Q3 Wks Research Articles

Phase II trial of bevacizumab (B) plus everolimus (E) for refractory metastatic colorectal cancer (mCRC).

3535 Background: For patients (pts) with mCRC, treatment options are absent after progression on 5-FU, oxaliplatin, irinotecan, bevacizumab, and cetuximab/panitumumab. Preclinical data demonstrate combined VEGF and mTOR inhibition has greater antiangiogenic and antitumor activity than either monotherapy, and phase I data demonstrated that the combination of B + E is safe and generally well tolerated. This phase II trial evaluates efficacy and tolerability of B+E in mCRC patients who have progressed on standard therapies. Methods: 50 pts with refractory mCRC were treated with B 10 mg/kg q2 wks and E 10 mg PO QD until progression. Blood, skin, and tumor biopsies pre- and on-treatment were collected for markers of response and resistance. Results: 47 of 50 pts had prior B exposure; 42 pts had previously progressed on B. Median number of prior regimens was 4. Although no complete or partial responses were seen, 46% of pts achieved disease control for a median duration of 6.1 months (mos) (range 2.3-12.6): 8 pts had minor responses (median duration of response 4.1 mos, range 2.3-11.9+) and an additional 15 patients had SD (median duration of response 6.7 mos, range 3.2-12.6+). Three patients with prolonged stable disease have been on treatment > 1 year. There was one grade (Gr) 4 adverse event (AE) of hypokalemia. Noteworthy grade 3 AEs related to treatment were hypertension (n = 7), mucositis/proctitis (n = 3), fistula/abcess (n = 3), bowel perforation (n = 1), azotemia/proteinuria (n = 2), fatigue (n = 2), thrombocytopenia (n = 2), hyperglycemia (n = 6), hypokalemia (n = 6), hypophosphatemia (n = 2), hyperlipidemia (n = 3) and hyperbilirubinemia (n = 2). There was one Gr 3 event each of rhabdomyolysis, neuropathy, volume depletion, prolonged QT interval, GI hemorrhage and neutropenia. Other events of interest were: Gr 1-2 mucositis (68%, n = 34), Gr 1-2 hyperlipidemia (64%, n = 32). Biomarker data is pending. Conclusions: B + E has promising activity in refractory mCRC (even in pts who have progressed on a B-based regimen) with a disease control rate of 46%, suggesting B + E may overcome resistance to B. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech, Novartis, Roche Genentech, Novartis, Roche Genentech, Novartis

Randomized phase II study of pemetrexed in combination with cisplatin or carboplatin as first-line chemotherapy in advanced non-small cell lung cancer.

7628 Background: Pemetrexed (P) combined with cisplatin (C) was approved in 1st-line treatment (Tx) of non-small cell lung cancer (NSCLC) in pts with other than predominantly squamous histology. For pts unable to tolerate C, P + carboplatin (Car) might offer an alternative. Methods: Multicenter, open-label phase II trial in pts with stage IIIb/IV NSCLC. 133 pts were randomized to P (500 mg/m2)+C (75 mg/m2) or P (500 mg/m2) + Car (AUC6) d1 q3 wks, for 6 cycles. Primary outcome was 6-mo progression-free survival (PFS) rate, estimate based on exponential distribution, independently for each arm. Secondary outcomes included overall survival (OS) (Kaplan-Meier estimate), objective response rate (ORR), and tolerability. Results: Treatment groups were balanced. The Table shows the results. Conclusions: Both regimens showed efficacy according to study hypothesis. The observed trend in favor of P+C regarding PFS and OS related to histology is consistent with the results of larger phase III trials. N= 133 random/130 treated Median age (yrs) P+C (N = 65) 64 (42-78) P+Car (N = 65) 63 (45-80) n % n % Sex male 42 64.6 46 70.8 Histopathology Squamous 12 18.5 13 20.0 Nonsquamous 53 81.5 52 80.0 Stagea IIIb 5 7.6 9 13.4 IV 61 92.4 58 86.6 6 month PFS rate % [95% CI]b 52.8 [40.3; 65.3] 39.3 [27.8; 50.8] Squamous hist. 34.9 [9.4; 60.4] 42.0 [16.8; 67.3] Nonsquamous hist. 57.6 [43.7; 71.5] 38.5 [25.6; 51.5] Median OS, months [95% CI] 11.7 [9.2; 14.9] 8.9 [6.0; 12.2] Squamous hist. 7.4 [3.5; - ] 9.8 [4.4; 25.7] Nonsquamous hist. 11.9 [9.4;15.2] 8.5 [6.0,13.3] 12-month OS rate (%) [95% CI] 47.5 [34.5; 59.4] 39.2 [27.2; 51.1] ORR, n responders (all PR, %) 21 (32.3) 13 (20.0) Exposure Cycles completed, median 4 6 Cycle delays 40 61.5 41 63.1 Dose reductionsc 3 4.6 16 24.6 Median dose intensity % [25th, 75th percentile] P 98.2 [92.0;100.0] 98.6 [91.6;99.7] C 97.8 [91.6;99.8] – Car – 96.3 [83.1; 99.5] Discontinuationsa Tx complete 28 42.4 32 47.8 AE 11 16.7 4 6.0 Progression 13 19.7 20 29.9 Pt/physician decision 10 15.2 6 9.0 Tolerability Pts ≥ 1 related G 3/4 TEAEd 29 44.6 36 55.4 Pts ≥ 1 related TE SAEd,e 11 16.9 15 23.1 Abbreviations: n, pts; N, pt population. a All pts random. b H0 6 mo PFS rate ≤ 25%. c All compounds. d Possibly related, e 13 deaths [C/Car] (3/10); 1/2 study drug tox. 0/3 unrelated AE. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Lilly Lilly Lilly Lilly

Phase III trial comparing 4-cycle doxorubicin plus cyclophosphamide followed by 4-cycle taxan with 8-cycle taxan as adjuvant therapy for node-positive breast cancer: Results of N-SAS-BC02 trial

