Citations

8522 Background: CC-223 is an ATP-competitive inhibitor of the mTOR kinase, including both TORC1 and TORC2 complexes. CC-223 was selected to address resistance of rapamycin analogues mediated by TORC2 activation. Methods: Following establishment of the MTD (reported at ASCO 2012), subjects with advanced DLBCL, MM and select solid tumors were enrolled in parallel expansion cohorts of up to 20 evaluable subjects. CC-223 was dosed at 45 mg once daily in 28 day cycles until disease progression. Results: As of 09 January, 2013, 35 subjects were enrolled including DLBCL (21) and MM (14). Results in solid tumor cohorts are reported separately. The most common (> 20%) related adverse events (all grades) were fatigue, hyperglycemia, rash, anorexia, nausea, vomiting and diarrhea. In addition, related serious adverse events included infection (2), pneumonitis (1), renal insufficiency (2), pancreatitis (1) and thrombocytopenia (1). CC-223 dose reduction was required in 9 subjects (27%), usually during cycle 1 or 2, and 4 additional subjects with DLBCL dropped out during cycle 1 due to toxicity. Systemic exposure was similar between the two tumor cohorts and was associated with inhibition of TORC1 (p4EBP1) and TORC2 (pAKT) biomarkers in blood cells. Reduction in glucose uptake (32 – 98% decrease) on PET imaging at day 15 was observed in 7/7 DLBCL subjects with results currently available. Three of 17 evaluable subjects with DLBCL had partial responses (PR) after 2 cycles; two with rapid and near complete regression (> 90%) of target lesions by CT and PET with PR confirmed and treatment ongoing at 6 and 8 cycles. Both had failed multiple prior treatment regimens (5 and 3, respectively), including autologous stem cell transplant (ASCT). No responses were observed in 10/14 evaluable subjects with MM although 2 subjects have prolonged stable disease (SD) with treatment ongoing at 12 and 14 cycles. Conclusions: Encouraging signals of biomarker and clinical activity were observed in DLBCL, including two near complete responses, which are ongoing. Due to dose reductions and interruptions, a starting dose of 30 mg QD is recommended for future studies. Clinical trial information: NCT01177397.

8517 Background: An increased risk of SPM in MM pts treated with len has been reported. We performed an IPD metanalysis to estimate the incidence of SPM according to len exposure. Methods: Randomized studies of MM, from PubMed and ASCO/IMW/ASH (after 2000), that met the following criteria, were included: randomization to treatment with len (len-trials); randomization to treatment including new drug but not len (no-len-trials); available SPM data. Primary aim was to estimate cumulative incidence of SPMs by len exposure, corrected for death (competing event). Results: Data from 6,383 pts (3,218 from 8 len-trials, 3,165 from 10 no-len-trials) were analyzed. Median age was 69 years. During follow-up (median=30 mos) 420 (6.6%) SPMs were reported: 188 (2.9%) hematologic and 232 (3.6%) solid cancers. Solid tumors occurred with similar incidence in all groups. Incidence of hematologic SPM was significantly higher in patients receiving len (3.2 vs 1.1, p=0.04), but risk is limited to patients treated with melphalan+len (4.1, 95%CI: 2.4-5.8) with no excess in other combinations (len without melphalan: 1.2, 0.0-2.6; melphalan without len: 1.1, 0.0-2.7) (p=0.003). The cumulative incidence of death for any cause was much higher than the risk of SPM. Conclusions: The risk of hematologic SPMs was higher in pts receiving melphalan+len. The benefit/risk profile of len treatment remains positive. Cumulative incidence (%) of SPMs and death (95%CI). [Table: see text]

