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BACKGROUND Busulfan (Bu) is the cornerstone of conditioning regimens prior to hematopoietic stem cell transplantation, widely used in both adults and children for the treatment of malignant and nonmalignant diseases. Despite an intravenous formulation, interindividual variability (IIV) remains high and optimal exposure difficult to achieve, especially in neonates and infants. PROCEDURE To ensure both efficacy and safety, we set up in 2005 an observational study designed for children not fully assessed during the drug registration procedure. From a large cohort of 540 patients, we developed a Bu population pharmacokinetic model based on body weight (BW) and maturation concepts to reduce IIV and optimize exposure. A new dosing nomogram was evaluated to better fit the population pharmacokinetic model. RESULTS Bu clearance IIV was significantly decreased from 61.3% (covariate-free model) to 28.6% when combining BW and maturation function. Median Bu area under the curve (AUC) was 1179 µmol/L × min compared to 1025 with the EMA dosing nomogram for children

BACKGROUND A previous randomized trial in recurrent Head and Neck squamous-cell carcinoma (HNSCC) has shown re-irradiation combined with chemotherapy after salvage surgery significantly improved disease-free survival (DFS). The objective of this randomized trial was to compare two methods of re-irradiation in terms of toxicity and survival. PATIENTS AND METHODS Patients with recurrence/second primary in previously irradiated area were randomly allocated to receive either 60 Gy over 11 weeks with concomitant 5FU - hydroxyurea (VP-arm), or 60 Gy (1.2 Gy twice daily) over 5 weeks with cetuximab (HFR-arm). Primary endpoint was treatment interruption >15 days (acute toxicity). RESULTS Twenty-six patients were included in VP-arm and 27 in HFR-arm. One patient in VP-arm experienced >15 days interruption due to toxicity, and none in HFR-arm. In both arms, all patients received at least 60 Gy. In VP-arm, 8/26 patients had chemotherapy delay and/or dose reduction. In HFR-arm, 4/27 patients had

Background LKB1/STK11 ( STK11 ) is among the most inactivated tumor-suppressor genes in non-small cell lung cancer (NSCLC). While evidence concerning the biologic role of STK11 is accumulating, its prognostic significance in advanced NSCLC has not been envisaged yet. Materials and methods This retrospective analysis included consecutive NSCLC patients with available STK11 information who underwent a platinum-based chemotherapy. STK11 mutational status was correlated to clinico-pathological and mutational features. Kaplan–Meier and Cox models were used for survival curves and multivariate analyses, respectively. Results Among the 302 patients included, 267 (89%) were diagnosed with stage IIIB/IV NSCLC and 25 (8%) harbored a STK11 mutation ( STK11mut ). No statistical differences were observed between STK11 status and clinico-pathological variables. We detected a significant correlation between STK11 and KRAS status (p = 0.008); among the 25 STK11mut patients, 13 (52%) harbored a concomitant KRAS mutation. Overall survival (OS) was shorter for STK11mut (median OS = 10.4 months) compared to wild-type patients ( STK11wt ; median OS = 17.3 months) in univariate analysis (p = 0.085). STK11 status did not impact upon OS in multivariate analysis (p = 0.45) and non-significant results were observed for progression-free survival. The co-occurrence of KRAS and STK11 mutations suggest a trend toward detrimental effect in OS (p = 0.12). Conclusions In our cohort enriched for advanced NSCLC patients who received platinum-based chemotherapy, STK11 mutations were not specifically associated with clinico-pathological features and they did not impact upon survival. We confirm the positive correlation between STK11 and KRAS mutations. The co-occurrence of KRAS and STK11 mutations could label a more aggressive molecular subtype of NSCLC.

International audience; BACKGROUND:Early risk-stratified chemotherapy is a standard treatment for breast, colorectal, and lung cancers, but not for high-risk localised prostate cancer. Combined docetaxel and estramustine improves survival in patients with castration-resistant prostate cancer. We assessed the effects of combined docetaxel and estramustine on relapse in patients with high-risk localised prostate cancer.METHODS:We did this randomised phase 3 trial at 26 hospitals in France. We enrolled patients with treatment-naive prostate cancer and at least one risk factor (ie, stage T3-T4 disease, Gleason score of ≥8, prostate-specific antigen concentration >20 ng/mL, or pathological node-positive). All patients underwent a staging pelvic lymph node dissection. Patients were randomly assigned (1:1) to either androgen deprivation therapy (ADT; goserelin 10·8 mg every 3 months for 3 years) plus four cycles of docetaxel on day 2 at a dose of 70 mg/m(2) and estramustine 10 mg/kg per day on days 1-5, every 3 weeks, or ADT only. The randomisation was done centrally by computer, stratified by risk factor. Local treatment was administered at 3 months. Neither patients nor investigators were masked to treatment allocation. The primary endpoint was relapse-free survival in the intention-to-treat population. Follow-up for other endpoints is ongoing. This study is registered with ClinicalTrials.gov, number NCT00055731.FINDINGS:We randomly assigned 207 patients to the ADT plus docetaxel and estramustine group and 206 to the ADT only group. Median follow-up was 8·8 years (IQR 8·1-9·7). 88 (43%) of 207 patients in the ADT plus docetaxel and estramustine group had an event (relapse or death) versus 111 (54%) of 206 in the ADT only group. 8-year relapse-free survival was 62% (95% CI 55-69) in the ADT plus docetaxel and estramustine group versus 50% (44-57) in the ADT only group (adjusted hazard ratio [HR] 0·71, 95% CI 0·54-0·94, p=0·017). Of patients who were treated with radiotherapy and had data available, 31 (21%) of 151 in the ADT plus docetaxel and estramustine group versus 26 (18%) of 143 in the ADT only group reported a grade 2 or higher long-term side-effect (p=0·61). We recorded no excess second cancers (26 [13%] of 207 vs 22 [11%] of 206; p=0·57), and there were no treatment-related deaths.INTERPRETATION:Docetaxel-based chemotherapy improves relapse-free survival in patients with high-risk localised prostate cancer. Longer follow-up is needed to assess whether this benefit translates into improved metastasis-free survival and overall survival.FUNDING:Ligue Contre le Cancer, Sanofi-Aventis, AstraZeneca, Institut National du Cancer.

