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We report the clinical activity, safety, and identification of a predictive biomarker for bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of TGFβRII (a TGF-β "trap") fused to a human IgG1 mAb blocking PD-L1, in patients with advanced triple-negative breast cancer (TNBC).In this expansion cohort of a global phase 1 study, patients with pretreated, advanced TNBC received bintrafusp alfa 1200 mg every 2 weeks intravenously until disease progression, unacceptable toxicity, or withdrawal. The primary objective was confirmed best overall response by RECIST 1.1 assessed per independent review committee (IRC).As of May 15, 2020, a total of 33 patients had received bintrafusp alfa, for a median of 6.0 (range, 2.0-48.1) weeks. The objective response rate was 9.1% (95% CI, 1.9%-24.3%) by IRC and investigator assessment. The median progression-free survival per IRC was 1.3 (95% CI, 1.2-1.4) months, and median overall survival was 7.7 (95% CI, 2.1-10.9) months. Twenty-five patients (75.8%) experienced treatment-related adverse events (TRAEs). Grade 3 TRAEs occurred in 5 patients (15.2%); no patients had a grade 4 TRAE. There was 1 treatment-related death (dyspnea, hemolysis, and thrombocytopenia in a patient with extensive disease at trial entry). Responses occurred independently of PD-L1 expression, and tumor RNAseq data identifiedBintrafusp alfa showed clinical activity and manageable safety in patients with heavily pretreated advanced TNBC.NCT02517398.

Background: Ataxia telangiectasia and Rad3-related (ATR) protein kinase plays a critical role in the DNA damage response. M1774, a potent, selective, orally administered ATR inhibitor with antitumor activity in preclinical models, was evaluated as monotherapy in Part A1 of the first-in-human open-label, single-arm study (NCT04170153). M1774 was well-tolerated and pharmacodynamic analyses showed that maximum target engagement was reached from the dose of 130 mg QD. The totality of evidence, including quantitative model-based analyses, suggested the recommended dose for expansion (RDE) as 180 mg QD 2 weeks on/1 week off.1 One patient with platinum and PARP inhibitor-resistant BRCAwt ovarian cancer and ATRX mutation on local tumor testing achieved an unconfirmed RECIST v1.1 partial response. Retrospective analyses were conducted to explore the molecular portrait and evolution of the underlying disease of patients treated with M1774. Methods: Archival tumor biopsies, baseline and serial on-treatment circulating tumor DNA (ctDNA) samples collected from patients enrolled in the study were analyzed by next generation sequencing. Somatic putative CHIP mutations and cases with mutation variant allele frequency (VAF) < 0.3% in circulating free DNA at baseline were excluded. Molecular response (MR) was defined as at least 50% reduction of VAF. Results: Molecular data were generated from archival biopsies collected for 33/55 patients and ctDNA samples from 55/55 patients enrolled in the study. High impact mutations were detected in ARID1A (N=10), ATM (N=5), ATRX (N=3), BRCA1/2 (N=13), and other homologous recombination-related genes (N=5). MRs were observed in 11/34 (32%) patients treated with more than 130 mg QD, none were observed in the 10 patients treated with lower doses. The MRs were enriched in patients with ovarian (3/8, 38%), prostate (4/8, 50%), and breast cancer (1/3, 33%), while less frequent (3/15, 25%) in other indications. TP53 mutations were significantly associated with MR, independently of tumor type. Complete MRs were achieved for any mutations in ARID1A (2/7), ATRX (2/5), DAXX (1/3), BRCA1/2 (1/10). A complete MR was seen in a patient with ovarian cancer with prolonged stable disease by RECIST (200 days), and ARID1A mutation in ctDNA. Conclusions: M1774 induced MRs in patients treated with doses in the predicted efficacious concentration range. TP53 alterations were significantly associated with MR. Complete MRs were detected for mutations in the genes ARID1A, ATRX, DAXX that are being tested for participant selection in the ongoing biomarker expansion cohorts of the DDRiver 301 study. 1TA Yap, et al. Ann Oncol. 2022; 33(suppl_7): S197-S224. Citation Format: Anthony W. Tolcher, Timothy A. Yap, Ruth Plummer, Thomas Grombacher, Danyi Wang, Corinna Schaffroth, Christine Hicking, Zoltan Szucs, Giuseppe Locatelli, Johann S. de Bono. Translational analyses of ATR inhibitor M1774 in a Phase I study in patients with solid tumors (DDRiver Solid Tumors 301) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT271.

M4076 is a potent and selective oral inhibitor of ataxia-telangiectasia mutated (ATM), a key kinase of the DNA damage response (DDR) involved in double-strand break repair. Preclinically, M4076 when combined with DNA damage-inducing therapy or other DDR inhibitors caused unrestricted cell cycle progression and DNA damage accumulation, resulting in tumor cell death. Part 1A of this ongoing open-label study (NCT04882917) evaluated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and maximum tolerated dose (MTD) of M4076 monotherapy in patients (pts) with advanced solid tumors. Dose escalation was guided by safety, along with Bayesian analysis, PK, and PD. In total, 22 pts received M4076 at 4 different dose levels (100-400 mg once daily [QD]); 21 pts (95.5%) discontinued treatment (progressive disease: 11 [50%], adverse events [AEs]: 5 [22.7%]). Dose-limiting toxicities (DLTs) were reported in 4 pts. Overall, 6 pts had ≥1 treatment-related AE (TRAE) of Grade ≥3 (including one Grade 4 hypersensitivity). The most common TRAEs were rash and anemia (Table 1). MTD was determined at 300 mg QD. As per preliminary PK across cohorts, M4076 was rapidly absorbed with median Tmax ~0.5-2 h and mean elimination half-life (t1/2) ~2-10 h; exposure increased in a dose-related manner, with minimum accumulation after multiple QD doses. At ≥200 mg QD, unbound steady state plasma concentration exceeded in vivo pCHK2 IC90 throughout the dosing interval. PD evaluation was based on the modulation of γ-H2AX (a direct ATM target) in ex vivo bleomycin stimulated CD45+ lymphocytes, by flow cytometry. Preliminary analyses showed a trend of reduction of γ-H2AX levels from day 1 to day 2, reaching 80-100% of target inhibition on day 2 with the dose range 100-400 mg QD. The MTD of M4076 was determined, and target exposure and engagement were achieved without significant hematological toxicity. Future investigations on M4076 as combination therapy are planned. Table 1. Safety overview Dose (Safety set) Patients with TRAEs (Grade ≥3) DLT analysis set (Patients with ≥80% of the planned dose or DLT per investigator) DLT DLT AE terms 100 mg(n = 2) No n = 2 No NA 200 mg(n = 7) n = 1 (decreased lymphocyte count, maculo-papular rash) n = 5 Yes(n = 1) Grade 3 maculo-papular rash (TRAE, required drug withdrawal; resolved) 300 mg(n = 9) n = 3 (anemia, spontaneous bacterial peritonitis) n = 7 Yes(n = 1) Grade 1 maculo-papular rash; Grade 2 fever (TRAEs, required treatment discontinuation; resolved) 400 mg(n = 4) n = 2 (nausea, maculo-papular rash, hypersensitivity) n = 4 Yes(n = 2) Grade 3 maculo-papular rash (TRAEs, required dose reduction/interruption and/or concomitant medication; resolved) MedDRA version 23.0, NCI-CTCAE version 5.0. Data cutoff: 2 Nov 2022 AE, adverse event; DLT, dose-limiting toxicity; NA, not applicable; TRAE, treatment-related AE Citation Format: Lillian L. Siu, Timothy A. Yap, Sofia Genta, Gregory Pennock, Christine Hicking, Xiaoli You, Jatinder K. Mukker, Giuseppe Locatelli, Anthony W. Tolcher. A first-in-human phase I study of the ATM inhibitor M4076 in patients with advanced solid tumors (DDRiver Solid Tumors 410): Part 1A results [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT171.

Background: Ataxia telangiectasia and Rad3-related (ATR) protein kinase plays a critical role in the DNA damage response. M1774, a potent, selective, orally administered ATR inhibitor with antitumor activity in preclinical models, was evaluated in Part A1 of an open-label, single-arm study (NCT04170153) for safety, tolerability, maximum tolerated dose, pharmacokinetics (PK) and pharmacodynamics (PD). M1774 monotherapy in patients with advanced solid tumors was well-tolerated and the totality of evidence, including quantitative model-based analyses, suggested the recommended dose for expansion (RDE) as 180 mg QD 2 weeks on/1 week off.1 Here, we report findings of the M1774 PD and immunophenotyping analyses. Methods: M1774 PD was explored by assessing phosphorylation by ATR of CHK1 (p-CHK1) in tumor and of H2AX (γ-H2AX) in serial blood samples, stimulated ex vivo with the radiomimetic 4-Nitroquinoline N-oxide or Dimethyl sulfoxide as control. A flow cytometry quantitative assay was used to measure γ-H2AX in the CD45+ lymphocytes fraction. The effect of M1774 on the immunophenotype was explored by flow cytometry. Blood samples were collected at baseline, 3 and 24 hours after first M1774 administration on day 1 of cycle 1 for the γ-H2AX analysis, and on Days 1 and 15 of Cycles 1 and 2 before treatment for immunophenotyping. Results: Preclinical tumor tissue-blood bridging PD analyses in a mouse model demonstrated that the inhibition of γ-H2AX in lymphocytes highly correlated with inhibition of p-CHK1 in tumor. Clinical data of γ-H2AX levels and immunophenotyping were generated for the blood samples collected from the 55 participants of Part A1 of the study. Exploratory PK-PD analysis using γ-H2AX levels 3 h post-dose on day 1 across the doses predicted target inhibition >80% for doses ≥130 mg, suggesting target engagement. The levels of ɣ-H2AX at 24 h after first dose intake were variable and mean levels rebounded to baseline value. M1774 treatment did not cause any significant and consistent change in the levels of all explored immune cell subsets at the tested dose levels, including myeloid-derived suppressor cells, T and B lymphocytes, monocytes, and natural killer cells. Conclusions: PD analyses showed that M1774 efficiently inhibited ATR at the RDE without impacting the immunophenotype. 1TA Yap, et al. Ann Oncol. 2022; 33(suppl_7): S197-S224. Citation Format: Ruth Plummer, Anthony W. Tolcher, Timothy A. Yap, Giuseppe Sessa, Jatinder K. Mukker, Annick Seithel-Keuth, Christine Hicking, Zoltan Szucs, Ioannis Gounaris, Giuseppe Locatelli, Johann S. de Bono. Pharmacodynamic and immunophenotyping analyses of ATR inhibitor M1774 in a Phase I study in patients with solid tumors (DDRiver Solid Tumors 301) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT272.

