Non-progression Rate Research Articles

A Multicenter Phase II Study of Erlotinib and Sorafenib in Chemotherapy-Naïve Patients with Advanced Non–Small Cell Lung Cancer

This multicenter, phase II study evaluates the efficacy and safety of erlotinib, an epidermal growth factor receptor (EGFR) inhibitor, plus sorafenib, a multityrosine kinase inhibitor against vascular endothelial growth factor receptors, in patients with previously untreated advanced non-small cell lung cancer (NSCLC). Chemotherapy-naïve patients with stage IIIB/IV NSCLC received erlotinib (150 mg once a day) and sorafenib (400 mg twice a day) until disease progression or unacceptable toxicity. The primary end point was the rate of nonprogression at 6 weeks. Secondary end points included objective response rate (ORR), time to progression, overall survival, and adverse events. Exploratory end points included pretreatment EGFR and KRAS mutation status, pharmacokinetics, and cytochrome P450 polymorphisms. Fifty patients initiated therapy. The nonprogression rate at 6 weeks was 74%: 12 (24%) partial response and 25 (50%) stable disease. Ultimately, the ORR was 28%. Median time to progression was 5.0 months [95% confidence interval (95% CI), 3.2-6.8 months]. Median overall survival was 10.9 months (95% CI, 3.8-18.1 months). Grade 3/4 adverse events included fatigue (16%), hand-foot skin reaction (16%), rash (16%), diarrhea (14%), and hypophosphatemia (42%). There was one treatment-related fatal pulmonary hemorrhage. Patients with wild-type EGFR had a higher ORR (19%) than previously reported for single-agent erlotinib/sorafenib. Erlotinib levels were lowered. This was associated with CYP3A4 polymorphism and was possibly due to sorafenib. Despite a possible drug interaction, sorafenib plus erlotinib has promising clinical activity in patients with stage IIIB/IV NSCLC and has an acceptable safety profile. Further evaluation of this combination as potential salvage therapy in EGFR mutation-negative patients and the possible drug interaction is warranted.

Can the combination of temsirolimus and bevacizumab improve the treatment of metastatic renal cell carcinoma (mRCC)? Results of the randomized TORAVA phase II trial.

4516 Background: Temsirolimus (T) and bevacizumab (B) have been approved for the treatment of mRCC. The T-B combination has proven feasible at full doses of each agent with promising activity in phase I. This study was aimed to promptly determine whether this combination could improve the results of available treatments. Methods: Untreated mRCC patients (pts) with ECOG PS £ 2 and measurable disease were randomized using a 2:1:1 ratio to T-B combination (arm A), sunitinib (arm B) or bevacizumab and a-interferon (arm C) in an open label, multicenter, non comparative phase II trial. Pts were treated until disease progression or unacceptable toxicity. The primary objective was to estimate the non-progression rate at 48 weeks (NPR-48) for arm A. Using Fleming's single-stage procedure and a NPR- 48 of 50% as the minimum needed for the combination to warrant further study, the planned sample size for arm A was 80 pts (assuming NPRs-48 of 35% in the pivotal trials [Motzer et al 2007, Escudier et al 2007]). Major secondary endpoints were toxicity, response rate (RR) and survival. Results: From 03/2008 to 05/2009, 171 pts were randomized: 88 (51%), 42 (25%) and 41 (24%) to arms A, B and C, respectively. Treatments were prematurely stopped for other reasons than progression in 43% (A), 12% (B) and 23% (C). Grade 3/4 events were observed in 36%, 14% and 27% pts in arms A, B, C respectively; two toxic deaths occurred in arm A. In an intent-to-treat analysis with a median follow-up of 43 weeks, NPRs-48 were 43.2% (95% CI, 32.7-54.2), 47.6% (95% CI, 32.0-63.6) and 65.9% (95% CI, 49.4-79.9) in arms A, B and C respectively. Best RRs (RECIST) were 25%, 24% and 34% respectively. Conclusions: The toxicity profile of the T-B combination was higher than expected, leading to a high drop-out rate. The results do not suggest any evidence of a synergistic/additive efficacy of this combination. Patients continue to be followed and updated data will be reported. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AVEO, Bayer, GlaxoSmithKline, Novartis, Pfizer, Roche, Wyeth Bayer, GlaxoSmithKline, Novartis, Pfizer, Wyeth GlaxoSmithKline, Roche, Wyeth

Superiority of Docetaxel + Capecitabine Compared to Docetaxel + Epirubicin as First-Line Therapy for Metastatic Breast Cancer – Final Results of the ERASME-4 Study.