Background This phase I study evaluated the safety and efficacy of the oral mTOR inhibitor everolimus in combination with thoracic radiotherapy followed by consolidation chemotherapy in locally advanced or oligometastatic untreated non-small-cell lung cancer (NSCLC). Patients and methods Everolimus dose was escalated in incremental steps [sequential cohorts of three patients until the occurrence of dose-limiting toxicity (DLT)] and administered orally weekly (weekly group: dose of 10, 20 or 50 mg) or daily (daily group: 2.5, 5 or 10 mg), 1 week before, and during radiotherapy until 3.5 weeks after the end of radiotherapy. Two cycles of chemotherapy (cisplatin–navelbine) were administrated 4.5 weeks after the end of radiotherapy. Results Twenty-six patients were included in two centers, 56% had adenocarcinoma and 84% had stage III disease. In the weekly group (12 assessable patients), everolimus could be administered safely up to the maximum planned weekly dose of 50 mg; however, one patient experienced a DLT of interstitial pneumonitis at the weekly dose level of 20 mg. In the daily group (9 assessable patients): one DLT of interstitial pneumonitis with a fatal outcome was observed at the daily dose level of 2.5 mg; two other DLTs (one grade 3 esophagitis and one bilateral interstitial pneumonitis) were found at the daily dose level of 5 mg. Overall there were five patients with G3–4 interstitial pneumonitis related to treatment. Among 22 assessable patients for response, there were 9 (41%) partial response and 7 (32%) stable disease. At a median follow-up of 29 months, the 2-year overall survival and progression-free survival actuarial rates were 31% and 12%, respectively. Conclusion In previously untreated and unselected NSCLC patients, the recommended phase II dose of everolimus in combination with thoracic radiotherapy is 50 mg/week. Pulmonary toxicity is of concern and should be carefully monitored to establish the potential role of mTOR inhibitor with concomitant radiotherapy. EudraCT N 2007-001698-27.

Introduction The class I human leucocyte antigen (HLA) molecules play a critical role as an escape mechanism of antitumoral immunity. HLA-A2 status has been evaluated as a prognostic factor in lung cancer, mostly in localized disease and with inconsistent findings. We evaluated the role of HLA-A2 status as a prognostic factor in a large and homogeneus cohort of advanced NSCLC patients. Methods Advanced NSCLC patients eligible for platinum-based chemotherapy were consecutively included in a single center between October 2009 and July 2015 in the prospective MSN study (NCT02105168). HLA-A2 status was analysed by flow cytometry. Clinical, pathological and molecular data were collected. A Cox model was used for prognostic analyses. Results Of 545 stage IIIB/IV NSCLC patients included, 344 (63%) were male, 466 (85%) were smokers, 447 (83%) had PS 0–1, 508 (93%) had stage IV, 407 (75%) had an adenocarcinoma and median age was 61 years (range, 21–84). Incidence of patients with EGFRmut, ALK-positive and KRASmut was 14% (49/361), 9% (29/333) and 31% (107/350), respectively. The overall rate of HLA-A2 positivity was 48%. No association was observed between HLA-A2 status and any patient or tumor characteristics analyzed. With a median follow-up of 27.1 months, median OS was 12.8 months [95%CI 11.0–14.6] in HLA-A2+ vs. 12.5 months [95%CI 10.4–15.3] in HLA-A2- patients (HR 1.05 [95%CI 0.86–1.29], p = 0.61). Median progression-free survival was similar in the two cohorts. Conclusion HLA-A2 status was not identified as prognostic for benefit in a large advanced NSCLC population treated with platinum-based chemotherapy.