Abstract Light chain cast nephropathy (LCCN) in multiple myeloma often leads to severe and poorly reversible acute kidney injury. Severe renal impairment influences the allocation of chemotherapy and its tolerability; it also affects patient survival. Whether renal biopsy findings add to the clinical assessment in predicting renal and patient outcomes in LCCN is uncertain. We retrospectively reviewed clinical presentation, chemotherapy regimens, hematologic response, and renal and patient outcomes in 178 patients with biopsy-proven LCCN from 10 centers in Europe and North America. A detailed pathology review, including assessment of the extent of cast formation, was performed to study correlations with initial presentation and outcomes. Patients presented with a mean estimated glomerular filtration rate (eGFR) of 13 ± 11 mL/min/1.73 m2, and 82% had stage 3 acute kidney injury. The mean number of casts was 3.2/mm2 in the cortex. Tubulointerstitial lesions were frequent: acute tubular injury (94%), tubulitis (82%), tubular rupture (62%), giant cell reaction (60%), and cortical and medullary inflammation (95% and 75%, respectively). Medullary inflammation, giant cell reaction, and the extent of cast formation correlated with eGFR value at LCCN diagnosis. During a median follow-up of 22 months, mean eGFR increased to 43 ± 30 mL/min/1.73 m2. Age, β2-microglobulin, best hematologic response, number of cortical casts per square millimeter, and degree of interstitial fibrosis/tubular atrophy (IFTA) were independently associated with a higher eGFR during follow-up. This eGFR value correlated with overall survival, independently of the hematologic response. This study shows that extent of cast formation and IFTA in LCCN predicts the quality of renal response, which, in turn, is associated with overall survival.

5546 Background: CHFR, an E3 ubiquitin ligase that regulates Aurora A and Pololike Kinase 1, plays a critical role in the cellular response to mitotic stress. In particular, cells containing CHFR arrest in G2 when microtubule dynamics are disrupted. Conversely, low CHFR expression is associated with hypersensitivity to mitotic spindle poisons in breast cancer cell lines. Despite the extensive use of taxanes in front line treatment of epithelial ovarian cancer (EOC), little is known about CHFR expression in this disease. We examined CHFR expression and its relationship with clinical characteristics and outcome in women with EOC. Methods: Pretreatment EOC samples from women enrolled in the Mayo Clinic Biospecimen Resource for Ovarian Cancer Research who underwent initial surgical debulking between 1999-2009 were stained in triplicate with anti-CHFR antibodies. Samples were scored in a blinded fashion for CHFR expression. Associations between CHFR staining and histology, grade, and stage were assessed using chi-squared tests; associations between CHFR and overall survival (OS) or time to disease recurrence (TTR) were assessed using Cox proportional hazards models. Results: Samples from 354 women were stained; median age at diagnosis was 60.5 (range 21-93). At a median follow-up of 67 months, 221 women (62%) had died. Across all patients, moderate/strong CHFR staining was associated with poor OS (HR = 1.39, 95% CI: 1.07-1.81, p = 0.015). Moreover, moderate/strong CHFR expression was strongly associated with serous histology (p < 0.0001), high grade (p < 0.0001) and advanced stage (p = 0.0002). To assess whether the association between CHFR expression and OS was related to taxane sensitivity, a subgroup analysis was performed in the subset of patients (N=131) with high-grade serous EOC who received initial platinum/taxane chemotherapy. Moderate/strong CHFR expression failed to correlate with OS (HR=0.91, 95% CI: 0.57-1.45, p = 0.68) or TTR from the start of chemotherapy (HR = 0.85, 95% CI: 0.55-1.31, p = 0.55) in this subset. Conclusions: CHFR expression is associated with poor OS and adverse clinical characteristics in patients with EOC but does not appear to be related to taxane sensitivity in high-grade serous tumors.

