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1527Background: Li Fraumeni syndrome (LFS) is a rare cancer predisposition caused by TP53 germline mutation associated with a broad tumor spectrum making surveillance very complex. Whole body MRI (...

Purpose To assess objective response rate (ORR) after two cycles of temozolomide in combination with topotecan (TOTEM) in children with refractory or relapsed neuroblastoma. Patients and Methods This multicenter, non-randomised, phase II study included children with neuroblastoma according to a two-stage Simon design. Eligibility criteria included relapsed or refractory, measurable or metaiodobenzylguanidine (mIBG) evaluable disease, no more than two lines of prior treatment. Temozolomide was administered orally at 150mg/m 2 followed by topotecan at 0.75mg/m 2 intravenously for five consecutive days every 28days. Tumour response was assessed every two cycles according to International Neuroblastoma Response Criteria (INRC), and reviewed independently. Results Thirty-eight patients were enroled and treated in 15 European centres with a median age of 5.4years. Partial tumour response after two cycles was observed in 7 out of 38 evaluable patients [ORR 18%, 95% confidence interval (CI) 8–34%]. The best ORR whatever the time of evaluation was 24% (95% CI, 11–40%) with a median response duration of 8.5months. Tumour control rate (complete response (CR)+partial response (PR)+mixed response (MR)+stable disease (SD)) was 68% (95% CI, 63–90%). The 12-months Progression-Free and Overall Survival were 42% and 58% respectively. Among 213 treatment cycles (median 4, range 1–12 per patient) the most common treatment-related toxicities were haematologic. Grade 3/4 neutropenia occurred in 62% of courses in 89% of patients, grade 3/4 thrombocytopenia in 47% of courses in 71% of patients; three patients (8%) had febrile neutropenia. Conclusion Temozolomide–Topotecan combination results in very encouraging ORR and tumour control in children with heavily pretreated recurrent and refractory neuroblastoma with favourable toxicity profile.

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Background The ACCORD 16 phase II trial aimed to evaluate the objective response rate after combination of conventional chemoradiotherapy (CRT) and cetuximab in locally advanced anal canal carcinoma (LAACC). Patients and methods Immunocompetent patients with histologically confirmed LAACC received CRT [45 gray (Gy)] in 25 fractions over 5 weeks, fluorouracil and cisplatin during weeks 1 and 5), in combination with weekly dose of cetuximab (250 mg/m2 with a loading dose of 400 mg/m2 1 week before irradiation), and a standard dose boost (20 Gy). The trial was originally designed to include 81 patients to detect a 15% of objective response increase with the new combination in comparison with CRT. Results The trial was prematurely stopped after the declaration of 15 serious adverse events (SAEs) in 14 out of 16 patients. Five patients received the entire planned treatment, and the compliance was higher after amendments of the protocol. Among the 15 SAEs, 6 were unexpected. Grade (G) 3/4 acute toxic effects, observed in 88% patients, were general (n = 13, 81%), digestive (n = 9, 56%), dermatological (n = 5, 31%), infectious (n = 4, 25%), haematological (n = 3, 19%), and others (n = 9); and three patients suffered from six G3/4 late toxic effects. No treatment-related death was reported. All 11 assessable patients had an objective response consisting of six complete (55%) and five partial (45%) response 2 months after the end of the treatment. Thirteen patients were followed up with a median of 22 months [95% confidence interval (CI ): 18–27] and had a 1-year colostomy-free survival, progression-free and overall survival rate of 67% (95% CI: 40%–86%), 62% (95% CI: 36%–82%), and 92% (95% CI: 67%–99%), respectively. Conclusion CRT plus cetuximab was unacceptably toxic in this population of patients. Results of others phase II trials evaluating this combination are awaited to confirm these findings. Eudra CT No 2007-007029-38.

10555Background: Chemotherapy (CT) is frequently used as first adjuvant treatment for low-grade gliomas (LGG) when surgery cannot be completed. Relapses are frequent and new rescue regimens are nee...