Objectives Dynamic contrast-enhanced (DCE) ultrasonography (US) is a functional imaging technique enabling quantitative assessment of solid tumor perfusion in metastatic patients treated with antiangiogenic therapies.The objective of this prospective single-center study was to evaluate in real-life conditions (in routine clinical practice) the intrapatient variability and reproducibility of DCE-US parameters. Materials and methods Each patient provided written informed consent and had 2 DCE-US examinations (preprandial and postprandial) at baseline, day 15, and 1 month after treatment initiation. Perfusion curves were recorded after Sonovue injections to determine 7 perfusion parameters. Dynamic contrast-enhanced US examinations were analyzed in pairs: preprandial and postprandial. Log transformed values were used to determine the variability of the pairs (within-subject coefficient of variation) and their reproducibility (Spearman correlation coefficient). Results We included 60 patients (23 colon cancers, 36 kidney cancers, and 1 breast cancer) treated with axitinib (26 patients), sunitinib (27 patients), and other antiangiogenic treatments (7 patients). The 60 patients included 38 men (63%) and 22 women (37%) with a median age of 62 (range, 25-82 years). Thirty patients had hepatic and 30 had extrahepatic target lesions. Data were analyzed for 128 pairs of DCE-US: 45 (baseline), 45 (day 15), and 38 (1 month). Preprandial and postprandial values were not significantly different. For area under the curve and area under the washout, the correlation coefficient between preprandial and postprandial values was 0.89; the associated within-subject coefficients of variation were 61% and 64%, respectively. However, the range of individual variations (postprandial value/preprandial value) was less than 2 logs for a range of parameter values of about 4 logs. Variability was independent of the metastatic site. Conclusions This study showed that area under the curve and area under the washout are the 2 most reproducible DCE-US parameters.

International audience; Despite considerable progress in hematological malignancies (HM) biology during the last decades, translation into clinical benefit remains a major challenge. To improve patient selection and identify patients most likely to benefit from phase I trials, we designed and validated, in an independent cohort, a simple prognostic score. Treatment outcome, toxicity, and survival data from 82 consecutive patients enrolled in 14 phase I trials were reviewed (January 2008-February 2012). We validated these results on a prospectively collected cohort (17 phase I trials, February 2012-May 2014, 88 patients). Within a median follow-up of 19.1 months (range: 2.1-43.8 months), the median progression-free and overall survival (OS) were, respectively, 4.1 months [95% confidence interval (CI): 3.0-5.3] and 19.8 months (95% CI: 16.1-36.8). Best overall response and disease control rates were similar to HM salvage regimens (28 and 64%, respectively). Through multivariate analysis of independent prognostic factors, we designed and prospectively validated a simple prognostic score based on histological subtype, performance status, and albumin. Patients with a low-risk score experienced significantly better OS compared with patients with an intermediate or a high score (median OS: 37 vs. 17 vs. 5 months; hazard ratio=11.68, 95% CI: 4.09-33.3). Our data indicate the safety and efficacy of phase I trials in a significant number of relapsed/refractory HM patients, with clinical benefit achieved in more than half of patients. Our simple scoring system offers a valuable selection tool encouraging HM patient inclusions in phase I trials.

Background Preclinical studies suggest synergistic antitumour effects of mammalian target of rapamycin (mTOR) inhibitor such as temsirolimus combined with anti-EGFR monoclonal antibody such as cetuximab. Methods Temsirolimus (T) and cetuximab (C) were combined and escalated in cohorts of patients with advanced or metastatic solid tumours, respectively from 15 to 25 mg and 150–250 mg/m2, until the maximum tolerated dose (MTD) was determined. Effort was made in the expansion cohort to enrol patients harbouring a molecular aberration in the human epidermal growth factor receptor (EGFR) and/or phosphoinositide 3-kinase (PI3K) pathways. Paired biopsies were optional to evaluate pathway modulation. Results Among 39 patients enrolled, three experienced dose-limiting toxicities (DLTs): pulmonary embolism (C200 + T20), stomatitis (C250 + T20) and acneiform rash (C250 + T25). The weekly C 250 mg/m2 and T 25 mg dose level was selected as the MTD. The most common treatment-related adverse events were: acneiform rash (97%), oral mucositis (82%), fatigue (59%), nausea (41%) and diarrhoea (36%). The median progression-free survival (PFS) and overall survival (OS) were respectively 2.0 months [95% CI: 1.8, 3.5] and 7.5 months [95% CI: 5.5, 11.9]. Among all patients, partial responses (PRs) and stable diseases (SDs) were observed in 2 (5.1%) and 18 patients (46.2%), respectively. The objective response rate (ORR) in patients with a molecular aberration was 2/14 (14%), versus 0/24 in those without molecular aberration. Conclusions Combination of T + C showed significant but manageable toxicities. Due to modest clinical activity, further evaluation is not recommended. Molecular selection could potentially increase the objective response rate and should be implemented during drug development.

