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Background: Chemotherapy-induced damage of hematopoietic stem and progenitor cells (HSPC) causes multi-lineage myelosuppression. Trilaciclib is an intravenous CDK4/6 inhibitor in development to proactively preserve HSPC and immune system function during chemotherapy (myelopreservation). Preclinically, trilaciclib transiently maintains HSPC in G1 arrest and protects them from chemotherapy damage, leading to faster hematopoietic recovery and enhanced antitumor immunity., Patients and Methods: This was a phase Ib (open-label, dose-finding) and phase II (randomized, double-blind placebo-controlled) study of the safety, efficacy and PK of trilaciclib in combination with etoposide/carboplatin (E/P) therapy for treatment-naive extensive-stage small-cell lung cancer patients. Patients received trilaciclib or placebo before E/P on days 1-3 of each cycle. Select end points were prespecified to assess the effect of trilaciclib on myelosuppression and antitumor efficacy., Results: A total of 122 patients were enrolled, with 19 patients in part 1 and 75 patients in part 2 receiving study drug. Improvements were seen with trilaciclib in neutrophil, RBC (red blood cell) and lymphocyte measures. Safety on trilaciclib+E/P was improved with fewer ≥G3 adverse events (AEs) in trilaciclib (50%) versus placebo (83.8%), primarily due to less hematological toxicity. No trilaciclib-related ≥G3 AEs occurred. Antitumor efficacy assessment for trilaciclib versus placebo, respectively, showed: ORR (66.7% versus 56.8%, P = 0.3831); median PFS [6.2 versus 5.0 m; hazard ratio (HR) 0.71; P = 0.1695]; and OS (10.9 versus 10.6 m; HR 0.87; P = 0.6107)., Conclusion: Trilaciclib demonstrated an improvement in the patient's tolerability of chemotherapy as shown by myelopreservation across multiple hematopoietic lineages resulting in fewer supportive care interventions and dose reductions, improved safety profile, and no detriment to antitumor efficacy. These data demonstrate strong proof-of-concept for trilaciclib's myelopreservation benefits., Clinical Trail Number: NCT02499770., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Vemurafenib prolongs survival in patients with BRAF V600 -mutated advanced melanoma. In vitro studies show cytochrome P450 (CYP) 3A4 is involved in vemurafenib metabolism, but the effect of strong inducers or inhibitors of CYP3A4 on vemurafenib exposure in vivo is unknown. This phase 1, open-label, multicenter study evaluated the effect of rifampicin, a CYP3A4 inducer, on the pharmacokinetics of single-dose vemurafenib in 27 patients with BRAF V600 mutation-positive metastatic malignancy. Patients received a single oral dose of vemurafenib 960 mg on day 1, oral rifampicin 600 mg daily on days 8-16 (period B), and a single oral dose of vemurafenib 960 mg on day 17 and rifampicin 600 mg daily for days 17-23 (period C), with plasma samples obtained up to 168 hours after vemurafenib dosing. The geometric mean ratio (period C/period A) of area under the concentration-time curve from time zero to last measurable concentration time point and area under the concentration-time curve from time zero to infinity for vemurafenib (n = 23 for the pharmacokinetic analysis) was 0.61 (90% confidence interval, 0.48-0.78) and 0.60 (90% confidence interval, 0.47-0.76), respectively, indicating rifampicin significantly decreased vemurafenib plasma exposure by approximately 40%. The geometric mean ratio of the maximum concentration for vemurafenib was 1.1; this slight increase is likely owing to one outlier in period C. Adverse events were consistent with those previously seen for rifampicin and for vemurafenib monotherapy. Caution is advised when dosing vemurafenib concurrently with CYP3A4 inducers., (© 2018, The American College of Clinical Pharmacology.)

Background: In the Mammary Oncology Assessment of LEE011's (Ribociclib's) Efficacy and Safety (MONALEESA-2) study, combination treatment with the selective inhibitor of cyclin-dependent kinases 4/6 ribociclib with letrozole significantly improved progression-free survival (PFS) versus letrozole alone in postmenopausal women with hormone receptor-positive HR + /HER2 - advanced breast cancer (ABC). Herein we present results from the subset of US patients enrolled in MONALEESA-2., Patients and Methods: Postmenopausal women with HR + /HER2 - ABC without previous treatment for advanced disease were randomized (1:1) to ribociclib 600 mg/d (3 weeks on/1 week off) with letrozole 2.5 mg/d (continuous) or placebo with letrozole. The primary end point was locally assessed PFS., Results: Overall, 213 US patients were enrolled in MONALEESA-2 (ribociclib, n = 100; placebo, n = 113). Baseline characteristics were similar between treatment groups and consistent with the global population. With a median follow-up of 27 months, 38 (38%) and 29 (26%) patients in the ribociclib and placebo groups, respectively, had continued to receive treatment. Median PFS was 27.6 months with ribociclib and 15.0 months with placebo (hazard ratio, 0.53). The most common all-cause adverse events were neutropenia (ribociclib, 72.0% [n = 72]; placebo, 4.6% [n = 5]), nausea (ribociclib, 69.0% [n = 69]; placebo, 44.0% [n = 48]), and fatigue (ribociclib, 60.0% [n = 60]; placebo, 50.5% [n = 55]). Two patients (ribociclib, 2.0%; placebo, 0%) experienced febrile neutropenia., Conclusion: In the US subset of MONALEESA-2, ribociclib with letrozole showed superior efficacy versus letrozole alone. These findings are consistent with the global population and support first-line use of ribociclib with letrozole in patients with HR + /HER2 - ABC., (Copyright © 2019. Published by Elsevier Inc.)

Background: In a prior open-label study, the combination of dalantercept, a novel antiangiogenic targeting activin receptor-like kinase 1 (ALK1), plus axitinib was deemed safe and tolerable with a promising efficacy signal in patients with advanced renal cell carcinoma (RCC)., Methods: In the current phase 2, randomized, double-blind, placebo-controlled study, patients with clear cell RCC previously treated with 1 prior angiogenesis inhibitor were randomized 1:1 to receive axitinib plus dalantercept versus axitinib plus placebo. Randomization was stratified by the type of prior therapy. The primary endpoint was progression-free survival (PFS). Secondary endpoints were PFS in patients with ≥2 prior lines of anticancer therapy, overall survival, and the objective response rate., Results: Between June 10, 2014, and February 23, 2017, a total of 124 patients were randomly assigned to receive axitinib plus dalantercept (59 patients) or placebo (65 patients). The median PFS was not found to be significantly different between the treatment groups (median, 6.8 months vs 5.6 months; hazard ratio, 1.11 [95% CI, 0.71-1.73; P = .670]). Neither group reached the median overall survival (hazard ratio, 1.39 [95% CI, 0.70-2.77; P = .349]). The objective response rate was 19.0% (11 of 58 patients; 95% CI, 9.9%-31.4%) in the dalantercept plus axitinib group and 24.6% (15 of 61 patients; 95% CI, 14.5%-37.3%) in the placebo plus axitinib group. At least 1 treatment-emergent adverse event of ≥grade 3 was observed in 59% of patients (34 of 58 patients) in the dalantercept group and 64% of patients (39 of 61 patients) in the placebo group. One treatment-related death occurred in the placebo plus axitinib group., Conclusions: Although well tolerated, the addition of dalantercept to axitinib did not appear to improve treatment-related outcomes in previously treated patients with advanced RCC., (© 2019 American Cancer Society.)

BRAF and RAS are the most frequently mutated mitogen-activated protein kinase (MAPK) genes in melanoma. Binimetinib is a highly selective MAPK kinase (MEK) 1/2 inhibitor with clinical antitumor activity in NRAS - and BRAF V600 -mutant melanoma. We performed a nonrandomized, open-label phase II study, where 183 metastatic melanoma patients received binimetinib 45 mg / 60 mg twice-daily ( BRAF arms), or binimetinib 45 mg twice-daily ( NRAS arm). Biomarker analyses were prespecified as secondary and exploratory objectives. Here we report the extent of MAPK pathway inhibition by binimetinib, genetic pathway alterations of interest, and potential predictive markers for binimetinib efficacy. Twenty-five fresh pre- and post-dose tumor sample pairs were collected for biomarker analyses, which included assessment of binimetinib on MEK/MAPK signaling by pharmacodynamic analysis of pERK and DUSP6 expression in pre- vs post-dose tumor biopsies; identification of pERK and DUSP6 expression/efficacy correlations; assessment of baseline tumor molecular status; and exploration of potential predictive biomarkers of efficacy of binimetinib. The postbaseline pERK and DUSP6 expression decreased across all arms; no association between reduced pERK or DUSP6 levels with clinical efficacy was observed. Genetic aberrations were similar to previously reported data on clinical melanoma samples. Genetic pathway alterations occurred predominantly within CDKN2A/B , PTEN , and TRRAP ( BRAF -mutation) and CDKN2A/B , TP53 , and NOTCH2 ( NRAS -mutation). Several patients with BRAF mutations had amplification of genes on chromosome 7q; these patients tended to have shorter progression-free survival than other patients with BRAF -mutant melanoma. Further analysis of genetic alterations, including amplifications of growth factor genes, will determine utility as biomarkers for efficacy., Competing Interests: CONFLICTS OF INTEREST CvH reports grants from Astra Zeneca, Merck, MSD, Novartis outside the submitted work. AH reports grants from Amgen, BMS, Celgene, Eisai, GSK, Merck Serono, MSD/Merck, Novartis, Roche, other from Amgen, BMS, MedImmune, MSD/Merck, Nektar Therapeutics, Novartis, Oncosec, Philogen, Provectus, Regeneron, Roche outside the submitted work; CB reports personal fees from Amgen, GSK, personal fees and non-financial support from Merck Sharp & Dohme, Novartis, BMS, and from Roche, personal fees from AstraZeneca, outside the submitted work; DS reports personal fees and other from Amgen, grants, personal fees and other from BMS, personal fees and other from Novartis, Roche, and Array, grants, personal fees and other from Merck/MSD, personal fees from Pfizer, outside the submitted work; PAA reports grants and personal fees from BMS, Roche-Genentech, Ventana, and Array, personal fees from Novartis, Amgen, and from Merck Sharp & Dohme, outside the submitted work; MCH reports grants and personal fees from Novartis, personal fees from MolecularMD, during the conduct of the study; grants and personal fees from Blueprint Medicines, personal fees from Pfizer, outside the submitted work; RRP, AD, VA, HN, AZ were employed by Novartis; RD reports research funding from Novartis, MSD, BMS, Roche, GSK, and has consultant or advisory board relationship with Novartis, MSD, BMS, Roche, GSK, and Amgen. All remaining authors have declared no conflicts of interest.

