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Stroke survivors with right-brain damage (RBD) often present with attentional deficits such as left unilateral spatial neglect. Some patients also present with contralesional visual hemi-field deficits. A late detection of visual hemi-field deficits (VHFD) contributes to hampering neurorehabilitation and functional outcome of patients with neglect. The Brentano Illusion Test (BRIT) may be used for an early detection of VHFD during the neuropsychological assessment. In the present study, we determined the sensitivity and specificity of the BRIT for screening VHFD in patients with neglect. Sixty-four consecutive RBD patients were examined. Forty-five presented with neglect. Of these, 23 presented with VHFD (hemianopia or quadrantanopia) as detected by the Humphrey automated static visual field testing (reference standard). Consecutive patients also included 19 participants without neglect, who did not have any VHFD. The sensitivity and specificity of the BRIT for neglect patients were 78.3% (95% CI: 61.4–95.1) and 90.9 (95% CI: 78.9–100.0), respectively. Positive predictive value (PPV) was 89.6% (95% CI: 76.4–100.0); negative predictive value (NPV) 80.7% (95% CI: 65.2–96.2). No false positives in the group without neglect were identified. We conclude that the BRIT is an effective tool for clinical neuropsychologists to screen for possible VHFD in neglect patients during the neuropsychological assessment, allowing the refinement of the clinical picture in the neuropsychological report. An early detection of VHFD also allows referring the patient to standard diagnostics for a formal visual field examination, right from the first neuropsychological assessment.

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Purpose: The cyclin-dependent kinase (CDK) 4/6 inhibitor, ribociclib (LEE011), displayed preclinical activity in neuroblastoma and malignant rhabdoid tumor (MRT) models. In this phase I study, the maximum tolerated dose (MTD) and recommended phase II dose (RP2D), safety, pharmacokinetics (PK), and preliminary activity of single-agent ribociclib were investigated in pediatric patients with neuroblastoma, MRT, or other cyclin D–CDK4/6–INK4–retinoblastoma pathway-altered tumors.Experimental Design: Patients (aged 1–21 years) received escalating once-daily oral doses of ribociclib (3-weeks-on/1-week-off). Dose escalation was guided by a Bayesian logistic regression model with overdose control and real-time PK.Results: Thirty-two patients (median age, 5.5 years) received ribociclib 280, 350, or 470 mg/m2. Three patients had dose-limiting toxicities of grade 3 fatigue (280 mg/m2; n = 1) or grade 4 thrombocytopenia (470 mg/m2; n = 2). Most common treatment-related adverse events (AE) were hematologic: neutropenia (72% all-grade/63% grade 3/4), leukopenia (63%/38%), anemia (44%/3%), thrombocytopenia (44%/28%), and lymphopenia (38%/19%), followed by vomiting (38%/0%), fatigue (25%/3%), nausea (25%/0%), and QTc prolongation (22%/0%). Ribociclib exposure was dose-dependent at 350 and 470 mg/m2 [equivalent to 600 (RP2D)–900 mg in adults], with high interpatient variability. Best overall response was stable disease (SD) in nine patients (seven with neuroblastoma, two with primary CNS MRT); five patients achieved SD for more than 6, 6, 8, 12, and 13 cycles, respectively.Conclusions: Ribociclib demonstrated acceptable safety and PK in pediatric patients. MTD (470 mg/m2) and RP2D (350 mg/m2) were equivalent to those in adults. Observations of prolonged SD support further investigation of ribociclib combined with other agents in neuroblastoma and MRT. Clin Cancer Res; 23(10); 2433–41. ©2017 AACR.