516 Background: Anthracyclines are the key agents in postoperative regimens for breast cancer (BC). However, relatively rare but life threatening toxicity such as cardiac failure and secondary leukemia are the major concern with anthracycline containing regimens. Retrospective analyses suggested that anthracyclines can be excluded in some pts. Methods: Eligibility included node positive BC age less than 70 yo. Pts were randomized to receive either AC (doxorubicin 60 mg/m2 + cyclophosphamide 600 mg/m2) every(q) 3 weeks(wks) x 4 -> P (paclitaxel) 175 mg/m2 q3 wks x 4 (ACP), the same AC -> D(docetaxel) 75 mg/m2 q3 wks x 4 (ACD), P 175 mg/m2 q3 wks x 8 (PTX) or D 75 mg/m2 q3 wks x 8(DTX). Comparison included P vs.D (ACP+PTX vs. ACD+DTX) and with AC or without AC (ACP+ACD vs. PTX+DTX). The primary endpoint was disease free survival (DFS) and the secondary endpoints included overall survival, adverse events (AE) and quality of life (QOL). The trial was powered to prove the non-inferiority of regimens without AC to those with AC (threshold hazard ratio [HR] 1.321) in terms of DFS. Results: 1,060 pts were accrued between Dec. 2000 and Mar.2006. 270 DFS events and 106 deaths after a median follow-up of 46.5 months were observed. In all randomised patients, 8 cycles taxane is not inferior to 4 cycles AC -> 4 cycles taxane in terms of DFS (HR:1.26, 95% CI; 0.99–1.60, p = 0.67). In the subset of HER-2 positive patients, 4 cycles AC -> 4 cycles taxane produced superior DFS to 8 cycles taxane (HR:1.63, 95% CI:1.05 - 2.54) but this is not observed in patients with HER-2 negative patients (HR:1.13, 95% CI: 0.85 - 1.50). D 75 mg/m2 tends to show superior DFS to P 175 mg/m2 (HR: 0.81, 95% CI; 0.64–1.03, p = 0.08). Nausea and vomiting was more frequent with AC -> a taxane than 8 cycles taxane. Edema and febrile neutropenia was more frequently observed with D 75 mg/m2 than P 175 mg/m2. The incidence of sensory neuropathy was higher with P 175 mg/m2 than D 75 mg/m2. Conclusions: AC improved DFS in the subset of pts with HER-2 overexpressing BC but not in non-selected population. DFS was better in the arms containing D than in the arms with P. Higher incidence of severe AEs was observed in the arms containing D than in arms with P. No significant financial relationships to disclose.

Randomized, open-label, multicenter phase II study of bevacizumab in combination with carboplatin and paclitaxel in chemotherapy-naive Japanese patients with advanced or recurrent nonsquamous non-small cell lung cancer (NSCLC): JO19907

8036^ Background: Two phase III trials (ECOG 4599 and BO17704) demonstrated that the addition of bevacizumab (Bev) to platinum-based regimens improved overall and/or progression-free survival (PFS) in patients (pts) with advanced non-squamous NSCLC (Sandler et al. NEJM 2006; Manegold et al. ESMO2008). However, no investigation with Bev has been conducted in Japanese NSCLC pts. Methods: This randomized, open-label phase II study compared a 3-weekly regimen of 15mg/kg of Bev plus carboplatin/paclitaxel (CP) versus CP alone. The primary endpoint was PFS; secondary endpoints included overall survival (OS), response rate (RR) and safety. Eligibility criteria: histologically or cytologically documented previously untreated advanced or recurrent non-squamous NSCLC; ECOG PS 0–1; no brain metastases. A size of 180 pts was planned to be randomized to: C AUC=6 and P 200mg/m2 q3 wks for up to 6 cycles plus Bev continued to progression at 15mg/kg q3 wks, or CP alone at the randomization ratio of 2:1. The study was designed to observe a 20% reduction in the risk of a PFS event in the Bev arm compared with control. Results: Between 4/07 and 3/08, 180 pts were accrued. Three pts of them were ineligible and 3 pts were not dosed at all. PFS (as assessed by investigators) and RR were significantly improved. OS is immature due to short duration of follow up. Updated PFS results as assessed by the central review committee and OS data will be provided. No new safety signals for Bev were detected. Conclusions: This is the first study of Bev in Japanese pts with NSCLC. The addition of 15mg/kg of Bev to CP significantly improved PFS and RR. The HR of PFS seemed at least as good as previous trials outside Japan. Safety of Bev was within a range already reported. This study confirms the efficacy and safety of Bev in Japanese pts with NSCLC. [Table: see text] [Table: see text] ASCO Conflict of Interest Policy and Exceptions In compliance with the guidelines established by the ASCO Conflict of Interest Policy (J Clin Oncol. 2006 Jan 20;24[3]:519–521) and the Accreditation Council for Continuing Medical Education (ACCME), ASCO strives to promote balance, independence, objectivity, and scientific rigor through disclosure of financial and other interests, and identification and management of potential conflicts. According to the ASCO Conflict of Interest Policy, the following financial and other relationships must be disclosed: employment or leadership position, consultant or advisory role, stock ownership, honoraria, research funding, expert testimony, and other remuneration (J Clin Oncol. 2006 Jan 20;24[3]:520). The ASCO Conflict of Interest Policy disclosure requirements apply to all authors who submit abstracts to the Annual Meeting. For clinical trials that began accrual on or after April 29, 2004, ASCO's Policy places some restrictions on the financial relationships of principal investigators (J Clin Oncol. 2006 Jan 20;24[3]:521). If a principal investigator holds any restricted relationships, his or her abstract will be ineligible for placement in the 2009 Annual Meeting unless the ASCO Ethics Committee grants an exception. Among the circumstances that might justify an exception are that the principal investigator (1) is a widely acknowledged expert in a particular therapeutic area; (2) is the inventor of a unique technology or treatment being evaluated in the clinical trial; or (3) is involved in international clinical oncology research and has acted consistently with recognized international standards of ethics in the conduct of clinical research. NIH-sponsored trials are exempt from the Policy restrictions. Abstracts for which authors requested and have been granted an exception in accordance with ASCO's Policy are designated with a caret symbol (^) in the Annual Meeting Proceedings. For more information about the ASCO Conflict of Interest Policy and the exceptions process, please visit www.asco.org/conflictofinterest .