Importance: Current treatment options for progressive ovarian cancer provide limited benefit, particularly in patients whose disease has become resistant to platinum-based chemotherapy., Objective: To assess the efficacy and safety of avelumab, an anti-programmed death-ligand 1 agent, in a cohort of patients with previously treated recurrent or refractory ovarian cancer., Design, Setting, and Participants: In an expansion cohort of a phase 1b, open-label study (JAVELIN Solid Tumor), 125 patients with advanced ovarian cancer who had received chemotherapy including a platinum agent were enrolled between November 6, 2013, and August 27, 2015. Statistical analysis was performed from December 31, 2016, to October 9, 2018., Intervention: Patients received avelumab, 10 mg/kg, every 2 weeks until disease progression, unacceptable toxic effects, or withdrawal from the study., Main Outcomes and Measures: Prespecified end points in this cohort included confirmed best overall response (per Response Evaluation Criteria In Solid Tumors, version 1.1), immune-related best overall response, duration of response, progression-free survival, overall survival, results of programmed death-ligand 1 expression-based analyses, and safety., Results: A total of 125 women (median age, 62.0 years [range, 27-84 years]) who had received a median of 3 prior lines of treatment (range, 0-10) for advanced disease were enrolled in the study. Patients received avelumab for a median of 2.8 months (range, 0.5-27.4 months), with a median follow-up of 26.6 months (range, 16-38 months). A confirmed objective response occurred in 12 patients (9.6%; 95% CI, 5.1%-16.2%), including a complete response in 1 patient (0.8%) and a partial response in 11 patients (8.8%). The 1-year progression-free survival rate was 10.2% (95% CI, 5.4%-16.7%) and median overall survival was 11.2 months (95% CI, 8.7-15.4 months). Infusion-related reactions occurred in 25 patients (20.0%). Other frequent treatment-related adverse events (any grade event occurring in ≥10% of patients) were fatigue (17 [13.6%]), diarrhea (15 [12.0%]), and nausea (14 [11.2%]). Grade 3 or higher treatment-related adverse events occurred in 9 patients (7.2%), of which only the level of lipase increased (3 [2.4%]) occurred in more than 1 patient. Twenty-one patients (16.8%) had an immune-related adverse event of any grade. No treatment-related deaths occurred., Conclusions and Relevance: Avelumab demonstrated antitumor activity and acceptable safety in heavily pretreated patients with recurrent or refractory ovarian cancer., Trial Registration: ClinicalTrials.gov identifier: NCT01772004.

Background: Metastatic colorectal cancer (mCRC) has low survival rates. We assessed if addition of veliparib, concurrent to FOLFIRI, improves survival in patients with previously untreated mCRC., Methods: This study compared veliparib (200 mg BID for 7 days of each 14-day cycle) to placebo, each with FOLFIRI. Bevacizumab was allowed in both arms. The primary endpoint was progression-free survival (PFS)., Results: Patients were randomised to receive veliparib (n = 65) or placebo (n = 65) in combination with FOLFIRI. Median PFS was 12 vs 11 months (veliparib vs placebo) [HR = 0.94 (95% CI: 0.60, 1.48)]. Median OS was 25 vs 27 months [HR = 1.26 (95% CI: 0.74, 2.16)]. Response rate was 57% vs 62%. Median DOR was 11 vs 9 months [HR = 0.73 (95% CI: 0.38, 1.40)]. AEs with significantly higher frequency (p < 0.05) in the veliparib group were anaemia (39% vs 19%, p = 0.019) and neutropenia (66% vs 37%, p = 0.001) for common AEs (≥20%); neutropenia (59% vs 22%, p < 0.001) for common Grade 3/4 AEs (≥5%); none in serious AEs. Haematopoietic cytopenias were more common with veliparib (79% vs 52%, p = 0.003). Fourteen percent of patients on veliparib and 15% on placebo discontinued treatment due to AEs., Conclusion: Veliparib added to FOLFIRI ± bevacizumab demonstrated similar efficacy as FOLFIRI ± bevacizumab in frontline mCRC patients. No unexpected safety concerns occurred.

Purpose: There are currently no targeted therapies approved for triple-negative breast cancer (TNBC). A tumor necrosis factor α ( TNFα)-based gene expression signature (GS) predictive of sensitivity to LCL161, inhibitor of apoptosis antagonist, was translated into a clinical assay and evaluated in a neoadjuvant trial., Patients and Methods: Women with localized TNBC (T2/N0-2/M0) were prospectively stratified by GS status and randomly assigned (1:1) to receive oral LCL161 (1,800 mg once per week) and intravenous paclitaxel (80 mg/m 2 once per week; combination arm) or paclitaxel alone (control arm) for 12 weeks, followed by surgery. The primary objective was to determine whether neoadjuvant LCL161 enhances efficacy of paclitaxel, defined by > 7.5% increase in the pathologic complete response (pCR, breast) rate, stratified by GS., Results: Of 209 patients enrolled (207 with valid GS scores), 30.4% had GS-positive TNBC. In the GS-positive group, pCR was higher in the combination versus the control arm (38.2% v 17.2%), with 88.8% posterior probability of > 7.5% increase in pCR. However, in the GS-negative group, the pCR was lower in the combination group (5.6% v 16.4%), with 0% posterior probability of > 7.5% increase in pCR. A higher incidence of grade 3 or 4 adverse events in the combination arm included neutropenia (24.5%) and diarrhea (5.7%). Overall, 19 patients (18.1%) in the combination arm discontinued treatment because of adverse events, including pyrexia (n = 5), pneumonia (n = 4), and pneumonitis (n = 4), versus five patients (4.9%) in the control arm., Conclusion: This neoadjuvant trial provides evidence supporting a biomarker-driven targeted therapy approach for selected patients with GS-positive TNBC and demonstrates the utility of a neoadjuvant trial for biomarker validation and drug development, but also highlights toxicity risk. Future neoadjuvant clinical trials should carefully weigh these considerations for targeted therapy development in biomarker-defined TNBC.

Purpose This phase III study evaluated ribociclib plus fulvestrant in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer who were treatment naïve or had received up to one line of prior endocrine therapy in the advanced setting. Patients and Methods Patients were randomly assigned at a two-to-one ratio to ribociclib plus fulvestrant or placebo plus fulvestrant. The primary end point was locally assessed progression-free survival. Secondary end points included overall survival, overall response rate, and safety. Results A total of 484 postmenopausal women were randomly assigned to ribociclib plus fulvestrant, and 242 were assigned to placebo plus fulvestrant. Median progression-free survival was significantly improved with ribociclib plus fulvestrant versus placebo plus fulvestrant: 20.5 months (95% CI, 18.5 to 23.5 months) versus 12.8 months (95% CI, 10.9 to 16.3 months), respectively (hazard ratio, 0.593; 95% CI, 0.480 to 0.732; P < .001). Consistent treatment effects were observed in patients who were treatment naïve in the advanced setting (hazard ratio, 0.577; 95% CI, 0.415 to 0.802), as well as in patients who had received up to one line of prior endocrine therapy for advanced disease (hazard ratio, 0.565; 95% CI, 0.428 to 0.744). Among patients with measurable disease, the overall response rate was 40.9% for the ribociclib plus fulvestrant arm and 28.7% for placebo plus fulvestrant. Grade 3 adverse events reported in ≥ 10% of patients in either arm (ribociclib plus fulvestrant v placebo plus fulvestrant) were neutropenia (46.6% v 0%) and leukopenia (13.5% v 0%); the only grade 4 event reported in ≥ 5% of patients was neutropenia (6.8% v 0%). Conclusion Ribociclib plus fulvestrant might represent a new first- or second-line treatment option in hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer.

Crizotinib, an inhibitor of anaplastic lymphoma kinase (ALK), MET, and ROS1, is approved for treatment of patients with ALK-positive or ROS1-positive advanced non-small-cell lung cancer (NSCLC). However, ALK rearrangements are also implicated in other malignancies, including anaplastic large-cell lymphoma and inflammatory myofibroblastic tumors (IMTs). In this ongoing, multicenter, single-arm, open-label phase 1b study (PROFILE 1013; NCT01121588), patients with ALK-positive advanced malignancies other than NSCLC were to receive a starting dose of crizotinib 250 mg twice daily. Primary endpoints were safety and objective responses based on Response Evaluation Criteria in Solid Tumors version 1.1 or National Cancer Institute International Response Criteria. Forty-four patients were enrolled (lymphoma, n = 18; IMT, n = 9; other tumors, n = 17). The objective response rate was 53% (95% confidence interval [CI], 28-77) for lymphoma, with 8 complete responses (CRs) and 1 partial response (PR); 67% (95% CI, 30-93) for IMTs, with 1 CR and 5 PRs; and 12% (95% CI, 2-36) for other tumors, with 2 PRs in patients affected by colon carcinoma and medullary thyroid cancer, respectively. The median duration of treatment was almost 3 years for patients with lymphoma and IMTs, with 2-year progression-free survival of 63% and 67%, respectively. The most common treatment-related adverse events were diarrhea (45.5%) and vision disorders (45.5%), mostly grade 1. These findings indicate strong and durable activity of crizotinib in ALK-positive lymphomas and IMTs. The safety profile was consistent with the known safety profile of crizotinib even with long-term treatment., (© 2018 The Authors American Journal of Hematology Published by Wiley Periodicals, Inc.)

Purpose: Determine the efficacy and safety of first-line ribociclib plus letrozole in patients with de novo advanced breast cancer., Methods: Postmenopausal women with HR+ , HER2- advanced breast cancer and no prior systemic therapy for advanced disease were enrolled in the Phase III MONALEESA-2 trial (NCT01958021). Patients were randomized to ribociclib (600 mg/day; 3 weeks-on/1 week-off) plus letrozole (2.5 mg/day; continuous) or placebo plus letrozole until disease progression, unacceptable toxicity, death, or treatment discontinuation. The primary endpoint was investigator-assessed progression-free survival; predefined subgroup analysis evaluated progression-free survival in patients with de novo advanced breast cancer. Secondary endpoints included safety and overall response rate., Results: Six hundred and sixty-eight patients were enrolled, of whom 227 patients (34%; ribociclib plus letrozole vs placebo plus letrozole arm: n = 114 vs. n = 113) presented with de novo advanced breast cancer. Median progression-free survival was not reached in the ribociclib plus letrozole arm versus 16.4 months in the placebo plus letrozole arm in patients with de novo advanced breast cancer (hazard ratio 0.45, 95% confidence interval 0.27-0.75). The most common Grade 3/4 adverse events were neutropenia and leukopenia; incidence rates were similar to those observed in the full MONALEESA-2 population. Ribociclib dose interruptions and reductions in patients with de novo disease occurred at similar frequencies to the overall study population., Conclusions: Ribociclib plus letrozole improved progression-free survival vs placebo plus letrozole and was well tolerated in postmenopausal women with HR+, HER2- de novo advanced breast cancer.