Background Antiprogrammed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) therapies have demonstrated promising activity in advanced head and neck squamous cell carcinoma (HNSCC), with overall response rates of approximately 20% in unselected populations and survival benefit. Whether induction docetaxel, platinum and fluorouracil (TPF) modifies PD-L1 expression or tumour immune infiltrates is unknown. Patients and methods Patients with locally advanced HNSCC treated at Gustave Roussy (Villejuif, France) between 2006 and 2013 by induction TPF followed by surgery were retrospectively considered. Patients with paired samples (pre-TPF and post-TPF) were kept for further analysis. PD-L1 expression was quantified by immunohistochemistry according to a validated protocol. The objective of the study was to compare PD-L1 expression on tumour cells (TC) and immune cells (IC) (positivity threshold of ≥5%) before and after TPF. CD8+ and Foxp3+ lymphocytes densities before and after TPF were also quantified. Results Out of 313 patients receiving induction TPF, 86 underwent surgery; paired samples were available for 21 of them. Baseline PD-L1 expression was ≥5% in two and five samples for TC and IC, respectively. A significant increase of PD-L1 expression was observed after TPF, with 15 samples (71%) presenting a positive staining in IC after induction chemotherapy (P=0.003; Wilcoxon rank-sum test) and eight samples (38%) in TC (P=0.005; Wilcoxon rank-sum test). Tumour-infiltrating CD8+ mean densities also significantly increased post-TPF (P=0.01). There was no significant difference in Foxp3+ expression, CD8/Foxp3 ratio or correlation with outcome. Conclusion TPF induction chemotherapy in advanced HNSCC increases PD-L1 positivity on tumour-infiltrating ICs, as well as CD8+ lymphocytes density. These results warrant independent validation on larger datasets and might help therapeutic strategy in advanced HNSCC.

5012 Background: Combining docetaxel to androgen deprivation therapy (ADT) improves survival in metastatic castration-sensitive prostate cancer (CSPC) (Vale C, Lancet Oncol 2016; 17: 243-56) and it also improves relapse-free survival (RFS) in high-risk localized CSPC (Fizazi K, Lancet Oncol 2015; 16: 787-94). However it is unlikely that all patients (pts) derive a benefit from docetaxel treatment and identifying predictive biomarkers remains a major unmet need. A subset of prostate cancers contains TMPRSS2-ERG gene fusions leading to ERG overexpression. Methods: Pre-treatment prostate core biopsies were collected from 255/413 pts and 79/385 pts enrolled respectively in the GETUG 12 and GETUG 15 (Gravis G, Eur Urol 2016; 70: 256-62) phase 3 trials testing early docetaxel in high-risk localized and metastatic CSPC. ERG, PTEN, Ki67 and Rb expression was assessed using immunohistochemistry. RFS curves were compared using the Logrank test. Results: The median age was 63 years (46-77) and 62 years (49-76) in GETUG 12 and GETUG 15. ERG staining was positive in 88/191 (46%) and 33/79 (42%) pts with available tissue, respectively. In GETUG 12, docetaxel-based chemotherapy was associated with improved RFS in pts with ERG+ expression (HR = 0.55 [0.29-1.03]; 6-year RFS : 80% ADT+docetaxel vs 68% ADT alone), but not in pts with ERG- (HR = 1.10 [0.66-1.85]; 6-year RFS 55% ADT+docetaxel vs 60% ADT alone), interaction test: p = 0.02. Similar findings were observed in GETUG 15, which was used as a validation set: the median RFS was 10.7 (6.5-14.3) and 18.8 (9.8-41) months in pts with ERG+ cancers receiving ADT alone and ADT+docetaxel, and 10.6 (4.8-25.3) and 13.2 (9.4-24) months in pts with ERG- cancers. In contrast, no difference in patient outcome by docetaxel treatment was observed by PTEN, Ki67 and Rb expression. Conclusions: Docetaxel-related benefit in men with CSPC is predicted by ERG expression. This biomarker may help better select pts for docetaxel treatment.

Background Clinical implications of KRAS mutational status in advanced non-small cell lung cancer (NSCLC) remain unclear. To clarify this point, we retrospectively explored whether KRAS mutations could impact tumor response, and disease control rate (DCR) to first-line platinum-based chemotherapy (CT) as well as progression-free survival (PFS) or overall survival (OS). Methods Between June 2009 and June 2012, 340 patients with advanced (stage IIIB/IV) NSCLC were reviewed in a single institution (Institut Gustave Roussy). Two hundred and one patients had a biomolecular profile and received a platinum-based first-line CT. Patients with an unknown mutational status or with actionable alterations were excluded. We retained two groups: patients with KRAS mutated tumor (MUT) and patients with wild-type KRAS / EGFR (WT). Multivariate analyses with Cox model were used. Survival curves were calculated with Kaplan–Meier method. Results One hundred and eight patients were included in the analysis: 39 in the MUT group and 69 in the WT group. Baseline radiological assessment demonstrated more brain ( P =0.01) and liver ( P =0.04) metastases in MUT patients. DCR was 76% for MUT vs. 91% for WT group ( P =0.03), regardless of the type of platinum-based CT (use of pemetrexed or not). Although no statistically significant differences were found, shorter PFS (4.9 vs. 6.0 months; P =0.79) and OS (10.3 vs. 13.2 months; P =0.40) were observed for patients with KRAS mutated tumors in univariate analysis. Conclusions KRAS mutant tumors had a lower DCR after the first-line platinum-based CT, but this difference did not translate in PFS or OS. The presence of KRAS mutations may confer a more aggressive disease, with greater baseline incidence of hepatic and cerebral metastases.