Abstract Background: Docetaxel plus capecitabine (DC) combination therapy improves both time to disease progression and overall survival over docetaxel alone in metastatic breast cancer (MBC). The aim of the ERASME-4 trials was to assess the efficacy of DC vs. docetaxel plus epirubicin (DE) combination regimens as first-line therapy for MBC.Material and Methods: Patients with MBC, previously untreated with chemotherapy were randomly assigned to receive either DC (docetaxel 75 mg/m² on day 1 and oral capecitabine 1,000 mg/m² twice daily on days 1 to 14 every 3 weeks) or DE (docetaxel 75 mg/m² and epirubicin 75 mg/m² on day 1 every 3 weeks). The primary endpoint was progression-free rate 6 months after randomization. The planned sample sizes were 106 patients (pts), based on a randomized phase II selection design. The main secondary endpoints were progression-free survival (PFS) and overall survival (OS).Results: Between June 2004 and April 2006, 68 pts were randomized. Slow accrual led to premature termination the study. Final analysis included 33 pts randomized to DC and 35 pts to DE. This sample size allowed to effectively selecting the best arm for non-progression rate with a power of 82%. Patient characteristics were well balanced between the two treatment arms, except for pleural metastasis, alkaline phosphatase and SBR III more present in DE arm or adjuvant hormonotherapy given in more DC patients. Toxicity has been mild or moderate; 62% of patients reported at least one grade 3-4 episode. Hand-foot syndrome grade 3-4 was reported for 18% of DC arm patients, vs. none in the DE arm (p=0.008).Complete/partial response rates were 20/44% in DC and 7/41% in DE (p=0.3). Six months after randomization, 75.8% (95%CI: 57.7-88.9) of pts in the DC arm vs. 65.7% (95%CI: 47.8-80.9) in the DE arm were progression-free (p=0.36). After a median follow-up of 42 months, (95%CI: 32.5-21.1), median PFS was 12 months and 7 months in the DC and DE groups, respectively (p=.004). Median OS was 27 and 37 months for DE and DC respectively (p=0.49).Conclusion: Despite our low accrual, these results show that DC combination therapy is associated with a superior progression-free rate at 6 months and a longer PFS than DE.DC provides a highly active, non-anthracycline-containing, first-line treatment option for MBC patients previously exposed to anthracycline in the adjuvant setting. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2099.

Randomized, Placebo-Controlled, Phase II Study of Sequential Erlotinib and Chemotherapy As First-Line Treatment for Advanced Non–Small-Cell Lung Cancer

This study investigated whether sequential administration of erlotinib and chemotherapy improves clinical outcomes versus chemotherapy alone in unselected, chemotherapy-naïve patients with advanced non-small-cell lung cancer (NSCLC). Previously untreated patients (n = 154) with stage IIIB or IV NSCLC and Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned to receive erlotinib (150 mg/d) or placebo on days 15 to 28 of a 4-week cycle that included gemcitabine (1,250 mg/m(2) days 1 and 8) and either cisplatin (75 mg/m(2) day 1) or carboplatin (5 x area under the serum concentration-time curve, day 1). The primary end point was nonprogression rate (NPR) at 8 weeks. Secondary end points included tumor response rate, NPR at 16 weeks, duration of response, progression-free survival (PFS), overall survival (OS), and safety. The NPR at 8 weeks was 80.3% in the gemcitabine plus cisplatin or carboplatin (GC)-erlotinib arm (n = 76) and 76.9% in the GC-placebo arm (n = 78). At 16 weeks, the NPR was 64.5% for GC-erlotinib versus 53.8% for GC-placebo. The response rate was 35.5% for GC-erlotinib versus 24.4% for GC-placebo. PFS was significantly longer with GC-erlotinib than with GC-placebo (adjusted hazard ratio, 0.47; log-rank P = .0002; median, 29.4 v 23.4 weeks); this benefit was consistent across all clinical subgroups. There was no significant difference in OS. The addition of erlotinib to chemotherapy was well tolerated, with no increase in hematologic toxicity, and no treatment-related interstitial lung disease. Sequential administration of erlotinib following gemcitabine/platinum chemotherapy led to a significant improvement in PFS. This treatment approach warrants further investigation in a phase III study.

Updated outcome with long-term follow-up of imatinib for the treatment of progressive or recurrent aggressive fibromatosis (desmoid tumor): A FNCLCC/ French Sarcoma Group phase II trial