Purpose: Ribociclib (an oral, highly specific cyclin-dependent kinase 4/6 inhibitor) inhibits tumor growth in preclinical models with intact retinoblastoma protein (Rb+). This first-in-human study investigated the MTD, recommended dose for expansion (RDE), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of ribociclib in patients with Rb+ advanced solid tumors or lymphomas.Experimental Design: Patients received escalating doses of ribociclib (3-weeks-on/1-week-off or continuous). Dose escalation was guided by a Bayesian Logistic Regression Model with overdose control principle.Results: Among 132 patients, 125 received ribociclib 3-weeks-on/1-week-off and 7 were dosed continuously. Nine dose-limiting toxicities were observed among 70 MTD/RDE evaluable patients during cycle 1, most commonly neutropenia (n = 3) and thrombocytopenia (n = 2). The MTD and RDE were established as 900 and 600 mg/day 3-weeks-on/1-week-off, respectively. Common treatment-related adverse events were (all-grade; grade 3/4) neutropenia (46%; 27%), leukopenia (43%; 17%), fatigue (45%; 2%), and nausea (42%; 2%). Asymptomatic Fridericia's corrected QT prolongation was specific to doses ≥600 mg/day (9% of patients at 600 mg/day; 33% at doses >600 mg/day). Plasma exposure increases were slightly higher than dose proportional; mean half-life at the RDE was 32.6 hours. Reduced Ki67 was observed in paired skin and tumor biopsies, consistent with ribociclib-mediated antiproliferative activity. There were 3 partial responses and 43 patients achieved a best response of stable disease; 8 patients were progression-free for >6 months.Conclusions: Ribociclib demonstrated an acceptable safety profile, dose-dependent plasma exposure, and preliminary signs of clinical activity. Phase I–III studies of ribociclib are under way in various indications. Clin Cancer Res; 22(23); 5696–705. ©2016 AACR.

Fig. S1. Waterfall plot of duration of exposure vs. best percentage change from baseline; Figure S2. Duration of exposure in patients with stable disease treated for at least four cycles; Figure S3. Duration of exposure, best percentage change in target lesion, and genetic profile for the 53 patients with available genetic data.

A typical consequence of stroke in the right hemisphere is unilateral spatial neglect. Distinct forms of neglect have been described, such as space-based (egocentric) and object-based (allocentric) neglect. However, the relationship between these two forms of neglect is still far from being understood, as well as their neural substrates. Here, we further explore this issue by using voxel lesion symptoms mapping (VLSM) analyses on a large sample of early subacute right-stroke patients assessed with the Apples Cancellation Test. This is a sensitive test that simultaneously measures both egocentric and allocentric neglect. Behaviourally, we found no correlation between egocentric and allocentric performance, indicating independent mechanisms supporting the two forms of neglect. This was confirmed by the VLSM analysis that pointed out a link between a damage in the superior longitudinal fasciculus and left egocentric neglect. By contrast, no association was found between brain damage and left allocentric neglect. These results indicate a higher probability to observe egocentric neglect as a consequence of white matter damages in the superior longitudinal fasciculus, while allocentric neglect appears more “globally” related to the whole lesion map. Overall, these findings on early subacute right-stroke patients highlight the role played by white matter integrity in sustaining attention-related operations within an egocentric frame of reference.

BACKGROUND: Hemispatial neglect is a complex syndrome associated with a reduced capability to orient attentional resources toward the contralateral side of space, that involves a collection of symptoms [1]. We used three functional magnetic resonance imaging (fMRI) tasks (i.e., visual search, VS; line bisection, LB; extinction, EX), performed by 25 healthy subjects, to investigate the behavioral and neural correlates under these symptoms. MATERIALS AND METHODS: During fMRI, participants were presented with: 1) VS: an array containing 8-12 stimuli such as O-like (target) and Q-like (distractors) shapes projected on both sides; 2) LB: a bisected line covering 18° of visual angle; 3) EX: a black square (target) of 2x2° that equiprobably appeared on either the left, right or both hemifields. Participants pressed one of three response buttons to indicate: left, right and bilateral (i.e., for EX) or central (i.e., for LB). RESULTS: fMRI data showed an increased activation in the right angular gyrus comparing bilateral vs. unilateral stimulus in EX, and a bilateral occipital activation comparing high vs. low load stimulus in VS, highlighting that in both cases subjects make an effort performing the task. These results are confirmed behaviourally, in fact subjects are less accurate when they are presented with bilateral (97,8% vs. 99,5% in unilateral) and high load (88,9% vs. 93,1% low load) stimulus. There are no significant activations regarding LB task. CONCLUSIONS: We found that in healthy conditions the right attentional network is involved in processing simultaneous stimuli and bilateral visual cortex is involved in processing the high load of stimuli. Our findings provide a prior knowledge that can be used to compare with attentional mechanisms in neglect patients performing the same tasks. This will allow us to cluster at least three neglect symptoms, in terms of brain activations raised from compensation mechanisms, due to brain impairments. [This work was funded by a grant from the Italian Ministry of Health (GR-2013-02358098) awarded to B. Spano'].