Introduction Cladribine Tablets (MAVENCLAD®) selectively reduce absolute lymphocyte counts (ALCs) in patients with multiple sclerosis. The recommended cumulative dose of Cladribine Tablets is 3.5 mg/kg over 4–5 days in months 1 and 2 of treatment years 1 and 2, followed by prolonged efficacy with no additional treatment. After the cladribine-induced reduction, ALCs recover to normal within each treatment year in most patients. Those patients with slow ALC recovery can develop Grade 3–4 lymphopenia, especially those patients with Grade ≥ 2 lymphopenia at the start of year 2. Guidelines allowing treatment postponements during year 2 have been proposed for patients with a low ALC, subsequent to CLARITY, the pivotal clinical trial. Methods A virtual population was generated using characteristics from CLARITY patients. A clinical trial simulation was performed to determine the impact of alternative treatment scenarios on ALC and relapse rate, by postponing treatment in year 2 to allow for longer ALC recovery time in patients who required it. Should a patient not recover to normal ALC (Grade 0) or Grade 1 lymphopenia within the period defined in the treatment algorithm, treatment in year 2 was suspended. Results Results were similar across considered scenarios, which implemented different postponement durations. Specifically, ~ 92% of virtual subjects did not require treatment postponement and

Background: In the CLARITY (CLAdRIbine Tablets treating multiple sclerosis orallY) study, Cladribine Tablets significantly improved clinical and magnetic resonance imaging (MRI) outcomes (vs placebo) in patients with relapsing-remitting multiple sclerosis. Objective: Describe two clinically relevant definitions for patients with high disease activity (HDA) at baseline of the CLARITY study (utility verified in patients receiving placebo) and assess the treatment effects of Cladribine Tablets 3.5 mg/kg compared with the overall study population. Methods: Outcomes of patients randomised to Cladribine Tablets 3.5 mg/kg or placebo were analysed for subgroups using HDA definitions based on high relapse activity (HRA; patients with ⩾2 relapses during the year prior to study entry, whether on DMD treatment or not) or HRA plus disease activity on treatment (HRA + DAT; patients with ⩾2 relapses during the year prior to study entry, whether on DMD treatment or not, PLUS patients with ⩾1 relapse during the year prior to study entry while on therapy with other DMDs and ⩾1 T1 Gd+ or ⩾9 T2 lesions). Results: In the overall population, Cladribine Tablets 3.5 mg/kg reduced the risk of 6-month-confirmed Expanded Disability Status Scale (EDSS) worsening by 47% vs placebo. A risk reduction of 82% vs placebo was seen in both the HRA and HRA + DAT subgroups (vs 19% for non-HRA and 18% for non-HRA + DAT), indicating greater responsiveness to Cladribine Tablets 3.5 mg/kg in patients with HDA. There were consistent results for other efficacy endpoints. The safety profile in HDA patients was consistent with the overall CLARITY population. Conclusion: Patients with HDA showed clinical and MRI responses to Cladribine Tablets 3.5 mg/kg that were generally better than, or at least comparable with, the outcomes seen in the overall CLARITY population.

Background: Neuroimaging studies have used magnetic resonance imaging-derived methods to assess brain volume loss in multiple sclerosis (MS) as a reliable measure of diffuse tissue damage. Methods: In the CLARITY study ( ClinicalTrials.gov NCT00213135), the effect of 2 years’ treatment with cladribine tablets on annualized percentage brain volume change (PBVC/y) was evaluated in patients with relapsing MS (RMS). Results: Compared with placebo (–0.70% ± 0.79), PBVC/y was reduced in patients treated with cladribine tablets 3.5 mg/kg (–0.56% ± 0.68, p = 0.010) and 5.25 mg/kg (–0.57% ± 0.72, p = 0.019). After adjusting for treatment group, PBVC/y showed a significant correlation with the cumulative probability of disability progression (HR = 0.67, 95% CI = 0.571, 0.787; p Conclusions: Cladribine tablets given annually for 2 years in short-duration courses in patients with RMS in the CLARITY study significantly reduced brain atrophy in comparison with placebo treatment, with residual rates in treated patients being close to the physiological rates.

Background: Immune reconstitution therapies (IRT) for patients with multiple sclerosis are used for short, intermittent treatment periods to induce immune resetting and allow subsequent treatment-free periods. Cladribine tablets are postulated to be an IRT that causes selective and transient reductions in CD19 + B cells and T cells, followed by reconstitution of adaptive immune function. Objective: To characterize long-term lymphocyte count changes in pooled data from the 2-year CLARITY and subsequent 2-year CLARITY Extension studies, and the PREMIERE registry (Long-term CLARITY cohort). Methods: Data from patients randomized to placebo (n = 435) or cladribine tablets 10 mg (MAVENCLAD ® ; 3.5 mg/kg cumulative dose over 2 years, referred to as cladribine tablets 3.5 mg/kg; n = 685) in CLARITY or CLARITY Extension, including time spent in the PREMIERE registry were pooled to provide long-term follow-up data. The study investigated absolute lymphocyte counts (ALC) up to 312 weeks and B and T cell subsets up to 240 weeks after the first dose, in patients receiving placebo or cladribine tablets 3.5 mg/kg administered as two short (4 or 5 days) weekly treatments at the start of months 1 and 2 in each treatment year, followed by no further active treatment. Results: Treatment with cladribine tablets 3.5 mg/kg resulted in selective reductions in B and T lymphocytes. Lymphocyte recovery began soon after treatment in each of years 1 and 2. Median ALC recovered to the normal range and CD19 + B cells recovered to threshold values by week 84, approximately 30 weeks after the last dose of cladribine tablets in year 2. Median CD4 + T cell counts recovered to threshold values by week 96 (approximately 43 weeks after the last dose of cladribine tablets in year 2). Median CD8 + cell counts never dropped below the threshold value. Conclusion: These results show the dynamics of lymphocyte count changes following treatment with cladribine tablets 3.5 mg/kg. The immune cell repopulation results provide further evidence that cladribine tablets may represent a form of IRT.

Glioblastomas are malignant brain tumors with poor prognosis. Lately, data from clinical studies assessing the role of co-medications in different cancer types suggested reduced mortality and potential anti-tumor activity for statins, angiotensin-I converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (sartans). Here, we analysed the association of co-treatment with statins, ACEI or sartans with outcome in a cohort of 810 patients enrolled in the phase III CENTRIC and phase II CORE trials on the role of the integrin antagonist, cilengitide, in newly diagnosed glioblastoma with or without O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. Progression-free survival (PFS) and overall survival (OS) were analysed for each medication in the pooled patient group. No association was found for co-medication with either drug for PFS or OS. Median OS was 22.1 (statins) versus 22.2 (control) months (HR 1.06, 95% CI 0.81-1.39, p = 0.69), 20.4 (ACEI) versus 22.6 (control) months (HR 1.25, 95% CI 0.96-1.62, p = 0.10), and 21.7 (sartans) versus 22.3 (control) months (HR 0.86, 95% CI 0.61-1.21, p = 0.38). None of the comparisons showed a signal for different PFS or OS when analyses were controlled for MGMT promoter methylation or treatment group (TMZ/RT → TMZ vs. RT + CIL + TMZ → TMZ + CIL). This secondary analysis of two large glioblastoma trials thus was unable to detect evidence for an association of the use of statins, ACEI or sartans with outcome in patients with newly diagnosed glioblastoma. These data challenge the rationale for prospective studies on the possible role of these non-tumor-specific drugs within the concept of drug repurposing.

// Michael Weller 1 , Louis Burt Nabors 2 , Thierry Gorlia 3 , Henning Leske 4 , Elisabeth Rushing 4 , Pierre Bady 5, 6, 7 , Christine Hicking 8 , James Perry 9 , Yong-Kil Hong 10 , Patrick Roth 1 , Wolfgang Wick 11, 12 , Simon L. Goodman 8 , Monika E. Hegi 7 , Martin Picard 8 , Holger Moch 13 , Josef Straub 8 , Roger Stupp 14 1 Department of Neurology, University Hospital Zurich and University of Zurich, Zurich, Switzerland 2 University of Alabama at Birmingham, Birmingham, AL, USA 3 EORTC Data Centre, Brussels, Belgium 4 Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland 5 Department of Education and Research, University of Lausanne, Lausanne, Switzerland 6 SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland 7 Department of Clinical Neurosciences, University Hospital Lausanne, Lausanne, Switzerland 8 Department of Translational and Biomarkers Research, Oncology, Merck KGaA, Darmstadt, Germany 9 Sunnybrook Health Sciences Centre, Toronto, ON, Canada 10 The Catholic University of Korea, Seoul St. Mary’s Hospital, Seoul, Korea 11 Neurology Clinic, University of Heidelberg, Heidelberg, Germany 12 Clinical Cooperation Unit (CCU) Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany 13 Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland 14 Department of Oncology, University Hospital Zurich, Zurich, Switzerland Correspondence to: Michael Weller, e-mail: michael.weller@usz.ch Keywords: glioblastoma, integrin, pSmad, TGF-β, biomarker Received: January 03, 2016 Accepted: January 29, 2016 Published: February 22, 2016 ABSTRACT Integrins αvβ3 and αvβ5 regulate angiogenesis and invasiveness in cancer, potentially by modulating activation of the transforming growth factor (TGF)-β pathway. The randomized phase III CENTRIC and phase II CORE trials explored the integrin inhibitor cilengitide in patients with newly diagnosed glioblastoma with versus without O 6 -methylguanine DNA methyltransferase ( MGMT ) promoter methylation. These trials failed to meet their primary endpoints. Immunohistochemistry was used to assess the levels of the target integrins of cilengitide, αvβ3 and αvβ5 integrins, of αvβ8 and of their putative target, phosphorylation of SMAD2, in tumor tissues from CENTRIC (n=274) and CORE (n=224). αvβ3 and αvβ5 expression correlated well in tumor and endothelial cells, but showed little association with αvβ8 or pSMAD2 levels. In CENTRIC, there was no interaction between the biomarkers and treatment for prediction of outcome. In CORE, higher αvβ3 levels in tumor cells were associated with improved progression-free survival by central review and with improved overall survival in patients treated with cilengitide. Integrins αvβ3, αvβ5 and αvβ8 are differentially expressed in glioblastoma. Integrin levels do not correlate with the activation level of the canonical TGF-β pathway. αvβ3 integrin expression may predict benefit from integrin inhibition in patients with glioblastoma lacking MGMT promoter methylation.

Background This multicentre, open-label, randomized, controlled phase II study evaluated cilengitide in combination with cetuximab and platinum-based chemotherapy, compared with cetuximab and chemotherapy alone, as first-line treatment of patients with advanced non-small-cell lung cancer (NSCLC). Patients and methods Patients were randomized 1:1:1 to receive cetuximab plus platinum-based chemotherapy alone (control), or combined with cilengitide 2000 mg 1×/week i.v. (CIL-once) or 2×/week i.v. (CIL-twice). A protocol amendment limited enrolment to patients with epidermal growth factor receptor (EGFR) histoscore ≥200 and closed the CIL-twice arm for practical feasibility issues. Primary end point was progression-free survival (PFS; independent read); secondary end points included overall survival (OS), safety, and biomarker analyses. A comparison between the CIL-once and control arms is reported, both for the total cohorts, as well as for patients with EGFR histoscore ≥200. Results There were 85 patients in the CIL-once group and 84 in the control group. The PFS (independent read) was 6.2 versus 5.0 months for CIL-once versus control [hazard ratio (HR) 0.72; P = 0.085]; for patients with EGFR histoscore ≥200, PFS was 6.8 versus 5.6 months, respectively (HR 0.57; P = 0.0446). Median OS was 13.6 for CIL-once versus 9.7 months for control (HR 0.81; P = 0.265). In patients with EGFR ≥200, OS was 13.2 versus 11.8 months, respectively (HR 0.95; P = 0.855). No major differences in adverse events between CIL-once and control were reported; nausea (59% versus 56%, respectively) and neutropenia (54% versus 46%, respectively) were the most frequent. There was no increased incidence of thromboembolic events or haemorrhage in cilengitide-treated patients. avb3 and avb5 expression was neither a predictive nor a prognostic indicator. Conclusions The addition of cilengitide to cetuximab/chemotherapy indicated potential clinical activity, with a trend for PFS difference in the independent-read analysis. However, the observed inconsistencies across end points suggest additional investigations are required to substantiate a potential role of other integrin inhibitors in NSCLC treatment. Clinical trial registration ID number NCT00842712.

BACKGROUND: Survival outcomes for patients with glioblastoma remain poor, particularly for patients with unmethylated O(6)-methylguanine-DNA methyltransferase (MGMT) gene promoter. This phase II, randomized, open-label, multicenter trial investigated the efficacy and safety of 2 dose regimens of the selective integrin inhibitor cilengitide combined with standard chemoradiotherapy in patients with newly diagnosed glioblastoma and an unmethylated MGMT promoter. METHODS: Overall, 265 patients were randomized (1:1:1) to standard cilengitide (2000 mg 2×/wk; n = 88), intensive cilengitide (2000 mg 5×/wk during wk 1-6, thereafter 2×/wk; n = 88), or a control arm (chemoradiotherapy alone; n = 89). Cilengitide was administered intravenously in combination with daily temozolomide (TMZ) and concomitant radiotherapy (RT; wk 1-6), followed by TMZ maintenance therapy (TMZ/RT→TMZ). The primary endpoint was overall survival; secondary endpoints included progression-free survival, pharmacokinetics, and safety and tolerability. RESULTS: Median overall survival was 16.3 months in the standard cilengitide arm (hazard ratio [HR], 0.686; 95% CI: 0.484, 0.972; P = .032) and 14.5 months in the intensive cilengitide arm (HR, 0.858; 95% CI: 0.612, 1.204; P = .3771) versus 13.4 months in the control arm. Median progression-free survival assessed per independent review committee was 5.6 months (HR, 0.822; 95% CI: 0.595, 1.134) and 5.9 months (HR, 0.794; 95% CI: 0.575, 1.096) in the standard and intensive cilengitide arms, respectively, versus 4.1 months in the control arm. Cilengitide was well tolerated. CONCLUSIONS: Standard and intensive cilengitide dose regimens were well tolerated in combination with TMZ/RT→TMZ. Inconsistent overall survival and progression-free survival outcomes and a limited sample size did not allow firm conclusions regarding clinical efficacy in this exploratory phase II study.

9569 Background: Avelumab, an FDA-approved human anti–PD-L1 IgG1 monoclonal antibody for patients (pts) with metastatic Merkel cell carcinoma, showed an objective response rate (ORR; by RECIST v1.1) of 31.8% in a second-line phase 2 trial (NCT02155647). We assessed the association of tumor mutational burden (TMB; nonsynonymous somatic variants/megabase), PD-L1 expression, Merkel cell polyomavirus (MCPyV) status, and CD8+ tumor-infiltrating T-cell density with ORR and survival. Molecular profiles (RNAseq and WEX) also were analyzed. Methods: Baseline tumors (n = 36) were profiled using RNAseq and WEX sequencing. PD-L1 expression (≥1% cutoff), MCPyV status, and CD8+ T-cell density at the tumor invasive margin were evaluated by IHC. MHC locus expression was measured with OptiType and loss of heterozygosity (LOH) with LOHHLA. Results: Of 36 pts profiled, 12 had a response, 27 were PD-L1+, and 23 were MCPyV+. The TMB upper tertile and quartile values were 1.34 and 3.16, respectively. Consistent with literature, MCPyV− pts had a higher median TMB (2.72) than MCPyV+ pts (0.49). PD-L1+ tumors trended toward a higher TMB. An empirical cohort-specific TMB cutoff of ≥2 was chosen to include sufficient pts per subgroup. Pts with TMB ≥2 vs TMB < 2 had higher ORR (5 of 11 [45.5%] vs 7 of 25 [28.0%]) and 6-mo PFS rates (60% vs 38%). Among pts with TMB ≥2, the highest ORRs were reported in MCPyV− (4 of 7 pts), PD-L1+ (5 of 9 pts), and CD8+ T-cell density higher than median (5 of 6 pts) subgroups. MHC expression trended with ORR and survival. Higher mean MHC expression was found in pts with CD8+ T-cell density higher than median (p < 0.05). Mutations in antigen presentation genes were detected: LOH at the HLA locus in 9 of 30 pts (28%), including 4 with a response; an NK cell activation signature was also associated with response. These data may suggest that ADCC contributes to response. Factorial analysis of gene signature scores identified signatures (eg, IFNγ, TP53 pathway) associated with MCPyV status and response. Conclusions: Responses in this data set were not attributed to any specific biomarker alone. Future analysis is focused on validating these results and identifying rational drug combinations with avelumab. Clinical trial information: NCT02155647.

Summary Background Cilengitide is a selective αvβ3 and αvβ5 integrin inhibitor. Data from phase 2 trials suggest that it has antitumour activity as a single agent in recurrent glioblastoma and in combination with standard temozolomide chemoradiotherapy in newly diagnosed glioblastoma (particularly in tumours with methylated MGMT promoter). We aimed to assess cilengitide combined with temozolomide chemoradiotherapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter. Methods In this multicentre, open-label, phase 3 study, we investigated the efficacy of cilengitide in patients from 146 study sites in 25 countries. Eligible patients (newly diagnosed, histologically proven supratentorial glioblastoma, methylated MGMT promoter, and age ≥18 years) were stratified for prognostic Radiation Therapy Oncology Group recursive partitioning analysis class and geographic region and centrally randomised in a 1:1 ratio with interactive voice response system to receive temozolomide chemoradiotherapy with cilengitide 2000 mg intravenously twice weekly (cilengitide group) or temozolomide chemoradiotherapy alone (control group). Patients and investigators were unmasked to treatment allocation. Maintenance temozolomide was given for up to six cycles, and cilengitide was given for up to 18 months or until disease progression or unacceptable toxic effects. The primary endpoint was overall survival. We analysed survival outcomes by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00689221. Findings Overall, 3471 patients were screened. Of these patients, 3060 had tumour MGMT status tested; 926 patients had a methylated MGMT promoter, and 545 were randomly assigned to the cilengitide (n=272) or control groups (n=273) between Oct 31, 2008, and May 12, 2011. Median overall survival was 26·3 months (95% CI 23·8–28·8) in the cilengitide group and 26·3 months (23·9–34·7) in the control group (hazard ratio 1·02, 95% CI 0·81–1·29, p=0·86). None of the predefined clinical subgroups showed a benefit from cilengitide. We noted no overall additional toxic effects with cilengitide treatment. The most commonly reported adverse events of grade 3 or worse in the safety population were lymphopenia (31 [12%] in the cilengitide group vs 26 [10%] in the control group), thrombocytopenia (28 [11%] vs 46 [18%]), neutropenia (19 [7%] vs 24 [9%]), leucopenia (18 [7%] vs 20 [8%]), and convulsion (14 [5%] vs 15 [6%]). Interpretation The addition of cilengitide to temozolomide chemoradiotherapy did not improve outcomes; cilengitide will not be further developed as an anticancer drug. Nevertheless, integrins remain a potential treatment target for glioblastoma. Funding Merck KGaA, Darmstadt, Germany.

BackgroundThe CLARITY study demonstrated the benefit of cladribine tablets 3.5 mg/kg (CT3.5) for patients with relapsing MS (RMS). Patients with high disease activity (HDA) RMS are at risk of clinical activity and disability progression.ObjectivePost-hoc analysis of MRI outcomes in CLARITY for CT3.5 vs placebo.MethodsRetrospective analysis using HDA definitions based on relapse history, prior treatment, and MRI characteristics: high relapse activity (HRA) and HRA plus disease activity on treatment (HRA+DAT).ResultsFor cumulative new T1 Gd+ lesions, relative risk ratios (RRR) for both subgroups (HRA: 0.087; 95% CI: 0.052 to 0.144; pConclusionsThe treatment benefit of CT3.5 on MRI outcomes was similar in HDA RMS subgroups and the overall CLARITY study population.Disclaimerhttp://medpub-poster.merckgroup.com/ABN2018DISC_HDAMRI.pdf

BackgroundLymphopenia is expected from the mechanism of action of cladribine tablets 3.5 mg/kg (CT3.5)ObjectiveInvestigate absolute lymphocyte counts (ALC; 312 weeks) and subsets (240 weeks) in RRMS patients receiving 2 annual courses of CT3.5.MethodsPooled data from patients randomised to CT3.5 over 2 years in CLARITY/CLARITY-Extension inclusive of the PREMIERE registry (n=685).ResultsBaseline: median ALC=1.86 × 109/L. Year-1: ALC reached nadir at 9 weeks post-treatment with CT3.5 (1.00 × 109/L). Year-2: ALC reached nadir at Week-55 (0.81 × 109/L), then recovered to the normal range (≥1.00 × 109/L; Week-96). ALC was in normal range in 75% of patients by Week-144. Baseline median CD4+ were 851 cells/µL. Nadirs occurred at Week-16 (385 cells/µL) in Year-1 and at Week-60 (292 cells/µL) in Year-2; values increased after nadirs and regained threshold (350 cells/µL, ~Week-120). Baseline median CD8+ were 378 cells/µL. Nadirs occurred at Week-16 (239 cells/µL; Year 1) and Week-72 (232 cells/µL; Year 2). CD8+ recovered quickly after treatment and remained above 200 cells/µL at all times. Baseline median CD19+ were 205 cells/µL. Nadirs occurred at Week-9 (18 cells/µL; Year-1) and Week-52 (31 cells/µL; Year-2). CD19+ then reached threshold of 100 cells/µL by the end of Year-2.ConclusionLymphocyte recovery begins soon after CT3.5. ALC, CD19+ B and CD4+ T cells; reached threshold by 7.5, 12 and 18 months. CD8+ cells remained above threshold.Disclaimerhttp://medpub-poster.merckgroup.com/ABN2018DISC_LongLymph.pdf

BackgroundPatients with high disease activity (HDA) relapsing-remitting MS are less likely to attain no evidence of disease activity (NEDA; no relapses, MRI activity or progression).ObjectivePost-hoc analysis to compare the proportion of patients with NEDA with cladribine tablets 3.5 mg/kg (CT3.5) vs placebo.MethodsPatients from CLARITY were retrospectively stratified using 2 definitions of HDA based on relapse history, prior treatment, and MRI characteristics: HRA (n=261) and HRA plus disease activity on treatment (HRA+DAT) [n=289]). Data for patients treated with CT3.5 or placebo who fulfilled these criteria and achieved NEDA status were compared over the 2 years using odds ratios (OR) and 95% CI.ResultsHRA subgroup: 76% of CT3.5-treated patients were relapse-free and 84% were T1 Gd+ lesion free vs 49% and 31%, respectively, for placebo. HRA+DAT subgroup: 77% of CT3.5-treated were relapse-free and 85% were T1 Gd+ lesion free vs 50% and 32%, respectively, for placebo. In the HRA and HRA+DAT subgroups, 43.2% and 43.7%, respectively, of CT3.5-treated patients were disease activity free compared with 8.7%, (OR: 8.02; 95% CI: 3.93 to 16.35; pConclusionsTreatment with CT3.5 significantly increased the proportion of HDA patients with NEDA vs placebo.Disclaimerhttp://medpub-poster.merckgroup.com/ABN2018DISC_NEDA.pdf

BackgroundIn CLARITY, cladribine tablets 3.5 mg/kg (CT3.5) demonstrated efficacy in relapsing MS patients. The most common AE was lymphopenia, reflecting cladribine’s mode of action. Integrated safety analysis showed infection incidence was not higher in patients receiving CT3.5 vs placebo, bar a small increase of herpes zoster (HZV).ObjectivePost-hoc analysis examined infectious AEs occurring concurrently with Grade 3/4 lymphopenia (G3/4) in CT3.5 treated patients.MethodsThe AE profile for CT3.5 during the periods of G3/4 was analysed. Adjusted-AE incidences per 100 patient years (Adj-AE/100PY) were calculated in a cohort of patients receiving CT3.5 monotherapy in clinical trials.ResultsData are presented as Adj-AE/100PY: G3/4 vs without G3/4. Adj-AE/100PY for any infections/infestations was 57.53 vs 24.50. Infections were similar between periods. ≥50% cases with G3/4 were easily-treatable upper- respiratory-tract infections (nasopharyngitis: 13.48 vs 5.24; upper-respiratory-tract infection: 9.67 vs 3.41; pharyngitis: 4.51 vs 0.73). HZV occurred in 4 patients with G3/4 (4.50 vs 0.73); cases were dermatomal and mild-to- moderate in severity. Single occurrences were reported for most infectious AEs. Opportunistic infections were single occurrences, not severe, serious or difficult-to-treat.ConclusionsG3/4 increased frequency of infections but did not affect the type of infectious AEs in CT3.5 treated patients. HZV profile was uncomplicated, consistent with findings of previous analyses.Disclaimerhttp://medpub-poster.merckgroup.com/ABN2018DISC_Grade34.pdf

BackgroundCladribine tablets 3.5 mg/kg (CT3.5) demonstrated efficacy in RMS patients in CLARITY/CLARITY-Extension. Lymphopenia was common (CT3.5: mechanism of action).ObjectiveEvaluate whether lymphopenia persists following treatment/re-treatment with CT3.5 in CLARITY/CLARITY- Extension.MethodsLymphopenia by grade for patients randomised to CT3.5 throughout CLARITY/CLARITY-Extension (7 mg/kg cumulative 4 year dose; n=186) are reported. Patients with Grade 0 (G0) lymphopenia (≥1.0 × 109 cells/L) before the first course of CT and G0/1 (≥0.8 × 109 cells/L) before subsequent treatment in Years 2 (Y2), 3 and 4 were analysed.Results176 patients were G0 at the start of CLARITY (167 were G0/1; CLARITY-Extension). G3 lymphopenia was observed in 1% patients (Week-13, Y1), and in 7%, 11% and 12% patients at Week-12 in Y2, 3 and 4. In each year, G3 lymphopenia was observed in 1%, 4%, 4% and 4% patients (Week-24), in 1%, 2%, 2% and 2% patients (Week-36), and in 1% patients (Week-48) in Y2 only. G3 lymphopenia was reported in ConclusionsIn patients meeting treatment/re-treatment guidelines, no G4 lymphopenia occurred at the end of any treatment year; G3 lymphopenia was uncommon. Lymphocyte-based re-treatment criteria minimised the incidence of severe, sustained lymphopenia during 4 years’ treatment with CT.Disclaimerhttp://medpub-poster.merckgroup.com/ABN2018DISC_Year1-4.pdf

ObjectiveTo evaluate the safety and efficacy of cladribine tablets in patients still experiencing active relapsing MS despite interferon (IFN)-β treatment.MethodsA 96-week phase II study, randomizing patients treated with IFN-β to cladribine tablets 3.5 mg/kg/IFN-β or placebo/IFN-β. Patients were to receive cladribine tablets 3.5 mg/kg/IFN-β or placebo/IFN-β in a 2:1 ratio (n = 172) with safety and exploratory efficacy outcomes being assessed.ResultsAdverse events (AEs) and serious AEs were similar across treatment groups, except lymphopenia. Fifty of 124 (40.3%) cladribine/IFN-β recipients vs 0% of placebo/IFN-β recipients reported lymphopenia as an AE, with grade 3/4 lymphopenia (laboratory lymphocyte count < 500 cells/mm3) experienced by 79/124 (63.7%) vs 1 (2.1%), respectively. Patients treated with cladribine tablets 3.5 mg/kg/IFN-β were 63% less likely to have a qualifying relapse than placebo/IFN-β recipients, and cladribine tablets 3.5 mg/kg/IFN-β reduced most MRI measures of disease activity.ConclusionsIn patients with active relapsing MS despite IFN-β treatment, cladribine tablets 3.5 mg/kg/IFN-β reduced relapses and MRI lesion activity over 96 weeks compared with placebo/IFN-β but led to an increased incidence of lymphopenia.Classification of evidenceThis study provides Class I evidence that for patients with active relapsing MS despite IFN-β treatment, cladribine tablets added to IFN-β reduced relapses and MRI lesion activity over 96 weeks and increased the incidence of lymphopenia.Clinical trial registrationNCT00436826.

IntroductionAn independent meta-analysis; Pakpoor et al. Neurol Neuroimmunol Neuroinflamm 2015;2:e158) in Phase III trials (with a 2 year duration) of disease modifying drugs (DMDs) in patients with relapsing multiple sclerosis found no increased rate of malignancy with cladribine tablets (CT) versus other DMD treatments. Data from additional trials involving CT 3.5 mg/kg (CT3.5) and a safety registry (up to 8 years’ follow-up) allow further insights into malignancy risk. Objective is to assess malignancy risk with CT3.5 monotherapy and placebo (PBO) in data from 3 Phase III trials and a registry, and compare the incidence rate with a global database.MethodsThe CT 3.5 population comprised 923 patients (3433 patient-years’ [PY] total exposure time) and the PBO group comprised 641 patients (2026 PY). Individual case reports of malignancies were reviewed by independent, blinded adjudication committee. Standardised incidence ratios (SIR) were calculated using the GLOBOCAN reference population (excluding non-melanoma skin cancers [NMSCs]) and a Danish reference population for NMSC rates.ResultsThe incidence per 100 PY of confirmed malignancy was CT3.5 0.293 (95%CI 0.158–0.544) and PBO 0.148 (95%CI 0.048–0.460); the risk difference 95% CI included 0 (−0.166–0.414). The CT 3.5 malignancy SIR was almost identical (0.97, 95% CI 0.44–1.85) to the GLOBOCAN matched reference population. The PBO group SIR was numerically lower (0.48, 95% CI 0.14–1.53). There were no cases of haematological, lymphoproliferative or virus-induced cancers. There was no clustering of specific tumour types, and the incidence of skin cancer was not increased after treatment with CT3.5 versus PBO. The incidence of malignancies with CT3.5 was constant and did not increase over time.ConclusionAnalysis of malignancy rates in a cohort that includes patients with up to 8 years’ follow-up confirms the Conclusion of the earlier meta-analysis; the incidence of malignancies with CT3.5 is similar to a matched reference population.

IntroductionThe CLARITY and CLARITY Extension studies demonstrated the efficacy of cladribine tablets in patients with relapsing multiple sclerosis. The most common adverse event was lymphopenia, consistent with the mechanism of action of cladribine tablets. Objective was to evaluate whether lymphopenia persists following annual treatment with cladribine tablets.MethodsLymphopenia by grade (NCI CTCAE v3.0) for patients randomised to cladribine tablets 3.5 mg/kg in CLARITY and re-randomised to cladribine tablets 3.5 mg/kg in CLARITY Extension (7 mg/kg cumulative dose over 4 years; n=186) are reported. Patients with Grade 0 lymphopenia (≥1.0×109 cells/L) before the first course of cladribine tablets and Grade 0/1 (≥0.8×109 cells/L) prior to administration in Years 2, 3 and 4 were included in the analysis.Results176 patients were Grade 0 at CLARITY baseline and 167 were Grade 0/1 at CLARITY Extension baseline. Grade 3 lymphopenia was observed in 1% of patients at Week 13 in Year 1, and in 7%, 11% and 12% at Week 12 in Years 2, 3 and 4, respectively. By Week 24 in Years 1, 2, 3 and 4, Grade 3 lymphopenia was observed in 1%, 4%, 4% and 4% of patients, respectively. By Week 36 in Years 1, 2, 3 and 4, Grade 3 lymphopenia was observed in 1%, 2%, 2% and 2% of patients, respectively. Grade 3 lymphopenia was only observed in Week 48 of Year 2 (1% of patients). Grade 3 lymphopenia was reported in ConclusionNo patients included in this analysis experienced Grade 4 lymphopenia at the end of any treatment year. Grade 3 lymphopenia was uncommon. This study demonstrates the effectiveness of lymphocyte-based treatment criteria in minimising the incidence of severe, sustained lymphopenia during treatment with cladribine tablets.

9507Background: Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer with poor prognosis. Studies of second-line chemotherapy for metastatic MCC (mMCC) have reported median progression-fre...

2584Background: M2698 is a potent and selective dual inhibitor of p70S6K and AKT1/3 in the PAM pathway. M2698 has the advantages of being an oral, brain penetrant, PAM pathway inhibitor, which can ...

Introduction La lymphopenie etait l’effet indesirable le plus frequent dans les etudes CLARITY/CLARITY Extension. La numeration absolue des lymphocytes (NAL) revenait a la normale avec le temps. Objectifs Evaluer les effets de cladribine comprimes a la dose de 3,5 mg/kg (CC 3,5) sur les cellules immunitaires innees dans les donnees de patients randomises pour recevoir CC 3,5 (n = 685) ou un placebo (PBO, n = 435). Methodes A l’inclusion (debut de l’etude CLARITY ou CLARITY Extension), la numeration mediane (Q1–Q3) des neutrophiles etait : CC 3,5 = 4,19 × 10E9/L (3,30–5,31) et PBO = 4,20 × 10E9/L (3,41–5,35). A la fin de la 1re annee, la numeration mediane des neutrophiles etait : CC 3,5 = 3,80 × 10E9/L (2,91–4,94) et PBO = 4,24 × 10E9/L (3,28–5,50). A la fin de la 2e annee, la numeration des neutrophiles etait : CC 3,5 = 3,71 × 10E9/L (2,90–4,70) et PBO = 4,30 × 10E9/L (3,32–5,46). Resultats A la fin de la 3e et 4e annee, la numeration des neutrophiles avec CC 3,5 atteignait un plateau a 3,60 × 10E9/L, et avec PBO un plateau a 4,28 × 10E9/L (3,30–5,25) et 3,46 × 109/L (2,49–5,80), respectivement. Avec CC 3,5, la numeration des neutrophiles restait dans la normale (> 2,03 × 10E9/L) pendant les 2 annees de traitement et au-dela, et ≤ 6 ( Discussion A la fin de la 3e et 4e annee, la numeration des neutrophiles avec CC 3,5 atteignait un plateau a 3,60 × 10E9/L, et avec PBO un plateau a 4,28 × 10E9/L (3,30–5,25) et 3,46 × 10E9/L (2,49–5,80). Avec CC 3,5, la numeration des neutrophiles restait dans la normale (> 2,03 × 10E9/L) pendant les 2 annees de traitement et au-dela, et ≤ 6 ( Conclusion Ces donnees de NAL confirment le concept que la selectivite de CC reduit la numeration des cellules immunitaires adaptatives avec un impact relativement mineur sur le systeme immunitaire inne.

Introduction Les etudes CLARITY/CLARITY Extension ont demontre l’efficacite de cladribine comprimes (CC) pour les formes recurrentes de la sclerose en plaques. L’effet indesirable le plus frequent etait la lymphopenie, qui est compatible avec le mecanisme d’action de CC. Objectifs Determiner si la lymphopenie persiste apres traitement et retraitement par CC a la dose de 3,5 mg/kg. Methodes Les grades de lymphopenie (CTCAE v3.0) sont rapportes pour les patients recevant CC 3,5 mg/kg dans l’etude CLARITY et CC 3,5 mg/kg dans l’etude CLARITY Extension (7 mg/kg pendant 4 ans ; n = 186). Les patients presentant une lymphopenie de grade 0 (≥ 1,0 ×109 cellules/L) avant le premier cycle de CC et de grade 0/1 (≥ 0,8 × 109 cellules/L) avant administration de tous les cycles ulterieurs au cours des annees (A) 2/3/4 etaient inclus selon les directives de traitement. Resultats Cent soixante-seize patients presentaient une lymphopenie de grade 0 au debut de l’etude CLARITY et 167 une lymphopenie de grade 0/1 au debut de l’etude CLARITY Extension. Une lymphopenie de grade 3 etait observee chez 1 % des patients au cours de la semaine (S) 13 de l’A1, et chez 7 %, 11 % et 12 % des patients au cours de la S12 de l’A2/3/4, respectivement. A la S24 de chacune des A1/2/3/4, une lymphopenie de grade 3 etait observee chez 1 %, 4 %, 4 % et 4 % des patients, respectivement. Discussion A la S36 des A1/2/3/4, une lymphopenie de grade 3 etait observee chez 1 %, 2 %, 2 % et 2 % des patients, respectivement. A la S48, une lymphopenie de grade 3 n’etait observee qu’au cours de l’A2 (1 % des patients). Une lymphopenie de grade 3 etait rapportee chez Conclusion Les resultats de cette etude demontrent l’efficience des criteres de traitement bases sur les lymphocytes pour minimiser l’incidence de la lymphopenie severe et prolongee pendant un traitement par CC de quatre ans. Informations complementaires Cette etude a ete financee par EMD Serono Inc., une entite de Merck KGaA, Darmstadt, Allemagne (aux Etats-Unis) et Merck Serono SA, Geneve, une filiale de Merck KGaA Darmstadt, Allemagne.

Introduction L’etude CLARITY a demontre l’efficacite de cladribine comprimes (CC) chez des patients atteints d’une forme recurrente de SEP. Les patients a haute activite de la maladie (HDA, pour high diesease activity) ont un risque plus eleve de poussees et de progression du handicap. Objectifs Comparer les resultats d’imagerie par resonance magnetique (IRM) pour CC a la dose de 3,5 mg/kg (CC 3,5) vs. PBO dans deux sous-groupes de patients presentant des signes d’HDA a l’inclusion. Methodes Analyse retrospective de patients randomises pour recevoir CC 3,5 ou PBO a l’aide de criteres HDA (antecedents de poussees/traitement anterieur/caracteristiques de l’IRM) : – activite de poussee elevee (HRA pour high relapse activity ; ≥ 2 poussees au cours de l’annee precedente ± traitement par DMD) ; – HRA + activite de la maladie sous traitement (DAT pour disease activity on treatment). DAT etait caracterisee par ≥ 1 poussee ET ≥ 1 lesion T1 Gd+ ou ≥ 9 lesions T2 au cours de l’annee precedente tout en prenant des DMD. Resultats Nouvelles lesions T1 Gd+ cumulees : le ratio de risque relatif (RRR) pour HRA (0,087) etait significativement inferieur pour CC 3,5 (n = 130) vs. PBO (n = 131). Pour HRA + DAT, le RRR (0,077) etait favorable a CC 3,5 (n = 140) vs. PBO (n = 149). Pour les lesions T2 actives cumulees, le RRR etait egalement favorable a CC 3,5 vs. PBO pour HRA (0,263) et HRA + DAT (0,254). Le RRR pour les lesions uniques combinees cumulees etait favorable a CC 3,5 vs. PBO pour HRA (0,212) et HRA + DAT (0,203). Discussion Il n’y avait aucune interaction significative entre les sous-groupes HDA/non HDA. Lesions T1 Gd+ : les reductions des risques (RR) pour HRA + DAT etaient de 91 % et 92 % (population globale de l’etude CLARITY ; 90 %). Lesions T2 : les RR etaient de 74 % et 75 % (population globale de l’etude CLARITY ; 73 %). Lesions uniques combinees : les RR etaient de 79 % et 80 % (population globale de l’etude CLARITY ; 77 %). Conclusion Chez les patients HDA, CC 3,5 a produit des effets IRM similaires dans l’ensemble de la population CLARITY. Informations complementaires Cette etude a ete financee par EMD Serono Inc, une entite de Merck KGaA, Darmstadt, (aux Etats-Unis) et Merck Serono SA, Geneve, une filiale de Merck KGaA Darmstadt, Allemagne.

Introduction Cladribine comprimes (CC) s’est revele efficace par rapport au placebo (PBO) chez des patients atteints d’une forme recurrente de SEP (etude CLARITY). Les patients a haute activite de la maladie sont moins susceptibles de ne presenter aucun signe d’activite de la maladie. Objectifs Comparer CC a la dose de 3,5 mg/kg (CC 3,5) vs. PBO sur la proportion de patients NEDA dans deux sous-groupes de patients HDA a l’inclusion. Methodes Analyse retrospective de patients randomises pour recevoir CC 3,5 ou PBO a l’aide de criteres HDA (antecedents de poussees/traitement anterieur/caracteristiques de l’IRM) : – activite de poussee elevee (HRA pour high relapse activity ; ≥ 2 poussees au cours de l’annee precedente ± traitement par DMD) ; – HRA + activite de la maladie sous traitement (DAT pour disease activity on treatment). DAT etait caracterisee par ≥ 1 poussee ET ≥ 1 lesion T1 Gd+ ou ≥ 9 lesions T2 au cours de l’annee precedente tout en prenant des DMD. Resultats Dans chaque sous-groupe HDA, la proportion de patients repondant aux criteres individuels NEDA etait superieure avec CC 3,5. Pour HRA, 76 % de patients traites par CC 3,5 (n = 130) n’ont pas eu de poussees et 84 % n’ont pas eu de lesions T1 Gd+ vs. 49 % et 31 %, respectivement, pour PBO (n = 131). Pour HRA + DAT, 77 % n’ont pas eu de poussees et 85 % n’ont pas eu de lesions T1 Gd+ avec CC 3,5 (n = 140) vs. 50 % et 32 %, respectivement pour PBO (n = 149). Discussion Score composite : 43,2 % du sous-groupe HRA et 43,7 % du sous-groupe HRA + DAT chez les patients traites par CC 3,5 ont repondu au critere NEDA par rapport a 8,7 %, et 9,0 % respectivement, pour PBO. Les valeurs etaient significativement moins favorables dans le sous-groupe HRA + DAT que dans le sous-groupe non HDA. Pour l’ensemble de la population de l’etude CLARITY, le score composite NEDA etait egalement favorable a CC 3,5 vs. PBO. Conclusion Chez les patients atteints d’une forme active de SEP recurrente, le traitement par CC 3,5 a significativement augmente la proportion de patients HDA repondant au critere NEDA par rapport au PBO.

Background In the CLARITY study, treatment with cladribine tablets (CT) vs placebo showed strong efficacy in patients with RMS. Post-hoc analysis may provide insights into the efficacy of CT in patients with HDA. Objective To compare the effects of CT 3.5 mg/kg (CT3.5) vs placebo using two HDA definitions. Methods Patients randomised to CT3.5 (n=433) or placebo (n=437) were analysed using two HDA definitions based on high relapse activity ([HRA]≥2 relapses in the previous year) regardless of prior treatment, or a HRA plus treatment nonresponse ([HRA +TNR]≥2 relapses in the previous year, or ≥1 relapse in previous year while on DMD therapy and ≥1 T1 Gd +or ≥9 T2 lesions). Results In the overall population, CT3.5 reduced risk of 6 month EDSS progression by 47% (HR=0.53,95%CI:0.36;0.79) vs placebo. A larger risk reduction for CT3.5 vs placebo of 82% was seen in the HRA and HRA +TNR subgroups (HR=0.18 each,95%CI:0.08;0.44 and 0.07;0.43). ARR was lower with CT3.5 than placebo in the overall population (RR=0.42,95%CI:0.33;0.52), and even lower for HRA (RR=0.32,95%CI:0.22;0.47) and HRA +TNR (RR=0.33;95% CI:0.23;0.48). Conclusions Patients identified by HDA criteria showed clinical and MRI responses to CT3.5 that were generally better than, or at least comparable with, outcomes in the overall CLARITY population.

Background The most common adverse event in CLARITY was lymphopenia, consistent with cladribine tablets (CT) mechanism of action. Objective Investigate absolute lymphocyte count (ALC) in RRMS patients receiving CT 3.5 mg/kg (CT3.5). Methods Patients randomised to CT3.5 for 2 years in CLARITY/CLARITY Extension including time in PREMIERE (n=685) were pooled to provide long-term follow-up data. Patients randomised to placebo are also reported (PBO;n=435). Results At baseline (start of CLARITY/CLARITY Extension), median (Q1–Q3) ALC was 1.86×109/L (1.50–2.29) for CT3.5 and 1.91×109/L (1.54–2.32) for PBO. During Year 1, CT3.5 ALC reached a nadir 9 weeks post-treatment[1.00×109/L (0.80–1.30)]. At the end of Year 1 (48 weeks), ALC increased to 1.21×109/L (0.95–1.50). During Year 2, CT3.5 ALC reached a nadir 7 weeks after re-treatment[0.81×109/L (0.60–1.04)], increasing to 1.03×109/L (0.80–1.30) at the end of Year 2 (96 weeks). At the end of Years 3 and 4 (144 and 192 weeks), ALC in the CT3.5 group (with no further treatment) increased to 1.36×109/L (1.02–1.65) and 1.40×109/L (1.10–1.81), respectively, reaching 1.76×109/L (1.17–2.65) after 6.5 years (312 weeks). In PBO, ALC was between 1.69×109/L (1.45–2.05) and 1.95×109/L (1.59–2.38). Conclusions Rapid reductions in ALC after CT3.5 treatment in Years 1 and 2 were followed by gradual returns toward baseline. ALC was within normal range beyond Year 2 (96 weeks) in all patients with follow-up data.

Background In CLARITY, cladribine tablets (CT) significantly reduced relapse rates in patients with relapsing multiple sclerosis. CLARITY Extension (EXT) compared the effects of 2 years’ additional CT treatment vs no additional treatment. Objective Assess efficacy of 2 courses of CT or placebo (PBO) in CLARITY and 2 additional courses of CT or PBO in EXT. Methods Patients receiving PBO in CLARITY were assigned to CT3.5 mg/kg; those treated with CT (3.5 or 5.25 mg/kg) were re-randomised 2:1 to CT3.5 mg/kg or PBO. Annualised relapse rates (ARR) and proportions qualifying relapse free (RF) were compared for CLARITY vs EXT within the same treatment groups: CT3.5 mg/kg in CLARITY and PBO in EXT (n=98); CT3.5 mg/kg in CLARITY and CT3.5 mg/kg in EXT (n=186); CT5.25 mg/kg in CLARITY and CT3.5 mg/kg in EXT (n=186); PBO in CLARITY and CT3.5 mg/kg in EXT (n=244). Results No significant differences in ARR for CLARITY vs EXT except for PBO in CLARITY and CT3.5 mg/kg in EXT (0.26 vs 0.10, p 70%, except for PBO in CLARITY and CT3.5 mg/kg in EXT (58.0% vs 79.6%, p Conclusions Clinical benefits were maintained in patients who received CT in CLARITY and PBO in EXT demonstrating durable efficacy.

Background The CLARITY study in patients with RMS allows assessment of high disease activity (HDA) definitions for identifying patients with higher rate of relapse or disability progression. Objective Evaluate clinical/MRI criteria to identify HDA among placebo recipients in CLARITY. Methods Placebo recipients in CLARITY (n=437) were analysed using criteria of high relapse activity ([HRA]≥2 relapses in the previous year) regardless of prior treatment, or a HRA plus treatment nonresponse ([HRA +TNR]≥2 relapses in the previous year OR ≥1 relapse in previous year on DMD therapy and ≥1 T1 Gd +or ≥9 T2 lesions). Identification of HDA was assessed by relapse and disability outcomes. Results ARR was higher in the HRA (0.5, 95% CI 0.41–0.60) and HRA+TNR subgroups (0.47, 95% CI 0.40–0.57) than the overall placebo population (0.35, 95% CI 0.31–0.39), and non-HRA and non-HRA +TNR subgroups (0.29, 95% CI 0.24–0.34 each). Time to 6 month confirmed EDSS progression (10% of patients) was 110 days for the HRA subgroup (non-HRA=330 days), 162 days for the HRA+TNR subgroup (non-HRA +TNR =329 days) and 245 days (overall placebo). Conclusions HDA criteria based on relapse history, treatment history and MRI characteristics can identify patients at increased risk of experiencing relapses and disability progression.

Introduction L’efficacite de Cladribine comprime (CC) a ete demontree chez les patients atteints de SEP precoce ou recurrente (SEP-R). Le regroupement des donnees de tolerance pour les analyses integrees permet une caracterisation exhaustive du profil d’effets indesirables (EI) de CC. Objectifs Definir le profil d’EI a partir d’un ensemble integre de donnees de tolerance issues d’etudes evaluant CC a la dose de 3,5 mg/kg (CC3,5) en monotherapie chez des patients atteints de SEP precoce ou SEP-R. Patients et methodes La cohorte de patients recevant la dose de 3,5 mg/kg en monotherapie orale comprenait 923 patients (3432,65 patients-annees [PA] d’exposition) issus des etudes CLARITY, CLARITY Extension, ORACLE-MS et du registre PREMIERE ; dans cette cohorte, 641 patients ont recu le placebo (2025,97 PA). La periode moyenne d’etude pour les patients recevant CC etait de 194 semaines et de 165 semaines pour les patients recevant le placebo (Pbo). Resultats Le taux d’incidence ajuste d’EI pour 100 PA (Aj-EI/100PA) avec CC3,5 et Pbo etaient respectivement : 4 et 3,6 pour EI graves ; 0,26 et 0,25 EI entrainant le deces. Pour les evenements attendus avec CC, les Aj-EI/100PA pour la lymphopenie etaient de 7,94 (CC3,5) et 1,06 (Pbo), et pour la classe de systeme d’organes (SOC) infections et infestations 24,93 (CC3,5) et 27,05 (Pbo) ; zona 0,83 (CC3,5) et 0,20 (Pbo). Les Aj-EI/100PA pour les SOC tumeurs benignes, malignes et non precisees etaient de 1,14 (CC3,5) et 1,01 (Pbo). Discussion Des cas de lymphopenie etaient attendus en raison du mode d’action de Cladribine comprimes ; des cas de zona ont ete rapportes plus frequemment chez les patients presentant une lymphopenie de Grade 3 ou 4 ; pas de cluster de type de cancers et aucun cancer generalement associe a l’immunosuppression n’a ete observe. Conclusion Le profil d’EI pour CC3,5 en monotherapie a ete bien caracterise dans l’ensemble de la population de patients d’atteints de SEP precoce ou de SEP-R active. Informations complementaires L’etude a ete financee par Merck KGaA.

Introduction L’etude CLARITY chez des patients atteints de SEP recurrente a montre que Cladribine Comprimes (CC) administree annuellement pendant 2 ans apportait une amelioration clinique significative vs. placebo (PBO). Objectifs Evaluer l’efficacite de 2 annees de traitement supplementaires avec CC ou PBO dans une extension (EXT) de l’etude CLARITY en comparant les resultats a differents moments dans les memes groupes de patients. Patients et methodes Les taux annualises de poussees (TAP) et le pourcentage de patients consideres sans poussee ont ete compares pour CLARITY et CLARITY EXT dans quatre groupes : patients traites par 1) CC 3,5 mg/kg dans CLARITY et ensuite PBO dans CLARITY EXT ; 2) CC 3,5 mg/kg dans CLARITY et CC 3,5 mg/kg dans CLARITY EXT ; 3) CC 5,25 mg/kg dans CLARITY et CC 3,5 mg/kg dans CLARITY EXT ; 4) PBO dans CLARITY et CC 3,5 mg/kg dans CLARITY EXT. Resultats Aucune difference dans les TAP n’a ete observee entre CLARITY et CLARITY EXT sauf chez les patients recevant PBO dans CLARITY et CC 3,5 mg/kg dans CLARITY EXT (0,26 vs. 0,10, p 70 % des patients de chaque groupe etaient consideres sans poussee ; la seule difference significative a ete observee chez les patients traites par PBO dans CLARITY et CC 3,5 mg/kg dans CLARITY EXT (58,0 % vs. 79,6 %, p Discussion Les patients recevant CC dans CLARITY et PBO dans CLARITY EXT ont maintenu de faibles taux de poussee tout du long. Les patients recevant CC dans CLARITY et CLARITY EXT n’ont montre aucun benefice supplementaire par rapport au traitement par CC dans CLARITY uniquement. Pour les patients recevant PBO dans CLARITY, le passage a CC dans CLARITY EXT a significativement reduit le TAP et a augmente le pourcentage de patients sans poussee. Conclusion CC a entraine des benefices cliniques durables : les patients recevant CC dans CLARITY et PBO dans CLARITY EXT ont montre des resultats similaires aux patients recevant CC dans CLARITY et CLARITY EXT. Informations complementaires L’etude a ete financee par Merck KGaA.

The ADVANTAGE trial investigated cilengitide (CIL; integrin inhibitor) + cisplatin/5-fluorouracil/cetuximab (PFE) in recurrent/metastatic squamous cell cancer of the head/neck. In the here reported open-label, controlled phase 2 part, 182 patients were randomized to PFE alone or PFE + CIL 2000 mg once/twice weekly. In neither of the CIL arms a progression-free survival benefit vs PFE alone was seen., Background Recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M-SCCHN) overexpresses αvβ5 integrin. Cilengitide selectively inhibits αvβ3 and αvβ5 integrins and is investigated as a treatment strategy. Patients and methods The phase I/II study ADVANTAGE evaluated cilengitide combined with cisplatin, 5-fluorouracil, and cetuximab (PFE) in R/M-SCCHN. The phase II part reported here was an open-label, randomized, controlled trial investigating progression-free survival (PFS). Patients received up to six cycles of PFE alone or combined with cilengitide 2000 mg once (CIL1W) or twice (CIL2W) weekly. Thereafter, patients received maintenance therapy (cilengitide arms: cilengitide plus cetuximab; PFE-alone arm: cetuximab only) until disease progression or unacceptable toxicity. Results One hundred and eighty-two patients were treated. Median PFS per investigator read was similar for CIL1W + PFE, CIL2W + PFE, and PFE alone (6.4, 5.6, and 5.7 months, respectively). Accordingly, median overall survival and objective response rates were not improved with cilengitide (12.4 months/47%, 10.6 months/27%, and 11.6 months/36%, respectively). No clinically meaningful safety differences were observed between groups. None of the tested biomarkers (expression of integrins, CD31, Ki-67, vascular endothelial growth factor receptor 2, vascular endothelial-cadherin, type IV collagen, epidermal growth factor receptor, or p16 for human papillomavirus) were predictive of outcome. Conclusion Neither of the cilengitide-containing regimens demonstrated a PFS benefit over PFE alone in R/M-SCCHN patients.

Clinical features that are prognostic indicators of placebo response among dyskinetic Parkinson's disease patients were determined. Placebo-associated improvements occur in Parkinsonism, but responses in dyskinesia have not been studied. Placebo data from two multicenter studies with identical design comparing sarizotan to placebo for treating dyskinesia were accessed. Sarizotan (2 mg/day) failed to improve dyskinesia compared with placebo, but both treatments improved dyskinesia compared with baseline. Stepwise regression identified baseline characteristics that influenced dyskinesia response to placebo, and these factors were entered into a logistic regression model to quantify their influence on placebo-related dyskinesia improvements and worsening. Because placebo-associated improvements in Parkinsonism have been attributed to heightened dopaminergic activity, we also examined the association between changes in Parkinsonism and dyskinesia. Four hundred eighty-four subjects received placebo treatment; 178 met criteria for placebo-associated dyskinesia improvement and 37 for dyskinesia worsening. Older age, lower baseline Parkinsonism score, and lower total daily levodopa doses were associated with placebo-associated improvement, whereas lower baseline dyskinesia score was associated with placebo-associated worsening. Placebo-associated dyskinesia changes were not correlated with Parkinsonism changes, and all effects in the sarizotan group were statistically explained by the placebo-effect regression model. Dyskinesias are affected by placebo treatment. The absence of correlation between placebo-induced changes in dyskinesia and Parkinsonism argues against a dopaminergic activation mechanism to explain placebo-associated improvements in dyskinesia. The magnitude and variance of placebo-related changes and the factors that influence them can be helpful in the design of future clinical trials of antidyskinetic agents.

The objective of this study is to conduct a dose-finding study of sarizotan in Parkinson's disease (PD) patients with dyskinesia to identify a safe dose and to identify a sensitive dyskinesia rating measure. Sarizotan is a novel compound with full 5-HT(1A) agonist properties and additional high affinity for D(3) and D(4) receptors. An open label study documented improvements in PD patients with levodopa-induced dyskinesia. There is no precedent for study designs or outcome measures in pivotal trials of antidyskinesia therapies. The approach used here was a multicenter, randomized, placebo-controlled, double-blind, parallel study. Included were PD patients optimized to levodopa and dopaminergic drugs with moderately disabling dyskinesias present greater than or equal to 25% of the waking day. Interventions included sarizotan 2, 4, or 10 mg/day or matching placebo, given in two doses. There were two outcome measures: the primary measure was change from baseline in diary-based on time without dyskinesia; the secondary measures were change from baseline in scores on the Abnormal Involuntary Movement Scale (AIMS), the composite score of Unified Parkinson's Disease Rating Scale (UPDRS) Items 32+33 (dyskinesia duration and disability) and total UPDRS. A total of 398 subjects were randomized, with 381 included in the intention-to-treat population. No significant changes occurred on sarizotan compared to placebo on any diary-based measure of dyskinesia or the AIMS score. The composite score of UPDRS Items 32+33 was significantly improved with 2 mg/day sarizotan, with a trend at 10 mg/day. Adverse events were not significantly different in sarizotan- and placebo-treated patients, but off time significantly increased with sarizotan 10 mg/day. Sarizotan 2 mg/day is a safe agent in PD patients with dyskinesia. To test its role in abating dyskinesia, future studies should focus on this dose and will use the composite score of UPDRS Items 32+33 as the primary outcome.

Aim: CIL is a selective, competitive inhibitor of avb3 and avb5 integrins designed to attack the tumour and its microenvironment. CERTO is a multicentre, controlled, open-label phase II study (NCT00842712) for pts with histologically confirmed newly diagnosed advanced NSCLC. Methods: Pts were initially randomised 1:1:1 to receive cetuximab plus platinum-based chemotherapy alone (CTRL), or combined with CIL 2000 mg 1x/week (CIL1W) or 2x/week (CIL2W). During the study, an amendment triggered by cetuximab data from the FLEX study led to enrolment only of pts with EGFR histoscore ≥200, and closure of CIL2W due to feasibility issues. Primary endpoint was progression-free survival (PFS; independent read); secondary endpoints included overall survival (OS), safety, and biomarker analyses. Results: Overall, 220 pts were randomised: 85 to CIL1W; 51 to CIL2W; and 84 to CTRL. Baseline characteristics were balanced. Median PFS (independent read, ITT) was 6.2 mo in CIL1W vs 5.0 mo in CTRL (HR 0.72 [95% CI, 0.49, 1.05]; p = 0.085). For pts with EGFR ≥200, median PFS was 6.8 mo in CIL1W vs 5.6 mo in CTRL (HR 0.57 [95% CI, 0.32, 0.99], p = 0.045). Investigator-read PFS was not different between CIL1W and CTRL in either population. Median OS was 13.6 vs 9.7 mo in CIL1W vs CTRL, respectively (ITT; HR 0.81 [95% CI, 0.56, 1.17]; p = 0.265); in pts with EGFR ≥200 no difference between CIL1W vs CTR for OS was found. Generally, no relevant differences between adverse events across treatment arms were reported; nausea (56%), neutropaenia (49%), and anaemia (37%) were the most frequent, and there was no increased incidence of thromboembolic events or haemorrhages in CIL-treated pts. Biomarker sample size was small, but avb3 and avb5 expression did not reveal a prognostic correlation to PFS or OS, and was not predictive of treatment outcome. Conclusions: A benefit for addition of CIL1W to cetuximab and chemotherapy was seen for independent-read PFS, and a HR 0.81 for OS, equivalent to a 3.9 mo median survival improvement in favour of the combination, but no consistent efficacy was shown with CIL vs CTRL. The safety profile did not reveal any safety concerns for CIL. Disclosure: J.F. Vansteenkiste: Advisory board: advisory functions for Merck-Serono; F. Barlesi: Corporate-sponsored research: Merck; J. Bennouna: Advisory Board: Roche, Boehringer Ingelheim and Novartis; E. Goekkurt: Advisory board: Merck; H. Lena: Advisory board: Merck; C. Hicking: Ownership: Stock Ownership Merck KGaA Other substantive relationships: Employee of trial sponsor; J. Straub: Other substantive relationships:: Employee of the trial Merck; M. Picard: Other substantive relationships: Employee of the trial sponsor; W. Schuette: Advisory Board: Merck, Amgen, AstraZeneca, Roche Corporate-sponsored research: Roche, Lilly, AstraZeneca, Amgen, Genentech, Daiichi Sankyo; K. O' Byrne: Advisory board: for cetuximab non small lung cancer Corporate-sponsored research: Grant received for clinical trial which was completed 5 years ago Other substantive relationships: Honoraria for speaker bureau lectures. All other authors have declared no conflicts of interest.

LBA2009 Background: Cilengitide (CIL) is a selective αvβ3 and αvβ5 integrin inhibitor. In a phase II study in patients with newly diagnosed glioblastoma, CIL added to standard temozolomide (TMZ) and radiotherapy (RT) was well tolerated and appeared to confer improved survival in patients with glioblastoma and methylated MGMT gene promoter (Stupp et al. J Clin Oncol. 2010;28:2712-8). Methods: This multicenter, randomized, controlled, open-label, phase III study randomized (1:1) patients (≥ 18 years) with newly diagnosed, histologically proven supratentorial glioblastoma (WHO Grade IV) and centrally determined MGMT gene promoter methylation. Treatment consisted of CIL 2000 mg twice weekly i.v. plus standard TMZ/RT→TMZ (concomitant and adjuvant temozolomide and radiotherapy; Stupp et al. N Engl J Med. 2005;352:987-96) or standard TMZ/RT→TMZ alone. CIL was to be administered for ≥ 18 months, or until disease progression or unacceptable toxicity. Primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS) per investigator read and safety. Results: 272 patients received CIL plus TMZ/RT→TMZ, and 273 were treated with TMZ/RT→TMZ alone (intention-to-treat population). 54% and 52% of patients were male, and 42% and 44% had ECOG-PS ≥ 1, respectively. 75% of patients of both arms were ≥ 50 years old. Overall, baseline characteristics were well balanced across treatment arms. Median OS was 26.3 months in both arms (Hazard Ratio [HR] = 1.02 [95%CI: 0.81-1.29], p = 0.86). Median PFS per investigator read was 13.5 months in the CIL arm and 10.7 months in the control arm (HR = 0.93 [95%CI: 0.76-1.14], p = 0.48). Treatment was generally well tolerated and the known safety profile of CIL was confirmed. Conclusions: CIL failed to prolong PFS or OS in patients with newly diagnosed glioblastoma and methylated MGMT gene promoter. The previously reported safety profile of CIL in addition to standard therapy was confirmed. Clinical trial information: NCT00689221.

LBA2009 The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Sunday, June, 2, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Sunday edition of ASCO Daily News.

2010 Background: Prognosis of patients with recurrent glioblastoma multiforme (GBM) is poor. Cilengitide is an investigational selective αvβ3/5 integrin inhibitor with multiple anti-tumor effects. ...

TPS151 Background: Expected median survival is poor for patients with glioblastoma multiforme (GBM). Cilengitide, an investigational selective αvβ3/5 integrin inhibitor, has demonstrated antitumor activity against GBM in previous phase II studies. CORE (cilengitide in combination with temozolomide [TMZ] and radiotherapy [RTX]) will assess the efficacy and safety of 2 regimens of cilengitide in GBM patients with an unmethylated MGMT promoter. The study is a companion trial to CENTRIC, which includes patients with newly diagnosed GBM with methylated MGMT promoter. Methods: CORE is a phase II, randomized, multicenter, open-label, controlled, trial investigating 2 regimens of i.v. cilengitide in combination with standard therapy [RTX/TMZ then TMZ; Stupp et al NEJM 2005] vs standard therapy alone (2:2:1 ratio). The 2 cilengitide regimens compare 2,000 mg twice weekly vs. 2,000 mg 5 times weekly on each day of RTX during 6 weeks of RTX/TMZ, followed by cilengitide 2,000 mg twice-weekly combined with TMZ, follow...

Purpose Invasion and migration are key processes of glioblastoma and are tightly linked to tumor recurrence. Integrin inhibition using cilengitide has shown synergy with chemotherapy and radiotherapy in vitro and promising activity in recurrent glioblastoma. This multicenter, phase I/IIa study investigated the efficacy and safety of cilengitide in combination with standard chemoradiotherapy in newly diagnosed glioblastoma. Patients and Methods Patients (age ≥ 18 to ≤ 70 years) were treated with cilengitide (500 mg) administered twice weekly intravenously in addition to standard radiotherapy with concomitant and adjuvant temozolomide. Treatment was continued until disease progression or for up to 35 weeks. The primary end point was progression-free survival (PFS) at 6 months. Results Fifty-two patients (median age, 57 years; 62% male) were included. Six- and 12-month PFS rates were 69% (95% CI, 54% to 80%) and 33% (95% CI, 21% to 46%). Median PFS was 8 months (95% CI, 6.0 to 10.7 months). Twelve- and 24-month overall survival (OS) rates were 68% (95% CI, 53% to 79%) and 35% (95% CI, 22% to 48%). Median OS was 16.1 months (95% CI, 13.1 to 23.2 months). PFS and OS were longer in patients with tumors with O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation (13.4 and 23.2 months) versus those without MGMT promoter methylation (3.4 and 13.1 months). The combination of cilengitide with temozolomide and radiotherapy was well tolerated, with no additional toxicity. No pharmacokinetic interactions between temozolomide and cilengitide were identified. Conclusion Compared with historical controls, the addition of concomitant and adjuvant cilengitide to standard chemoradiotherapy demonstrated promising activity in patients with glioblastoma with MGMT promoter methylation.