10518 Background: We present updated results from a previously reported phase II trial assessing clinical efficacy of imatinib in progressive or recurrent aggressive fibromatosis (Fayette et al. ASCO 2007) Methods: Patients with aggressive fibromatosis not amenable to radiotherapy or non-mutilating surgery were eligible and received imatinib 400mg daily (increased to 800mg daily in case of progression) up to 1 year then stopped. The primary end point was non-progressive disease rate at 3 months. Independent radiological committee reviewed responses. The number of patients was calculated according to a optimal 2-stages design. Results: Forty patients were included between September 2004 and October 2005 in 15 centers. The median follow up is 33 months [95% CI: 32–35]. Toxicity of imatinib is similar to that previously reported. At 3 months, the nonprogression rate was 91% [95% CI: 77–96] with 1 (2%) complete and 3 (8%) partial confirmed responses observed. The non progression rates at 6, 9, and 12 months were 80%, 69% and 66% respectively. The median time to progression was 9.5 months. The 2-year progression-free survival (PFS) was 55%. No plateau was observed. The 2-year-overall survival was 95%. Two patients with mesenteric aggressive fibromatosis died from progressive disease. In multivariate analysis including clinical factors, only previous radiotherapy was associated with reduced progression free survival. None of the biological factors tested using IHC on TMA (PDGFR α, PDGFR β, β catenin, c-kit, E cadherine, MCSFR, cycline D1 and Erk) were found correlated to response, progression free or overall survival. Conclusions: With a 2.8 years median follow up, this is the largest study which confirms the high efficacy of imatinib (400 mg daily) in patients presenting with aggressive fibromatosis failing local treatment and with documented evidence of progressive disease before imatinib treatment. [Table: see text]

Oral metronomic chemotherapy using cyclophosphamide in metastatic patients (pts) after standard treatment: Results of a randomized phase II trial

e13519 Background: Oral metronomic chemotherapy (OMC) has antiangiogenic properties and megestrol acetate (MA) is an orexigen used to maintain the general condition in critically ill pts. Anecdotal responses have been reported with each treatment. We hypothesized that each treatment offer disease control without significant severe toxicity. Methods: This multi-center-randomized study was aimed to assess the efficacy and tolerance of both treatments. Primary endpoint was stable disease rate at 2 months: 2mSD (RECIST). Main eligibility criteria were as follows: non-breast cancer, pts with progressive disease refractory to standard therapies or without established standard care, ECOG=0–1, neither hypercalcemia nor hypoalbuminemia. Pts were randomized to receive MA 160 mg b.i.d or OMC 50 mg b.i.d until severe toxicity or progression. The sample size calculation was based on Simon Minimax design (α=10%, β =90%, P0=5%, P1=20%). The second stage was allowed because at least 2mSD were seen among 12 first pts. Results: 88 pts were included from 9/2006 to 12/2008 (44 in each arm). Median age was 61 (22–84). Most common primaries were: colorectal cancer (30 pts), soft tissue sarcoma (17), lung cancer (13), head & neck (8) and unknown primaries (4). The median number of previous lines of treatment was 4 (0–10). As of 28 December 2008, 80 pts are assessable for primary endpoint: 6/40 pts (15%) experienced 2mSD in OMC arm whereas 2/40 pts (5%) in MA arm. Three long-lasting SD (6 months +) are currently being observed in 3 pts receiving OMC (2 sarcomas and 1 RCC). No Grade 3 or 4 toxicity was notified. Treatment was discontinued in 1 case because of MA- induced deep venous thrombosis. Conclusions: OMC and MA offer SD in patients with advanced, refractory and progressive tumors, without any significant toxicity. The non-progression rate with OMC (15%) is in a same range of efficacy that was recently reported with new targeted therapy or anti-angiogenic agents administered in such pts. The accrual is now completed, and a longer follow-up is necessary to better analyze the clinical benefit and the prognostic factors. [Table: see text]

Clinical benefit in Phase-I trials of novel molecularly targeted agents: does dose matter?

Phase-I trials traditionally involve dose-escalation to determine the maximal tolerated dose (MTD). With conventional chemotherapy, efficacy is generally deemed to be dose-dependent, but the same may not be applicable to molecularly targeted agents (MTAs). We analysed consecutive patients included in Phase-I trials at the Royal Marsden Hospital from 5 January 2005 to 6 June 2006. We considered only trials of monotherapy MTAs in which the MTD was defined. Three patient cohorts (A, B, and C) were identified according to the dose received as a percentage of the final trial MTD (0–33%, 34–65%, >66%). Potential efficacy was assessed using the non-progression rate (NPR), that is, complete/partial response or stable disease for at least 3 months by RECIST. A total of 135 patients having progressive disease before enrolment were analysed from 15 eligible trials. Median age was 57 years (20–86); male : female ratio was 1.8 : 1. Cohort A, B, and C included 28 (21%), 22 (16%), and 85 (63%) patients; NPR at 3 and 6 months was 21% and 11% (A), 50% and 27% (B), 31% and 14% (C), respectively, P=0.9. Median duration of non-progression (17 weeks; 95% CI=13–22) was not correlated with the MTD level, P=0.9. Our analysis suggests that the potential for clinical benefit is not confined to patients treated at doses close to the MTD in Phase-I trials of MTAs.

