 90% (range: 60–100) were enrolled. 22 (88%) had GBM and only 1 patient had no prior chemotherapy. Thirteen pts were on enzyme-inducing anti-epileptic drugs, and 12 were not. Only 23 pts were evaluable for toxicity because two pts developed early progression (1 each in the 30 and 70 mg/day cohorts). One pt had a DLT of grade 3 hypoxia and peripheral edema after 18 days of dosing with Atrasentan at 90 mg/day. The 70 mg/day cohort was expanded to 10 patients with no observed DLT and was declared the MTD. The most common adverse events were rhinitis, headache, and peripheral edema. These events were reported as grade 1/2 and were probably related to Atrasentan. There were no events of myelosuppression. One GBM pt (90 mg/day) had a partial response (4% response rate) and 4 GBM pts had stable disease before progressing. To date, 18/25 (72%) pts have died. Kaplan-Meier median survival was 6.0 m (95% confidence interval, 4.2–9.5 m) and 6-month progression free survival was 13% (95% confidence interval, 3–32%). Conclusions: Chronic oral dosing of Atrasentan is safe in pts with recurrent malignant gliomas, and the MTD is 70 mg/day. Pharmacokinetic data are currently being analyzed. Further study of Atrasentan with radiation therapy in newly diagnosed malignant gliomas is planned. No significant financial relationships to disclose.