Background: STK11 (also called LKB1) is among the 3 most mutated genes in lung adenocarcinoma, but its prognostic and predictive significance in advanced NSCLC patients is still not clear. Recent preclinical and translational evidence suggest its role in conditioning KRAS mutant lung adenocarcinomas aggressiveness and response to targeted treatment. Materials and methods: This retrospective analysis, in a single center, included consecutive NSCLC patients who had undergone a platinum-containing regimen, for which standard or next generation (NGS) sequencing analyses of STK11 gene (exons 1-9) had been successfully performed. STK11 gene was considered mutated if effect on protein was predicted as deleterious. Clinical features along with EGFR (exons 18-21), KRAS (exons 2-4) and TP53 (exons 1-11) mutational status were correlated to STK11 status. Kaplan-Meier methods, log-rank test, and Cox proportional hazards models were used for survival analysis, adjusting for stage (advanced yes/no) and histology for progression-free survival (PFS), and smoking status, stage, EGFR/KRAS status and number of lines of chemotherapy for overall survival (OS). Results: Among the 302 patients included between November 2007 and January 2015, 63% were male, 16% non-smoker and median age was 60 year; 75% had an adenocarcinoma, 88% a stage IIIB or IV and 80% no previous treatment for advanced disease; 25 (8%) patients had a STK11 mutation, 30 (10%) an EGFR mutation and 81 (27%) a KRAS mutation. Deletions/insertions, missense and false-sense mutations mainly involved exon 4-6 of STK11. No statistical differences were observed between STK11 status and sex, smoking status, age, stage at diagnosis or histology (adenocarcinoma versus others). Among the 25 patients with STK11 mutation, 13 patients (52%) had a KRAS mutation, compared with 67 (24%) among those without STK11 mutation (p = 0.008). No correlation between STK11 and EGFR or TP53 mutational status was observed. Median follow-up time was 34.8 months (95% confidence interval [CI95]: 30.7-42.3). In univariate analysis, OS was shorter for STK11 mutated patients compared to wild type ones (p = 0.085; HR: 1.53; CI95: 0.94-2.49) with a median OS of 10.4 (CI95: 6.1-15.7) and 17.3 (CI95: 14.0-21.1) months for mutated and wild-type STK11 patients respectively. In multivariate analysis, the HR was 1.21 (CI95: 0.74-1.99; p = 0.45). Similar non-significant results were observed for PFS. Conclusion: We confirm the reported data of a positive correlation between STK11 and KRAS mutations. No correlation between STK11 status and PFS or OS in patients receiving platinum-based treatment was observed when taking into account other prognostic covariates. Citation Format: Francesco Facchinetti, Maria Virginia Bluthgen, Gabrielle Tergemina Clain, Laura Faivre, Jean-Pierre Pignon, David Planchard, Jean-Charles Soria, Benjamin Besse, Ludovic Lacroix. STK11 mutations in non-small cell lung cancer (NSCLC): descriptive analysis and prognostic significance. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2250.

11509Background: Alterations of crizotinib (crz) molecular targets ALK, MET, ROS1 are found in a wide range of adult and pediatric (ped) cancers. Crz is approved for the treatment of adult patients...

11563Background: Radiogenomics is focused on defining the relationship between image and molecular phenotypes. Therefore, we assess the association between metastatic sites at baseline CT and molec...

6086Background: SGC of head and neck (SGCHN) are rare tumors including adenoid cystic carcinoma (ACC) and non-ACC, with no standard systemic treatment for R/M patients (pts). Pazopanib (Pb) is an o...

8065 Background: Molecular alterations of crizotinib (crz) targets (ALK, MET, ROS1) are found in a wide range of malignancies. To avoid uncontrolled off-label use and allow for a nationwide safe access to crz for patients (pts) with an ALK, MET or ROS1 positive (+) tumor, the French National Cancer Institute (INCa) launched the AcSe program, funding both access to tumor molecular diagnosis and an exploratory multi-tumor 2-stage design phase II trial. We report the preliminary results of the ROS1+ NSCLC cohort. Methods: ROS1 status was determined in 28 regional INCa molecular genetic centers by break-apart FISH assays. Patients with ROS1 rearrangements, progressing after at least one standard treatment (including a platinum-based doublet, unless pts were considered as unfit for chemotherapy) were proposed to receive crz 250 mg BID. Responses were centrally assessed using RECIST v1.1. The objective response rate (ORR) and disease control rate (DCR) were assessed every 8 weeks. Results: From Aug. 5, 2013 to ...

2599 Background: Preclinical studies suggest that temsirolimus (T), an inhibitor of mammalian target of rapamycin (mTOR) combined with cetuximab (C), an anti-EGFR monoclonal antibody, may have syne...