The triadic taxonomy posits that three distinct types of body representations do exist, namely the body schema (BS), which corresponds to the representation derived from multiple sensory and motor inputs, the body structural representation (BSR), which corresponds to the structural description of spatial relations among the body parts, and the body semantics (SEM), which corresponds to the lexical-semantic representation of the body. Although several studies have assessed neural correlates of these representations, no study has compared them in brain-damaged patients, controlling for deficits in other cognitive domains. Also, little is known about the contribution of the right hemisphere to different body representations. Here we used a computerized battery to test these three body representations in twenty-six right brain damaged patients, controlling for other cognitive deficits by means of tests tapping similar spatial and lexical processes on non-body related stimuli. Residual scores corresponding to the BS, the BSR and the SEM were used to test neural correlates, which were assessed by integrating topological and hodological approaches to lesion-deficit analyses. We found that the BSR was associated with lesion of the superior temporal gyrus, the insula, the supramarginal gyrus and the temporo-parietal junction, extending also to the Rolandic operculum and the inferior frontal gyrus. Also, it was associated with the disconnection probability of the posterior arcuate segment. The BS was associated with a small cluster of voxels in the precentral and postcentral gyri, whereas the SEM was associated with white matter lesion at the boundary between the parietal and temporal lobes. Overall, these results provide strong support to the regional and connectional contribution of the right hemisphere to body representation, and more specifically to the BSR.

It has been proposed that not completely overlapping brain networks support interval timing depending on whether or not an external, predictable temporal cue is provided during the task, aiding time estimation. Here we tested this hypothesis in a neuropsychological study, using both a topological approach - through voxel-based lesion-symptom mapping (VLSM), that assesses the relation between continuous behavioral scores and lesion information on a voxel-by-voxel basis - and a hodological approach, using an atlas-based tractography. A group of patients with unilateral focal brain lesions and their matched controls performed a duration reproduction task assessing time processing in two conditions, namely with regularly spaced stimuli during encoding and reproduction (Regular condition), and with irregularly spaced stimuli during the same task (Irregular condition). VLSM analyses showed that scores in the two conditions were associated with lesions involving partly separable clusters of voxels, with lower performance only in the Irregular condition being related to lesions involving the right insular cortex. Performance in both conditions correlated with the probability of disconnection of the right frontal superior longitudinal tract, and of the superior and middle branches of the right superior longitudinal fasciculus. These findings suggest that the dissociation between timing in regular and irregular contexts is not complete, since performance in both conditions relies on the integrity of a common suprasecond timing network. Furthermore, they are consistent with the hypothesis that tracking time without the aid of external cues selectively relies on the integration of psychophysiological changes in the right insula.

Purpose: The cyclin-dependent kinase (CDK) 4/6 inhibitor, ribociclib (LEE011), displayed preclinical activity in neuroblastoma and malignant rhabdoid tumor (MRT) models. In this phase I study, the maximum tolerated dose (MTD) and recommended phase II dose (RP2D), safety, pharmacokinetics (PK), and preliminary activity of single-agent ribociclib were investigated in pediatric patients with neuroblastoma, MRT, or other cyclin D–CDK4/6–INK4–retinoblastoma pathway-altered tumors. Experimental Design: Patients (aged 1–21 years) received escalating once-daily oral doses of ribociclib (3-weeks-on/1-week-off). Dose escalation was guided by a Bayesian logistic regression model with overdose control and real-time PK. Results: Thirty-two patients (median age, 5.5 years) received ribociclib 280, 350, or 470 mg/m2. Three patients had dose-limiting toxicities of grade 3 fatigue (280 mg/m2; n = 1) or grade 4 thrombocytopenia (470 mg/m2; n = 2). Most common treatment-related adverse events (AE) were hematologic: neutropenia (72% all-grade/63% grade 3/4), leukopenia (63%/38%), anemia (44%/3%), thrombocytopenia (44%/28%), and lymphopenia (38%/19%), followed by vomiting (38%/0%), fatigue (25%/3%), nausea (25%/0%), and QTc prolongation (22%/0%). Ribociclib exposure was dose-dependent at 350 and 470 mg/m2 [equivalent to 600 (RP2D)–900 mg in adults], with high interpatient variability. Best overall response was stable disease (SD) in nine patients (seven with neuroblastoma, two with primary CNS MRT); five patients achieved SD for more than 6, 6, 8, 12, and 13 cycles, respectively. Conclusions: Ribociclib demonstrated acceptable safety and PK in pediatric patients. MTD (470 mg/m2) and RP2D (350 mg/m2) were equivalent to those in adults. Observations of prolonged SD support further investigation of ribociclib combined with other agents in neuroblastoma and MRT. Clin Cancer Res; 23(10); 2433–41. ©2017 AACR.