Phase II Trial of Weekly Paclitaxel for Unresectable Angiosarcoma: The ANGIOTAX Study

The objective of this phase II trial was to assess the efficacy and toxicity of weekly paclitaxel for patients with metastatic or unresectable angiosarcoma. Thirty patients were entered onto the study from April 2005 through October 2006. Paclitaxel was administered intravenously as a 60-minute infusion at a dose of 80 mg/m(2) on days 1, 8, and 15 of a 4-week cycle. The primary end point was the nonprogression rate after two cycles. The progression-free survival rates after 2 and 4 months were 74% and 45%, respectively. With a median follow-up of 8 months, the median time to progression was 4 months and the median overall survival was 8 months. The progression-free survival rate was similar in patients pretreated with chemotherapy and in chemotherapy-naïve patients (77% v 71%). Three patients with locally advanced breast angiosarcoma presented partial response, which enabled a secondary curative-intent surgery with complete histologic response in two cases. One toxic death occurred as a result of a thrombocytopenia episode. Six patients presented with grade 3 toxicities and one patient presented with a grade 4 toxicity. Anemia and fatigue were the most frequently reported toxicities. Weekly paclitaxel at the dose schedule used in the current study was well tolerated and demonstrated clinical benefit.

An open phase II trial of gemcitabine, oxaliplatin and vinorelbine combination as first-line therapy in advanced non-small cell lung cancer patients

The purpose of this multicentric Phase II study was to evaluate the safety and efficacy of a gemcitabine/oxaliplatin/vinorelbine combination as first-line therapy in advanced non-small cell lung cancer patients. Patients followed a fortnightly drug schedule, receiving on day 1, vinorelbine 25mg/m2 (20-min infusion); gemcitabine 700mg/m2 (70-min infusion, fixed 10mg/m2/min); and on day 2, oxaliplatin 85mg/m2 (2-h infusion). Thirty-nine patients with a median age of 58 years received a total of 306 cycles (median 8 cycles); 67% were males. Most had adenocarcinoma (51%), large-cell (23%) and squamous cell carcinoma (21%); 15% had stage IIIB and 85% stage IV. There was one complete response (3%; 95% CI: 0.1–13%), 15 partial responses (PR) (38%; 95% CI: 23–55%), and 13 patients with stable disease (33%; 95% CI: 19–50%) of at least 2 months duration, for an overall non-progression rate of 74%. Median progression-free survival (PFS) was 4.1 months (95% CI: 3.1–8.7) and overall survival was 11.7 months (95% CI: 7.7–19.4). No treatment-related deaths occurred and very few grade 3–4 events were observed. Overall, the regimen was well tolerated and the planned recommended dose intensity was safely delivered to more than 95% of patients. This triple combination therapy study yielded favourable efficacy and toxicity results, which merit further evaluation in prospective randomised trials.

O-Mel-Inib: A Cancéro-pôle Nord-Ouest multicenter phase II trial of high-dose Imatinib mesylate in metastatic uveal melanoma

Nowadays, there is no consensual and effective treatment in metastatic uveal melanoma (MUM). Numerous preclinical data (for example, 75% of MUM express c-kit) suggest that imatinib mesylate (IM) may be a potential treatment of UMM. The primary objective of this phase II trial was to determine the non-progression rate at 3 months for patients receiving IM at dose of 400 mg twice per day orally. The study was based on a Simon's optimal design, which allows entry a total of 29 patients, if at least two non-progressions among ten first patients were observed. Thirteen patients including ten assessable patients were enrolled in 12 months. No objective response and only one stable disease with duration of 5 months were noted. Five and one out of 13 enrolled patients experienced grade 3 and grade 4 toxicities, respectively. The most common severe adverse events were abdominal pain. The overall survival was 10.8 months. Despite promising preclinical data, IM is an inactive single agent in MUM. This phase II clinical trial has been stopped at the first step.

A phase II study of first-line erlotinib in patients (pts) with stage IIIB/IV non-small-cell lung cancer (NSCLC) including dose escalation to toxicity in current and former smokers (C/FS)