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

1029 Background: Pac/bev is superior to pac alone as first-line therapy for MBC. Ixa/bev has greater preclinical activity than pac/bev in human tumor models. The primary objective of this trial was to evaluate objective response rates (ORR) of ixa/bev given weekly or every 3 weeks relative to pac/bev as 1st line therapy for women with advanced breast cancer. Methods: Women with measurable disease and no prior chemotherapy for advanced breast cancer (locally advanced or MBC) were randomized in a 3:3:2 ratio to Arm A (ixa 16 mg/m2 IV on days 1, 8 & 15 q28 days/ bev 10 mg/kg IV q 2 wks), Arm B (ixa 40 mg/m2 IV q3 wks / bev 15 mg/kg IV q 3 wks) or Arm C (pac 90 mg/m2 IV, schedule/bev as in Arm A). Treatment was continued until disease progression or unacceptable toxicity. Results: Key efficacy and safety results from a pre-planned analysis of all randomized subjects after at least 24 weeks of follow-up are presented. Baseline characteristics were balanced between arms except for liver metastasis. Conclusions: The combination of ixa/bev weekly or q 3 wks demonstrated encouraging clinical activity and safety comparable to 1st line pac/bev in E2100. Final PFS will be provided when data is mature. These results support ongoing clinical trials of ixa given weekly or q 3wk in 1st line MBC, and in combination with bev. [Table: see text] [Table: see text]

Safety and efficacy of single-day GemOx (S-GemOx) regimen in pts with pancreatobiliary cancer (PBC)

e15577 Background: GemOx (G 1000 mg/m2 over 100 mins on d1 and Oxaliplatin (Ox) 100 mg/m2 on d2 q2 wks) achieved a RR of 26.8%, improved PFS but failed to demonstrate a benefit in OS vs G in PBC. This regimen has regained attention after recent pooled- and meta-analysis suggesting a survival benefit of G-platinum doublets over G. However, GemOx is associated with inconvenience to pts, early cumulative dose to develop neuropathy and thrombocytopenia. In addition, prolonged infusion of G showed no benefit over 30 mins in ECOG 6201study. Pharmacokinetic profile of both drugs did not show statistically significant differences regardless the order of administration. We modified GemOx as S-GemOx (G 1000 mg/m2 over 30 mins and Ox 85–100 mg/m2over 2 hrs on d1 q2 wks) given on same day to create a more convenient and equally effective regimen for these pts. Methods: A retrospective study was conducted to evaluate PBC pts who received S-GemOx from Sep 06 to Dec 08. Adverse events were graded according to NCI-CTC v3.0. Response was assessed with RECIST by a CT scan q 8 wks. Results: 34 pts (median age 60y, M/F: 17/17) who received S-GemOx were evaluated: PC (26), BC (7) and ampullary ca (1). 7 pts received S-GemOx plus a biological agent (3 bevacizumab, 3 cetuximab and 1 panitumumab). Median duration of therapy was 12 wks (r: 2–56). Median cumulative dose of Ox was 510mg/m2(r: 85–2380). 27 pts were evaluated for efficacy after initial staging: 1 (3.7%) CR, 4 (14.8%) PR, 18 (66.7%) SD and 4 (14.8%) PD. ORR (CR+PR) and ODC (CR+PR+SD) were 18.5% and 85.2% respectively. Median EFS, PFS and OS were 12, 16.7 and 37.6 wks respectively. 13 (38%) pts required Ox dose reduction due to toxicities (cytopenia, HSR, elevated LFTs and diarrhea). G3/4 hematological toxicities include anemia (8%), neutropenia (11%), thrombocytopenia (5%), N/V (3%), diarrhea (3%), HSR (14%) and neuropathy (3%). No deaths occurred due to therapy. 1 pt received a total of 1,025 mg/m2 of Ox on OPTIMOX approach. 9 pts discontinued therapy due to PD and 19 due to toxicities. Currently 4 pts are still receiving therapy. Conclusions: S-GemOx regimen provides convenient schedule, appears to be less toxic (G3/4 neuropathy: 3% vs 19.1%; thrombocytopenia 5% vs 14 %) and has comparable efficacy vs GemOx. Prospective studies of S-GemOx in a large pt population are warranted. [Table: see text]

Bevacizumab (B) plus everolimus (E) in refractory metastatic colorectal cancer (mCRC)

4080 Background: For patients (pts) with mCRC, no standard therapy exists after progression on 5-FU, oxaliplatin, irinotecan, bevacizumab, and/or cetuximab/panitumumab. Preclinical data demonstrate combined VEGF and mTOR inhibition has greater anti-angiogenic and anti-tumor activity than either monotherapy. B inhibits VEGF; E inhibits mTOR. Phase I data in patients demonstrated B + E was safe and activity was seen in several pts with refractory mCRC. Methods: 25 pts with refractory mCRC were enrolled in an expanded cohort of B + E. Doses: B 10 mg/kg q2 wks; E 10 mg PO QD. Blood, skin, and tumor biopsies pre- and on-treatment were collected for markers of response and resistance. Results: At this time, 19 pts (10M: 9F) are evaluable for toxicity; 17 for efficacy. Median age 57 years (range 35–78). Median number prior regimens 3. All pts had prior B exposure; 17 pts had progressive disease on prior B-based therapy. There was one Grade (Gr) 4 adverse event (AE) of hypokalemia. Grade 3 AE related to treatment were bowel perforation/fistula, (n=2), hyperglycemia (3), hypokalemia (3), hypertension (2), fatigue (1), alk phos elevation (1; lab only), hypoalbuminemia (1), and volume depletion (1). Other events of interest were: Gr1–2 mucositis (n=10), Gr1 hyperlipidemia (11). Of 17 pts evaluable for response, 4 pts had SD as best response (median 24 wks, range 17–31+ wks); there were 3 minor responses in pts who had progressed on B (median 16 wks, range 16–27 wks). No CR or PR were seen. Biomarker data is pending. Conclusions: B+E has activity in refractory mCRC in pts who had progressed on a B-based regimen, suggesting B+E may overcome resistance to B. Patient accrual is continuing and updated data will be presented. [Table: see text]

Phase I trial with a combination of docetaxel and 153Sm- EDTMP in patients (pts) with castration-resistant metastatic prostate cancer (mCRPC)