Background: Robust advances in our understanding of NSCLC molecular biology and host immunity have expanded the field of cancer therapy with new immunotherapeutic approaches that unlock the immune response, such as blockade of the T-cell lymphocyte-4 (CTLA-4) obtained with Trem, and molecularly targeted agents, including EGFR tyrosine kinase inhibitors (TKI) such as Gef. A Phase I open-label multicenter study was initiated to evaluate the association of Trem with Gef in EGFR-mut NSCLC (NCT02040064). Methods: Key inclusion criteria included advanced/metastatic lung cancer with an activating mutation of EGFR (i.e., exon 19 deletion or exon 21 L858R point mutation), progression on any prior EGFR TKI (first line or beyond), measurable disease, adequate PS (0-1) and organ function. Patients (pts) may have received chemotherapy between EGFR TKI and inclusion. The primary objective was to determine the safety and tolerability of the combination of Gef (oral 250mg once-daily) with escalating doses of Trem (starting dose of 3mg/kg IV every 4 weeks for 6 cycles and beyond every 12 weeks) and to establish a recommended phase 2 dose (RP2D). A rolling 6 design and a dose limiting toxicity period of 42 days were applied. Three escalating doses of Trem were pre-planned (3, 6 and 10mg/kg). Data included here are preliminary and will be updated for presentation. Results: Between January, 2014 and March, 2015, 20 stage IV pts received at least one dose of Trem (median age of 66 years, female 70%, never smoker 65% and 60% had received ≥2 lines). Seventeen pts were evaluable for dose-limiting toxicities (DLT). DLTs occurred in 4 pts, 1 at 3mg/Kg (grade 3 colitis, cycle 1), 1 at 6mg/Kg (grade 3 colitis, cycle 1) and 2 at 10mg/Kg (one grade 3 diarrhea and one AST-ALT increase grade 3, cycle 2) of Trem. All toxicities were reversible with discontinuation of Trem. Consequently, Trem 10mg/Kg plus Gef 250mg daily exceeded the maximum tolerable dosage. Most common (≥20%) adverse events (AEs/grade 3-4 AEs) were diarrhea (90%/30%), asthenia (55%/5%), dry skin (55%/5%), nausea (25%/0%), decreased of appetite (25%/10%), dyspnea (25%/0%), colitis (25%/15%), and vomiting (20%/0%). No pneumonitis or increases in cutaneous toxicity related to treatments were observed. To date, 3 pts remain on therapy (past cycles 4, 6 and 9) and 5 patients experienced long-term benefit (≥4months). Longest duration of treatment is 12 months thus far. A translational research program on biomarkers and PK data is currently being performed. Conclusions: The recommended dose of Trem in phased combination with Gef in EGFR-mut pts with NSCLC was identified as 3mg/kg. The safety profile was consistent with the previously defined AE profile. An expansion cohort is enrolling pts at RP2D. Citation Format: David Planchard, Fabrice Barlesi, Carlos Gomez-Roca, Julien Mazieres, Andrea Varga, Laurent Greillier, Nathalie Chaput-Gras, Emilie Lanoy, Cedric Parlavecchio, Katty Malekzadeh, Maud Ngocamus, Sarah ZAHI, Benjamin Besse, Audrey Poterie, Jean-Charles Soria. Phase I, safety, tolerability and preliminary efficacy study of Tremelimumab (Trem) in combination with Gefitinib (Gef) in EGFR-mutant (EGFR-mut) NSCLC (GEFTREM). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A51.