Background: Treating relapsed/refractory lymphoma remains a challenge. While phase 1 trials classically aim to determine the recommended phase 2 dose (RP2D), the search of anti-tumor activity is increasingly evaluated. We aimed to assess the tolerance and efficacy of phase 1 trial and to determine a simple scoring system to identify patients who will prematurely discontinue phase 1 studies (before six weeks), in a large cohort of patients with relapsed/refractory lymphoma. Patients and Methods: Data from 105 consecutive patients with relapsed/refractory lymphoma treated within a panel of 17 phase 1 trials were collected, between 2008 and 2014. At inclusion, median age was 66 years [range: 23-83]. Lymphoma histological patient's types were: 58 (55%) aggressive non-Hodgkin lymphoma (34 diffuse large B-cell lymphoma, 7 T-cell lymphoma and 17 Mantle cell lymphoma), 31 (30%) indolent non-Hodgkin lymphoma and 16 (15%) Hodgkin lymphoma. The predefined Gustave Roussy (GR) score combined two simple variables, PS and baseline serum albumin (+1 if PS = 0, +1 if albumin ≤ 35g/l). Results: Grade 3 or 4 adverse events were experienced by 40/105 (38%) patients. With a median follow-up of 10 months, median OS and progression free survival (PFS) were respectively 19 (CI95%: 12-37) and 4 (CI95%: 2-5) months. Best overall response rate and disease control rate were 22% and 56%, respectively. Histological type's analysis shown median OS was 10, 45 and 47 months in aggressive-NHL, Hodgkin and indolent-NHL, respectively (p 0, baseline albumin ≤ 35 g/l and baseline LDH ≥ 250 UI/L were significantly associated with poorer OS. Patients with a GR score = 0 experienced significantly better OS compared to patients with a score = 1 and a score = 2 (37 months vs 17 months vs 9 months; p = 0.007). A premature study discontinuation was recorded in 28/105 patients (27%). The GR score distinguishes patients most likely to remain on study for more than 6 weeks. Conclusion: The three parameters WHO performance status (PS) > 0, baseline albumin ≤ 35 g/l and baseline LDH ≥ 250 UI/L are associated with OS and premature withdrew of study. Both PFS and OS survival curves demonstrates a plateau, in favor of therapeutic effect potentially maintained.

Background: Treating relapsed/refractory non-Hodgkin and Hodgkin lymphoma in fit young and elderly patients represents a considerable challenge for clinicians. Combined cytotoxic agents are rapidly ineffective, especially when relapse occurs after autologous stem cell transplantation (ASCT). Alternative regimens are often sparse. In the era of personalized medicine, phase I clinical trials offer an alternative therapeutic option through a multitude of immunotherapy and targeted drugs in development. Phase I trials aim to determine the recommended phase II dose (RP2D) through toxicity and pharmacokinetic assessments. Documenting signal of activity is also a major objective, underlying the importance of including patients susceptible to remain on study until first lymphoma response evaluation (usually 6 weeks, 2 cycles). We aimed to assess a simple scoring system that could identify patients who will discontinue phase I studies before 6 weeks. Patients and Methods: Data from all lymphoma patients treated within a phase I trial in Gustave Roussy (GR) Cancer Center were retrospectively collected. 83 consecutive patients were enrolled in 17 phase I trials at GR between January 2008 and May 2014. All patients had progressive lymphoma at time of enrollment, after a median of 3 prior therapeutic lines (range 1;13). 37 patients (45%) received an ASCT prior to phase I inclusion. Median age was 67 years (range: 23-92) and WHO performance status (PS) was 0 in 36 patients (43%), 1 in 43 patients (52%) and 2 in 4 patients (5%). Median time from lymphoma diagnosis to phase I inclusion was 47 months. Lymphoma histological subtypes were represented as follows: 21% Hodgkin lymphoma, 36% aggressive non-Hodgkin lymphoma (83% diffuse large B cell lymphoma, 17% T cell lymphoma), 24% indolent non-Hodgkin lymphoma (70% follicular lymphoma, 25% marginal zone lymphoma, 5% Waldenström macroglobulinemia) and 19% mantle cell lymphoma. Univariate analysis on this cohort allowed identifying simple factors significantly associated with overall survival (OS). A simple scoring system, predictive for OS was pre-established and validated through a multivariate analysis in 2 large cohorts of various hematological malignancies by our group. Statistical tests were conducted on this relapsed/refractory lymphoma cohort, to evaluate this score's OS and early study discontinuation predictive ability. Results: Within a median follow up of 19 months, median OS and progression free survival (PFS) were respectively 18 (CI95%: 12; 37) and 3 (CI95%: 1.7; 3.6) months. Best overall response rate (ORR) and disease control rate (DCR: objective response and stable disease rates) were respectively 18% and 61%. Thirty-four patients (41%) experienced grade 3 or 4 adverse events and 7 patients (8%) a dose limiting toxicity (DLT). WHO performance status (PS) > 0 at inclusion, baseline albumin ≤ 35 g/l and baseline LDH ≥ 250 UI/L were significantly associated with poorer OS. The predefined GR prognostic score combined 2 simple variables, PS and baseline serum albumin (+1 if PS 0, +1 if albumin≤ 35 g/l). In our lymphoma cohort, patients with a GR score = 0 experienced significantly better OS compared to patients with a score = 1 and a score = 2 (37 months vs 17 months vs 9 months; p = 0.007). This simple score, distinguishes patients most likely to remain on study for more than 6 weeks, considered as the minimum required period for response and toxicity evaluation (classical DLT and targeted therapies associated long term toxicities). Among patients prematurely withdrawn from clinical trials, 91% had a GR score ≥ 1 (p=0,007). Main study discontinuation reason was progressive disease (77%), drug related toxicity was only responsible for study discontinuation in 13 % of cases. Conclusion: Our data demonstrate efficacy and safety of phase I clinical trials in lymphoma, thus offering an interesting alternative therapeutic option for fit young and elderly relapsed/refractory lymphoma patients. The GR simple score, can both help in selecting patients most likely to benefit from a phase I trial (better OS) and to determine the phase II recommended dose (reduced early trial discontinuation). Disclosures No relevant conflicts of interest to declare.