5155 Background: Bone targeted therapy holds great promise for improving outcomes in mCRPC. Preclinical data strongly supported biological synergism of docetaxel (Tax) and 153Sm-EDTMP (Sm) in mCRPC. Concurrent Tax and Sm regimens were reported feasible and tolerable in phase I studies. This study was designed to evaluate toxicity and preliminary efficacy of 2 cycles (12 wks/cycle, C) of concomitant standard dose/schedule of Sm plus Q3 wks schedule of Tax in mCRPC. Methods: mCRPC pts with progressive bone metastases were treated in 4 cohorts ( CH). Previous Tax and palliative RT to bone was admissible. Dose escalation of Tax was implemented if no DLT was observed in the preceding CH. Tax doses (on days 1, 22, per 12 wk cycle) were given as follows: CH 1- 50mg/m2 (C1 and 2); CH 2–75mg/m2 (C1) and 50mg/m2 (C2); CH3 - 75mg/m2 (C1 and 2) and CH4 ( Tax day 1, 22, 43 per 12 wk C) 75mg/m2 (C1 and 2). Sm was administered on days 2 (Q12 wks X 2) at dose of 1 mCi/kg/cycle (max. of 2 cycles). Disease status was assessed (with bone /CT scans and PSA) after every cycle. Results: Thirteen pts with progressive bone metastases were enrolled. Three had prior Tax and 3 had prior palliative radiation. Thirteen pts received total 20 cycles in 4 cohorts. Toxicity was primarily hematological. There were total 34 episodes Grade 3/4 neutropenia with a median 7 (range 7 -14) days to recovery to ≤ grade1. Tax dose was reduced to 50% in 2 CH4 pts at C2. Only 1 DLT G3 thrombocytopenia occurred on cohort 4 with duration of 9 wks. Median baseline PSA was 100.4 ng/ml (range 8.6 - 1064), 9/13 (69%) pts had PSA>50% decrease. Median time to disease progression was 147 days (range 72 days - 10 months+); 6/13 (46%) pts had stable/improved bone scans at 6 months and 8/8 (100%) symptomatic pts had improvement in pain. Conclusions: Concurrent 6-month administration of 2 and possibly 3 full dose /standard schedule of Tax with 2 full doses of Sm is feasible with reversible bone marrow suppression. The combination may provide additional clinical benefits for mCRPC pts with extensive bone metastasis. No significant financial relationships to disclose.

Correlation between prior therapeutic dendritic cell vaccination and the outcome of patients with metastatic melanoma treated with ipilimumab

e20006 Background: Ipilimumab (Ipi) is an anti-cytotoxic T lymphocyte associated antigen 4 (CTLA4) IgG1 monoclonal antibody active against metastatic melanoma. Ipi acts by reinforcement of CTL-activation trough B7/CD28 receptor stimulation. A pre- existing anti-tumor CTL repertoire, induced by dendritic cell (DC) vaccination, could influence the therapeutic effect of Ipi. The influence of prior DC-vaccination on the outcome of melanoma patients (pts) treated with Ipi at a single center was analyzed to evaluate this hypothesis. Methods: Data were obtained from the medical files of pts treated at the UZ Brussel with Ipi in protocols CA184–022, -025, and the BMS Ipi medical need program. Ipi (0.3, 3 or 10 mg/kg) was administered iv q3 wks x4 q12 wks thereafter. Results: 20 pts (10M/10F; med age 51y, range 28–72) were identified. Prior therapy: autologous DC-vaccine loaded with melanoma associated antigens (14 pts) ± IFN-a2b (9/14 pts), cytotoxic agents (17 pts). Baseline characteristics: AJCC st IV melanoma (20 pts); baseline LDH > ULN (16 pts). Ipi dose: 0.3 mg/kg (4 pts), 3 mg/kg (2 pts), 10 mg/kg (14 pts). Serial LDH measurements were available for 17 pts; 4 types of LDH-response following Ipi administration were observed: increase (11 pts), decrease (1 pt), fluctuation (4 pts), stable (1 pt). Objective response according to mWHO or irWHO: 3 PR, 1 SD, 16 PD. One pt received 0.3 mg/kg of Ipi (CA184–022) and had SD but no LDH response; at PD she received DC-vaccine and subsequently 10 mg/kg Ipi (medical need program) resulting in a fluctuating LDH-response and regression of an orbita-metastasis. Increasing LDH values following Ipi were less often observed in pts with prior DC-vaccination (5/6 pts (83%) without prior DC-vaccination had increasing LDH-values vs 6/12 pts (50%) with prior vaccination). DC- vaccination also correlated with regression of metastases and disease control (3/15 pts (20%) who were vaccinated had a PR/SD vs 1/6 (17%) PR for those who had not received prior DC-vaccinations). Conclusions: These data represent a small sample size from a single institution; however, our results suggests a potential correlation between prior therapeutic DC vaccination and outcomes in advanced melanoma patients treated with ipilimumab. [Table: see text]

Pemetrexed in combination with cisplatin or carboplatin as adjuvant chemotherapy in early-stage NSCLC

7565 Background: Platinum based chemotherapy after complete resection of stage I-IIIa non-small cell lung cancer (NSCLC) has improved 5-yr survival by 4–15%. Pemetrexed (P) in combination with cisplatin (C) or carboplatin (Carb) has shown to be effective and safe in first-line Tx of advanced NSCLC, thus being a promising option in the adjuvant setting. Methods: Multicenter, open phase 2 in pts with resected stage Ib/II NSCLC. Pts were randomized to P (500 mg/m2)+C (75mg/m2) or P (500 mg/m2)+Carb (AUC5) d1 q3 wks, for 4 cycles; adequate organ function and ECOG PS 0–1 required. Primary endpoint was feasibility of the regimen defined as compliance to 4 Tx cycles with ≥ 95% of planned dose without ≥ Grade 3 toxicities (tox) at 30 d after last infusion. A regimen was deemed feasible if the rate (feasible pts/total pts) was >60%. Results: Please see Table for results. Conclusions: According to the strict definitions in this protocol neither regimen was feasible. The reason was poor compliance with at least one of the components that defined feasibility, but dose intensity and % pts completing cycle 4 was notably high, compared to other adjuvant trials. P+C was the more favourable regimen concerning feasibility and tolerability. In terms of tolerability pemetrexed could be combined with either platinum compound. [Table: see text] [Table: see text]

Activity and tolerability of cisplatin (CDDP) and fotemustine (FTM) in non-small cell lung cancer (NSCLC) patients (PTS) with brain metastases (BM): A multicentric phase II study of the Gruppo Oncologico dell’Italia Meridionale (GOIM)

e19085 Background: More than 50% of BM occurs in advanced NSCLC. In most cases BM are multiple and their standard therapy is whole-brain radiation therapy (WBRT) since the role of systemic therapies for is still a matter for investigation due to concerns on the drugs ability cross the blood brain barrier (BBB). FTM is a nitrosourea able to cross BBB and CDDP remains the backbone for medical treatment of NSCLC. Methods: Pts with advanced NSCLC, ECOG PS 0–1 and multiple BM were treated with 2 cycles of FTM 80 mg/m2 d1,8 and CDDP 80 mg/m2 d1 q3 wks followed by WBRT 30 Gy/3 Gy daily; radiological response using Recist Criteria were analysed before WBRT to assess the role of FTM/CDDP both for cranial and extracranial disease. Pts with disease control (DC) received further CT up to 6 cycles. Barthel ADL Index was administered every 2 cycles. The trial has a two step design according to Simon: 29 pts were required to verify if FTM/CDDP was able to achieve a >25% response rate both for cranial and extracranial disease (step 1), and if this was true further pts had to be enrolled up to 81 pts (step 2). Results: At first evaluation 4/29 pts were excluded from the study (2 not treated/ 1 never included/1 not eligible). Therefore patient's demographics were: median age 61 (range 48–73), M/F 16/9, adeno 11, squamous 5, large cell 2, nos 7; PS 0/1: 1/14, Barthel Index median value at the starting point 20 (13–20). Overall 3/25 (12%) partial responses were observed with 9 (36%) stable diseases and 13 (52%) progressions of disease. These data did not satisfy the pre-planned hypothesis and the study was stopped at the first step. Before WBRT after the first 2 CT cycles 13/25 pts (48%) had a systemic DC in contrast with 15/25 pts (60%) with brain tumour DC. WBRT seemed not useful to further modify the results of CT. CT was relatively well tolerated with asthenia as the most relevant specific toxicity while the hematological toxicity was mild. Conclusions: CDDP and FTM combined with WBRT could represent a therapeutic option for patients with NSCLC even if the global therapeutic index was not satisfactory. Further studies evaluating the combination of systemic treatments with WBRT are warranted. No significant financial relationships to disclose.

Phase III two by two factorial comparison of doxorubicin and cyclophosphamide followed by a taxan vs. a taxan alone, and paclitaxel vs. docetaxel in operable node positive breast cancer – results of the first interim analysis of NSASBC02 trial.

Abstract Abstract #4103 Background: Evidence suggests that anthracycline-containing regimens can be excluded in some patients(pts) with operable breast cancer. It is also suggested that docetaxel (D) is more effective than paclitaxel (P) in metastatic breast cancer (BC) pts.
 Methods: Eligibility included axillary lymph node positive BC age less than 70 years old. Pts were randomized to receive either AC(doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2) every(q) 3 weeks(wks) x 4 followed by P 175 mg/m2 q3 wks x 4 (ACP), same AC followed by D 75 mg/m2 q3 wks x 4(ACD), P 175 mg/m2 q3 wks x 8 (PTX) or D 75 mg/m2 q3 wks x 8(DTX). Comparison included taxane (ACP+PTX vs. ACD+DTX) and with AC or without AC (ACP+ACD vs. PTX+DTX). The primary endpoint was disease free survival (DFS) and the secondary endpoints included overall survival, adverse events(AE) and quality of life (QOL). The trial was powered to prove the non-inferiority of regimens without AC to those with AC(threshold hazard ratio 1.321) in terms of DFS.
 Results: A total of 1,060 eligible pts were accrued from 84 centers between Dec. 2000 and Mar.2006. 270 DFS events and 106 deaths after a median follow-up of 46.5 months were observed. The hazard ratio (HR) of DFS between ACD+DTX and ACP+PTX was 0.81(95% Confidence Interval (CI); 0.64-1.03) (p=0.08). The HR of DFS between PTX+DTX and ACP+ACD was 1.26 (95% CI; 0.99-1.60) ( p=0.67) in all eligible pts but was 1.85 (95% CI; 1.11-3.07)(p=0.017) in pts with HER2 overexpressing BC and 1.11(95% CI; 0.85-1.46)( p=0.44) in pts with HER2 non-overexpressing BC. AEs of grade 3 or 4 were observed in the lowest incidence in PTX arm and edema was observed in 11% of pts in DTX arm(p=0.01), neutropenic fever was more frequent in D cotaining arms(Table1). Conclusions: DFS was better in the arms containing D than in the arnms with P. AC improved DFS in the subset of pts with HER2 overexpressing BC but not in non-selected population. Higher incidence of severe AEs was observed in the arms containing D than in arms with P.
 
 Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4103.

Significant improvement in recurrence-free survival (RFS) when capecitabine (X) is integrated into docetaxel (T) → 5-FU + epirubicin + cyclophosphamide (CEF) adjuvant therapy for high-risk early breast cancer (BC): interim analysis of the FinXX-trial.

Abstract Abstract #82 Background: Adding X to T extends survival in patients (pts) with metastatic BC. The primary objective of the FinXX-trial is to compare RFS with XT→CEX vs. T→CEF as adjuvant therapy in pts with early BC. Secondary objectives are comparison of overall survival, distant RFS and safety. Methods: Between Jan 2004 and May 2007, 1500 pts were randomized to receive T x 3 → CEF x 3 (T 80mg/m² d1 → C 600mg/m² d1, E 75mg/m² d1, F 600mg/m² d1, q3 wks) or XT x 3 → CEX x 3 (T 60mg/m² d1 + X 900mg/m² bid d1–15 → C 600mg/m² d1, E 75mg/m² d1, X 900mg/m² bid d115, q3 wks). Results: 1496 pts were included in the ITT analysis (two pts withdrew consent, two had metastatic disease). The study population represented a high-risk group (90% node positive, 19% HER2 positive, 88% poorly or moderately differentiated tumors). The baseline characteristics were well balanced in the two treatment arms. After median follow-up of 3 years, there have been 134 events (deaths, distant or local relapses; Table). The significantly improved RFS rate was achieved despite a higher number of study treatment discontinuations in the X-containing arm (178 vs. 23 pts in the control arm; when XT was discontinued, the remaining XT cycles were replaced with an equal number of T cycles, and CEX cycles with CEF cycles). 75% of pts in the X-containing arm received all six planned cycles of therapy compared with 96% in the control arm. The adverse effect profiles of XT→CEX and T→CEF were in part different (Gr. 3/4 neutropenic fever/infection 10.0% vs. 20.2%, hand-foot syndrome 11.1% vs. 0.3%, diarrhea 6.2% vs. 3.4%, stomatitis 4.2% vs. 1.6%, myalgia 1.9% vs. 8.0%, respectively).
 
 Conclusions: The primary endpoint of this trial, to demonstrate a significant improvement in RFS, was achieved after median follow-up of 3 years. The hazard ratio of 0.66 (95% CI 0.47–0.94; p=0.020) for RFS translates into a 34% reduction in the rate of recurrences or deaths in pts receiving XT→CEX. This significant benefit was seen using an X dose of 900 mg/m² bid, and with a lower T dose in the XT arm than with T monotherapy. Overall survival data are not yet mature but a trend towards improvement (hazard ratio 0.66 [95% CI 0.401.07]; p=0.089) can be seen in the XT→CEX arm. The results suggest that the risk of breast cancer recurrence can be reduced substantially with integration of capecitabine into a taxane-/anthracycline-based regimen. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 82.

Final results of a first line multicenter phase II metastatic breast cancer trial of vinflunine monotherapy and in combination with trastuzumab in HER2+ patients.

Abstract Abstract #3148 Background: Vinflunine (VFL) is a novel microtubule inhibitor agent of the vinca alkaloid class that inhibits tubulin polymerization without stabilization, resulting in cell cycle arrest in mitosis and apoptosis. Weak tubulin binding at the vinca-binding site accounts for its reduced neurotoxicity. VFL has demonstrated activity in anthracycline and taxane pretreated patients (pts) and in combination with capecitabine. This trial evaluates the activity and safety of VFL monotherapy and in combination with trastuzumab (T) in HER2+ pts as 1st line therapy metastatic breast cancer (MBC).
 Methods: Eligibility: 0 prior regimens for MBC, > 6 mo from adjuvant therapy, RECIST criteria measurable disease, ECOG PS 0-2, adequate organ function, peripheral neuropathy < G2. Treatment: HER2 unspecified: VFL 320 mg/m2 IV q3 wks; FISH HER2+ pts: VFL 280 mg/m2 plus T 6 mg/kg q3 wks. Response evaluations q9 wks; treatment continued until disease progression or toxicity.
 Results: Due to termination of VFL licensing between BMS and Pierre Fabre Medicament, the study closed prematurely with only 31 evaluable pts of a planned 48 pts in each treatment arm of VFL monotherapy or VFL in combination with T. 10 pts received VFL and 21 pts were treated with VFL + T. Median age: 59 yrs (35-78). ECOG PS 0-18 pts, 1-11 pts, 2-2 pts. 48% were ER+. Prior adjuvant anthracyclines and taxanes noted in 17 and 19 pts respectively. 4 pts presented with de novo stage IV disease, all HER2 positive. 45% had 3 or more metastatic disease sites with bone (17 pts), liver (16 pts) and lung (15 pts) predominating. Median of # cycles: 4 (range 1-19). There were 10 PRs (32%), all in VFL + T, and 9 pts (29%) with PD (VFL-4 pts, VFL + T-5pts). SD was reported in 10 pts (32%). 2 pts (7%) were unevaluable, divided equally between the two arms. G3/4 neutropenia occurred in 11 pts (35%); none with fever. G3 nonhematologic toxicity consisted of pain, attributed to treatment in 5 pts (16%) (sites: abdomen-2, chest, back, and infusion site each in 1 pt), and GI toxicity characterized by N/V 3 pts (10%) as well as abdominal pain, diarrhea, constipation, occurring each in 2 pts (6%). There were no G4 events. 10 pts were hospitalized (GI -4 pts, pain 2 pts, pulmonary 2 pts, and other 2 pts). Median PFS was 3.5 months for VFL and 6.6 months for VFL + T. Median overall survival was 9 months for VFL and has not been reached for VFL + T.
 Conclusions: The combination of vinflunine and trastuzumab is active in the first line treatment of MBC, producing a 48% response rate. Adverse events were as expected, manageable and consisted primarily of neutropenia, pain and GI toxicity. This encouraging activity compares favorably with other trastuzumab combination regimens and merits further evaluation. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3148.

Seizure associated with palonosetron

In 2003, FDA approved palonosetron as an effective drug for the control ofnausea and vomitingassociated tochemotherapy. Palonosetron is suggested in case of emetogenic chemotherapy schedules, in particular, in the case of cisplatin, high-dose cyclophosphamide, and anthracyclines. Palonosetron differs from the older 5-HT3 antagonists in its prolonged half-life (approximately 40 h) and its greater binding affinity for the 5-HT3 receptor. In three randomized prospective clinical trials, it compares favorably with the older 5-HT3 in terms of effectiveness and safety [1]. Most commonly reported adverse reactions include headache (9%) and constipation (5%). Less frequent side effects (<1%) involved cardiovascular system (tachycardia, sinus arrhythmia, supraventricular extrasystoles and QT prolongation), gastrointestinal system (diarrhea, dyspepsia, abdominal pain, dry mouth, hiccups, and flatulence), nervous system (dizziness, somnolence, insomnia, hypersomnia, paresthesia), and alterations of hearing and vision. We report the occurrence of generalized tonic clonic seizure after i.v. palonosetron in a breast cancer patient receiving anthracycline-based chemotherapy. To our best knowledge, this side effect has never been reported in literature for this drug. A 43-year-old women with early breast cancer and no prior history of seizure was planned for CEF chemotherapy (cyclophosphamide 600 mg/m 2 , 5-FU 600 mg/m 2 , and epirubicin 90 mg/m 2 q3 wks). The antiemetic treatment consisted of 8 mg dexamethasone and 0.25 mg of palonosetron administered i.v. bolus 30 min before chemotherapy. During the fourth cycle of chemotherapy, 1 h after the antiemetic therapy while the patient was on chemotherapy with 5-FU, she developed generalized tonic clonic seizure lasting for 8 min followed by a period of drowsiness. Upon physical examination, blood pressure was 120/ 75 mmHg with pulse of 102 per minute regular; electrocardiogram and compute tomography scan of the head were normal. Her biochemical and hematological parameters were essentially normal. The patient was treated with diazepam 10 mg i.v. and saline infusion. Detailed investigations (neurological examination, electroencephalogram, Holter monitoring) failed to reveal anything abnormal and the patient was discharged after 2 days in good clinical conditions. We suspected palonosetron to be implicated in the occurrence of seizure and the patient received the following two cycles of chemotherapy with metoclopramide (20 mg i.v. every 8 h for 2 days) and dexamethasone without any problems. After excluding other causes and since an older selective 5-HT3 antagonist (i.e., ondansentron) has been reportedly associated with seizure [2, 3], we suspect palonosetron to be the one responsible for the seizure. Open Access This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.

GM-CSF Secreting Leukemia Cell Vaccination after Allogeneic Reduced Intensity Hematopoietic Stem Cell Transplantation for Advanced Myeloid Malignancies

Studies have shown that leukemia specific donor immune responses can be elicited by cancer vaccination after allogeneic SCT. Given the likelihood of disease progression in patients with active leukemia at the time of transplant, potential anti-tumor vaccines must be administered early post-transplant if they are to exert a meaningful effect. Early vaccination after SCT could capitalize upon the rapid homeostatic lymphoid expansion associated with post conditioning lymphopenia. However, there is concern about the efficacy of vaccinations early after allogeneic transplant when patients remain on immune suppression to prevent GVHD. GVAX, a cancer vaccine composed of leukemia cells genetically modified to secrete GM-CSF, has demonstrated activity in MDS and AML. We completed a trial investigating the feasibility and safety of administering GVAX early after allogeneic HLA matched reduced intensity conditioning (RIC) SCT for patients with MDS-RAEB or active AML. Prior to SCT, autologous myeloblasts were harvested and transfected with an adenovirus vector bearing the GM-CSF gene to generate the GVAX vaccine. Conditioning consisted of fludarabine 30mg/m2/d IV × 4, and busulfan 0.8mg/kg IV q12H × 8 doses prior to allogeneic PBSC infusion. GVHD prophylaxis included tacrolimus and mini-methotrexate. Vaccination started between day +30 to +45 post SCT if there was adequate count recovery and no grade II–IV acute GVHD. GVAX was administered SC/ID weekly × 3 doses, then q2 wks × 3 doses. Taper of tacrolimus began after vaccine completion (» d+120). Twenty four patients (13 URD, 11 MRD) were transplanted: 16 AML, 6 MDS/RAEB, 2 CML myeloid blast crisis. Median age was 62 (range, 41–71 years). Median marrow blast content at transplant was 22% (range, 6–91%). GVAX was successfully generated for all patients. Of the 24 patients transplanted, 9 could not start vaccine due to rapid leukemia progression (4); acute GVHD requiring systemic steroids (3); sepsis (1) and IPS (1); Among the 15 patients who started vaccination per protocol, 10 completed all 6 vaccines. Mild injection site reaction with induration, erythema, and pruritus was the only common side effect. After vaccination, 3/15 patients developed grade II acute GVHD and 7/15 had cGVHD. Relapse free (RFS) and overall survival (OS) at 2 years for patients who started GVAX were 46% and 56%, respectively. This is superior to the 2-yr DFS and OS of 12% and 16% (p=0.02), respectively, in a matched cohort of 34 patients with the same disease receiving RIC SCT during the same time period. Among the patients who completed all 6 vaccines, 9/10 remain in complete remission (6 AML, 3 MDS-RAEB) with median follow-up of 22.5 months post SCT (range, 7–38 mos). Three patients with disease relapse/progression early post SCT entered CR after vaccination and taper of tacrolimus. Pathologic examination of vaccination and leukemia cell DTH sites revealed significant infiltration with inflammatory cells and eosinophils in all patients who responded. Concordant with prior studies showing that anti-cancer activity after GM-CSF secreting tumor cell vaccines is associated with NKG2D-target-cell interactions mediated by NK and NK-T cells, our immunologic studies revealed progressively decreasing levels of soluble NKG2D ligands in patients with sustained remission after GVAX. Our results demonstrate that GVAX vaccination early after RIC SCT elicits important biologic activity despite administration during full immune suppression with tacrolimus. Given that all of the patients had active disease at transplant and received a reduced intensity conditioning regimen, we would have expected few to enter complete and sustained remission. Our encouraging results suggest GVAX vaccination is safe and may have anticancer activity in patients with MDS/AML after allogeneic SCT.

HER2 guided neoadjuvant treatment of advanced breast cancer: Clinico-biological correlations

11559 Background: Tailoring neoadjuvant chemotherapy (NACT) ± trastuzumab (T) according to tumor/host features remains an open issue, with special reference to anthracycline omission in HER2+ cases. Methods: Patients (pts) with breast cancer (BC), NACT candidate, were eligible. HER2+ pts (n=12) received 24 wks of weekly T 4mg/kg loading dose d1 then 2mg/kg and Paclitaxel (P) 80 mg/m2 before surgery, followed by additional 12 wks of TP and T for 1 year. HER2- pts (n=21) received 8 cycles of epirubicin (E) and docetaxel (D) (90 and 75mg/m2 respectively, q3 wks) before surgery, followed by 3 CMF cycles. Hormone therapy was suggested in all hormone sensitive cases. The primary endpoint was pCR and its correlation with Topo2α expression and the extent of spontaneous T cell responses to HER2 and other BC-associated antigens. Results: The TP regimen gave a clinical response in all 8 evaluable pts (clinical complete remission (CR) in 3 pts, partial remission (PR) in 5). Radical mastectomy (RM and quadrantectomy (Q) were performed in 6 and 2 pts, respectively. Pathologic (p) response rate was 87% with 3 pCR. Nodal pCR occurred in 5/7 pts. The ED regimen gave a 79% clinical response rate in the 14 evaluable pts (CR in 7, PR in 4). RM and Q were performed in 8 and 6 pts, respectively. P response rate was 78.6% with 2 pCR. Nodal pCR occurred in 3/12 pts. Toxicity: onychopathy G3, alopecia G2, paresthesia G2 and mucositis G3 more frequent in the TP pts, neutropenia G3–4, febrile neutropenia, anemia G3 and alopecia G2 more frequent in ED. No cardiotoxicity was observed. Conclusions: This interim analysis suggests that the TP as NACT in HER2+ BC has a good efficacy and tolerability. Clinico-biological correlations are underway. No significant financial relationships to disclose.

Pegylated liposomal doxorubicin (PLD)-carboplatin (C) (C-D) vs paclitaxel-carboplatin (C-P) in relapsing sensitive ovarian cancer (OC): A 500-patient interim safety analysis of the CALYPSO GCIG Intergroup phase III study

5565 Background: The preliminary results from the phase III study of carboplatin - PLD (C-D) vs Paclitaxel-Carboplatin (C-P) in patients (pts) with OC in late relapse is presented. While the primary endpoint of the study is PFS, the specific toxicity observed from these 2 regimens is critically important. Methods: From 4/05 to 10/07, 974 pts were recruited. Pts were randomized to either (C-P) ([C] AUC 5 iv d1 + [P] 175 mg/m2 iv d1, q3 wks) or (C-D) ([C] + PLD [D] 30 mg/m2 iv d1 q4 wks) for at least 6 cycles. Results: The data from the first 500 pts (C-D, n=251; C-P, n=249) were analyzed (Table). Median number of cycles received was 6 (1- 14) in two arms. Haematological toxicity contributed to more cycle delays in the CD (21%) than in the CP (14%) arm. Neutropenia & infection rates were similar in both arms. G-CSF was administered more frequently to pts in C-D arm (21%) than in C-P arm (15%). Grade (G) > 2 non-haematological toxicity was more frequent in the C-P arm. There were 104 (76 related) severe adverse events (SAE) in the C-P arm vs. 81 (44 related) in the C-D arm. Conclusions: This planned interim safety analysis on the first 500 patients confirmed different toxicity profiles in the two arms, with less drug-related SAE and less early therapy termination in the C-D arm. TOXICITY % Pts in C-D arm % Pts in C-P arm Anaemia G3–4 13 7 Thrombocytopenia G3–4 18 4 Alopecia G>2 9 85 Neuropathy G>2 3 29 Allergic reactions G>2 6 19 Arthralgia /myalgia G>2 4 20 Hand-foot syndrome G>2 13 2 Mucositis G>2 15 7 Early treatment termination (toxicity related) 6 14 No significant financial relationships to disclose.

Induction of immune responses and clinical activity in a phase II trial of IDM-2101, a 10-epitope CTL vaccine, in metastatic NSCLC patients

8057 Background: IDM-2101 is a 10-peptide vaccine designed to induce multi-specific CTL responses against MHC class I epitopes of CEA, p53, HER-2/neu and MAGE 2/3. Seven epitopes are modified for enhanced MHC binding or heteroclitic T-cell activation and 2 epitopes are native wild-type (WT) sequences. Also included is the class II helper epitope PADRE. We report here immune responses and clinical activity from a Phase 2 trial of IDM-2101. Methods: 68 HLA-A2+ good performance patients (pts) with Stage IIIB/IV or recurrent NSCLC were enrolled. Patients were required to have a tumor volume <125 cm2. Pts received 6 induction doses (0.5 mg/epitope) q3 wks followed by maintenance treatments at 2–3 month intervals. 63 pts were treated with one or more doses. 72 HLA-A2 negative pts who were otherwise eligible were retrospectively selected as relevant controls. Endpoints included survival, clinical responses and induction of immune responses. CTL responses in peripheral blood MNC were measured, at predefined time points, after a 10 day in vitro stimulation with peptide followed by an IFNγ ELISPOT assay. Results: 30 of 33 available pts (91%) that were monitored for CTL showed positive responses to 1 or more epitopes and 21 of 33 pts (64%) responded to at least 3 epitopes. All 9 vaccine epitopes were immunogenic in at least 1 patient. CTL responses were detected in 3 of 4 pts tested at 12 months. T helper-cell responses against PADRE measured with a direct IFNγ ELISPOT assay were observed in 18 of the 33 pts (55%) tested. Toxicities attributable to vaccine were mild and consisted mostly of injection site reactions. Clinical responses included 1 CR, 1 PR and SD of ≥3 months in 54 of 63 pts (86%). 14 pts completed 2 years of dosing and remain without evidence of progression. Interim analysis of one-year survival in IDM-2101 treated pts was 60%, compared to 49% in the HLA-A2 negative group and median survival for treated pts was 17.3 months compared to 12.0 months for pts in the HLA-A2 negative group. A trend toward longer survival was observed in pts who responded to more epitopes. Conclusions: IDM-2101 was well- tolerated, induced broadly-specific CTL responses and may provide a survival benefit in metastatic NSCLC patients. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration IDM Pharma, Inc, Pharmexa-Epimmune

Feasibility and toxicity report from a phase II study of accelerated twice-daily (BDRT) versus high dose once-daily thoracic radiotherapy (ODRT) with concurrent chemotherapy for limited stage small cell lung cancer (LS-SCLC)

7583 Background: Early concurrent twice-daily (BD) chemo-radiotherapy (BDRT) is a standard of care for LS-SCLC (1) but logistical issues and high grade 3+ esophagitis rate of 32% have impeded widespread adoption. Toxicity of BDRT (45 Gy in 30 fractions BD) may be less with modern radiotherapy (RT) techniques. ODRT (66 Gy in 33 daily fractions) may also be less toxic with better local control. As an international randomized phase III trial of BDRT versus ODRT (CONVERT C17052/A8152) starts in Europe we report on phase II feasibility and toxicity data for these regimens. Methods: Patients (pts) with LS-SCLC, PS 0–1 and suitable for radical radiotherapy received cisplatin (P), 60 mg/m2 IV d1 with etoposide (E) 120 mg/m2 IV d1–3, q3 wks x 4 cycles with concurrent RT (3D conformal without elective nodal irradiation) from cycle 2. A pilot study of BDRT enrolled 6 pts and then a phase II trial randomized 21 pts to BDRT or ODRT. Common toxicity criteria 3.0 was used. Results: For 27 patients (ODRT n=11; BDRT n=16) the median age was 60 (28- 78) yrs, 63% were male and 74% were PS1. 26 pts completed all planned PE; 1 pt received carboplatin and etoposide from cycle 2. All patients received the full prescribed dose of RT. At a median follow up of 10.5 months, the median survival for all pts was 16.9 months (3.1, 30.6) and 1 year survival was 68%. The commonest grade 3 non-hematological toxicity was fatigue in 16% of patients; 13 pts (48%) experienced acute grade 2 esophagitis and only 1 pt (4%) had acute grade 3 esophagitis. One patient experienced acute grade 2 pneumonitis (4%). To date there are no grade 3 or 4 late radiation toxicities. The commonest grade 4 acute hematological toxicity was neutropenia (n=15, 55%) and 31% of patients required antibiotics. GCSF was prescribed as secondary prophylaxis to 38% of patients. No toxic deaths have occurred. Conclusions: Our preliminary findings are that these regimens are feasible and well tolerated with a lower than expected rate of acute grade 3+ esophagitis. The CONVERT trial will evaluate these regimens in 532 patients for the primary endpoint of survival. No significant financial relationships to disclose.