Purpose: Activin receptor-like kinase 1 (ALK1) is a novel target in angiogenesis. Concurrent targeting of ALK1 and VEGF signaling results in augmented inhibition of tumor growth in renal cell carcinoma (RCC) xenograft models. Dalantercept is an ALK1-receptor fusion protein that acts as a ligand trap for bone morphogenetic proteins 9 and 10. The DART Study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of dalantercept plus axitinib in patients with advanced RCC and determined the optimal dose for further testing. Experimental Design: Patients received dalantercept 0.6, 0.9, or 1.2 mg/kg subcutaneously every 3 weeks plus axitinib 5 mg by mouth twice daily until disease progression or intolerance. Results: Twenty-nine patients were enrolled in the dose escalation ( n = 15) and expansion ( n = 14) cohorts. There were no dose-limiting toxicities or grade 4/5 treatment-related adverse events. In addition to common VEGFR tyrosine kinase inhibitor effects, such as fatigue and diarrhea, commonly seen treatment-related adverse events were peripheral edema, epistaxis, pericardial effusion, and telangiectasia. The objective response rate by RECIST v1.1 was 25% with responses seen at all dose levels. The overall median progression-free survival was 8.3 months. Conclusions: The combination of dalantercept plus axitinib is well tolerated and associated with clinical activity. On the basis of safety and efficacy results, the 0.9 mg/kg dose level was chosen for further study in a randomized phase II trial of dalantercept plus axitinib versus placebo plus axitinib. Clin Cancer Res; 23(14); 3557-65. ©2016 AACR ., (©2016 American Association for Cancer Research.)

Background: RECORD-3 compared everolimus and sunitinib as first-line therapy, and the sequence of everolimus followed by sunitinib at progression compared with the opposite (standard) sequence in patients with metastatic renal cell carcinoma (mRCC). This final overall survival (OS) analysis evaluated mature data for secondary end points., Patients and Methods: Patients received either first-line everolimus followed by second-line sunitinib at progression (n = 238) or first-line sunitinib followed by second-line everolimus (n = 233). Secondary end points were combined first- and second-line progression-free survival (PFS), OS, and safety. The impacts of neutrophil lymphocyte ratio (NLR) and baseline levels of soluble biomarkers on OS were explored., Results: At final analysis, median duration of exposure was 5.6 months for everolimus and 8.3 months for sunitinib. Median combined PFS was 21.7 months [95% confidence interval (CI) 15.1-26.7] with everolimus-sunitinib and 22.2 months (95% CI 16.0-29.8) with sunitinib-everolimus [hazard ratio (HR)EVE-SUN/SUN-EVE, 1.2; 95% CI 0.9-1.6]. Median OS was 22.4 months (95% CI 18.6-33.3) for everolimus-sunitinib and 29.5 months (95% CI 22.8-33.1) for sunitinib-everolimus (HREVE-SUN/SUN-EVE, 1.1; 95% CI 0.9-1.4). The rates of grade 3 and 4 adverse events suspected to be related to second-line therapy were 47% with everolimus and 57% with sunitinib. Higher NLR and 12 soluble biomarker levels were identified as prognostic markers for poor OS with the association being largely independent of treatment sequences., Conclusions: Results of this final OS analysis support the sequence of sunitinib followed by everolimus at progression in patients with mRCC. The safety profiles of everolimus and sunitinib were consistent with those previously reported, and there were no unexpected safety signals., Clinical Trials Number: ClinicalTrials.gov identifier, NCT00903175., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Background: Stomatitis is a class effect associated with the inhibition of mTOR and is associated with everolimus therapy for breast cancer. Topical steroids might reduce stomatitis incidence and severity, and the need for dose reductions and interruptions of everolimus. Anecdotal use of topical steroid oral prophylaxis has been reported in patients with breast cancer. We aimed to assess dexamethasone-based mouthwash for prevention of stomatitis in patients with breast cancer., Methods: This US-based, multicentre, single-arm, phase 2 prevention study enrolled women aged 18 years and older with postmenopausal status who had histologically or cytologically confirmed metastatic hormone receptor-positive, HER2-negative breast cancer. Beginning on day 1 of cycle 1, patients received everolimus 10 mg plus exemestane 25 mg daily, with 10 mL of alcohol-free dexamethasone 0·5 mg per 5 mL oral solution (swish for 2 min and spit, four times daily for 8 weeks). After 8 weeks, dexamethasone mouthwash could be continued for up to eight additional weeks at the discretion of the clinician and patient. The primary endpoint was incidence of grade 2 or worse stomatitis by 8 weeks assessed in the full analysis set (patients who received at least one dose of everolimus and exemestane and at least one confirmed dose of dexamethasone mouthwash) versus historical controls from the BOLERO-2 trial (everolimus and exemestane treatment in patients with hormone receptor-positive advanced breast cancer who were not given dexamethasone mouthwash for prevention of stomatitis). This trial is registered at ClinicalTrials.gov, number NCT02069093., Findings: Between May 28, 2014, and Oct 8, 2015, we enrolled 92 women; 85 were evaluable for efficacy. By 8 weeks, the incidence of grade 2 or worse stomatitis was two (2%) of 85 patients (95% CI 0·29-8·24), versus 159 (33%) of 482 patients (95% CI 28·8-37·4) for the duration of the BOLERO-2 study. Overall, 83 (90%) of 92 patients had at least one adverse event. The most frequently reported grade 3 and 4 adverse events in the safety set were hyperglycaemia (seven [8%] of 92 patients), rash (four [4%]), and dyspnoea (three [3%]). Serious adverse events were reported in 20 (22%) patients; six (7%) were deemed treatment related, with dyspnoea (three [3%]) and pneumonia (two [2%]) reported most frequently. 12 (13%) of 92 patients had adverse events suspected to be related to treatment that led to discontinuation of everolimus and exemestane (the most common were rash, hyperglycaemia, and stomatitis, which each affected two [2%] patients)., Interpretation: Prophylactic use of dexamethasone oral solution substantially reduced the incidence and severity of stomatitis in patients receiving everolimus and exemestane and could be a new standard of oral care for patients receiving everolimus and exemestane therapy., Funding: Novartis Pharmaceuticals Corporation., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Phosphatidylinositol 3-kinase (PI3K) pathway activation in preclinical models of breast cancer is associated with tumor growth and resistance to anticancer therapies, including paclitaxel. Effects of the pan-Class I PI3K inhibitor buparlisib (BKM120) appear synergistic with paclitaxel in preclinical and clinical models., Patients and Methods: BELLE-4 was a 1:1 randomized, double-blind, placebo-controlled, adaptive phase II/III study investigating the combination of buparlisib or placebo with paclitaxel in women with human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer with no prior chemotherapy for advanced disease. Patients were stratified by PI3K pathway activation and hormone receptor status. The primary endpoint was progression-free survival (PFS) in the full and PI3K pathway-activated populations. An adaptive interim analysis was planned following the phase II part of the study, after ≥125 PFS events had occurred in the full population, to decide whether the study would enter phase III (in the full or PI3K pathway-activated population) or be stopped for futility., Results: As of August 2014, 416 patients were randomized to receive buparlisib (207) or placebo (209) with paclitaxel. At adaptive interim analysis, there was no improvement in PFS with buparlisib versus placebo in the full (median PFS 8.0 versus 9.2 months, hazard ratio [HR] 1.18), or PI3K pathway-activated population (median PFS 9.1 versus 9.2 months, HR 1.17). The study met protocol-specified criteria for futility in both populations, and phase III was not initiated. Median duration of study treatment exposure was 3.5 months in the buparlisib arm versus 4.6 months in the placebo arm. The most frequent adverse events with buparlisib plus paclitaxel (≥40% of patients) were diarrhea, alopecia, rash, nausea, and hyperglycemia., Conclusions: Addition of buparlisib to paclitaxel did not improve PFS in the full or PI3K pathway-activated study population. Consequently, the trial was stopped for futility at the end of phase II., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: As we move away from the traditional chemotherapy era to targeted therapy, the validity of old assessment paradigms associated with therapeutics are being raised in the context of immunotherapy. The old paradigm required elaborating on the toxicity assessment, with no expectation of efficacy in early phase trials. Safety data from Phase 1 and 2 studies with many immunotherapeutics show limited toxicities and draw attention to the need to demonstrate efficacy in the early evaluation of new agents., Methods: Literature searches indicate that molecular oncology mechanistic-based agents are being linked with molecular disease status and clinical benefit. Biomarkers and other endpoints are being employed to accomplish this. Perspectives for a meaningful context of integrating biomarkers and clinical trial design are reviewed., Results: The design and conduct of clinical trials have not been fully adjusted to the new era of personalized oncology, and so we are in transition. A part of this transition is the management of expectations and trial designs that need to be considered relative to preclinical experience in the development of therapeutics. For example, pathological complete response is now considered a surrogate marker for favorable prognosis in breast cancer patients who are treated in the neoadjuvant setting. This surrogate marker is tied to novel agents' mechanistic characteristics with no preclinical counterpart., Conclusion: The old paradigm considers patients equal with similar chances to respond to treatments, but the new paradigm considers patient's heterogeneity, a major fact that informs the design of clinical trials. By linking every treatment to a mechanism of action and to the presence of a specific biomarker, new trials are going to have more subjects who are likely to respond to the treatment., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Objectives: Cyclin D-cyclin-dependent kinase (CDK) 4/6-inhibitor of CDK4/6-retinoblastoma (Rb) pathway hyperactivation is associated with hormone receptor-positive (HR+) breast cancer (BC). This study assessed the biological activity of ribociclib (LEE011; CDK4/6 inhibitor) plus letrozole compared with single-agent letrozole in the presurgical setting., Materials and Methods: Postmenopausal women (N = 14) with resectable, HR+, human epidermal growth factor receptor 2-negative (HER2-) early BC were randomized 1:1:1 to receive 2.5 mg/day letrozole alone (Arm 1), or with 400 or 600 mg/day ribociclib (Arm 2 or 3). Circulating tumor DNA and tumor biopsies were collected at baseline and, following 14 days of treatment, prior to or during surgery. The primary objective was to assess antiproliferative response per Ki67 levels in Arms 2 and 3 compared with Arm 1. Additional assessments included safety, pharmacokinetics, and genetic profiling., Results: Mean decreases in the Ki67-positive cell fraction from baseline were: Arm 1 69% (range 38-100%; n = 2), Arm 2 96% (range 78-100%; n = 6), Arm 3 92% (range 75-100%; n = 3). Decreased phosphorylated Rb levels and CDK4, CDK6, CCND2, CCND3, and CCNE1 gene expression were observed following ribociclib treatment. Ribociclib and letrozole pharmacokinetic parameters were consistent with single-agent data. The ribociclib plus letrozole combination was well tolerated, with no Grade 3/4 adverse events over the treatment., Conclusion: The results suggest absence of a drug-drug interaction between ribociclib and letrozole and indicate ribociclib plus letrozole may reduce Ki67 expression in HR+, HER2- BC (NCT01919229)., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Unlabelled: We describe the rationale and design of the ongoing randomized, active-controlled, multicenter, Phase III study evaluating the efficacy of pixantrone and rituximab versus gemcitabine and rituximab in patients with diffuse large B-cell lymphoma or follicular grade 3 lymphoma, who are ineligible for high-dose chemotherapy and stem cell transplantation, and who failed front-line regimens containing rituximab. The administration schedule is pixantrone 50 mg/m(2) intravenously (iv.) or gemcitabine 1000 mg/m(2) iv. on days 1, 8 and 15, combined with rituximab 375 mg/m(2) iv. on day 1, up to six cycles. Pixantrone has a conditional European marketing approval for monotherapy in adults with multiple relapsed or refractory aggressive B-cell non-Hodgkin lymphoma. Our trial explores the efficacy of combining pixantrone with rituximab and completes postauthorization measures., Trial Registration Number: NCT01321541.