8111 Background: Skin rash has been associated with increased activity of erlotinib in retrospective analyses and plasma levels of erlotinib are lower in current vs former or non-smokers (NS), potentially due to tobacco-induced enzyme activation. This parallel phase II study was initiated to determine the efficacy of erlotinib in chemonaïve pts with advanced NSCLC, at a fixed dose in NS, and a toxicity- driven dose in C/FS. The study is still accruing pts. Methods: Oral erlotinib (150mg/d) was given once daily to all pts; this was increased by 50mg increments to a maximum of 300mg/d in C/FS. Each dose was given for 2 wks; if no treatment-related toxicity (TRT) ≥ gr 3 occurred, the dose was escalated. The primary endpoint was non-progression rate (NPR) after 8 wks. Secondary endpoints included response, disease control rate (DCR; CR+PR+SD), safety, and correlative efficacy analyses. Results: Data are available for 41 pts: 21 NS and 20 C/FS. NS were more likely to be women than men (81% vs 19%, compared with 45% vs 55% in C/FS) and there were no cases of squamous-cell carcinoma among NS, compared with 2 cases in C/FS. Dose escalation was possible in the majority of C/FS (16/18 pts with data available), including 5 pts who were escalated to 300mg/d and a further 7 pts escalated to 250mg/d. NPR (n=34) was 59% in all pts after 8 wks; NPR was 50% for C/FS (n=16) and 67% for NS (n=18). Data on best response are available for 8 C/FS and 13 NS. 4 NS had partial responses (PR) and 8 had stable disease (SD) (DCR 92%). 3 C/FS had a PR (1 at 200mg/d, 1 at 250mg/d and 1 at 300mg/d) and 4 had SD (1 at 250mg/d and 3 at 300mg/d) (DCR 88%). In safety analyses (evaluable n=38), 20% of pts reported a gr 3/4 TRT. 28 pts reported rash (12 C/FS, 16 NS; no gr 3/4) and 18 pts reported diarrhea (8 C/FS, 10 NS; 1 gr 3). Conclusions: Erlotinib is a well-tolerated and effective treatment option in first-line NSCLC, with a NPR of ≥50% and a DCR of >85% in all evaluable pts. Increasing the dose of erlotinib in pts with a history of smoking can potentially increase the activity of this agent in these pts. Pharmacokinetic and predictive biomarker analyses will be carried out. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Roche Roche

FAST-ACT: A phase II randomized double-blind trial of sequential erlotinib and chemotherapy as first-line treatment in patients (pts) with stage IIIB/IV non-small cell lung cancer (NSCLC)

8031 Background: Concurrent administration of EGFR TKIs and chemotherapy in 1st line failed to improve survival. Preclinical data suggested potential antagonism due to TKI-induced G1 arrest reducing cell cycle phase-dependent activity of chemotherapy, whereas sequential administration of EGFR-TKI following chemotherapy may improve efficacy [Gumerlock et al, ASCO 2003; Solit et al, Clin Can Res 2005]. Methods: All eligible pts with chemonaïve stage IIIB/IV NSCLC, performance status of 0/1 and adequate organ function were randomized to receive either erlotinib (E) 150mg/d or placebo (P) p.o. on d15–28 of 4-weekly chemotherapy cycles. Chemotherapy consisted of gemcitabine (G) 1250mg/m2 i.v. (d1, 8) plus either cisplatin (C) 75mg/m2 or carboplatin (C) 5xAUC (d1) for a maximum of 6 cycles. Responding pts continued to receive E or P until progression or unacceptable toxicity. The primary endpoint was non-progression rate (NPR: CR+PR+SD) at 8 wks using RECIST. Results: Between Aug 2006 and Apr 2007, 154 pts were enrolled from 7 countries. Median age was 57 years and 94% were Asian. Other baseline characteristics and efficacy results are shown in the table below. The median number of treatment cycles received was 6 vs 5 (GC-E vs GC-P). Rash-like events were noted in 66% of GC-E vs 35% of GC-P arm, and diarrhea was observed in 24% and 18% of pts, respectively. The most common grade 3–5 adverse events (GC-E vs GC-P) were neutropenia (20% vs 15%); anemia (8% vs 6%); thrombocytopenia (5% vs 5%); and vomiting (3% vs 8%). Overall safety profiles were similar between the two arms. A statistically significant improvement in PFS (p=0.005) was observed in the GC-E arm. Conclusions: 1st- line sequential administration of erlotinib with chemotherapy has demonstrated promising results. This treatment strategy warrants further investigation in advanced NSCLC. Baseline characteristics and efficacy results Characteristics (%) GC-E (n=76) GC-P (n=78) Male/Female 71/29 69/31 Never/Former/Current smoker 32/25/43 36/18/46 Adenocarcinoma/Others 67/33 67/33 Stage IIIB/IV 17/83 21/79 Efficacy NPR at 8 wks 80.3% 76.9% ORR (CR+PR) 36.8% 24.4% Median PFS * 7.2 mo 5.5 mo Median OS NR NR * HR=0.57 (95% CI 0.38; 0.84), p=0.005; NR=not reached Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Roche AstraZeneca, GlaxoSmithKline, Lilly, Pfizer, Roche Roche AstraZeneca, Eli Lilly, Pfizer, Roche AstraZeneca, Bayer, Lilly, Novartis, Roche AstraZeneca, Pfizer, Roche

Phase II study of RAD001 (Everolimus) in previously treated small cell lung cancer (SCLC)