Background: Phase I clinical trials are conducted to determine the recommended phase II dose through safety and pharmacokinetic assessments. Potential clinical benefit is also a key aim. To improve patient's selection and identify patients most likely to benefit from these studies in hematological malignancies (HM), we designed and then validated in an independent cohort, a prognostic score based on simple variables. Patients and Methods: We retrospectively collected data from 82 consecutive patients enrolled in 14 phase I trials at Gustave Roussy (GR) between January 2008 and February 2012 (cohort 1). A simple scoring system was established through multivariate analysis (MVA) of multiple potential prognostic factors (age, gender, BMI, smoking status, comorbidities, histological subtype, WHO performance status (PS), prior autologous stem cell transplant, prior radiotherapy, LDH, serum albumin and protein levels). We then prospectively collected data from 88 consecutive patients treated in 17 phase I trials in the GR phase I department from February 2012 to May 2014, to validate this prognostic score on an independent cohort (cohort 2). Stratification was done according to histology given the heterogeneity of diseases. Results: All patients had progressive HM after a median of 2 prior systemic standard therapeutic lines in cohort 1. The distribution of HM was: acute myeloid leukemia (AML) 23%, indolent non Hodgkin lymphoma (iNHL) 22%, myelofibrosis (MF) 21%, aggressive non-Hodgkin lymphoma (aNHL) 16%, chronic lymphoid leukemia (CLL) 10%, Hodgkin lymphoma (HL) 6% and multiple myeloma (MM) 2%. Median age was 73 years (range: 27-93) and 56 patients (67%) had more than one comorbidity. Best overall response rate (ORR) and disease control rate (DCR: objective response and stable disease rates) were 20% and 64 % respectively. Within a median follow up of 26 months, median progression-free survival (PFS) and overall survival (OS) were respectively 5 (CI95%: 4; 8) and 17 months (CI95%: 12; 26). One toxicity-related death (2%) occurred. Thirty-seven patients (45%) experienced grade 3 or 4 adverse events (AE) and 9 patients (11%) a dose-limiting toxicity (DLT). MVA identified PS > 0 at inclusion, baseline albumin ≤ 35 g/l and histological subtype as prognostic factors for OS. We defined the GR score using this MVA data: +1 if PS > 0, +1 if albumin ≤ 35 g/l. Patients with a GR score = 0 experienced significantly better OS compared to patients with a score = 1 and a score = 2 (37 months versus 17 months versus 8 months; p = 0.003). Cohort 2 patients were characterized by a median age of 64 years (range: 23-84) and a similar comorbidity rate (61%). Distribution among hematological entities was: 22% iNHL, 21% AML, 19% aNHL, 14% MM, 13% HL, 7% MF and 5% CLL. Patients received a median of 3 systemic therapeutic lines prior to phase 1 inclusion. Best ORR and DCR were respectively 28% and 57%. Within a median follow up of 11 months, median PFS and OS were 3 (CI95%: 1.5; 5) and 20 months (CI95%: 12; NA) respectively. No toxicity-related death occurred. Forty-seven patients (53%) experienced grade 3 or 4 toxicity and 1 patient (1%) a dose-limiting toxicity. Pre-established GR score was predictive of OS in this validation cohort (p=0.033). Main study discontinuation reason was progressive disease (75% and 80% in cohorts 1 and 2, respectively). Drug related toxicity was responsible for study discontinuation in 9% and 14% of cases in cohorts 1 and 2 respectively. The GR score distinguishes patients most likely to remain on study for more than 6 weeks, considered as the minimum required period for response and toxicity evaluation (classical DLT and targeted therapies associated long term toxicities). Among patients who discontinued prematurely clinical trials, GR score was ≥ 1 in 88% and 89% of cases respectively in cohort 1 (Cochran-Armitage: p= 0.02 and p=0.06) and cohort 2 (p=0.036). Conclusion: Our data demonstrate safety and efficacy of phase I trials in a significant number of relapsed/refractory HM patients with a clinical benefit achieved in more than half of patients. Response rates are higher than previously reported in solid tumors (Arkenau HT et al. 2008), thus encouraging HM patients inclusions in phase I trials. The simple GR score based on PS and albumin offers a valuable selection tool enabling OS and early trial discontinuation prediction. Disclosures No relevant conflicts of interest to declare.

5005 Background: Docetaxel-estramustine improves survival in patients (pts) with castrate-resistant prostate cancer (CaP). This phase III trial assessed docetaxel-estramustine in pts with high-risk...

3638 Background: Anti-angiogenic therapy plays a role in the treatment of colorectal cancer (CRC). We used monotherapy axitinib every other week given in refractory patients to evaluate the efficacy of this drug given at increasing doses and the role of Dynamic Contrast enhanced ultrasonography (DCE-US) to predict and measure its efficacy. Methods: Patients (pts) should have refractory metastatic CRC with at least one measurable lesion into the liver with DCE-US. They were given axitinib 5mg bid for one week followed by one week rest (Cycle 1) and then in case of good tolerance 7 mg bid for one week followed by one week rest (Cycle 2) and then 10 mg bid for one week followed by one week rest (Cycle 3). After 6 weeks of treatment a new CT-scan was performed to evaluate the efficacy of the treatment following RECIST criteria. If at least a stable disease was observed axitinib alone was continued at the same dose, if not addition of chemotherapy (CT) (Folfiri regimen) was allowed. DCE-US was performed on one...

e19021 Background: EGFRm and ALK+ are eligible to TKI. Predictive factors of response to TKI are poorly known, in particular the impact of the initial tumor burden. The objective of this study is t...

5063 Background: High-risk localized prostate cancer (CaP) is a heterogeneous disease and only a minority of patients (pts) ultimately die of their cancer. GETUG 12 is a phase III trial assessing a...

Background: Busulfan (Bu) is the corner stone of hematopoietic stem-cell transplantation (HSCT) regimens with a narrow therapeutic window (TW). Graft rejection or toxicities are reported according to plasmatic exposure. In very young children, Bu exhibits large pharmacokinetic (PK) variability. Bu clearance was demonstrated to be non-linearly related to body weight (BW) and thus BW is used to optimally define the Bu dosage in children [Vassal et al., CCP 2006]. Search for additional data to confirm the TW and to describe clinical outcomes is still a topical question to better understand Pk/Pd relationship and to safely use Bu in young children and infants. Objective: To study the Pk/Pd relationship of Bu in pediatric recipients of bone marrow transplantation (BMT) receiving Bu-based conditioning regimens (CR). To correlate early toxicities (mainly hepatic veno-occlusive disease (VOD), non infectious pulmonary disease (niPD) and outcome i.e. overall survival (OS) at last follow up with type of CR, the underlying diseases, age at transplantation and Pk of busulfan Patients and Method: This multicenter prospective observational study included 307 pts transplanted between 2006 and 2013 from 14 French Pediatric BMT units; median age at transplantation was 18.4 months [1.3-289], with a median BW of 11.3 kg [3.4-82]. 100 pts were younger than 1 year, 71 pts < 9 kg and 171 pts < 16 kg. Patients were mostly affected by non-malignant diseases (primary immune deficiency (n=143), inherited metabolic disorders (n=50), hemoglobinopathies (n=20) while 78 patients suffered from malignant disease. 257 patients received allogenic HSCT (genoidentical donor n=79, matched unrelated donor n=33, mismatch unrelated donor n=18, haploidentical intra-familial donor n=59, other mismatched intra familial donor n=8 or unrelated cord blood n=51) and 41 autologous BMT. All patients received Bu-based conditioning regimen in combination with cyclophosphamide (BuCy n=119), fludarabine (BuFlu n=88), melphalan (BuMel n=36) or thiotepa (BuTTP n=3). 40 patients received BuFlu associated with a second alkylating agent (Mel, TTP or Cy), 12 patients received BuCy associated with a third agent (Mel or VP16). Serotherapy was given in 70% of the patients. Starting doses of Bu were given according to the European SmPC or EBMT-ESID recommendations. The median posology was 1 mg/kg 4x/day for 4 days [0.6-1.3 mg/kg]. PK was assessed on plasma samples with area under the curve (AUC) evaluation from the 1st(D1), 9th (D9) and 13th (D13) dose in 150 patients, D1 and D9 in 40 patients, D1 and D13 in 46 patients while 62 patients were monitored on D1 only (684 PK datasets). PK analysis was performed using Non linear Mixed Effect Modelling. A one-compartment PK model suitably fitted the concentrations vs time data. Median follow up is 27 months (0.33 to 96 months post BMT). Results: At D1, 67% of patients were within the therapeutic window (TW) [900-1500 µM.min] and 66% of patients reached the cumulative TW [14400-24000 µM.min]. Incidence of VOD and niPD were respectively 35% and 14%. Both toxicities correlated with type of CR and age 900 µM.min. OS was 69.1% at last follow up and was not significantly associated with CR and age at transplantation. Conclusion: In this large series of pediatric BMT recipients, we found that toxicities as VOD and niPD correlated with type of CR and age at transplantation in univariate analysis. Combination of 2 alkylating agents with Bu or BuFlu and transplantation < 1 year of age were associated with the highest incidence of toxicites. The TW targeting performance was improved in this cohort compared to previous reported data (Paci et al. TDM 2012). Specific TW for each group of pathologies will be proposed. Disclosures No relevant conflicts of interest to declare.