Background: Treatment with an aromatase inhibitor for 5 years as up-front monotherapy or after tamoxifen therapy is the treatment of choice for hormone-receptor-positive early breast cancer in postmenopausal women. Extending treatment with an aromatase inhibitor to 10 years may further reduce the risk of breast-cancer recurrence., Methods: We conducted a double-blind, placebo-controlled trial to assess the effect of the extended use of letrozole for an additional 5 years. Our primary end point was disease-free survival., Results: We enrolled 1918 women. After a median follow-up of 6.3 years, there were 165 events involving disease recurrence or the occurrence of contralateral breast cancer (67 with letrozole and 98 with placebo) and 200 deaths (100 in each group). The 5-year disease-free survival rate was 95% (95% confidence interval [CI], 93 to 96) with letrozole and 91% (95% CI; 89 to 93) with placebo (hazard ratio for disease recurrence or the occurrence of contralateral breast cancer, 0.66; P=0.01 by a two-sided log-rank test stratified according to nodal status, prior adjuvant chemotherapy, the interval from the last dose of aromatase-inhibitor therapy, and the duration of treatment with tamoxifen). The rate of 5-year overall survival was 93% (95% CI, 92 to 95) with letrozole and 94% (95% CI, 92 to 95) with placebo (hazard ratio, 0.97; P=0.83). The annual incidence rate of contralateral breast cancer in the letrozole group was 0.21% (95% CI, 0.10 to 0.32), and the rate in the placebo group was 0.49% (95% CI, 0.32 to 0.67) (hazard ratio, 0.42; P=0.007). Bone-related toxic effects occurred more frequently among patients receiving letrozole than among those receiving placebo, including a higher incidence of bone pain, bone fractures, and new-onset osteoporosis. No significant differences between letrozole and placebo were observed in scores on most subscales measuring quality of life., Conclusions: The extension of treatment with an adjuvant aromatase inhibitor to 10 years resulted in significantly higher rates of disease-free survival and a lower incidence of contralateral breast cancer than those with placebo, but the rate of overall survival was not higher with the aromatase inhibitor than with placebo. (Funded by the Canadian Cancer Society and others; ClinicalTrials.gov numbers, NCT00003140 and NCT00754845.).

This open-label, multicenter, phase 1B/2 trial assessed AUY922 plus trastuzumab in patients with locally advanced or metastatic HER2-positive breast cancer previously treated with chemotherapy and anti-HER2 therapy. This study was composed of a dose-escalation part with AUY922 administered weekly at escalating doses with trastuzumab 2 mg/kg/week (phase 1B), followed by a phase 2 part using the same regimen at recommended phase 2 dose (RP2D). The primary objectives were to determine the maximum tolerated dose (MTD) and/or RP2D (phase 1B), and to evaluate preliminary antitumor activity (phase 2) of AUY922 plus trastuzumab at MTD/RP2D. Forty-five patients were treated with AUY922 plus trastuzumab (4 in phase 1B with AUY922 at 55 mg/m2 and 41 in phase 1B/2 with AUY922 at 70 mg/m2 [7 in phase 1B and 34 in phase 2]). One patient in phase 1B (70 mg/m2) experienced a dose-limiting toxicity (grade 3 diarrhea); the RP2D was weekly AUY922 70 mg/m2 plus trastuzumab. Of the 41 patients in the 70 mg/m2 cohort, the overall response rate (complete or partial responses) was 22.0% and 48.8% patients had stable disease. Study treatment-related adverse events occurred in 97.8% of patients; of these, 31.1% were grade 3 or 4. Forty-one patients (91.1%) reported ocular events (82.3% had grade 1 or 2 events). Two patients (4.4%) had ocular events leading to the permanent discontinuation of study treatment. AUY922 at 70 mg/m2 plus trastuzumab standard therapy is well tolerated and active in patients with HER2-positive metastatic breast cancer who progressed on trastuzumab-based therapy., Competing Interests: AK has served as an Advisory board member for GlaxoSmithKline. DR received honoraria from Novartis. SA has served as a consultant for Novartis, Pfizer, Boehringer Ingelheim, Pierre Fabre, and Eisai. EA has served as an Advisory board member for Roche, and Celgene, and served as speaker for Roche, Novartis, and Celgene. MC has served as a consultant for Novartis, Servier, Menarini, Sanofi, Astra-Zeneca, and Roche, attended speaker bureaus for Novartis, and received grant from Novartis. MAk, S-FH, CL are employees of Novartis. S-CL received honoraria from Novartis. All remaining authors have declared no conflicts of interest.

Purpose: This phase Ib study evaluated the safety and tolerability of PEGylated human recombinant hyaluronidase (PEGPH20) in combination with gemcitabine (Gem), and established a phase II dose for patients with untreated stage IV metastatic pancreatic ductal adenocarcinoma (PDA). Objective response rate and treatment efficacy using biomarker and imaging measurements were also evaluated., Experimental Design: Patients received escalating intravenous doses of PEGPH20 in combination with Gem using a standard 3+3 dose-escalation design. In cycle 1 (8 weeks), PEGPH20 was administrated twice weekly for 4 weeks, then once weekly for 3 weeks; Gem was administrated once weekly for 7 weeks, followed by 1 week off treatment. In each subsequent 4-week cycle, PEGPH20 and Gem were administered once weekly for 3 weeks, followed by 1 week off. Dexamethasone (8 mg) was given pre- and post-PEGPH20 administration. Several safety parameters were evaluated., Results: Twenty-eight patients were enrolled and received PEGPH20 at 1.0 (n = 4), 1.6 (n = 4), or 3.0 μg/kg (n = 20), respectively. The most common PEGPH20-related adverse events were musculoskeletal and extremity pain, peripheral edema, and fatigue. The incidence of thromboembolic events was 29%. Median progression-free survival (PFS) and overall survival (OS) rates were 5.0 and 6.6 months, respectively. In 17 patients evaluated for pretreatment tissue hyaluronan (HA) levels, median PFS and OS rates were 7.2 and 13.0 months for "high"-HA patients (n = 6), and 3.5 and 5.7 months for "low"-HA patients (n = 11), respectively., Conclusions: PEGPH20 in combination with Gem was well tolerated and may have therapeutic benefit in patients with advanced PDA, especially in those with high HA tumors. Clin Cancer Res; 22(12); 2848-54. ©2016 AACR., (©2016 American Association for Cancer Research.)