19017 Background: The mammalian Target of Rapamycin (mTOR) plays a central role in the PI3K/AKT signaling pathway, which may be important in the proliferative and antiapoptotic signaling in SCLC. RAD001 is an orally administered mTOR inhibitor with dose-dependent in vitro activity in SCLC cell lines and potent in vivo growth inhibition in xenograft models. Methods: Eligible patients (pts) had pathologically documented SCLC that relapsed after 1–2 prior chemotherapy regimens, ECOG performance status (PS) 0–2, and adequate bone marrow, kidney and liver function. Pts with untreated or symptomatic brain metastasis were excluded. RAD001 was administered orally continuously at a daily dose of 10 mg until disease progression or unacceptable toxicity. A cycle was 3 weeks with response assessment after every 2 cycles. The primary endpoint was the disease non-progression rate. Using a 2-stage design, 21 pts will be enrolled in the first stage. If ≥7 pts show disease stability or response, 21 additional pts will be accrued in the second stage. PI3K/AKT signaling pathway proteins (PTEN, AKT, pAKT, p-S6, p-4E-BP1) expression will be assessed by immunohistochemistry in baseline tumor tissue and will be correlated with response. Results: 17 pts have been enrolled: median age- 63 years (44 - 80); males- 6 (35%); PS0- 35%; PS1- 65%. Prior chemotherapy: Platinum/etoposide: 17 (100%), 2nd line- 2 (12%); prior radiation: chest- 8/17 (47%); brain- 9/17 (53%). 11 pts had sensitive relapses (i.e. >60 days from first-line chemotherapy completion). 1 pt did not complete the first cycle of RAD001, 5 received 1 cycle, and 10 (59%) ≥2 cycles; number of days on treatment: median- 42 days (3−117+). In 16 evaluable pts, there were no objective responses; 3 pts had stable disease (19%) as best response while 13 pts had progressive disease (81%). Duration of stable disease: 69 - 117+ days. No grade 3 or 4 toxicities were encountered. Grade 2 toxicities were as follows: fatigue (4), thrombocytopenia (3), elevated transaminases (2), anemia (2), rash (2), hypertriglyceridemia (1), and hypermagnesemia (1). Conclusions: Preliminary results show that RAD001 is well tolerated but has low activity as a single agent in unselected, previously treated pts with SCLC. Updated results and biomarker analysis will be available for presentation. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis

Angiosarcomas and Taxanes

Angiosarcomas (AS) are a heterogeneous group of rare and aggressive malignancies. The best treatment of localized AS includes wide resection following by adjuvant radiation therapy as possible. The current standard treatment of metastatic AS remains a doxorubicin-based regimen. This treatment provides a median progression-free survival and a median overall survival of about 4 and 8 months, respectively. Numerous case reports and retrospective studies have suggested that taxanes (paclitaxel or docetaxel) may provide some objective responses. The French Sarcoma Group has conducted a phase II clinical trial, which states the benefit of weekly paclitaxel in patients with unresectable or metastatic AS. After 2 cycles, the non-progression rate was 78% and complete histological responses were observed in 3 out of 30 cases. Further clinical studies are needed to confirm clinic impact of weekly paclitaxel on survival and to assess the role of taxanes in the multidisciplinary treatment of AS.

Significance of the craniocaudal distribution of cancer in radical prostatectomy specimens

To examine the differences in the distribution of prostate cancer (PCa) in the craniocaudal dimension and their potential significance. We studied 1253 patients with clinically localized PCa treated with radical prostatectomy (RP) from 1983 to 2000. We analyzed the clinicopathological features according to the craniocaudal distribution (apex, mid, base) of the largest cancer focus. Of these patients, 456 (36%) had the largest cancer focus in the apex, 728 (58%) in the mid, and 69 (6%) in the base. The cancers in the apex were less invasive than those in the mid or base, as evidenced by the lower frequency of extracapsular extension (27% vs 43%, 52%, respectively) and/or seminal vesicle involvement (5% vs 13%, 20%, respectively). The frequency of the largest cancer focus in the apex has increased significantly over time, from 26% before 1995 to 46% after 1995 (P < 0.001). Serum prostate specific antigen non-progression rate at 10 years for patients with a cancer at the apex was 83%, which was better than 76% and 77% of patients with a cancer at the mid or base (P = 0.029, P = 0.14, respectively). The cancers dominant at the apex are increasing over time and represent half of the patients treated by RP in recent years. These cancers tend to be less aggressive compared to those in the mid or base of the prostate. This knowledge may be useful in understanding the biology of and maximizing the detection of PCa.