3637 Background: In the CORRECT phase III trial, the multikinase inhibitor REG demonstrated significant improvement in overall survival and progression-free survival vs placebo (P) in patients with mCRC whose disease had progressed on other standard therapies. The most frequent grade 3 AEs were hand–foot skin reaction (HFSR), fatigue, diarrhea, hypertension, and rash. We examined when these AEs first occurred and what impact they had on REG dosing. Methods: Adults with mCRC progressing after all standard therapies were randomized to receive REG 160 mg (n=505) or P (n=255) orally once daily for the first 3 weeks of each 4-week cycle. AEs were managed with dose modifications (reduction and interruption) according to the protocol. Results: The safety population comprised 753 pts (REG n=500, P n=253). The mean ± SD treatment duration was 12.1 ± 9.7 weeks for REG and 7.8 ± 5.2 weeks for P. Treatment-emergent AEs occurred in 99.6% of REG pts and 96.8% of P pts. AEs occurring in ≥10% more REG than P pts were fatigue, HFSR, anorexia, diarrhea, weight loss, voice changes, hypertension, rash/desquamation, oral mucositis, fever, hyperbilirubinemia, and low platelet count. The incidence of grade ≥3 HFSR, fatigue, hypertension, and rash/desquamation typically peaked in cycle 1 and tapered to a relatively stable lower incidence over later cycles, while the incidence of diarrhea remained relatively constant throughout the study; median time to first occurrence and worst grade of these AEs is shown in the table. AEs led to dose modifications in 66.6% of REG pts and 22.5% of P pts. Conclusions: The most common AEs in the REG group typically occurred early during treatment. Close early monitoring of AEs and proper management by dose modification is recommended. Clinical trial information: NCT01103323. [Table: see text]

3514 Background: In the CORRECT phase III trial, the multikinase inhibitor regorafenib (REG) demonstrated significant improvement in overall survival (OS) and progression-free survival (PFS) vs placebo (Pla) in patients with metastatic colorectal cancer (mCRC) whose disease had progressed on other standard therapies. An exploratory biomarker subanalysis was conducted to identify protein biomarkers with potential predictive or prognostic value. Methods: Fifteen proteins of interest, many of which are involved in angiogenesis, were quantified by multiplex immunoassay or ELISA in baseline plasma samples collected at study entry from 80% (611/760) of patients. Potential predictive and prognostic effects were evaluated. Results: The biomarker subpopulation was representative of the overall study population in terms of OS and PFS. Using OS as the clinical endpoint, Tie-1 was the only protein whose level demonstrated significant correlation with efficacy (low protein group: REG/Pla, HR 0.87; high protein group, HR 0.56; interaction, p=0.035). Using PFS as the clinical endpoint, von Willebrand factor (VWF) was the only protein whose level demonstrated significant correlation with efficacy (low protein group: REG/Pla, HR 0.39; high protein group, HR 0.60; interaction, p=0.02). Following correction for multiple testing, neither Tie-1 nor VWF data retained statistical significance. Baseline levels of IL-8 and placental growth factor (PlGF) were found to have prognostic value for OS (IL-8: high/low protein levels, HR 3.48, p<0.001; PIGF: HR 1.81, p=0.002). IL-8 was also prognostic for PFS (high/low protein levels: HR 1.63, p<0.001). Conclusions: None of the plasma proteins examined showed significant predictive value for REG efficacy after multiple testing correction. The association between baseline levels of Tie-1/VWF and REG efficacy may be a hypothesis to be tested in further trials. Clinical trial information: NCT01103323.

e14507 Background: Regorafenib, an oral multikinase inhibitor of VEGFR2/3, PDGFRb, KIT, FGFR, RET, RAF and TIE2, is efficacious in refractory mCRC but its mechanism of action is unclear and predictive biomarkers are lacking. Methods: We assessed tumor and circulatory biomarkers in a phase 2 study of regorafenib in refractory mCRC patients. Regorafenib was administered orally at 160mg/d for 3 out of 4 weeks. Post cycle 2 response was assessed by RECIST 1.1. Subjects were scheduled for FDG PET-CT scans (pre + D15) and paired core needle tumor biopsies for IHC analysis (pre + D21) in cycle 1. Archival tumor mutations were evaluated using Sequenom MassARRAY OncoCarta Panel V1.0 assay. Results: 35 patients were treated; 49% received > 4 prior therapies and 43% had prior bevacizumab. Median PFS was 3.45 mths (95% CI: 3.40-3.49), ORR was 3% and disease control rate [DCR] (PR + SD at 8 wks) was 57%. Early PET responses (EORTC criteria) were seen in 49%, but did not predict for DCR (p=1.0). Fatigue, hand foot skin reaction (HFSR), voice change and diarrhea occurred in > 30% of subjects. Grade 3-5 toxicities occurred in 46%, the commonest being HFSR and rash (17% each). Median relative dose intensity was 92%; 43% required > 1 dose reduction, 60% required > 1 dose interruption. KRAS (29%), BRAF (9%), EGFR (9%), NRAS (6%) KIT (3%), PIK3CA (3%), PDGFRA (3%) and CDK (3%) mutations were detected in archival tumors. None predicted for ORR or DCR; PFS was identical in KRAS mutant vs wt patients (3.45 mths, p=0.39) and similar in BRAF mutant vs wt patients (3.48 vs 3.45 mths, p=0.10). The patient with the longest PFS (12.6 mths) had a BRAF mutation. Amongst the 10 paired tumor samples available, IHC markers upregulated in >50% cases were pMEK, pERK, pJun and pJNK, whilst those downregulated/ unchanged in >50% were pKIT, pVEGFR2, CD31 [vascular endothelial cells (ECs)] and podoplanin (lymphatic ECs). The greatest change was observed in podoplanin expression, corresponding to a 60% reduction in lymphatic vessel density. Conclusions: FDG-PET responses in cycle 1 did not predict for regorafenib clinical benefit in mCRC patients. Targeting lymphatic/vascular ECs in the tumor microenvironment may be a more significant antitumor mechanism of regorafenib than MAP kinase pathway inhibition. Clinical trial information: NCT01189903.

1596 Background: Structured feedback from community oncologists regarding trial design rarely occurs. Survey templates were created to assess trial feasibility, design and scientific interest from the community, with the aim of improving accrual. We report results from a survey regarding redesign of the Phase III CODEL trial for newly diagnosed 1p/19q codeleted AG, which employed this approach. Methods: A field-tested, online survey template was tailored for CODEL and emailed to U.S. and international oncologists. The survey assessed (a) practice changes resulting from ASCO 2012 data from RTOG 9402 (abstract # 2008b) and EORTC 26951 (abstract # 2); (b) scientific interest in a redesigned trial; and (c) potential accrual issues. Respondents reviewed a brief trial concept and answered 15 questions anonymously via a web-based system. Results: 173 oncologists completed the survey over 2 weeks in Sept 2012(48% US, 52% Int’l; 35% med oncs, 31% rad oncs, 29% neuro-oncs). Results from the 2 prior studies substantially influenced clinicians’ treatment decisions for patients with newly diagnosed 1p19q codeleted AG--from only 9% recommending RT+PCV prior to the ASCO reports, to 46% after the results were presented. Previously, 25% recommended RT alone, and after ASCO, no one did. Most indicated strong interest in the revised CODEL research questions, trial design, randomization arms, and in re-opening the revised trial. The most interesting schema was a 3-arm design (selected by 45% of respondents): (RT + procarbazine, CCNU and vincristine chemotherapy [PCV]) vs. (RT + Temozolomide [TMZ]) vs. (TMZ alone), with neuro-oncs (49%) preferring it most, and rad oncs least (36%). The second most interesting choice (27%) was RT+PCV vs. RT+TMZ; the third choice (20%) was RT+TMZ vs. TMZ alone. Most (61%) felt patients would accept any arm. Respondents encountered eligible patients frequently enough to meet projected CODEL accrual goals. Conclusions: Survey findings significantly influenced decisions on how best to redesign the CODEL trial. Rapid, web-based surveys of community oncologists can provide important feedback regarding level of interest, which might facilitate timely accrual and trial completion.

9047 Background: Symptomatic adverse events (AE) in cancer trials are reported by clinicians using the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE). To integrate the patient perspective into AE reporting, NCI contracted (HHSN261201000043C) to create a patient-reported outcomes companion tool (PRO-CTCAE). We report the validity and reliability of PRO-CTCAE’s 124 items reflecting 78 symptomatic AEs. Methods: English-speaking subjects (n=869; 44% male; median [mdn] age 59; 32% racial/ethnic minority; 34% high school or less; 17% ECOG Performance Status [PS] 2-4) receiving treatment for a range of cancers at 4 NCI-designated cancer centers and 5 sites in NCI's Community Cancer Centers Program completed a web-based survey in clinic including PRO-CTCAE and EORTC QLQ-C30. Pearson correlations were computed between PRO-CTCAE items and QLQ-C30 scales. Differences in PRO-CTCAE item scores between clinician-reported ECOG PS (0-1 vs 2-4) groups were computed. Test-retest reliability of 48 prespecified items was evaluated in a subset (n=79). Results: Correlations in the expected direction were observed for 116/124 PRO-CTCAE items with the QLQ-C30 global health scale (mdn r=-.21; range .08 to -.57). Stronger correlations were seen for PRO-CTCAE items with conceptually related QLQ-C30 domains: fatigue with physical, role and social functioning (-.54 to -.66); anxiety and depression with emotional functioning (-.54 to -.70); and concentration and memory problems with cognitive functioning (-.62 to -.72) [all p <0.001]. Fatigue, nausea, vomiting, pain, dyspnea, insomnia, appetite loss, constipation and diarrhea items strongly correlated with corresponding QLQ-C30 symptom scales (.69 to .79, all p <0.001). Scores for 98/124 PRO-CTCAE items were higher in the ECOG PS 2-4 vs 0-1 group (mdn effect size .3). Test-retest reliability was observed across all tested items (mdn intraclass correlation coeff .77; range .53 to .96). Conclusions: Results demonstrate favorable validity and reliability of PRO-CTCAE in a large, heterogeneous sample of patients undergoing cancer treatment. Further testing in multicenter treatment trials is underway.

e16569 Background: The National Cancer Institute’s (NCI) Cancer Trials Support Unit (CTSU) provides access to NCI-sponsored trials. To participate in a multi-center trial, sites must first complete the trial’s Protocol Specific Requirements (PSRs); interested sites are listed as “pending” in the CTSU database until all PSRs are completed. The aim of this investigation was to examine site activation delays for a study with multiple start-up steps and evaluate an intervention directed at helping sites more rapidly open it to patient accrual. Methods: NCCTG N0577, an anaplastic glioma trial named CODEL, was identified as a slow accruing trial with many sites listed as pending activation in the CTSU’s database (>85%; n=227 pending). Most N0577 pending sites had 1-2 incomplete PSRs (with 75% requiring only a neurocognitive certification), and we suspected that sites were not aware of these requirements. To accelerate site activation for N0577, we created an intervention using Awareness Theory. First, N0577 was amended to streamline the neurocognitive certification process. We then generated email lists of the 227 pending sites’ PIs (n=21; note: many were PIs of multiple sites) and their respective administrators (n=46), and created tailored email notices by PSR category explaining the necessary steps to complete N0577 activation at their site or to report their site as not planning to participate. Emails were sent to sites via the CTSU. Results: 31 sites (14%) registered activity for N0577 within 3 weeks of the intervention. Of these, 22 changed status to “approved,” 2 were disapproved, 1 withdrew, and 6 made changes but remained pending. This represents a marked increase (+520%) in site activity of the CTSU Regulatory Support Service (RSS) for N0577, compared with the monthly average (5 events/mo) during the preceding 6 months. Accrual is being monitored to observe for any increases and will be reported. Conclusions: Complicated and incomplete PSRs delay site activation of multi-center trials and may impact accrual. Streamlining PSR processes and early monitoring of CTSU site activation with notifications to sites of outstanding PSRs for trials can increase the timeliness of sites opening trials, with the potential to improve accrual.