Background: MUC1 is a tumour-associated antigen expressed by many solid tumours, including non-small-cell lung cancer. TG4010 is a modified vaccinia Ankara expressing MUC1 and interleukin 2. In a previous study, TG4010 combined with chemotherapy showed activity in non-small-cell lung cancer and the baseline value of CD16, CD56, CD69 triple-positive activated lymphocytes (TrPAL) was shown to be potentially predictive of TG4010 efficacy. In this phase 2b part of the phase 2b/3 TIME trial, we further assess TG4010 in combination with first-line chemotherapy and use of the TrPAL biomarker in this setting., Methods: In this phase 2b part of a randomised, double-blind, placebo-controlled, phase 2b/3 trial, we recruited previously untreated patients aged 18 years or older with stage IV non-small-cell lung cancer without a known activating EGFR mutation and with MUC1 expression in at least 50% of tumoural cells. Patients were randomly allocated (1:1) by an external service provider to subcutaneous injections of 10(8) plaque-forming units of TG4010 or placebo from the beginning of chemotherapy every week for 6 weeks and then every 3 weeks up to progression, discontinuation for any reason, or toxic effects, stratified according to baseline value of TrPAL (≤ or > the upper limit of normal [ULN]) and, in addition, a dynamic minimisation procedure was used, taking into account chemotherapy regimen, histology, addition or not of bevacizumab, performance status, and centre. Patients, site staff, monitors, the study funder, data managers, and the statistician were masked to treatment identity. The primary endpoint was progression-free survival, assessed every 6 weeks, to validate the predictive value of the TrPAL biomarker. If patients with TrPAL values of less than or equal to the ULN had a Bayesian probability of more than 95% that the true hazard ratio (HR) for progression-free survival was less than 1, and if those with TrPAL values of greater than the ULN had a probability of more than 80% that the true HR for progression-free survival was more than 1, the TrPAL biomarker would be validated. We did primary analyses in the intention-to-treat population and safety analyses in those who had received at least one dose of study drug and had at least one valid post-baseline safety assessment. Monitors, site staff, and patients are still masked to treatment assignment. This trial is registered with ClinicalTrials.gov, number NCT01383148., Findings: Between April 10, 2012, and Sept 12, 2014, we randomly allocated 222 patients (TG4010 and chemotherapy 111 [50%]; placebo and chemotherapy 111 [50%]). In the whole population, median progression-free survival was 5·9 months (95% CI 5·4-6·7) in the TG4010 group and 5·1 months (4·2-5·9) in the placebo group (HR 0·74 [95% CI 0·55-0·98]; one-sided p=0·019). In patients with TrPAL values of less than or equal to the ULN, the HR for progression-free survival was 0·75 (0·54-1·03); the posterior probability of the HR being less than 1 was 98·4%, and thus the primary endpoint was met. In patients with TrPAL values of greater than the ULN, the HR for progression-free survival was 0·77 (0·42-1·40); the posterior probability of the HR being greater than 1 was 31·3%, and the primary endpoint was not met. We noted grade 1-2 injection-site reactions in 36 (33%) of 110 patients in the TG4010 group versus four (4%) of 107 patients in the placebo group. We noted no grade 3 or 4 nor serious adverse events deemed to be related to TG4010 only. Four (4%) patients presented grade 3 or 4 adverse events related to TG4010 and other study treatments (chemotherapy or bevacizumab) versus 11 (10%) in the placebo group. No serious adverse event was related to the combination of TG4010 with other study treatments. The most frequent severe adverse events were neutropenia (grade 3 29 [26%], grade 4 13 [12%] in the TG4010 group vs grade 3 22 [21%], grade 4 11 [10%] in the placebo group), anaemia (grade 3 12 [11%] vs grade 3 16 [15%]), and fatigue (grade 3 12 [11%], grade 5 one [1%] vs grade 3 13 [12%]; no grade 4 events)., Interpretation: TG4010 plus chemotherapy seems to improve progression-free survival relative to placebo plus chemotherapy. These data support the clinical value of the TrPAL biomarker in this clinical setting; because the primary endpoint was met, the trial is to continue into the phase 3 part., Funding: Transgene, Avancées Diagnostiques pour de Nouvelles Approches Thérapeutiques (ADNA), and OSEO., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Purpose: Patients with advanced pancreatic adenocarcinoma have a poor prognosis and limited second-line treatment options. Evidence suggests a role for the Janus kinase (JAK)/signal transducer and activator of transcription pathway in the pathogenesis and clinical course of pancreatic cancer., Patients and Methods: In this double-blind, phase II study, patients with metastatic pancreatic cancer who had experienced treatment failure with gemcitabine were randomly assigned 1:1 to the JAK1/JAK2 inhibitor ruxolitinib (15 mg twice daily) plus capecitabine (1,000 mg/m(2) twice daily) or placebo plus capecitabine. The primary end point was overall survival (OS); secondary end points included progression-free survival, clinical benefit response, objective response rate, and safety. Prespecified subgroup analyses evaluated treatment heterogeneity and efficacy in patients with evidence of inflammation., Results: In the intent-to-treat population (ruxolitinib, n = 64; placebo, n = 63), the hazard ratio was 0.79 (95% CI, 0.53 to 1.18; P = .25) for OS and was 0.75 (95% CI, 0.52 to 1.10; P = .14) for progression-free survival. In a prespecified subgroup analysis of patients with inflammation, defined by serum C-reactive protein levels greater than the study population median (ie, 13 mg/L), OS was significantly greater with ruxolitinib than with placebo (hazard ratio, 0.47; 95% CI, 0.26 to 0.85; P = .011). Prolonged survival in this subgroup was supported by post hoc analyses of OS that categorized patients by the modified Glasgow Prognostic Score, a systemic inflammation-based prognostic system. Grade 3 or greater adverse events were observed with similar frequency in the ruxolitinib (74.6%) and placebo (81.7%) groups. Grade 3 or greater anemia was more frequent with ruxolitinib (15.3%; placebo, 1.7%)., Conclusion: Ruxolitinib plus capecitabine was generally well tolerated and may improve survival in patients with metastatic pancreatic cancer and evidence of systemic inflammation., Competing Interests: Authors' disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article., (© 2015 by American Society of Clinical Oncology.)

Aim: To evaluate feasible doses of weekly everolimus and irinotecan given with cetuximab for previously treated metastatic colorectal cancer (mCRC)., Patients and Methods: Adults with mCRC that progressed after 5-fluorouracil or capecitabine-plus-oxaliplatin were treated using a sequential dose escalation scheme. Dosing decisions were based on the probability of experiencing a dose-limiting toxicity (DLT) during the first two 21-day treatment cycles., Results: Patients received everolimus 30 mg/week plus irinotecan 350 mg/m2 q3w (n=5; dose A1) or everolimus 30 mg/week plus irinotecan 250 mg/m2 q3w (n=14; dose B1). Among patients evaluable for the maximum tolerated dose, two out of four in A1 and one out of eight in B1 experienced four DLTs. The trial was terminated early based on changes in clinical practice and emerging data on everolimus dosing., Conclusion: The feasible doses of everolimus and irinotecan administered with cetuximab as second-line therapy in mCRC were 30 mg/week and 250 mg/m2, respectively., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Introduction: PRONOUNCE compared the efficacy and safety of pemetrexed+carboplatin followed by pemetrexed (Pem+Cb) with paclitaxel+carboplatin+bevacizumab followed by bevacizumab (Pac+Cb+Bev) in patients with advanced nonsquamous non-small-cell lung cancer (NSCLC)., Methods: Patients ≥18 years of age with stage IV nonsquamous NSCLC (American Joint Committee on Cancer v7.0), and Eastern Cooperative Oncology Group performance status 0/1 were randomized (1:1) to four cycles of induction Pem+Cb (pemetrexed, 500 mg/m, carboplatin, area under the curve = 6) followed by Pem maintenance or Pac+Cb+Bev (paclitaxel, 200 mg/m, carboplatin, area under the curve = 6, and bevacizumab, 15 mg/kg) followed by Bev maintenance in the absence of progressive disease or discontinuation. The primary objective was progression-free survival (PFS) without grade 4 toxicity (G4PFS). Secondary end points were PFS, overall survival (OS), overall response rate (ORR), disease control rate (DCR), and safety. Resource utilization was also assessed., Results: Baseline characteristics of the patients randomized to Pem+Cb (N = 182) and Pac+Cb+Bev (N = 179) were well balanced between the arms. Median (months) G4PFS was 3.91 for Pem+Cb and 2.86 for Pac+Cb+Bev (hazard ratio = 0.85, 90% confidence interval, 0.7-1.04; p = 0.176); PFS, OS, ORR, or DCR did not differ significantly between the arms. Significantly more drug-related grade 3/4 anemia (18.7% versus 5.4%) and thrombocytopenia (24.0% versus 9.6%) were reported for Pem+Cb. Significantly more grade 3/4 neutropenia (48.8% versus 24.6%), grade 1/2 alopecia (28.3% versus 8.2%), and grade 1/2 sensory neuropathy were reported for Pac+Cb+Bev. Number of hospitalizations and overall length of stay did not differ significantly between the arms., Conclusions: Pem+Cb did not produce significantly better G4PFS compared with Pac+Cb+Bev. Pem+Cb was not superior in PFS, OS, ORR, or DCR compared with Pac+Cb+Bev. Both regimens were well tolerated, although, toxicity profiles differed.

Dickkopf-1 (DKK1), expressed by myeloma cells, suppresses osteoblast function and plays a key role in bone disease in multiple myeloma. BHQ880, a human neutralizing IgG1 anti-DKK1 monoclonal antibody, is being investigated for its impact on multiple myeloma-related bone disease and as an agent with potential anti-myeloma activity. The primary objectives of this Phase IB study were to determine the maximum tolerated dose (MTD) of BHQ880 and to characterize the dose-limiting toxicity (DLT) of escalating doses in combination with anti-myeloma therapy and zoledronic acid. Twenty-eight patients were enrolled and received BHQ880 at doses of 3-40 mg/kg. No DLTs were reported, therefore, the MTD was not determined. The recommended Phase II dose was declared as 10 mg/kg, based mainly on saturation data. There was a general trend towards increased bone mineral density (BMD) observed over time; specific increases in spine BMD from Cycle 12 onwards irrespective of new skeletal-related events on study were observed, and increases in bone strength at the spine and hip were also demonstrated in some patients. BHQ880 in combination with zoledronic acid and anti-myeloma therapy was well tolerated and demonstrated potential clinical activity in patients with relapsed or refractory multiple myeloma., (© 2014 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd.)

Squamous cell lung carcinoma accounts for approximately 30% of all non-small cell lung cancers (NSCLCs). Despite progress in the understanding of the biology of cancer, cytotoxic chemotherapy remains the standard of care for patients with squamous cell lung carcinoma, but the prognosis is generally poor. The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is one of the most commonly activated signaling pathways in cancer, leading to cell proliferation, survival, and differentiation. It has therefore become a major focus of clinical research. Various alterations in the PI3K/AKT/mTOR pathway have been identified in squamous cell lung carcinoma and a number of agents targeting these alterations are in clinical development for use as single agents and in combination with other targeted and conventional treatments. These include pan-PI3K inhibitors, isoform-specific PI3K inhibitors, AKT inhibitors, mTOR inhibitors, and dual PI3K/mTOR inhibitors. These agents have demonstrated antitumor activity in preclinical models of NSCLC and preliminary clinical evidence is also available for some agents. This review will discuss the role of the PI3K/AKT/mTOR pathway in cancer and how the discovery of genetic alterations in this pathway in patients with squamous cell lung carcinoma can inform the development of targeted therapies for this disease. An overview of ongoing clinical trials investigating PI3K/AKT/mTOR pathway inhibitors in squamous cell lung carcinoma will also be included., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Purpose: A multicenter, randomized phase II trial, RECORD-3, was conducted to compare first-line everolimus followed by sunitinib at progression with the standard sequence of first-line sunitinib followed by everolimus in patients with metastatic renal cell carcinoma., Patients and Methods: RECORD-3 used a crossover treatment design. The primary objective was to assess progression-free survival (PFS) noninferiority of first-line everolimus compared with first-line sunitinib. Secondary end points included combined PFS for each sequence, overall survival (OS), and safety., Results: Of 471 enrolled patients, 238 were randomly assigned to first-line everolimus followed by sunitinib, and 233 were randomly assigned to first-line sunitinib followed by everolimus. The primary end point was not met; the median PFS was 7.9 months for first-line everolimus and 10.7 months for first-line sunitinib (hazard ratio [HR], 1.4; 95% CI, 1.2 to 1.8). Among patients who discontinued first-line, 108 (45%) crossed over from everolimus to second-line sunitinib, and 99 (43%) crossed over from sunitinib to second-line everolimus. The median combined PFS was 21.1 months for sequential everolimus then sunitinib and was 25.8 months for sequential sunitinib then everolimus (HR, 1.3; 95% CI, 0.9 to 1.7). The median OS was 22.4 months for sequential everolimus and then sunitinib and 32.0 months for sequential sunitinib and then everolimus (HR, 1.2; 95% CI, 0.9 to 1.6). Common treatment-emergent adverse events during first-line everolimus or sunitinib were stomatitis (53% and 57%, respectively), fatigue (45% and 51%, respectively), and diarrhea (38% and 57%, respectively)., Conclusion: Everolimus did not demonstrate noninferiority compared with sunitinib as a first-line therapy. The trial results support the standard treatment paradigm of first-line sunitinib followed by everolimus at progression., (© 2014 by American Society of Clinical Oncology.)