Simplified LV5FU2-irinotecan (FOLFIRI) in the first-line therapy of well-differentiated endocrine carcinomas of the duodeno- pancreatic area: Preliminary results of the FFCD 0302 phase II trial with GTE participation

4620 Introduction: Few chemotherapies have been tested in the first-line treatment of endocrine carcinomas. The aim of the study was to evaluate the efficacy of FOLFIRI in the first-line therapy of evolutive, metastatic or locally invasive, well-differentiated endocrine carcinomas of the duodeno-pancreatic area. Methods: To show a 6-month tumoral non-progression (RECIST) rate ≥ 60% (a = 5%), 20 pts had to be included in a phase II, prospective, multicentric trial. Inclusion criteria were : well-differentiated endocrine carcinoma of the duodeno-pancreatic area, functioning or non functioning, with hepatic or extra-hepatic metastases or locally invasive tumor &gt; 50 mm, not resectable; tumoral growth within 6 months; no previous antitumoral therapy except interferon ( = 3 months) or somatostatin analogs; PS 0–2. Treatment administration every 14 days : D1 : irinotecan 180 mg/m2, folinic acid 400 mg/m2, 5 FU 400 mg/m2 bolus; D1-D2 : 5 FU 2,400 mg/m2 in 46 hrs. Evaluation (clinical, radiological, biological) every 3 months. In case of progression during a chemotherapy free-interval following an objective tumoral response, treatment was reintroduced. All analyses were performed in intent to treat. Data cut off was done at July 1st 2006. Results: Between May 2004 and July 2005, 20 pts (13 M, 7 F) were included with median age 57 yrs (37–82). 19 pts had liver metastases and 1 pt had metastatic lymph nodes. 5 tumors were functioning; 2 pts had MEN 1. Median proliferation index was 7% (0–58). All pts were treated and evaluation at 6 months for the primary endpoint was available in 19 pts. The 6-month non-progression rate was 75% (CI 95% = 51–91%,), including 14 stabilization (70%) and 1 partial response (5%). 4 pts had 1 chemotherapy free-interval and 2 pts had 2 with reintroduction of the same chemotherapy regimen. Median number of cycles was 11.5 (1–28). 80% had at least 1 grade 3–4 toxicity and 25% had grade 3–4 hematological toxicity. 10% had grade 3 diarrhoea.. Conclusion: FOLFIRI has an antitumoral effect in the first-line therapy of evolutive well-differentiated pancreatic endocrine carcinomas. Frequency of grade 3–4 toxicities can be explained by length of therapy. No significant financial relationships to disclose.

Cytoplasmic overexpression of ALCAM is prognostic of disease progression in breast cancer

Background: Activated leucocyte cell adhesion molecule (ALCAM, CD166) is a cell surface member of the immunoglobulin superfamily. ALCAM expression has prognostic relevance in prostate and colon cancer. Objective: To evaluate...

A 2-stage controlled phase 1/2 study of STA-4783 in combination with paclitaxel in patients with advanced metastatic melanoma

7561 Background: STA-4783 (S), a novel inducer of heat shock protein 70 (hsp70) is a bis-thiobenzoylhydrazide compound. S leads to upregulation of hsp70 in tumor cell lines. Xenograft modeling with solid tumor cell lines demonstrated dramatic antitumor activity in combination with paclitaxel (P). Mechanistic studies suggest that the P enhancement is immune-mediated, creating, in effect, a chemically-induced biochemotherapy. The combination of S and P has been studied in a Phase 1 trial with the drugs coadministered i.v. over 3 h every 3 weeks. Doses ranged from (S/P, mg/m2) 44/135 to 525/175. Based on dose-related HSP70 induction (evidence of biological activity) and demonstrated tolerability, we began a Phase 2 study of the combination in patients with metastatic melanoma. Methods: The study consists of an initial safety assessment of the weekly dose schedule for 3 weeks every 4 weeks at S 106 mg/m2 and P 80 mg/m2. S was then escalated to 213 mg/m2 in combination. The higher tolerated dose level was expanded to a total of 20 patients (Stage 1). The criterion for continuation to Stage 2 was >= 50% non-progression rate (NPR) at 2 months. Stage 2 is a randomized 2-arm study comparing the drug combination to P alone. A total of 78 patients are to be randomized 2:1 (combination:control). The primary endpoint is time to progression; secondary endpoints are response rate, survival, and quality of life. Pharmacodynamic parameters include pre- and post-dose measurements of NK cell activity in blood and, when possible, tumor biopsies. Results: A total of 7 patients were treated in the initial safety assessment, 3 at the lower dose level and 4 at the higher. In the absence of dose-limiting toxicities in either group, the higher dose level was chosen as the dose of interest and additional patients were enrolled to complete Stage 1. Adverse events seen were as expected for P chemotherapy administration. In preliminary evaluation of 20 patients, 11 were stable at 2 months, for 55% NPR. The randomized Stage 2 portion will proceed, pending confirmation of the stage 1 data. Conclusions: The addition of S to P was well-tolerated on the weekly schedule. Enrollment in the randomized portion will assess the activity of S + P vs. P alone. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Synta Synta Synta Synta