Visual-evoked potentials (VEPs) were recorded in seventeen patients with unilateral lesions of the right hemisphere (RH) and visuospatial neglect. Hemispheric differences were detected for VEP components in the time window from 130 to 280 msec; this result replicates data from a previous study using a larger group of patients (Di Russo et al., 2008). Three patients were tested twice; their hemispheric differences, i.e., the differences in latency and amplitude of VEPs to ipsilesional and contralesional stimuli, were evaluated at the beginning and end of visuospatial rehabilitation training for neglect. The hemispheric differences were limited to components anterior N1 (N1a), posterior N1 (N1p) and P2 (not C1 and P1) and showed a significant decrease after training; amelioration at the behavioural level was also observed. Fourteen patients were tested only once, at different steps of their training. For the overall group, we determined the correlation between VEP hemispheric differences and the number of sessions attended by the patients at the time of VEP recording. The correlation was negative, the higher the number of sessions, the lower the hemispheric asymmetry, and high, ranging from .45 to .64, for both the latency and amplitude of the N1p and P2 components, and for the amplitude of the N1a component. The correlation between VEP hemispheric differences and time from onset (TFO) of the pathological event was not significant. Overall, the hemispheric differences between specific components of the VEP responses to lateralised stimuli appear to be a good marker of recovery from neglect.

The aim of the present study was to verify if gender differences in verbal and visuo-spatial working memory would persist following right cerebral lesions. To pursue our aim we investigated a large sample (n. 346) of right brain-damaged patients and healthy participants (n. 272) for the presence of gender effects in performing Corsi and Digit Test. We also assessed a subgroup of patients (n. 109) for the nature (active vs. passive) of working memory tasks. We tested working memory (WM) administering the Corsi Test (CBT) and the Digit Span (DS) using two different versions: forward (fCBT and fDS), subjects were required to repeat stimuli in the same order that they were presented; and backward (bCBT and bDS), subjects were required to repeat stimuli in the opposite order of presentation. In this way, passive storage and active processing of working memory were assessed. Our results showed the persistence of gender-related effects in spite of the presence of right brain lesions. We found that men outperformed women both in CBT and DS, regardless of active and passive processing of verbal and visuo-spatial stimuli. The presence of visuo-spatial disorders (i.e., hemineglect) can affect the performance on Corsi Test. In our sample, men and women were equally affected by hemineglect, therefore it did not mask the gender effect. Generally speaking, the persistence of the men's superiority in visuo-spatial tasks may be interpreted as a protective factor, at least for men, within other life factors such as level of education or kind of profession before retirement.

Several rehabilitative approaches have been used to reduce neglect disorders. Some studies tried to demonstrate that hemineglect can be ameliorated by using tasks promoting attentional activation towards the neglected hemispace (Robertson et al., 1995, 2001). As a consequence, a functional link between level of attention and disorders of space exploration has been proposed. For this reason we tried to explore the possible role of attentional deficits on the efficacy of a standard neglect treatment based on visuo spatial rehabilitation. In this study we then examined the performances of a selected group of seven right brain damaged patients, suffering from both severe hemineglect and attentional deficits (of both phasic and tonic components of attention), to several tasks before and after a visuo-spatial training (VST) whose efficacy has been already demonstrated (Pizzamiglio et al., 1992). Results showed that VST induces a significant remission of hemineglect symptoms independently from disorders of attention. Moreover, after visuo-spatial rehabilitation, no improvement of attentional deficits is detectable.

Operating Characteristics 100 6.3 Methodology 1026.3.1 Base Model 102 6.3.2 Metrics for Dosing Recommendations 1046.3.2.1 Posterior Distributions 104 6.3.2.2 Predictive Distributions 106 6.3.2.3 Formal Decision Analysis 1066.3.3 Prior Distributions 106 6.3.3.1 Weakly Informative Priors 107 6.3.3.2 Prior Effective Sample Size 107 6.3.3.3 Meta-Analytic-Predictive (MAP) Priors 108 6.3.3.4 Mixture Priors 1096.3.4 Combination Models 111 6.3.4.1 Combination of Two Agents 112 6.3.4.2 Combination of Three Agents 1146.4 Applications 115 6.4.1 Dual-Combination Trial 1156.4.1.1 Study Design 115 6.4.1.2 Model and Prior Distributions 115 6.4.1.3 Trial Conduct: Dose Escalations andMTD Declaration 117 6.4.2 Triple-Combination Trial 1206.4.2.1 Study Design 120Phase I trials are still perceived by many as simple. Although this is controversial in the single-agent setting, it is certainly mistaken for combinations of two or more compounds. In oncology, the challenges are many: while keeping patient safety within acceptable limits, the trials should be small, adaptive, and enable a quick declaration of the maximum tolerable dose (MTD) and/or recommended phase II dose (RP2D).

Purpose: Ribociclib (an oral, highly specific cyclin-dependent kinase 4/6 inhibitor) inhibits tumor growth in preclinical models with intact retinoblastoma protein (Rb+). This first-in-human study investigated the MTD, recommended dose for expansion (RDE), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of ribociclib in patients with Rb+ advanced solid tumors or lymphomas. Experimental Design: Patients received escalating doses of ribociclib (3-weeks-on/1-week-off or continuous). Dose escalation was guided by a Bayesian Logistic Regression Model with overdose control principle. Results: Among 132 patients, 125 received ribociclib 3-weeks-on/1-week-off and 7 were dosed continuously. Nine dose-limiting toxicities were observed among 70 MTD/RDE evaluable patients during cycle 1, most commonly neutropenia (n = 3) and thrombocytopenia (n = 2). The MTD and RDE were established as 900 and 600 mg/day 3-weeks-on/1-week-off, respectively. Common treatment-related adverse events were (all-grade; grade 3/4) neutropenia (46%; 27%), leukopenia (43%; 17%), fatigue (45%; 2%), and nausea (42%; 2%). Asymptomatic Fridericia's corrected QT prolongation was specific to doses ≥600 mg/day (9% of patients at 600 mg/day; 33% at doses >600 mg/day). Plasma exposure increases were slightly higher than dose proportional; mean half-life at the RDE was 32.6 hours. Reduced Ki67 was observed in paired skin and tumor biopsies, consistent with ribociclib-mediated antiproliferative activity. There were 3 partial responses and 43 patients achieved a best response of stable disease; 8 patients were progression-free for >6 months. Conclusions: Ribociclib demonstrated an acceptable safety profile, dose-dependent plasma exposure, and preliminary signs of clinical activity. Phase I–III studies of ribociclib are under way in various indications. Clin Cancer Res; 22(23); 5696–705. ©2016 AACR.

The aim of this study was to evaluate the efficacy and safety of rivastigmine as add-on treatment to specific cognitive rehabilitation for unilateral spatial neglect (USN). Twenty patients were randomly assigned either to rehabilitation treatment only (No-RIV) or to rivastigmine (3 mg twice a day, for 8 weeks) add-on treatment (RIV+,). USN and functional status were evaluated by means of specific and validated instruments at baseline, at discharge and at one-month follow up. Compared with the untreated patients, the RIV+ subjects, at discharge, recorded significantly better discharge scores and higher effectiveness on two of the scales. However, subsequent further improvement of the No-RIV patients meant that at follow up there was no significant difference between the two groups. No other statistically significant difference was found. Rivastigmine as add-on treatment to specific cognitive training for USN may improve and accelerate recovery on some specific impairment tests as compared with cognitive training alone.

According to Kosslyn, two types of spatial relations can be used to arrange parts in mental imagery, i.e., categorical spatial relations and coordinate spatial relations, which are processed respectively by the left and right hemispheres. To investigate this possible hemispheric specialization in the imagery domain, we tested 34 left or right brain-damaged patients using both a categorical and a coordinate mental imagery task. The results show that left brain-damaged patients were selectively impaired on processing categorical representations, while right brain-damaged patients were more impaired on the processing the coordinate ones, regardless of the presence of visuo-spatial neglect. The present study partly support Kosslyn's theory and, despite data reported in previous studies of brain-damaged patients, it also supports the hypothesis of a possible bilateral neural representation of mental imagery, with the two hemispheres taking part in this process in different ways.

s S663 and refractory MM patients a significant humoral immune response against proteins related with these three conditions. Materials and Methods: We studied repository serum with clinical data included in MGUS, naive and refractory MM. We performed a systematic multivariate analysis of proteins overexpressed in monoclonal gammopathy as representative of a potential start to create preventive vaccines for MM and in refractory cancer patients who progress despite treatment. We found four potential oncogenic drivers such as HIF-1 alpha, RAD51, Sox2 and Mcl-1. Afterwards we performed an antigen–specific indirect ELISA for both IgG and IgA using recombinant proteins to interrogate human MGUS naive and refractory MM serum and demonstrated if they were immunogenic. Results: Using indirect ELISA both antigen specific IgG and IgA using recombinant proteins with the four proteins we only found a statistical difference for anti-Mcl-1 specific IgG in MGUS (p = 0.01), naive MM (p = 0.005) and relapsed MM (p = 0.05). For anti-Mcl-1 IgA we found in MGUS (p=0001), naive MM (p = 0.002) and relapsed MM (p = 0.01). Here, we showed that even in refractory MM the antigenspecific humoral immune response was detected and it was clear that patients with the highest immune responses had better clinical outcomes in terms of OS. Discussion: MM is a challenging hematological malignancy and immune therapy is a good possibility for treatment either to prevent recurrence or in combination to improve the outcomes of the current standard of care treatment. We showed that one out of the four proteins had biological and clinical relevance in MGUS, naive and relapsed MM is immunogenic both for IgG and IgA. We will move forward to prepare a peptide vaccine and test animal immunogenicity for Mcl-1. Also it could be a good approach in combination with standard of care treatment in progressive or active disease to improve clinical outcomes. No conflict of interest. Proffered Paper Session (Monday, 28 September) Melanoma and Skin Cancer

Aphasia is considered a risk factor for disability after stroke. The aim of this study was to assess the specific influence of aphasia on rehabilitation results.A case-control study in consecutive left brain-damaged stroke inpatients, enrolled in three homogeneous subgroups [nonaphasic (NA) patients, aphasic with comprehension deficit (CD), and without comprehension deficit (NCD)] matched for age and onset-admission interval. Rehabilitation results (gain, efficiency, effectiveness of treatment, percentage and odds ratio of dropouts and of each degree of therapeutic response, assessed by Barthel Index and Rivermead Mobility Index) were compared among the subgroups.Two hundred and forty patients with sequelae of a first stroke were enrolled. CD patients, as compared with NCD and NA ones, had a significantly more severe basal neurological and functional status at admission, minor effectiveness on ADL and mobility, a higher percentage of low responders on ADL and urinary incontinence at discharge, and a risk of low therapeutic response on ADL nearly 4 times higher than the other patients (OR = 4.22, 95% CI = 1.90-9.38). The rehabilitative behavior between NCD and NA was similar. However, all subgroups (NA, CD and NCD) showed a significant improvement (p0.001) between their basal and discharge score, both on BI and RMI.Comprehension language deficit was confirmed to be a strong negative rehabilitation prognostic factor despite the speech therapy done by all CD patients.

Aim: SMARCB1 mutations are observed in the majority of malignant rhabdoid tumors (MRTs) rendering them dependent on cyclin D1 (CCND1) for genesis and survival. Genetic aberrations in CCND1 and CDK4 are frequent in neuroblastoma cell lines. LEE011 is an orally bioavailable, selective inhibitor of CDK4/6 that has demonstrated tumor growth inhibition in MRT and neuroblastoma preclinical models. In this Phase I study, LEE011 is being investigated in patients (pts) with MRT, neuroblastoma, or other cancers with documented cyclin D–CDK4/6–INK4a–Rb pathway aberrations. Methods: Pts (aged 1–21 years) receive escalating once-daily doses of LEE011 on a 3-weeks-on, 1-week-off schedule. Dose escalation is guided by a Bayesian Logistic Regression Model with overdose control principle and real-time PK. Primary objective: MTD and/or recommended dose for expansion (RDE) determination. Secondary objectives: safety, PK, and efficacy. Results: As of April 8, 2014, 22 pts (11 MRT [9 primary central nervous system (CNS) and 2 extra-CNS], 10 neuroblastoma, and 1 CDK4-amplified alveolar rhabdomyosarcoma) have received LEE011: 5 at 280 mg/m2; 9 at 350 mg/m2; 8 at 470 mg/m2. The median age was 5 (1–20) years. Two DLTs were reported: 1 Grade (G)3 fatigue at 280 mg/m2; 1 G4 thrombocytopenia at 470 mg/m2. Study drug-related all-grade AEs (N = 20; ≥20%) included neutropenia (75%), leukopenia (65%), anemia (40%), thrombocytopenia (40%), lymphopenia (35%), vomiting (25%), decreased appetite (20%), electrocardiogram QT prolongation (20%), fatigue (20%), and nausea (20%). G3/4 AEs (>10%) included neutropenia (70%), leukopenia (35%), thrombocytopenia (25%), and lymphopenia (15%). Preliminary PK analysis showed that exposure following 280 and 350 mg/m2 is comparable to equivalent doses in adults and slightly higher at 470 mg/m2. LEE011 is rapidly absorbed with Tmax ranging from 1–4 hrs (median: 2–3 hrs) across dose levels. To date, best response obtained is stable disease. Conclusions: LEE011 demonstrated an acceptable safety profile and dose-dependent PK. Enrollment continues to identify the MTD/RDE and there will be expansion arms for pts with MRT or neuroblastoma at the RDE. Disclosure: S.G. Dubois: is the site PI for industry sponsored clinical trials (Merck and Novartis). He is also the study chair for a trial funded by Millennium; A. Marabelle: is a member of Advisory Boards for Novartis, BMS, Roche/Genentech, Celgene, Bayer, and Flexus Biotech; S. Modak: has served on an advisory board for Novartis for an unrelated drug; R. Kan: is an employee of and holds shares in Novartis Pharma AG A. Matano: is an employee of Novartis Pharma AG; S.G. Bhansali: is an employee of and holds shares in Novartis Pharmaceuticals Corporation; S. Parasuraman: is an employee of and holds shares in Novartis Pharma AG.All other authors have declared no conflicts of interest.

9009 Background: NRAS-mutant melanoma has poor prognosis with no approved targeted therapies. Enhanced MAPK pathway signaling and cell cycle checkpoint dysregulation are frequent in NRAS-mutant mel...

2528^ Background: LEE011, an orally bioavailable, highly specific CDK4/6 inhibitor, causes cell cycle arrest and tumor growth inhibition in multiple preclinical models with intact retinoblastoma pr...

535 Background: Aromatase inhibitors (AIs) are the recommended first-line endocrine therapy for postmenopausal (PM) patients (pts) with ER+/HER2– advanced/metastatic breast cancer (aBC). However, resistance develops over time. Activation of the PI3K/AKT/mTOR pathway and downstream cyclin D–cyclin-dependent kinase (CDK4/6) has been implicated in endocrine-therapy resistance. Combination of the mTOR inhibitor everolimus (EVE) with exemestane (EXE) significantly improved PFS of pts with ER+/HER2– aBC (BOLERO-2), and preclinical data suggest that combination of EXE, EVE, and the CDK4/6 inhibitor LEE011 may be even more effective in endocrine-resistant ER+/HER2– BC. Methods: During Phase (Ph) Ib, PM pts with ER+/HER2– aBC are being treated with escalating doses of LEE011 (3 wks on/1 wk off), EVE (continuous), and a fixed daily dose of EXE (25 mg/d; continuous; arm 1); or with a safety run-in of LEE011 (600 mg/d; 3 wks on/1 wk off) and EXE (25 mg/d; continuous; arm 2) to confirm the recommended Ph II dose (RP2D...

Background: LEE011 is an oral small molecule inhibitor with highly specific nanomolar inhibitory activity against CDK4/cyclinD1 and CDK6/cylinD3 complexes. Preclinical studies with LEE011 have demonstrated robust anti-tumor activity in several tumor models with functional retinoblastoma protein (pRb). Methods: The primary objective this phase 1 dose escalation study was to determine the maximum tolerated dose (MTD) based on cycle 1 dose-limiting toxicities (DLTs) and establish the recommended dose for expansion (RDE) of LEE011 in patients (pts) with pRb-positive advanced solid tumors or lymphomas. Using a Bayesian logistic regression model with overdose control principle, escalating doses of LEE011 were administered daily for 21 days of 28-day cycles. Following MTD determination, a continuous dosing schedule was also evaluated. Evaluation of safety and pharmacokinetics (PK) from all pts contributed to defining the RDE. Results: As of June 28, 2013, a total of 70 pts were treated in the escalation phase at doses from 50-1200 mg. DLTs are described in the table. MTD was defined at 900 mg on a 21 of 28-day dosing schedule. Additional patients were treated at 750 mg and 600 mg on the current schedule and at 600 mg on a continuous schedule to define the RDE and sustain optimal long-term dosing. Following review of PK and safety data, including AEs observed beyond cycle 1, the planned RDE is 600 mg for 21 days of a 28-day treatment cycle. Common adverse events (AEs) were gastrointestinal (nausea 40%, diarrhea 30%) and hematologic (anemia 43%, neutropenia 40%); the majority of AEs were grades 1/2 and reversible. Asymptomatic QTc prolongation was observed at the higher doses. LEE011 is absorbed orally with Tmax ≈ 4 hours and effective t1/2 ≈24 hours. Dose-dependent increases in exposure were observed. Preliminary evidence of activity was observed including stable disease for ≥ 6 cycles in 10/70 pts (14%) and 1 confirmed partial response in a pt with ER-positive breast cancer. Preliminary tumor pharmacodynamic data shows evidence of modulation at doses of 600 mg and above. Conclusions: LEE011, a highly selective inhibitor of CDK4/6, exhibited an acceptable safety profile, dose dependent PK, and preliminary clinical activity. Enrollment will continue in the expansion phase. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A276. Citation Format: Jeffrey R. Infante, Geoffrey I. Shapiro, Petronella O. Witteveen, John F. Gerecitano, Vincent Ribrag, Rashmi Chugh, Abhijit Chakraborty, Alessandro Matano, Xumei Zhao, Sudha Parasuraman, Philippe A. Cassier. Phase 1 multicenter, open label, dose-escalation study of LEE011, an oral inhibitor of cyclin-dependent kinase 4/6, in patients with advanced solid tumors or lymphomas. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A276.

A comprehensive assessment of both selective (focused attention, divided attention) and intensive (alertness and vigilance) attentional processes was performed on 106 patients with closed head injury using a computerised battery for the evaluation of attention. All patients were tested at least five months after their accident. A high percentage of patients were pathological in tests mapping the selective components of attention while only a minority were impaired on tests mapping the intensive components of attention. Three different subgroups of patients with consistent performance patterns were evidenced. The psychometric characteristics of the battery and its possible clinical usefulness are discussed.

530 Background: AUY922 is a novel HSP90 inhibitor that causes degradation of oncogenic proteins. A Phase I study in advanced solid tumors gave a recommended Phase II dose (RP2D) of 70 mg/m2. In the Phase II part of the study, single-agent AUY922 showed preliminary activity in HER2+ metastatic breast cancer (mBC) (Schröder et al ASCO 2011). This Phase Ib/II study assessed safety and efficacy of AUY922 + trastuzumab (T) in pts with T-refractory HER2+ advanced/mBC. Methods: Pts with HER2+ BC (ECOG PS ≤1) who progressed on 1–2 prior anti-HER2 regimens with at least 1 T-containing regimen, received weekly AUY922 (55 or 70 mg/m2, IV) + T (2 mg/kg) in a 28-day cycle. The Phase Ib primary objective was to define a MTD/RP2D of AUY922 combined with T using an adaptive Bayesian logistic regression model. The Phase II primary objective is to evaluate preliminary antitumor activity at this dose (ORR). Secondary objectives included evaluation of PK, safety and preliminary efficacy (PFS, OS). Results: In the Phase Ib part (11 pts) there was 1 DLT (Grade [Gr] 3 diarrhea), and the full standard single dose of AUY922 was recommended for use in combination with T. As of 11th January 2012, 31 HER2+ BC pts (median age 51 years [range 29–71]; 84% invasive ductal carcinoma; 52% estrogen receptor-positive; 81% had received ≥2 prior antineoplastic regimens) received AUY922 at 55 mg/m2 (n=5) or 70 mg/m2 (n=26) + T. The most common study drug-related AEs (all Gr) were diarrhea (25 [81%] pts), visual AEs (e.g. vision blurred, visual impairment, photopsia) (25 [81%] pts), and nausea (11 [35%] pts). Gr 3/4 AEs were rare; most frequently diarrhea and visual impairment (both 6%). Treatment was ongoing for 13 (37%) pts at the cutoff date. Preliminary Phase II best overall response data (RECIST, investigator assessed) was available for 22 pts at AUY922 70 mg/m2. Any partial responses were reported in 5/22 (23%) pts. Conclusions: The data suggests AUY922 + T is well tolerated. Common AEs were considered manageable, and eye disorders were reversible with treatment interruption, dose reduction or discontinuation. The combination of AUY922 + T is active in pts with HER2+ mBC who progressed on T-based therapy, and the regimen warrants further investigation.