The multicentre, open-label, two-stage, single-arm, phase 2, PILLAR (PIvotaL Lymphoma triAls of RAD001)-1 study (NCT00702052) assessed the efficacy and safety of everolimus 10 mg/d in adults with confirmed mantle cell lymphoma (MCL) refractory to or intolerant of bortezomib who received ≥1 other antineoplastic agent, either separately or in combination with bortezomib. Primary endpoint was overall response rate (ORR) per investigator review according to the response criteria for malignant lymphoma. Secondary endpoints included progression-free survival (PFS), overall survival (OS) and safety. Fifty-eight patients were enrolled from August 2008-January 2011. Five partial responses were observed (ORR 8·6%; 90% confidence interval [CI] 3·5-17·3%); the study did not meet the prespecified objective of ≥8 objective responses among 57 patients. Median PFS and OS were 4·4 months (95% CI 3·5-6·1) and 16·9 months (95% CI 14·4-29·9), respectively. Grade 3/4 non-haematological toxicities occurred in 70·7% of patients. Based on laboratory values, grade 3/4 thrombocytopenia, neutropenia and anaemia occurred in 13·8%, 13·8% and 8·6% of patients, respectively. Everolimus demonstrated modest activity and acceptable tolerability in heavily pretreated patients with MCL refractory to or intolerant of bortezomib. Future studies evaluating everolimus in a less refractory population or in combination with other targeted therapies in refractory MCL are warranted., (© 2014 John Wiley & Sons Ltd.)

Purpose: Phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway activation in patients with HER2-positive (HER2(+)) breast cancer has been implicated in de novo and acquired trastuzumab resistance. The purpose of this study was to determine the clinical activity of the PI3K inhibitor buparlisib (BKM120) in patients with HER2(+) advanced/metastatic breast cancer resistant to trastuzumab-based therapy., Experimental Design: In the dose-escalation portion of this phase I/II study, patients with trastuzumab-resistant locally advanced or metastatic HER2(+) breast cancer were treated with daily oral doses of buparlisib and weekly intravenous trastuzumab (2 mg/kg). Dose escalation was guided by a Bayesian logistic regression model with overdose control., Results: Of 18 enrolled patients, 17 received buparlisib. One dose-limiting toxicity of grade 3 general weakness was reported at the 100-mg/day dose level (the single-agent maximum tolerated dose) and this dose level was declared the recommended phase II dose (RP2D) of buparlisib in combination with trastuzumab. Common (>25%) adverse events included rash (39%), hyperglycemia (33%), and diarrhea (28%). The pharmacokinetic profile of buparlisib was not affected by its combination with trastuzumab. At the RP2D, there were two (17%) partial responses, 7 (58%) patients had stable disease (≥6 weeks), and the disease control rate was 75%. Pharmacodynamic studies showed inhibition of the PI3K/AKT/mTOR and RAS/MEK/ERK pathways., Conclusions: In this patient population, the combination of buparlisib and trastuzumab was well tolerated, and preliminary signs of clinical activity were observed. The phase II portion of this study will further explore the safety and efficacy of this combination at the RP2D. Clin Cancer Res; 20(7); 1935-45. ©2014 AACR.

The present exploratory analysis examined the efficacy, safety, and quality-of-life effects of everolimus (EVE) + exemestane (EXE) in the subgroup of patients in BOLERO-2 whose last treatment before study entry was in the (neo)adjuvant setting. In BOLERO-2, patients with hormone-receptor-positive (HR(+)), human epidermal growth factor receptor-2-negative (HER2(-)) advanced breast cancer recurring/progressing after a nonsteroidal aromatase inhibitor (NSAI) were randomly assigned (2:1) to receive EVE (10 mg/day) + EXE (25 mg/day) or placebo (PBO) + EXE. The primary endpoint was progression-free survival (PFS) by local assessment. Overall, 137 patients received first-line EVE + EXE (n = 100) or PBO + EXE (n = 37). Median PFS by local investigator assessment nearly tripled to 11.5 months with EVE + EXE from 4.1 months with PBO + EXE (hazard ratio = 0.39; 95 % CI 0.25-0.62), while maintaining quality of life. This was confirmed by central assessment (15.2 vs 4.2 months; hazard ratio = 0.32; 95 % CI 0.18-0.57). The marked PFS improvement in patients receiving EVE + EXE as first-line therapy for disease recurrence during or after (neo)adjuvant NSAI therapy supports the efficacy of this combination in the first-line setting. Furthermore, the results highlight the potential benefit of early introduction of EVE + EXE in the management of HR(+), HER2(-) advanced breast cancer in postmenopausal patients.

Background: This phase Ib study aimed to establish the feasible everolimus dose given with standard-dose etoposide plus cisplatin (EP) for extensive-stage small-cell lung cancer (SCLC)., Patients and Methods: An adaptive Bayesian dose-escalation model and investigator opinion were used to identify feasible daily or weekly everolimus doses given with EP in adults with treatment-naive extensive-stage SCLC. A protocol amendment mandated prophylactic granulocyte colony-stimulating factor (G-CSF). Primary end point was cycle 1 dose-limiting toxicity (DLT) rate. Secondary end points included safety, relative EP dose intensity, pharmacokinetics, and tumor response., Results: Patients received everolimus 2.5 or 5 mg/day without G-CSF (n=10; cohort A), 20 or 30 mg/week without G-CSF (n=18; cohort B), or 2.5 or 5 mg/day with G-CSF (n=12; cohort C); all received EP. Cycle 1 DLT rates were 50.0%, 22.2%, and 16.7% in cohorts A, B, and C, respectively. Cycle 1 DLTs were neutropenia (cohorts A and B), febrile neutropenia (all cohorts), and thrombocytopenia (cohorts A and C). The most common grade 3/4 adverse events were hematologic. Best overall response was partial response (40.0%, 61.1%, and 58.3% in cohorts A, B, and C, respectively)., Conclusions: Everolimus 2.5 mg/day plus G-CSF was the only feasible dose given with standard-dose EP in untreated extensive-stage SCLC.

Objective: Everolimus (EVE)+exemestane (EXE; n = 485) more than doubled median progression-free survival versus placebo (PBO) + EXE (n = 239), with a manageable safety profile and no deterioration in health-related quality-of-life (HRQOL) in patients with hormone-receptor-positive (HR(+)) advanced breast cancer (ABC) who recurred or progressed on/after nonsteroidal aromatase inhibitor (NSAI) therapy. To further evaluate EVE + EXE impact on disease burden, we conducted additional post-hoc analyses of patient-reported HRQOL., Research Design and Methods: HRQOL was assessed using EORTC QLQ-C30 and QLQ-BR23 questionnaires at baseline and every 6 weeks thereafter until treatment discontinuation because of disease progression, toxicity, or consent withdrawal. Endpoints included the QLQ-C30 Global Health Status (QL2) scale, the QLQ-BR23 breast symptom (BRBS), and arm symptom (BRAS) scales. Between-group differences in change from baseline were assessed using linear mixed models with selected covariates. Sensitivity analysis using pattern-mixture models determined the effect of study discontinuation on/before week 24. Treatment arms were compared using differences of least squares mean (LSM) changes from baseline and 95% confidence intervals (CIs) at each timepoint and overall., Clinical Trial Registration: Clinicaltrials.gov: NCT00863655., Main Outcome Measures: Progression-free survival, survival, response rate, safety, and HRQOL., Results: Linear mixed models (primary model) demonstrated no statistically significant overall difference between EVE + EXE and PBO + EXE for QL2 (LSM difference = -1.91; 95% CI = -4.61, 0.78), BRBS (LSM difference = -0.18; 95% CI = -1.98, 1.62), or BRAS (LSM difference = -0.42; 95% CI = -2.94, 2.10). Based on pattern-mixture models, patients who dropped out early had worse QL2 decline on both treatments. In the expanded pattern-mixture model, EVE + EXE-treated patients who did not drop out early had stable BRBS and BRAS relative to PBO + EXE., Key Limitations: HRQOL data were not collected after disease progression., Conclusions: These analyses confirm that EVE + EXE provides clinical benefit without adversely impacting HRQOL in patients with HR(+) ABC who recurred/progressed on prior NSAIs versus endocrine therapy alone.

Purpose: Panobinostat is a potent oral pan-deacetylase inhibitor with promising clinical activity in hematologic malignancies. Panobinostat was shown to inhibit CYP2D6 activity in vitro; thus understanding the magnitude of the potential clinical inhibition of panobinostat on co-medications that are CYP2D6 substrates becomes important., Methods: This study evaluated the effects of co-administration of panobinostat with a sensitive CYP2D6 substrate, dextromethorphan (DM), in patients with advanced cancer who have functional CYP2D6 genes. Patients received 60 mg DM alone on day 1, panobinostat at 20 mg alone on days 3 and 5, and both agents on day 8. Plasma concentrations of DM and its metabolite dextrorphan (DX) were determined by liquid chromatography-tandem mass spectrometry following serial blood collections on day 1 (DM alone) and day 8 (in combination with panobinostat)., Results: Panobinostat increased DM exposure by 64 % [geometric mean ratio (GMR), 1.64 (90 % confidence interval (CI), 1.17-2.31)] and DX exposure by 29 % (GMR, 1.29 [90 % CI, 1.10-1.51]). These results indicated that panobinostat weakly inhibited a sensitive CYP2D6 substrate in cancer patients by increasing DM exposure by less than twofold., Conclusion: Safety monitoring of sensitive CYP2D6 substrates with narrow therapeutic index is recommended when co-administering with panobinostat in future clinical practice.

Background: The randomized, controlled BOLERO-2 (Breast Cancer Trials of Oral Everolimus) trial demonstrated significantly improved progression-free survival with the use of everolimus plus exemestane (EVE + EXE) versus placebo plus exemestane (PBO + EXE) in patients with advanced breast cancer who developed disease progression after treatment with nonsteroidal aromatase inhibitors. This analysis investigated the treatment effects on health-related quality of life (HRQOL)., Methods: Using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) questionnaire, HRQOL was assessed at baseline and every 6 weeks thereafter until disease progression and/or treatment discontinuation. The 30 items in 15 subscales of the QLQ-C30 include global health status wherein higher scores (range, 0-100) indicate better HRQOL. This analysis included a protocol-specified time to definitive deterioration (TDD) analysis at a 5% decrease in HRQOL versus baseline, with no subsequent increase above this threshold. The authors report additional sensitivity analyses using 10-point minimal important difference decreases in the global health status score versus baseline. Treatment arms were compared using the stratified log-rank test and Cox proportional hazards model adjusted for trial stratum (visceral metastases, previous hormone sensitivity), age, sex, race, baseline global health status score and Eastern Cooperative Oncology Group performance status, prognostic risk factors, and treatment history., Results: Baseline global health status scores were found to be similar between treatment groups (64.7 vs 65.3). The median TDD in HRQOL was 8.3 months with EVE + EXE versus 5.8 months with PBO + EXE (hazard ratio, 0.74; P = .0084). At the 10-point minimal important difference, the median TDD with EVE + EXE was 11.7 months versus 8.4 months with PBO + EXE (hazard ratio, 0.80; P = .1017)., Conclusions: In patients with advanced breast cancer who develop disease progression after treatment with nonsteroidal aromatase inhibitors, EVE + EXE was associated with a longer TDD in global HRQOL versus PBO + EXE., (Copyright © 2013 American Cancer Society.)

Purpose: We assessed adding the multikinase inhibitor sorafenib to gemcitabine or capecitabine in patients with advanced breast cancer whose disease progressed during/after bevacizumab., Experimental Design: This double-blind, randomized, placebo-controlled phase IIb study (ClinicalTrials.gov NCT00493636) enrolled patients with locally advanced or metastatic human epidermal growth factor receptor 2 (HER2)-negative breast cancer and prior bevacizumab treatment. Patients were randomized to chemotherapy with sorafenib (400 mg, twice daily) or matching placebo. Initially, chemotherapy was gemcitabine (1,000 mg/m(2) i.v., days 1, 8/21), but later, capecitabine (1,000 mg/m(2) orally twice daily, days 1-14/21) was allowed as an alternative. The primary endpoint was progression-free survival (PFS)., Results: One hundred and sixty patients were randomized. More patients received gemcitabine (82.5%) than capecitabine (17.5%). Sorafenib plus gemcitabine/capecitabine was associated with a statistically significant prolongation in PFS versus placebo plus gemcitabine/capecitabine [3.4 vs. 2.7 months; HR = 0.65; 95% confidence interval (CI): 0.45-0.95; P = 0.02], time to progression was increased (median, 3.6 vs. 2.7 months; HR = 0.64; 95% CI: 0.44-0.93; P = 0.02), and overall response rate was 19.8% versus 12.7% (P = 0.23). Median survival was 13.4 versus 11.4 months for sorafenib versus placebo (HR = 1.01; 95% CI: 0.71-1.44; P = 0.95). Addition of sorafenib versus placebo increased grade 3/4 hand-foot skin reaction (39% vs. 5%), stomatitis (10% vs. 0%), fatigue (18% vs. 9%), and dose reductions that were more frequent (51.9% vs. 7.8%)., Conclusion: The addition of sorafenib to gemcitabine/capecitabine provided a clinically small but statistically significant PFS benefit in HER2-negative advanced breast cancer patients whose disease progressed during/after bevacizumab. Combination treatment was associated with manageable toxicities but frequently required dose reductions., (©2013 AACR)

Background: Patients with melanoma harbouring Val600 BRAF mutations benefit from treatment with BRAF inhibitors. However, no targeted treatments exist for patients with BRAF wild-type tumours, including those with NRAS mutations. We aimed to assess the use of MEK162, a small-molecule MEK1/2 inhibitor, in patients with NRAS-mutated or Val600 BRAF-mutated advanced melanoma., Methods: In our open-label, non-randomised, phase 2 study, we assigned patients with NRAS-mutated or BRAF-mutated advanced melanoma to one of three treatment arms on the basis of mutation status. Patients were enrolled at university hospitals or private cancer centres in Europe and the USA. The three arms were: twice-daily MEK162 45 mg for NRAS-mutated melanoma, twice-daily MEK162 45 mg for BRAF-mutated melanoma, and twice-daily MEK162 60 mg for BRAF-mutated melanoma. Previous treatment with BRAF inhibitors was permitted, but previous MEK inhibitor therapy was not allowed. The primary endpoint was the proportion of patients who had an objective response (ie, a complete response or confirmed partial response). We report data for the 45 mg groups. We assessed clinical activity in all patients who received at least one dose of MEK162 and in patients assessable for response (with two available CT scans). This study is registered with ClinicalTrials.gov, number NCT01320085, and is currently recruiting additional patients with NRAS mutations (based on a protocol amendment)., Findings: Between March 31, 2011, and Jan 17, 2012, we enrolled 71 patients who received at least one dose of MEK162 45 mg. By Feb 29, 2012 (data cutoff), median follow-up was 3·3 months (range 0·6-8·7; IQR 2·2-5·0). No patients had a complete response. Six (20%) of 30 patients with NRAS-mutated melanoma had a partial response (three confirmed) as did eight (20%) of 41 patients with BRAF-mutated melanoma (two confirmed). The most frequent adverse events were acneiform dermatitis (18 [60%] patients with NRAS -mutated melanoma and 15 [37%] patients with the BRAF-mutated melanoma), rash (six [20%] and 16 [39%]), peripheral oedema (ten [33%] and 14 [34%]), facial oedema (nine [30%] and seven [17%]), diarrhoea (eight [27%] and 15 [37%]), and creatine phosphokinase increases (11 [37%] and nine [22%]). Increased creatine phosphokinase was the most common grade 3-4 adverse event (seven [23%] and seven [17%]). Four patients had serious adverse events (two per arm), which included diarrhoea, dehydration, acneiform dermatitis, general physical deterioration, irregular heart rate, malaise, and small intestinal perforation. No deaths occurred from treatment-related causes., Interpretation: To our knowledge, MEK162 is the first targeted therapy to show activity in patients with NRAS -mutated melanoma and might offer a new option for a cancer with few effective treatments., Funding: Novartis Pharmaceuticals., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: This phase II study estimated the difference in objective response rate (ORR) among patients with advanced nonsquamous non-small-cell lung cancer (NSCLC) receiving paclitaxel-carboplatin (CP) plus motesanib or bevacizumab., Patients and Methods: Chemotherapy-naive patients (N = 186) were randomized 1:1:1 to receive CP plus motesanib 125 mg once daily (qd) (arm A), motesanib 75 mg twice daily (b.i.d.) 5 days on/2 days off (arm B), or bevacizumab 15 mg/kg every 3 weeks (q3w) (arm C). The primary end point was ORR (per RECIST). Other end points included progression-free survival (PFS), overall survival (OS), motesanib pharmacokinetics, and adverse events (AEs)., Results: ORRs in the three arms were as follows: arm A, 30% (95% confidence interval 18% to 43%); arm B, 23% (13% to 36%); and arm C, 37% (25% to 50%). Median PFS in arm A was 7.7 months, arm B 5.8 months, and arm C 8.3 months; median OS for arm A was 14.0 months, arm B 12.8 months, and arm C 14.0 months. Incidence of AEs was greater in arms A and B than in arm C. More grade 5 AEs not attributable to disease progression occurred in arm B (n = 10) than in arms A (n = 4) and C (n = 4). Motesanib plasma C(max) and C(min) values were consistent with its pharmacokinetic properties observed in previous studies., Conclusions: The efficacy of 125 mg qd motesanib or bevacizumab plus CP was estimated to be comparable. Toxicity was higher but manageable in both motesanib arms. Efficacy and tolerability of motesanib 125 mg qd plus CP in advanced nonsquamous NSCLC are being further investigated in a phase III study.

Platinum-resistant ovarian cancer continues to be a difficult therapeutic problem. Clearly, molecularly targeted agents should be evaluated in this patient population. Patients were eligible for this phase II study with stage III or IV ovarian cancer, whose tumor expressed Kit (CD117) or platelet-derived growth factor receptor (PDGFR) and with relapse of measurable disease within 6 months of completing frontline, platinum- and taxane-based chemotherapy. Patients were treated daily with 400 mg of imatinib mesylate orally. It was assumed that the agent would be of no further interest if the population response rate was less than 10%. A two-stage design was used for patient accrual. A total of 34 patients were registered to the study. Of these, 15 were found to be ineligible or not evaluable (8 because their tumor samples were negative for both DC117 and PDGFR). Of 19 evaluable patients, 2 (11%) tested positively for c-Kit and 17 (89%) tested positively for PDGFR. There were no objective responders. Thirteen patients (68%) had increasing disease or symptomatic deterioration, and six (32%) went off protocol during the first month due to adverse events. Median progression-free survival was 2 months (95% CI 1-3 months) and median overall survival was 10 months (95% CI 6-18 months). Eleven percent of patients experienced grade 4 hematologic/metabolic toxicity and 37% experienced grade 3 nonhematologic toxicity. We conclude that imatinib mesylate as a single agent does not appear to have useful clinical activity in c-Kit and/or PDGFR positive, recurrent ovarian cancer in heavily pretreated patients with ovarian cancer.

Purpose: Treatment with aromatase inhibitors decreases bone mineral density (BMD) and may increase the risk of fractures in postmenopausal women with early-stage breast cancer. The addition of zoledronic acid to adjuvant letrozole therapy may protect against bone loss., Patients and Methods: Patients receiving adjuvant letrozole were randomly assigned to receive either upfront or delayed-start zoledronic acid (4 mg intravenously every 6 months). The delayed group received zoledronic acid when lumbar spine (LS) or total hip (TH) T score decreased to less than -2.0 or when a nontraumatic fracture occurred. The primary end point of this study was to compare the change in LS BMD at month 12 between the groups. Secondary end points included change in TH BMD and changes in serum bone turnover markers at month 12., Results: The upfront and delayed groups each included 301 patients. At month 12, LS BMD was 4.4% higher in the upfront group than in the delayed group (95% CI, 3.7% to 5.0%; P < .0001), and TH BMD was 3.3% higher (95% CI, 2.8% to 3.8%; P < .0001). In the upfront group, mean serum N-telopeptide and bone-specific alkaline phosphatase concentrations decreased by 15.1% (P < .0001) and 8.8% (P = .0006), respectively, at month 12, whereas concentrations increased significantly in the delayed group by 19.9% (P = .013) and 24.3% (P < .0001), respectively., Conclusion: With 1 year of follow-up, results of the primary end point of the Zometa-Femara Adjuvant Synergy Trial (Z-FAST) indicate that upfront zoledronic acid therapy prevents bone loss in the LS in postmenopausal women receiving adjuvant letrozole for early-stage breast cancer.

Purpose: Given the activity and tolerability of pemetrexed/platinum combinations in non-small-cell lung cancer, and the success of novel therapeutic strategies employed in recent extensive-stage small-cell lung cancer (ES-SCLC) trials, a randomized phase II trial was initiated to evaluate the use of cisplatin or carboplatin plus pemetrexed in previously untreated ES-SCLC., Patients and Methods: Patients were randomly assigned to receive pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 or pemetrexed plus carboplatin area under the concentration curve 5. Treatment was administered once every 21 days for a maximum of six cycles. All patients received folic acid, vitamin B12, and steroid prophylaxis., Results: Between December 19, 2002, and May 17, 2004, 78 patients were enrolled onto this multicenter trial. Median age was 63 years (range, 46 to 82 years) for cisplatin/pemetrexed and 66 years (range, 47 to 75 years) for carboplatin/pemetrexed. Median survival time (MST) for cisplatin/pemetrexed was 7.6 months, with a 1-year survivorship of 33.4% and a response rate of 35% (95% CI, 20.6% to 51.7%). The MST for carboplatin/pemetrexed was 10.4 months, with a 1-year survivorship of 39.0% and a response rate of 39.5% (95% CI, 24.0 to 56.6). Median time to progression for cisplatin/pemetrexed was 4.9 months and for carboplatin/pemetrexed was 4.5 months. Median dose-intensity (actual/planned dose) was 98.94% for cisplatin and 99.95% for pemetrexed in the cisplatin/pemetrexed group and 93.21% for carboplatin and 98.50% for pemetrexed in the carboplatin/pemetrexed group. Grade 3/4 hematologic toxicities included neutropenia (15.8% v 20.0%) and thrombocytopenia (13.2% v 22.9%) in the cisplatin/pemetrexed and carboplatin/pemetrexed treatment groups, respectively., Conclusion: Pemetrexed/platinum doublets had activity and appeared to be well-tolerated in first-line ES-SCLC.

Background: Gemcitabine and carboplatin combination therapy is an active and tolerable regimen in the treatment of non-small-cell lung cancer (NSCLC). Twenty-eight- and 21-day regimens without day-15 administration of gemcitabine are common; however, it remains unclear which offers the optimal therapeutic index., Methods: This trial evaluated two schedules of the combination of gemcitabine and carboplatin: gemcitabine (1100 mg/m on days 1 and 8) plus carboplatin (area under the curve = 5 on day 8) every 28 days, or gemcitabine (1000 mg/m on days 1 and 8) plus carboplatin (area under the curve = 5 on day 1) every 21 days. Eligible patients in this trial had stage IIIB (with malignant pleural effusion) or stage IV NSCLC with no prior chemotherapy. The primary objective was to evaluate progression-free survival, with secondary objectives of overall survival, response rate, and toxicity., Results: One hundred patients were randomized and enrolled from October of 2000 to January of 2002 into this multi-institutional study (48 for the 28-day regimen and 52 for the 21-day regimen). Baseline demographics were well matched, and a majority of patients (85%) enrolled with stage IV disease. Median progression-free survival and response rates were 3.8 months and 22.9%, respectively, with the 28-day regimen, and 4.9 months and 40.4%, respectively, with the 21-day regimen. Median survival was 8.7 months with the 28-day regimen and 8.0 months for the 21-day regimen. One- and 2-year survival rates were 34.7% and 8.7%, respectively, with the 28-day regimen, and 36.5% and 16.8%, respectively, with the 21-day regimen. Differences in progression-free survival (log-rank statistic, p = 0.5786), response rate (Fisher's exact test, p = 0.0859) and overall survival (log-rank statistic, p = 0.3568) were not statistically significant. Grade 3 to 4 hematologic toxicities occurred with a greater frequency in the 21-day regimen. No grade 3 to 4 nonhematologic toxicity (except nausea/vomiting with the 28-day regimen) was observed in more than 10% of patients in either treatment arm., Conclusion: Gemcitabine plus carboplatin is active and well tolerated in advanced NSCLC. Both regimens may be considered for further study. Although the 21-day regimen appeared to be associated with preferable outcomes, differences between treatment groups were not statistically significant.

Chloroplast DNA sequences are a primary source of data for plant molecular systematic studies. A few key papers have provided the molecular systematics community with universal primer pairs for noncoding regions that have dominated the field, namely trnL-trnF and trnK/matK. These two regions have provided adequate information to resolve species relationships in some taxa, but often provide little resolution at low taxonomic levels. To obtain better phylogenetic resolution, sequence data from these regions are often coupled with other sequence data. Choosing an appropriate cpDNA region for phylogenetic investigation is difficult because of the scarcity of information about the tempo of evolutionary rates among different noncoding cpDNA regions. The focus of this investigation was to determine whether there is any predictable rate heterogeneity among 21 noncoding cpDNA regions identified as phylogenetically useful at low levels. To test for rate heterogeneity among the different cpDNA regions, we used three species from each of 10 groups representing eight major phylogenetic lineages of phanerogams. The results of this study clearly show that a survey using as few as three representative taxa can be predictive of the amount of phylogenetic information offered by a cpDNA region and that rate heterogeneity exists among noncoding cpDNA regions.

Background: Single-agent chemotherapy with dacarbazine continues to be the standard of care for the treatment of metastatic melanoma. However, there is a large population of patients who have failed first-line therapy and might benefit from additional treatment. In the current study, the authors evaluated the antitumor effects and toxicity of vinorelbine therapy in patients who had failed one prior systemic therapy., Methods: Patients were required to have a histologic diagnosis of melanoma and be of Stage IV with measurable disease, a Southwest Oncology Group (SWOG) performance status (PS) of 0-2, no evidence of brain metastases, and adequate bone marrow and liver function. Treatment was comprised of vinorelbine given at a dose of 30 mg/m(2)/week by intravenous bolus., Results: Twenty-four patients were registered to the study, 3 of whom were determined to be ineligible. The 21 eligible patients had a median age of 58 years with a SWOG PS of 0 in 7 patients, 1 in 13 patients, and 2 in 1 patient. There were no complete or partial responses observed, for a response rate of 0 of the 21 patients studied (95% confidence interval [95% CI], 0-16%); the study closed after the first stage of accrual. The estimated median progression-free survival was 2 months (95% CI, 1.5-3.3 months) and the estimated median overall survival was 6 months (95% CI, 3.7-8.3 months). There was one death due to febrile neutropenia reported, with six patients experiencing one or more Grade 4 toxicities, including neutropenia/granulocytopenia, leukopenia, dyspnea, and fatigue., Conclusions: Despite impressive preclinical activity against melanoma, vinorelbine does not appear to have enough clinical activity to be of interest in previously treated patients with disseminated melanoma. The progression-free and overall survival results noted in previously treated patients in the current study were similar to results reported in prior SWOG Phase II trials in untreated patients. The group of previously treated patients may be used to evaluate new agents for the treatment of disseminated melanoma., (Copyright 2004 American Cancer Society.)

In the course of developing a cost-effective, scaleable process for the purification of a recombinant protein from Chinese hamster ovary (CHO) suspension cell culture, we investigated direct capture of this molecule using expanded bed adsorption (EBA). EBA combines clarification, purification, and concentration of the product into a single step. The unclarified bioreactor material was directly applied to a STREAMLINE 25 column containing an affinity STREAMLINE adsorbent. This work focused on simplifying the EBA operations and minimizing the overall processing time by running the EBA column unidirectionally, eluting in the expanded bed mode, and coupling the EBA column directly with ion exchange or hydrophobic interaction chromatography. Unidirectional EBA was clearly a simpler unit operation and did not require the use of specialized equipment. The increase in the elution pool volume was insignificant, especially when the EBA column was eluted directly onto the downstream column. Scale-down was simple and could be automated. Coupling of unidirectional EBA with a downstream purification step reduced processing time, equipment requirements and cost.

The extracellular portion of the interleukin-1 receptor (IL-1R) is sufficient for high-affinity binding to IL-1; however, the structural basis for binding of the receptor to IL-1 is not known. To produce individual domains of IL-1 receptor for structural studies, we constructed a molecular fusion of IL-1 receptor with immunoglobulin G heavy chain that contains a protease specific sequence joining the two portions of the molecule (IL-1R-G-IgG). We introduced the hexapeptide sequence AAHY:TL (where ":" denotes the scissile bond) at the junction of the IL-1R and IgG regions, for specific cleavage by an H64A variant of subtilisin BPN' (Genenase I), an endoprotease that cleaves selectively at this sequence (Carter et al., (1989) Proteins 6, 240-248). Plasmid DNA encoding the fusion protein was used to transfect human embryonic kidney 293 cells transiently, and secreted IL-1R-G-IgG was purified from cell supernatants by protein A chromatography. The IL-1 receptor's extracellular region was then generated by enzymatic cleavage with Genenase I which was immobilized on controlled-pore glass. Incubation of IL-1R-G-IgG with immobilized Genenase I resulted in specific cleavage at the target site, as confirmed by SDS-PAGE, immunoblotting and direct sequencing of the newly generated termini. The resulting soluble IL-1R was separated from the immunoglobulin Fc cleavage product by re-chromatography on protein A. The purified, soluble IL-1R retained quantitatively the ability to bind to its ligand, IL-1 beta. This approach offers a generic means by which the extracellular region of a given type I transmembrane receptor can be expressed as an immunoadhesin, released enzymatically and then easily purified for crystallographic or ligand binding studies.