A phase II study of erlotinib as first-line treatment of advanced non-small cell lung cancer

7073 Background: Erlotinib (TarcevaTM) is an orally available selective EGFR tyrosine-kinase inhibitor. In patients with advanced NSCLC, 2nd/3rd-line erlotinib significantly prolonged survival (Shepherd et al. ASCO 2004) with a response rate (RR) of 9%. This phase II trial evaluated the efficacy and safety of 1st line erlotinib in patients with advanced NSCLC. Methods: Chemotherapy-naïve, stage IIIB/IV, PS 0–2, NSCLC patients have been enrolled to receive erlotinib 150 mg/day until disease progression or withdrawal. The primary endpoint of the study was the rate of non-progression in >50% of patients after 6 weeks of treatment. Secondary endpoints included objective response, disease control rate, duration of response, time to progression, survival and safety. Exploratory analyses included QoL, EGFR expression and mutation analysis, and FDG-PET response at 3 weeks in a subset of patients. Results: 54 patients were enrolled from January to July 2004 from 3 institutions. 53 patients received erlotinib and are assessable. Demographics: M/F 20/33; median age 61; PS 0/1/2 13/32/8; pathology adeno 23, squamous cell 9, bronchioloalveolar (BAC) 6, large cell 8, other 7; smoking status current/former/never 10/25/18. The non-progression rate was 55%. Best response was: 1CR, 12 PR, 16 SD, 17 PD, 7 NE (RR 24.5%; 95% CI 13.8–38.3). To date, 14 patients have not progressed and 12 have been treated for 6 months or longer. Responses were observed in males (1CR, 3 PR) and in females (9 PR), mostly in adenocarcinoma (7) and in BAC (4), in non or former smokers (12). The most common adverse events were diarrhea and rash (28 patients each), primarily of grades 1/2. Five patients had a grade 3 event: 2 rash, 1 lethargy, 1 diarrhea, 1 conjunctivitis. No grade 4 events. Bilirubin elevation was reported for 6 patients (4 grade 1, 2 grade 2). EGFR and PI3K mutations were not found in 15 patients so far assessed (1 responder) but 8 had K-ras mutations. Conclusions: Erlotinib is active and well tolerated as first-line monotherapy in advanced NSCLC. Responses were seen in both genders including a CR in a male with adenocarcinoma, but were more common in women, adenocarcinomas/BAC and non-smokers. Further assessment of erlotinib in this setting is warranted. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche AstraZeneca, Roche AstraZeneca, Roche AstraZeneca, Roche

Phase II trial of single agent bevacizumab in patients with relapsed, aggressive non-Hodgkin’s lymphoma (NHL): Southwest Oncology Group Study S0108

6592 Background: VEGF is overexpressed in a number of malignancies. We previously found high expression of VEGF and its receptors in a sample of aggressive NHL specimens. Based on these results, we initiated this trial. Methods: Patients (pts) were treated every 2 weeks with bevacizumab (BV), a recombinant monoclonal antibody against VEGF, at a dose of 10mg/kg IV. Eligibility was limited to advanced stage aggressive NHL histologies in 1st or 2nd relapse. Results: 51 pts were registered (5 ineligible). Median age was 70 yrs (range: 36–87). 44 pts have been evaluated for toxicity. One died of pulmonary emboli and another died of probable progressive disease (possible causal relationship to drug could not be ruled out). 15 pts had grade 3 toxicities. The most common were cytopenias (10); fatigue, malaise, or lethargy (5); dyspnea (3); hypertension (2); hyponatremia (2); and dehydration (2). 40 eligible pts were evaluated for best response. There were 2 PR for an overall response rate of 5% (95% C.I. 1–17%). Eight pts had SD as their best response. The non-progression rate (PR + SD) was 25%. The median TTP was 5 months, range 4–18 months, in non-progressing pts. In all pts, 6-month PFS estimate was 14% (95% C.I.: 4–24%). The 6-month OS was 58% (95% C.I.: 43–73%). IHC was performed on diagnostic tumor for VEGF and its receptors. 19 samples were adequate for analysis with 14 (74%) expressing VEGF and 13 expressing one or both receptors. Additional studies included baseline, week 8, and at-time-of-progression measurements of circulating endothelial cells (CEC), and plasma and urine angiogenic markers (VEGF, VCAM, and bFGF). Over the course of therapy, CEC (p=.12) and plasma VEGF (p<.001) levels decreased while plasma VCAM (p=.02) levels increased. Conclusions: Therapy with BV was well-tolerated in this pre-treated group of pts with prolonged stabilization of disease seen in a small, but significant subset. The high rate of concordance between expression of VEGF and receptors suggests an autocrine pathway may play an important role in NHL pathogenesis. These results provide a strong rationale for studying the addition of BV to standard chemotherapy in the treatment of aggressive NHL. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech