Months In Arm Research Articles

A phase II study of the anti-IGFR antibody MK-0646 in combination with cetuximab and irinotecan in the treatment of chemorefractory metastatic colorectal cancer

4127 Background: Evidence of cross-talk between EGFR and IGFR signaling pathways provide a logical rationale for combining anti-EGFR and anti-IGFR strategies in the treatment of cancer. Prior to commencing a blinded randomised phase II study, an opened-labelled safety run-in was undertaken to assess the tolerability of a three-drug combination utilizing irinotecan (Ir), cetuximab (Cx) and two schedules of MK-0646 (Mk). Methods: Eligible patients (pts) had previously failed both Ir and oxaliplatin and had progressed on or within 3 months of their last therapy. Pts were required to have measurable disease and tissue samples available for tumour KRAS testing. Pts were randomised to receive either Mk 10mg/kg weekly (Arm A) or Mk 15mg/kg loading followed by 7.5mg/kg every alternate week (Arm B). All randomised pts also received Cx 400mg/m2 loading followed by 250mg/m2 weekly and Ir according to the same dose and schedule as they had previously received. Patients continued on treatment until disease progression with radiological response assessments undertaken every 6 weeks. Results: 10 pts were recruited to Arm A and 8 to Arm B. Pt characteristics: median age 60.5 years, male 67%, PS 0/1 33%/67%. Median number of prior chemotherapy regimens 3. The median number of cycles of Mk received in Arm A and B is 25 and 8 respectively. Reported grade III/IV toxicities in Arm A and Arm B were: neutropenia 30% and 0%, diarrhoea 30% and 25%, hypomagnesemia 0% and 25%. Hyperglycemia (≥ grade 2) was seen in 10% of Arm A and 25% in Arm B. Acneiform skin toxicity (≥ grade 2) was seen in 30% of Arm A and 62% of Arm B. The radiological response rate was 33% in Arm A and 14% in Arm B. The median time on study drug is 5.8 months in Arm A and 3.9 months in Arm B. 2 pts on Arm A and 1 in Arm B remain on study therapy. Tumour KRAS testing is in progress. Conclusions: The combination of MK-0646, cetuximab and irinotecan is tolerable with no concerning overlapping toxicities highlighted. PFS and KRAS data will be available for presentation. The efficacy of this three drug combination is under evaluation in an ongoing randomised phase II/III study. [Table: see text]

Phase II randomized, open-label study of cetuximab (Cet) and bevacizumab (Bev) in combination with paclitaxel (P) and carboplatin (C) in patients with stageIII/IV non-small cell lung cancer (NSCLC)

8046^ Background: Cet, a monoclonal antibody (mAb) that specifically targets epidermal growth factor receptor (EGFR) and Bev (anti-VEGF mAb) combined with chemotherapy has resulted in superior survival compared to chemotherapy alone in some stage IV NSCLC trials. Combining both mAb's with chemotherapy might increase survival in stage IV NSCLC pts. Methods: Chemotherapy naïve advanced NSCLC patients with ECOG status <1, adequate hematologic, hepatic, and renal function received Cet (400 mg/m2 on Day 1 as initial dose and weekly thereafter at 250 mg/m2) plus Bev (15 mg/kg on Day 8 of each 3-week cycle) for 6 cycles in combination with either 6 cycles (Arm A) or 3 cycles (Arm B) of P (200 m/kg) and C (AUC=6) on Day 1 of each 3-week cycle. Patients without progressive disease (PD) after 6 cycles continued Cet until PD or other withdrawal criteria were met. Comparison of progression-free survival (PFS) for arm A vs B is the primary objective. Results: Accrual is completed. Data are available for 85 pts: 47% women, median age 65 yrs, and 88% Caucasian. Median PFS for arm A was 6.0 vs 4.2 months for arm B, hazard ratio of 0.57 for arm A relative to arm B. Objective response was Arm A=31% and B=30%. Most frequent AEs ≥Grade 3 in pts were neutropenia [9 (10.6%), A=8, B=1], fatigue [8 (9.4%), A=4, B=4], dermatitis acneiform [6 (7.1%), A=3, B=3].13 pts withdrew due to AEs (A=4, B=9), 4 were related to Cet (2 per arm). Two pts discontinued due to death (A=2, B=0) unrelated to Cet. Conclusions: Adding both mAb's to PC resulted in acceptable toxicity. The trend for superior PFS with 6 courses of PC suggests that 3 courses of PC are not optimal. [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 .

Prospective Randomized Multicenter Adjuvant Dermatologic Cooperative Oncology Group Trial of Low-Dose Interferon Alfa-2b With or Without a Modified High-Dose Interferon Alfa-2b Induction Phase in Patients With Lymph Node–Negative Melanoma

PURPOSE Interferon alfa (IFN-alpha) has shown clinical efficacy in the adjuvant treatment of patients with high-risk melanoma in several clinical trials, but optimal dosing and duration of treatment are still under discussion. It has been argued that in high-dose IFN-alpha (HDI), the intravenous (IV) induction phase might be critical for the clinical benefit of the regimen. PATIENTS AND METHODS In an attempt to investigate the potential role of a modified high-dose induction phase, lymph node-negative patients with resected primary malignant melanoma of more than 1.5-mm tumor thickness were included in this prospective randomized multicenter Dermatologic Cooperative Oncology Group trial. Six hundred seventy-four patients were randomly assigned to receive 4 weeks of a modified HDI scheme. This schedule consisted of 5 times weekly 10 MU/m(2) IFN-alpha-2b IV for 2 weeks and 5 times weekly 10 MU/m(2) IFN-alpha-2b administered subcutaneously (SC) for another 2 weeks followed by 23 months of low-dose IFN-alpha-2b (LDI) 3 MU SC three times a week (arm A). LDI 3 MU three times a week was given for 24 months in arm B. Results Of 650 assessable patients, there were 92 relapses among the 321 patients receiving high-dose induction as compared with 95 relapses among the 329 patients receiving LDI only. Five-year relapse-free survival rates were 68.0% (arm A) and 67.1% (arm B), respectively. Likewise, melanoma-related fatalities were similar between both groups, resulting in 5-year overall survival rates of 80.2% (arm A) and 82.9% (arm B). CONCLUSION The addition of a 4-week modified HDI induction phase to a 2-year low-dose adjuvant IFN-alpha-2b treatment schedule did not improve the clinical outcome.

Randomized Phase II and Pharmacogenetic Study of Pemetrexed Compared With Pemetrexed Plus Carboplatin in Pretreated Patients With Advanced Non–Small-Cell Lung Cancer

We performed a randomized phase II trial comparing pemetrexed with pemetrexed plus carboplatin (PC) in patients experiencing relapse after platinum-based chemotherapy. Main eligibility criteria were histologic or cytologic proof of advanced non-small-cell lung cancer (NSCLC), relapse more than 3 months after platinum-based chemotherapy, normal organ function, and Eastern Cooperative Oncology Group performance status 0 to 2. Patients were randomly assigned to pemetrexed 500 mg/m(2) (arm A) or carboplatin area under the curve 5 and pemetrexed 500 mg/m(2) (arm B), both administered intravenously every 3 weeks. Response assessment was performed every 6 weeks; toxicity assessment was performed every 3 weeks. Primary end point was time to progression (TTP); secondary end points were objective response rate (ORR), overall survival (OS), and toxicity. The study was designed to detect a 33% decrease in the hazard of disease progression in the combination arm (alpha = 0.05, two-sided log-rank test). Polymorphisms of thymidylate synthase, the reduced folate carrier, gamma-glutamyl hydrolase, and methylenetetrahydrofolate reductase (MTHF) were investigated in peripheral WBCs of consenting patients. Two hundred forty patients were enrolled. Median TTP was 2.8 months for arm A versus 4.2 months for arm B (hazard ratio, 0.67; 95% CI, 0.51 to 0.89; P = .005). Median OS was 7.6 months and 8.0 months and ORR was 4% and 9% for arms A and B, respectively. Subgroup analyses found adenocarcinoma to be associated with favorable outcome. Toxicities in both arms was negligible, with one potential toxic death in arm A. Patients with MTHFR C677T homozygous mutation had increased progression-free survival compared with patients with wild-type or heterozygous mutations (P = .03). PC as second-line treatment for relapsed NSCLC resulted in a significant 33% reduction of the hazard of disease progression as compared with pemetrexed alone.

Randomised multicenter phase II study of two schedules of docetaxel and gemcitabine or cisplatin/gemcitabine followed by docetaxel as first line treatment for advanced non-small cell lung cancer

Background In the attempt to optimize the efficacy of chemotherapy in advanced non-small cell lung cancer (NSCLC) several strategies need to be investigated including the use of non-platinum combinations and the sequential use of different agents. Patients and methods In a phase II randomised study 165 patients with stage IIIB or IV NSCLC were assigned to receive docetaxel 40 mg/m 2 days 1 and 8 plus gemcitabine 1200 mg/m 2 days 1 and 8 every 21 days (arm A, N = 54) or docetaxel 50 mg/m 2 days 1 and 15 plus gemcitabine 1600 mg/m 2 days 1 and 15 every 28 days (arm B, N = 57) or gemcitabine 1200 mg/m 2 days 1 and 8 plus cisplatin 100 mg/m 2 day 2 every 21 days for 3 cycles followed by docetaxel 75 mg/m 2 day 1 every 21 days for 3 cycles (arm C, N = 54). The primary endpoint of the trial was overall response rate. Secondary end points included safety, progression-free and overall survival. Results Response rate was 22.2%, 23.2% and 33.3% after 3 cycles, whereas at the end of treatment was 24.1%, 12.5% and 27.8% in arm A–C, respectively. Median time to progression was similar in all the 3 arms: 6.7 months in arm A (95% CI: 4.8–9.7), 5.6 in arm B (5.0–7.9) and 6.6 in arm C (5.7–9.1). The median survival time was 10.7 months in arm A (95% CI: 6.8–15.6), 8.9 in arm B (7.4–12.5) and 14.6 in arm C (8.0–22.4) and 1-year survival rate was 46.3%, 37.9% and 53.9%, respectively. Grade 3–4 haematological toxicities were more frequent in arm C while non-haematological were more common in the gemcitabine and docetaxel arms. Conclusions The results of this phase II randomised clinical trial do not indicate a clear superior efficacy of one of the tested combinations according to the planned statistical design and none of these regimens is sufficiently active or less toxic to warrant further investigation in a phase III study.

Randomized multicenter phase II trial of navcap (vinorelbine and capecitabine) versus navcap followed by weekly docetaxel as first line treatment in HER-2/neu negative metastatic breast cancer patients: updated results.

Abstract Abstract #6116 Background: Capecitabine (C), vinorelbine (V) and docetaxel (D) are effective in the 1st line treatment of metastatic breast cancer (MBC). Based on the efficacy and the tolerability of Navcap (M. Ghosn et al. Antican Res 2006) and Navcap followed by docetaxel in MBC (M. Ghosn et al. Can Chemother Pharmacol 2008), we initiated a randomized phase II study. Primary Objective: To compare the objective response rate (ORR) of 8 cycles of Navcap vs. 4 cycles of Navcap followed by 12 weekly Docetaxel in the 1st line setting of MBC. Methods: Patients (pts) with measurable disease, no prior chemotherapy in MBC and Her-2/neu negative are eligible. All pts will receive Navcap (V 25 mg/m2 on d1 & d8 as IV push and C 825 mg/m2 bid D1-14 q3w) for 4 cycles. Pts progressing under treatment with Navcap are withdrawn and receive Docetaxel as 2nd line treatment. Pts responding or stable after completing 4 cycles of Navcap are randomized to: Arm A (4 Navcap) or Arm B (12 weekly Docetaxel 25 mg/m²/week). Results: From July 2004 to June 2008, a total of 110 pts were enrolled. At the time of this analysis 78 pts had completed the first 4 cycles of Navcap with an ORR of 55% (CR 13%) and a stable disease of 19%. 20 pts (26%) were excluded from randomization due to PD. 58 pts were randomized: Arm A: 30 pts and Arm B: 28 pts. Patient characteristics are summarized in table 1. All pts were evaluable for response with objective response rates of 70% & 78% in Arms A and B respectively. The median TTP & overall survival are 10 & 34 months in Arm A; 11 & 34 months in Arm B. Statistical comparison for efficacy & survival outcomes will be done once all pts are randomized & long term follow-up is available. All pts were evaluable for toxicity. The majority of adverse events were mild. Arm A: Gr 4 neutropenia (3%), Gr 3 anemia (6%). Arm B: Gr 3-4 anemia (9.6%), Gr 3 leukopenia (4.8%) & Gr 2 alopecia (14.3%). Conclusions: These preliminary results show that Navcap confirms its high response rate in 1st line treatment for HER-2/neu negative MBC. By the date of the meeting all pts will be randomized and will have completed their treatment. Mature data will be presented accordingly. (Protocol initiated & coordinated by the Cancer Research Group/Collaborative Group, Beirut–Lebanon).
 
 Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6116.

Phase II study of pegylated liposomal doxorubicin (PLD) and carboplatin (Cb) can be administered with trastuzumab (H) in patients with metastatic breast cancer.

Abstract Abstract #6118 Background: PLD and Cb are active in metastatic breast cancer (MBC) but no data exist regarding the antitumor activity of the combination. Both agents are synergistic with H in preclinical studies. The primary objective of this study was to determine the objective response rates (ORR) produced by PLD+Cb ± H.
 Patients and Methods: 133 patients (pts) were registered to the study; 125 pts were treated and were stratified by HER2 status; 124 pts are currently evaluable for response. Pts had measurable disease per RECIST criteria and had received no more than 1 prior chemotherapy regimen for MBC; HER2+ pts received therapy first-line therapy for metastatic and 4% received prior adjuvant H. All pts received PLD 30 mg/m2 IV followed by Cb, AUC=5 IV on Day 1 of 28-day cycles. In addition to PLD+Cb, HER2+ pts received H on Day 1 and Day 15 (8 mg/kg IV first dose; 4 mg/kg IV subsequent doses).
 Results: 79 pts and 46 pts received at least 1 dose of study drug on PLD+Cb (Arm 1) and PLD+Cb+H (Arm 2), respectively. Median age was 56 years. Estrogen receptor (ER) or progesterone receptor (PR) + pts and ER and PR- pts in Arm 1/Arm 2 were 63%/55% and 36%/45%, respectively, 49%/43%; pts were treated with prior doxorubicin in Arm 1/Arm 2 and 51%/30%. With prior taxane in Arm 1/Arm 2, of 79 pts on Arm 1 evaluable for response, 27% had an objective response compared with 53% of the 45 pts currently evaluable on Arm 2. Median overall survival was 17 months in Arm 1 and as not been reached in Arm 2. Median PFS is 5 and 10 months for Arm 1 and 2, respectively. The most common Grade 3-4 treatment-related toxicities for Arm 1/Arm 2 were: neutropenia 23%/35%, leukopenia 13%/22%, thrombocytopenia 20%/17%, fatigue 6%/13%, and anemia 11%/9%.
 Conclusion: PLD+Cb in combination have moderate activity in MBC; also, the addition of H to PLD+Cb in HER2+ pts enhanced its activity. Preliminary toxicity results suggest that PLD can be safely combined with H with minimal cardiac toxicity. Final data analyses from this fully enrolled study will be reported at SABCS 2008.
 This research was supported, in part, by a research grant from Ortho Biotech Clinical Affairs, LLC, Bridgewater, NJ. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6118.

How to improve loco-regional control in stages IIIa–b NSCLC?: Results of a three-armed randomized trial from the Swedish Lung Cancer Study Group

Background A combination of chemotherapy and radiotherapy is the treatment base for locally advanced non-small cell lung cancer (NSCLC). However, both loco-regional and distant failure is frequent. Attempts to improve the loco-regional control were made in three separate phase II studies in Swedish University Hospitals, where accelerated radiotherapy or concurrent daily or weekly chemotherapy with conventional radiotherapy were tested. Comparatively good results from these studies lead to this national randomized phase II study, the RAKET-study, where the different concepts were investigated on a wider basis for further phase III studies. Methods Inoperable stage III non-small cell lung cancer patients in good performance status (PS < 2) were equally randomized to either of three arms in eight institutions. All arms started with two cycles of induction chemotherapy: paclitaxel 200 mg/m 2 and carboplatin AUC6. Arm A: a third identical cycle was given concomitant with start of accelerated radiotherapy, 1.7 Gy BID to 64.6 Gy in 4.5 weeks. Arm B consisted of daily concomitant paclitaxel 12 mg/m 2 with conventionally fractionated radiotherapy: 2 Gy to 60 Gy in 6 weeks. Arm C: weekly concomitant paclitaxel 60 mg/m 2 and identical radiotherapy to 60 Gy. Primary endpoint: TTP. Secondary: OS, toxicity, QL and relapse pattern. Results Between June 2002 and May 2005 152 patients were randomized and of them 151 were evaluable: 78 men and 73 women, median age 62 years (43–78), 55% had performance status 0 and 45% PS 1. Thirty-four percent had stage IIIa and 66% IIIb. Histology: adenocarcinoma 48%, squamous cell carcinoma 32% and 20% non-small cell carcinoma. The three arms were well balanced. Toxicity was manageable with 12% grades 3–4 esophagitis, 1% grades 3–4 pneumonitis and there was no clear difference between the arms. The QL data did not differ either. Median time to progression was 9.8 (8.3–12.7) months (8.8, 10.3 and 9.3 months for arms A, B and C, respectively). Median survival was 17.8 (14.4–23.7) months (17.7, 17.7 and 20.6 months for A, B and C, respectively). The 1-, 3- and 5-year overall survival was 63, 31 and 24%. Sixty-nine percent of the patients relapsed with distant metastases initially and 31% had loco-regional tumor progression, without significant differences between treatment arms. Thirty-four percent developed brain metastases. Conclusions Treatment results are quite equal by intensifying the loco-regional treatment either by accelerated fractionated radiotherapy or daily or weekly concomitant chemo-radiotherapy both in terms of survival, toxicity and quality of life. The optimal treatment schedule for patients with locally advanced NSCLC is still to be decided and investigated in future clinical studies. Relapse pattern with distant metastases and especially brain metastases is a great problem and need further research for better therapy options and higher cure rate for this patient group.

Final Analysis of HOVON-50 Randomized Phase III Study on the Effect of Thalidomide Combined with Adriamycine, Dexamethasone (AD) and High Dose Melphalan (HDM) in Patients with Multiple Myeloma (MM)

The randomised, open-label, phase III trial HOVON-50 was designed to evaluate whether the addition of Thalidomide to AD and HDM would prolong event-free survival (EFS) in patients with newly diagnosed MM. Patients with Salmon & Durie stage II or III, age 18–65 years inclusive were randomly assigned to arm A: 3 cycles of VAD or to arm B, the same regimen but with Thalidomide 200 orally, days 1–28 instead of Vincristine (TAD). Thalidomide was started at day 1 of the first TAD cycle and was stopped 2 weeks before stem cell mobilization was started. Patients in arm B received thrombosis prophylaxis consisting of subcutaneously Low Molecular Weight Heparin (LMWH). Stem cells were mobilized using the CAD regimen, including cyclophosphamide 1000 mg/m2 iv day 1, and G-CSF. After induction therapy all patients were to receive 1 or 2 courses of high dose Melphalan (HDM) 200 mg/m2 with autologous stem cell rescue followed by maintenance therapy with ƒÑ-Interferon (3 „e 106 IU, thrice weekly, arm A) or Thalidomide 50 mg daily (arm B). Between November 27, 2001 and May 31, 2005, 556 patients were randomised of which 18 patients were not eligible, while from 2 patients data were incomplete. EFS was defined as time from randomisation to induction failure, progression, or death from any cause. Patients (n=109) who received a non-myeloablative allogeneic transplant after HDM 1 before progression, were censored at the date of allo-SCT; those patients were usually entered into the HOVON-54 trial. Both arms were comparable with regard to age, myeloma stage and prognostic factors. Best responses achieved on protocol were significantly higher in the patients randomized to thalidomide: Minimal PR rates were 87% and 79 % (p<0.01), VGPR 65 % and 54% (p<0.01), CR% 30% and 21 % (p=0.03), respectively. Thalidomide also significantly improved EFS from median 22 months to 33 months (p<0.001) and PFS from median 25 to 33 months (p<0.001). Overall survival however in both arms was comparable, 62 months in arm A and 59 months in arm B (P=0.96). LDH>ULN at diagnosis and higher ISS were identified as adverse prognostic factors for response and survival endpoints. Abnormalities of chromosome 13 as determined by FISH or conventional karyotyping had no prognostic impact. 96 patients (18%) went off protocol treatment without receiving HDM, mainly due to excessive toxicity (5 %), intercurrent death (4%) or ineligibility for further treatment (3%) comparable in both arms. IFN maintenance in 34% of patients of which 23 % stopped due to toxicity. Thalidomide maintenance started in 57% of patients in arm B of which 63% stopped due to toxicity Thalidomide resulted in significantly higher response rates and improved EFS and PFS. However, this did not translate into better overall survival

Adding cetuximab to capecitabine plus oxaliplatin (XELOX) in first-line treatment of metastatic colorectal cancer: a randomized phase II trial of the Swiss Group for Clinical Cancer Research SAKK

BackgroundTo determine the activity and tolerability of adding cetuximab to the oxaliplatin and capecitabine (XELOX) combination in first-line treatment of metastatic colorectal cancer (MCC). Patients and methodsIn a multicenter two-arm phase II trial, patients were randomized to receive oxaliplatin 130 mg/m2 on day 1 and capecitabine 1000 mg/m2 twice daily on days 1–14 every 3 weeks alone or in combination with standard dose cetuximab. Treatment was limited to a maximum of six cycles. ResultsSeventy-four patients with good performance status entered the trial. Objective partial response rates after external review and radiological confirmation were 14% and 41% in the XELOX and in the XELOX + Cetuximab arm, respectively. Stable disease has been observed in 62% and 35% of the patients, with 76% disease control in both arms. Cetuximab led to skin rash in 65% of the patients. The median overall survival was 16.5 months for arm A and 20.5 months for arm B. The median time to progression was 5.8 months for arm A and 7.2 months for arm B. ConclusionDifferences in response rates between the treatment arms indicate that cetuximab may improve outcome with XELOX. The correct place of the cetuximab, oxaliplatin and fluoropyrimidine combinations in first-line treatment of MCC has to be assessed in phase III trials.

A Phase II Study of Tg4010 (Mva-Muc1-Il2) in Association with Chemotherapy in Patients with Stage III/IV Non-small Cell Lung Cancer

TG4010 is a recombinant viral vector expressing both the tumor-associated antigen MUC1 and Interleukine-2. This vector is based on the modified virus of Ankara, a significantly attenuated strain of vaccinia virus. TG4010 has been designed to induce or amplify a cellular immune response directed against tumor cells expressing MUC1. A multicenter, randomized phase II study has explored two schedules of the combination of TG4010 with first line chemotherapy in patients with stage IIIB/IV non-small cell lung cancer. In Arm 1, TG4010 was combined upfront with cisplatin (100 mg/m day 1) and vinorelbine (25 mg/m day 1 and day 8). In Arm 2, patients were treated with TG4010 monotherapy until disease progression, followed by TG4010 plus the same chemotherapy as in Arm1. Response rate was evaluated according to RECIST. Median time to progression and median overall survival were calculated according to the Kaplan-Meier method. Sixty-five patients were enrolled, 44 in Arm 1 and 21 in Arm 2, in accordance with the two stage Simon design of the statistical plan. In Arm 1, partial response was observed in 13 patients out of 37 evaluable patients (29.5% of the intent to treat population, 35.1% of the evaluable patients). In Arm 2, two patients experienced stable disease for more than 6 months with TG4010 alone (up to 211 days), in the subsequent combination with chemotherapy, one complete and one partial response were observed out of 14 evaluable patients. Arm 2 did not meet the criteria for moving forward to second stage. The median time to progression was 4.8 months for Arm 1. The median overall survival was 12.7 months for Arm 1 and 14.9 for Arm 2. One year survival rate was 53% for Arm 1 and 60% for Arm 2. TG4010 was well tolerated, mild to moderate injection site reactions, flu-like symptoms, and fatigue being the most frequent adverse reactions. A MUC1-specific cellular immune response was observed in lymphocyte samples from all responding patients evaluable for immunology. The combination of TG4010 with standard chemotherapy in advanced non-small cell lung cancer is feasible and shows encouraging results. A randomized study evaluating the addition of TG4010 to first line chemotherapy in this population is in progress.

A randomised phase II study of gemcitabine versus mitomycin C versus gemcitabine/mitomycin C in patients with advanced pancreatic cancer

15658 Background: The prognosis of patients with advanced pancreatic cancer remains poor. However, chemotherapy can improve life quality and median survival. We have shown that the combination of gemcitabine and mitomycine has a tolerable toxicity profile. It can be easily administred in an outpatients setting. Based on our previous results a multicenter randomised phase II study was initiated. Primary aim was to demonstrate a longer progression free survival time for patients, who were treated with the combination of Gemcitabine (GEM)/Mitomycin C (MMC) compared to those receiving monotherapy with either agent. Secondary aims were response rates, toxicity and influence on life quality. Methods: Recruitment started in 02/04. Meanwhile 69 patients (of planned 138 in total) were enclosed. Patients older than 18 years with stage III or IV pancreatic adecarcinoma were randomised into ARM A (24 patients; GEM 800mg/m2, d 1,8,15 + MMC 6mg/m2, d1; q29), into ARM B (23 patients; MMC 10mg/m2 d1, q29) or ARM C (22 patients; GEM 1000mg/m2 d 1,8,15). Altogether 6 cycles were scheduled in all treatment arms. Results: Mean age was 64 years. 10% of the patients had locally advanced and 90% metastatic tumors. A medium of 3 cycles were given in ARM A, and a medium of 2 cycles in both ARMs B and C. Medium time to progression was 3 months in ARM A, 1.7 months in ARM B and 1.8 months in ARM C. Medium overall survival times were 7 months in ARM A, 3,1 months in ARM B and 2.8 months in ARM C. Hemotological toxicity was moderate with no grade 4 toxicity. Grade 3 thrombopenia (15%) did not result in bleeding complications and there was no case of neutropenic fever or sepsis in patients with grad 3 leukopenia (7%). There were no cases of HUS. Pneumonitis 1° and 2° occurred in 2 patients (Arm A). 5 patients are alive (ARMs A+C: 3 patients, ARM B; 1 patient) with a medium follow up of 4 months. Conclusions: Due to the limited number of patients no definite conclusions can be drawn. However the interim analysis shows that the combination of GEM/MMC is a safe and beneficial treatment modality in patients with advanced pancreatic cancer. Additionally the monotherapies of MMC vs. GEM are not significantly different. A statistical analysis and an update will be presented at the meeting. No significant financial relationships to disclose.

Accelerated hyperfractionated radiotherapy weekend less (CHARTWEL) in combination with cisplatin and vinorelbine versus conventional radiotherapy combined with the same drugs in the treatment of locally advanced (stage IIIA and IIIB) NSCLC

7551 Background: The aim of this prospective randomized study was to evaluate the effect of accelerated hyperfractionated radiotherapy weekend less (CHARTWEL) when combined with chemotherapy (cisplatin and vinorelbine) versus conventional radiotherapy combined with the same drugs in the treatment of locally advanced (stage IIIA and IIIB) NSCLC. Methods: Forty eligible patients were randomized to be treated in two arms (arm A and arm B) during the period from April 2003 to April 2005. Arm A included 20 eligible patients who received conventional radiotherapy 6,120 cGy to the primary tumor and mediastinal lymph nodes,180 cGy/ fraction once per day, 5 days per week in 5.5 weeks combined with cisplatin 60 mg/m2 D1 and vinorelbine 16 mg/m2 D1 and D8 to be repeated every 21 days during the course of irradiation. Arm B included 20 eligible patients who received CHARTWEL protocol 5400 cGy to the primary and mediastinal lymph nodes, 150 cGy / fraction 3 times/ day over 16 days combined with the same drugs and same doses given in Arm A. Patients who responded or even showed stable disease completed on chemotherapy to a total of six cycles but with cisplatin 80 mg/m2 D1 and vinorelbine 25 mg/m2 D1 and D8 every 3 weeks. Results: One patient (5%) in each Arm reached CR, 70% of patients in Arm A had PR while 25% of patients in Arm B had PR (P=0.011), 20% had S.D in Arm A and 5% had S.D in Arm B (P=0.399). Thirty percent of patients in Arm A experienced GI-II neutropenia while 40% in Arm B. Grade III to IV esophigitis was experienced by all patients in Arm B and resolved in only 40% of patients and was the cause of death in the remaining 60% of patients. The 1 and 2 year survival rates for arm A were 60% and 25% respectively while for Arm B were 25% and 15% respectively. Median PFS was 10 months in Arm A and one month in Arm B (P=0.0001). Median OAS was 5 months in Arm A and 3 months in Arm B (P=0.002). Conclusions: Combination of cisplatin and vinorelbine conventional radiotherapy is well tolerated by patients with locally advanced NSCLC with PS 0 to 1 and gives satisfactory results, while the combination of CHARTWEL with chemotherapy is very toxic to the patients. No significant financial relationships to disclose.

Randomized phase II trial of first-line gefitinib, gemcitabine or docetaxel in performance status (PS) 2 or 3 non-small-cell lung cancer (NSCLC) patients (IFCT-0301)

8086 Background: PS 2 or 3 patients are usually excluded from clinical trials. Optimal treatment in this setting remains a challenge. The aim of this study was to evaluate 3 monotherapy modalities. Methods: PS 2 or 3 patients with confirmed stage IIIB or IV NSCLC were enrolled into a multicenter randomized phase II trial: arm A, gefitinib (250 mg/day, every 3 weeks), arm B gemcitabine (1250 mg/m², day 1 and 8, every 3 weeks) and arm C docetaxel (75 mg/m², day 1, every 3 weeks). Treatments were maintained until progression or unacceptable toxicity. Second-line treatment consisted of: arm A, docetaxel (75 mg/m², day 1, every 3 weeks) and arm B and C, gefitinib (250 mg/day). The primary endpoint was Progression-Free Survival (PFS). Results: Between December 2004 and June 2007, 128 patients were enrolled. The characteristics of the 127 eligible patients (43 in arm A, 42 in arm B and 42 in arm C) were balanced: median age 71 years (range 30–80), male 83 %, PS=2 69%, PS=3 31%, adenocarcinoma 49%, squamous cell 28%, stage IV 82%, stage IIIB 18%, 72 % of patients had at least a 5% weight loss. The median number of cycles administered was 2 in arm A, 2 in arm B and 3 in arm C. 46 patients received a second-line treatment (12 in arm A, 13 in arm B and 21 in arm C). PR and stable disease rates were 20.9 % in arm A, 33.4% in arm B and 38.1% in arm C. Median PFS was 1.9 months in arm A, 2.1 in arm B and 2 in arm C. Median overall survival was 2.2 months in arm A, 2.4 in arm B and 3.5 in arm C. In PS 2 patients, median overall survival was 3.4 months in arm A, 3.2 in arm B and 6.6 in arm C. The number of fatal events related to treatment was: 3 in patients treated with docetaxel (febrile neutropenia) and 1 patient treated with gefitinib (bowel obstruction). Grade 4 toxicity occurred in 4% of patients in arm A, 14% in arm B and 11% in arm C. Conclusions: Docetaxel, gemcitabine or gefitinib were well tolerated and showed comparable PFS in this poor prognosis population. There was a trend in favour of first line docetaxel regarding overall survival in the entire population and in the subgroup of PS 2 patients. Survival results will be updated for the conference. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Lilly, sanofi-aventis Lilly

Randomized phase II study of concurrent and sequential combinations of rituximab (R) plus CHOP (R-CHOP) in untreated indolent B-NHL: 7-year follow-up results

8616 Background: R-CHOP is regarded as one of the most effective initial treatments for indolent B-cell Non-Hodgkin lymphoma (B-NHL); however, the information on its long term outcome is limited. Methods: Sixty-nine patients (pts) with untreated indolent B-NHL of advanced stages were randomized in the concurrent or sequential combinations of R-CHOP. Pts in the concurrent arm (Arm C) received 6 times of R (375 mg/m2), 2 days prior to each cycle of CHOP, and pts in the sequential arm (Arm S) received weekly 6 times of R (375 mg/m2) following 6 cycles of CHOP. No maintenance therapy was given in both arms. The last pt was enrolled in July, 2000, and the planned observation was completed in May, 2007. Results: A total of 69 pts were randomized but 2 were withdrawn before receiving treatment because of neutropenia or concomitant cancer. Sixty-five pts (94%) had follicular lymphoma, and 31 pts were in low, 27 in intermediate and 11 in high risk group according to the Follicular Lymphoma International Prognostic Index, respectively. We previously reported that overall response rate (ORR) in Arm C was 94%, including a 66% complete response (CR) compared with 97%, including a 68% CR in Arm S, and the time to achieving response was shorter in Arm C than Arm S (p=0.322) (Cancer Sci 2006;97;305). The median progression-free survival (PFS) of the 67 pts was 49 months; 36 months in Arm C (n=34) and 62 months in Arm S (n=33) (p= 0.417). And at 7years the estimated probability of PFS of the 67 pts was 33% (95% CI; 22–44%); 28% in Arm C and 39% in Arm S. Three pts (Arm C, 1; Arm S, 2) died. Six pts (18%) in Arm C and 11 (33%) in Arm S were progression-free at 7 years. Overall survival (OS) of the 67 pts was 96%. During the follow-up periods, clinically significant adverse event was not observed. Conclusions: R-CHOP is a highly effective initial treatment for untreated indolent B-NHL in terms of ORR and OS. However, its long-term PFS is not good enough either in a concurrent or sequential combination, warranting further investigations on post-remission therapy after R-CHOP. No significant financial relationships to disclose.

CAPIRI (capecitabine, irinotecan) + bevacizumab vs FOLFIRI (folinic acid, 5 fluorouracil, irinotecan) + bevacizumab for the treatment of patients with metastatic colorectal cancer (mCRC): Interim analysis for safety of a randomized phase III trial

15008 Background: CAPIRI has been reported to be associated with significant toxicity. Therefore, an unplanned interim analysis for safety of a randomized trial evaluating CAPIRI + Bevacizumab vs FOLFIRI + Bevacizumab regimens for the treatment of mCRC was performed. Methods: Assuming time to tumor progression (TTP) of 7.5 months for Arm B and 5.5 months for Arm B, 280 patients should be enrolled in the study (two-tailed log-rank test; a=0.05, b=0.8).Patients were randomized to receive either (Arm A) CPT-11 (250 mg/m2, d1) and Capecitabine (2,000 mg/m2, d1–14) every 3 weeks (Arm A) or CPT-11 (180 mg/m2, d1), LV (200 mg/m2, d1+2) and 5-FU (400 mg/m2/d bolus and 600 mg/m2/d, 22h infusion, d1+2) every 2 weeks (Arm B). Results: Among the 156 enrolled patients (Arm A = 74; Arm B = 82), were evaluable for toxicity (administered cycles: 1061). Treatment delays were observed in 4% and 2% Arm A and B patients, respectively (p=0.09). Dose reduction was required in 9.5% and 4.5% Arm A and B patients, respectively (p=0.002). Treatment discontinuation due to treatment related toxicity occurred in 13% and 4.5% Arm A and B patients, respectively. Sixty days mortality rate was low in both arms (Arm A: 1.5%, Arm B: 1.2%). There was no difference between the two regimens in terms of objective response rate, TTP and OS (n = 142 patients). Conclusions: These preliminary results show that CAPIRI + Bevacizumab regimen could safely administered in patients with mCRC. No significant financial relationships to disclose.

LV5FU2-cisplatin followed by gemcitabine or the reverse sequence in metastatic pancreatic cancer: Preliminary results of a randomized phase III trial (FFCD 0301)

4513 Background: Pts with metastatic pancreatic adenocarcinoma (MPA) have a poor prognosis with no major survival improvement since the introduction of gemcitabine (Burris 1997). The LV5FU2-P regimen was reported as safe and active with a 9 months median overall survival (OS) in a phase II trial (Taïeb 2002). This randomized multicenter phase III trial compared LV5FU2-P followed by gemcitabine in arm A versus gemcitabine followed by LV5FU2-P in arm B to evaluate the best sequence. Methods: Pts with measurable MPA, PS 0–2, non prior CT, were randomly assigned to receive either LV5FU2-P (2-hour infusion of LV 200 mg/m2 followed by a FU bolus 400 mg/m2 and 46-hour infusion 2,400 mg/m2 every 2 weeks, with cisplatin 50 mg/m2 as a 2-hour infusion on D1 or 2, followed by gemcitabine (1,000 mg/m2 for 7 weeks out of 8 and then 3 weeks out of 4) at progression or toxicity (arm A) or the opposite sequence (arm B). Randomization was done using minimization with stratification according to center, PS tumoral localization and infusion duration. Primary endpoint was OS. It was required to include 202 pts and observe 170 deaths to detect an expected improvement in median OS from 6.5 to 10 months in arm A (bilateral α = 5% and β = 20%). Secondary endpoints included progression free-survival (PFS) after first and second line, toxicity, quality of life (QLQ-C30) and percentage of second line in each arm. Results: From 08/2003 to 05/2006, 202 pts were included in 33 centers, 102 in arm A and 100 in arm B. Median age (62 [40 - 84] vs 64 [39 - 81] years), male/female ratio (1.7 vs 1.7), PS 0–1 (76.5% vs 83%), previous surgery (22.5% vs 27%). After a median follow-up of 33,6 months [min 17; max 48], 185 pts had died. Median OS for arm A was 6.6 months [95% CI- 5.2 to 8.4] versus 8.2 months [95% CI- 6.1 to 9.7] for arm B (HR B vs A 0.95 [95% CI 0.71 - 1.27], Log Rank p = 0.72). 1- year and 2-year survival rates were 29.5% and 8% for arm A versus 34.5% and 3.5% for arm B, respectively. Conclusions: This trial failed to reach its primary endpoint and both sequences achieved a similar efficacy with no significant differences between the two arms in median OS. Updated results (including response, PFS and toxicity analyses) will be presented at the meeting. No significant financial relationships to disclose.

Individual Fluorouracil Dose Adjustment Based on Pharmacokinetic Follow-Up Compared With Conventional Dosage: Results of a Multicenter Randomized Trial of Patients With Metastatic Colorectal Cancer

A phase III, multicenter, randomized study compared conventional dosing of fluorouracil (FU) plus folinic acid with pharmacokinetically guided FU dose adjustment in terms of response, tolerability, and survival. Two hundred eight patients with measurable metastatic colorectal cancer were randomly assigned to one of two arms: arm A (104 patients; 96 assessable), in which the FU dose was calculated based on body-surface area; and arm B (104 patients; 90 assessable), in which the FU dose was individually determined using pharmacokinetically guided adjustments. The initial regimen was 1,500 mg/m(2) FU plus 200 mg/m(2) folinic acid infusion during a continuous 8-hour period administered once weekly. FU doses were adjusted weekly in arm B based on a single-point measurement of FU plasma concentrations at steady state until the therapeutic range (targeted area under the curve 20-25 mg x h x L(-1)) previously established in other studies was reached. An intent-to-treat analysis of the 208 patients showed the objective response rate was 18.3% in arm A and 33.7% in arm B (P = .004). Median overall survival was 16 months in arm A and 22 months in arm B (P = .08). The mean FU dose throughout treatment was 1,500 mg/m(2)/wk in arm A and 1,790 +/- 386 mg/m(2)/wk (range, 900 to 3,300 mg/m(2)/wk) in arm B. Toxic adverse effects were significantly more frequent and severe in arm A compared with arm B (P = .003). Individual FU dose adjustment based on pharmacokinetic monitoring resulted in significantly improved objective response rate, a trend to higher survival rate, and fewer grade 3/4 toxicities. These results support the value of pharmacokinetically guided management of FU dose in the treatment of metastatic colorectal patients.

Febrile neutropenia, related hospitalizations and chemotherapy delivery in breast cancer patients younger than 65 years receiving pegfilgrastim primary prophylaxis vs current practice neutropenia management

Alternating induction and maintenance phases is a common strategy in metastatic colorectal cancer (mCRC). Metronomic chemotherapy (metroCT) may represent a well-tolerated chemotherapy backbone for maximising bevacizumab effect during maintenance. The MOMA trial was designed to compare metroCT plus bevacizumab versus bevacizumab alone as maintenance following 4 months of induction with FOLFOXIRI plus bevacizumab.In this phase II study, patients with unresectable mCRC were randomised to receive up to 8 cycles of FOLFOXIRI plus bevacizumab, followed by bevacizumab (arm A) or the same regimen followed by bevacizumab plus metroCT (capecitabine 500 mg/three times per day and cyclophosphamide 50 mg/die, arm B) until disease progression. The primary end-point was progression-free survival (PFS). According to the Rubinstein and Korn's design, to detect a hazard ratio[HR] of 0.75 favouring arm B, with 1 sided-alpha and beta errors of 15% and 80%, 173 events and 222 patients were required.Between May 2012 and March 2015, 232 patients, mostly with RAS (65%) or BRAF (9%) mutant tumours, were randomised in 16 Italian centres.At a median follow-up of 47.8 months, 210 and 164 progression and death events were registered. The primary end-point was not met. Median PFS was 10.3 and 9.4 months in arm B and A, respectively (HR: 0.94 [70% confidence interval {CI}: 0.82–1.09], p = 0.680). No significant differences were reported in terms of overall survival (OS) (median OS arm B/A: 22.5/28 months; HR: 1.16 [95%CI: 0.99–1.37], p = 0.336).Response rate with FOLFOXIRI plus bevacizumab was 63% (arm B/A: 58%/68%). In the liver-limited subgroup, the secondary resection rate was 49% (arm B/A: 45%/55%).The addition of metroCT to maintenance with bevacizumab does not significantly improve PFS of mCRC patients. The activity of FOLFOXIRI plus bevacizumab is confirmed in a population with high prevalence of RAS/BRAF mutations treated with a 4-months induction.www.clinicaltrials.gov NCT02271464.

Randomized phase II study of cetuximab plus cisplatin/vinorelbine compared with cisplatin/vinorelbine alone as first-line therapy in EGFR-expressing advanced non-small-cell lung cancer

BackgroundThe Lung Cancer Cetuximab Study is an open-label, randomized phase II pilot study of cisplatin and vinorelbine combined with the epidermal growth factor receptor (EGFR)-targeted monoclonal antibody cetuximab versus cisplatin and vinorelbine alone, in patients with advanced EGFR-expressing, non-small-cell lung cancer (NSCLC). End points of the study are activity, safety and pharmacokinetics. Patients and methodsFollowing randomization, for a maximum of eight cycles, patients received three-weekly cycles of cisplatin (80 mg/m2, day 1) and vinorelbine (25 mg/m2 on days 1 and 8) alone or following cetuximab treatment (initial dose 400 mg/m2, followed by 250 mg/m2 weekly thereafter). ResultsEighty-six patients were randomly allocated to the study (43 per arm). Confirmed response rates were 28% in the cisplatin/vinorelbine arm (A) and 35% in the cetuximab plus cisplatin/vinorelbine arm (B). Median progression-free survival (PFS) was 4.6 months in arm A and 5.0 months in arm B, with PFS rates at 12 months of 0% and 15%, respectively. Median survival was 7.3 months in arm A and 8.3 months in arm B. The 24-month survival rates were 0% and 16%, respectively. The cetuximab combination was well tolerated. ConclusionIn the first-line treatment of advanced NSCLC, the combination of cetuximab plus cisplatin/vinorelbine demonstrated an acceptable safety profile and the potential to improve activity over cisplatin/vinorelbine alone.