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: Treatment options for patients (pts) with EGFR-mut NSCLC who have failed standard chemotherapy and first generation tyrosine kinase inhibitors (TKIs) are limited. Treatment with EGFR TKIs influences the release of chemokines leading to increased T cell recruitment, and tumor cell death induced by TKIs leads to increased antigen release and immune priming. Trem is a human immunoglobulin G2 (IgG2) kappa monoclonal antibody (mAb) that is directed against the CTLA-4 (cytotoxic T lymphocyte-associated antigen 4). This trial is aimed at elucidating whether or not adding anti-CTLA-4 therapy to existing Gef would complement and enhance its effects. Trial design: This phase I multicenter, single-arm study is designed to evaluate Gef (oral 250mg once-daily) plus Trem (starting dose of 3mg/kg IV every 4 weeks for 6 cycles and beyond every 12 weeks) in pts with EGFR-mut advanced NSCLC who have failed EGFR TKI. A rolling 6-cycle design and a dose limiting toxicity period of 42 days will be implemented. Three escalating doses of Trem are planned (3, 6 and 10mg/kg). Six pts will be enrolled for each dose level (up to 24 evaluable pts will be enrolled). Pts may have received chemotherapy between the EGFR TKI and inclusion in this study but must present a systemic objective progression. To prevent a tumor flare when starting Gef + Trem therapy, pts not previously treated with Gef will receive Gef treatment for 2 weeks before the addition of Trem. Pts with ECOG performance status ≥2, history of chronic inflammatory or autoimmune disease, untreated brain metastases or requiring systemic steroids are not eligible. The primary objective is to determine the safety and tolerability of the combination and to establish a recommended phase 2 dose. Secondary/exploratory objectives include evaluating response endpoints (overall response rate, progression free survival according to RECIST 1.1), determining immunogenicity and identifying immune biomarkers of this combination (peripheral blood mononuclear cell, sera and sequential tumor biopsies), and describing the pharmacokinetics for each agent in combination. The study is recruiting in 3 sites in France since February 2014. ClinicalTrials.gov identifier NCT02040064. Disclosure: D. Planchard: Advisory board with Astra-Zeneca to disclose; F. Barlesi: Consultant or advisory relationship with AstraZeneca to disclose; N. Byrne: Nathalie Byrne is an employee of AstraZeneca and owns stock/stock options in AstraZeneca; Besse: research grants from AstraZeneca; A. Nash: Anthony Nash is an employee of AstraZeneca and owns stock/stock options in AstraZeneca; A. Di Pietro: Alessandra DiPietro is an employee of MedImmune and owns stock/stock options in AstraZeneca; J. Soria: JC Soria have honoraria from AstraZeneca to disclose. All other authors have declared no conflicts of interest.

9517 Background: Temozolomide and topotecan have shown activity in several pediatric cancers, including neuroblastoma. Resistance to alkylating agents due to MGMT expression, MMR deficiency or microsatellite instability may be overcome through the combination with topoisomerase I inhibitors. The combination of temozolomide and topotecan (TOTEM) was well tolerated and showed preliminary activity in children with neuroblastoma and glioma (Rubie et al, 2010). Methods: This multicenter, non-randomized, multi-cohort Phase II study included children with neuroblastoma according to a 2-stage Simon design, and patients with central nervous system (CNS) and extra-cranial solid tumors in a descriptive design. Temozolomide was administered orally at 150 mg/m2 followed by topotecan at 0.75 mg/m2 intravenously for 5 consecutive days every 28 days. The main endpoint was objective response (OR), i.e., Complete or Partial Response (CR+PR), evaluated after 2 cycles according to WHO criteria, or INRC criteria for neuroblastoma patients with mIBG-positive lesions, by an independent radiological review. Independent review of mIBG imaging is pending. Results: 103 patients, median age 9.4 years (range 1-21), were treated between June 2009 and May 2011 in 18 centers: 38 neuroblastoma, 33 CNS tumors and 32 other solid tumors. Overall 420 cycles were administered (median 3 per patient; range 1-12). Grade 3 or 4 neutropenia was frequent (55% courses), though only 6% of patients developed febrile neutropenia. In the neuroblastoma cohort, 1 CR and 7 PR were observed, leading to an estimated OR rate of 21% (95%CI, 10-37%). Additionally 22 patients had disease stabilization (SD), leading to an overall tumor control (CR+PR+SD) of 79% (63-90%), and a 12-month progression-free survival rate of 47% (31-64%). Overall, 17/102 evaluable patients achieved an OR (17%, 10-25%), with 1 CR and 3 PR in 9 medulloblastoma (44%, 14-79%), 2 PR in 4 PNET, 1 PR in 12 malignant glioma, and 2 PR in 9 RMS. Conclusions: Temozolomide-topotecan combination results in significant tumor control in children with neuroblastoma and medulloblastoma/PNET with favorable toxicity profile.