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Treatment options for patients with biliary tract cancer are limited, and the prognosis is poor. CTX-009, a novel bispecific antibody targeting both DLL4 and VEGF-A, has demonstrated antitumor activity in patients with advanced cancers as both a monotherapy and in combination with chemotherapy. In a phase II study of patients with advanced biliary tract cancer who had received one or two prior therapies, CTX-009 with paclitaxel demonstrated a 37.5% overall response rate (ORR). Described here is the design of and rationale for COMPANION-002, a randomized phase II/III study, which will evaluate the safety and efficacy of CTX-009 in combination with paclitaxel versus paclitaxel alone as second-line treatment for patients with advanced biliary tract cancer. The primary end point is ORR, and crossover is allowed. Clinical Trial Registration: NCT05506943 (ClinicalTrials.gov).

Background: The DNA methyltransferase inhibitors azacitidine and decitabine for individuals with myelodysplastic syndromes or chronic myelomonocytic leukaemia are available in parenteral form. Oral therapy with similar exposure for these diseases would offer potential treatment benefits. We aimed to compare the safety and pharmacokinetics of oral decitabine plus the cytidine deaminase inhibitor cedazuridine versus intravenous decitabine., Methods: We did a registrational, multicentre, open-label, crossover, phase 3 trial of individuals with myelodysplastic syndromes or chronic myelomonocytic leukaemia and individuals with acute myeloid leukaemia, enrolled as separate cohorts; results for only participants with myelodysplastic syndromes or chronic myelomonocytic leukaemia are reported here. In 37 academic and community-based clinics in Canada and the USA, we enrolled individuals aged 18 years or older who were candidates to receive intravenous decitabine, with Eastern Cooperative Oncology Group performance status 0 or 1 and a life expectancy of at least 3 months. Participants were randomly assigned (1:1) to receive 5 days of oral decitabine-cedazuridine (one tablet once daily containing 35 mg decitabine and 100 mg cedazuridine as a fixed-dose combination) or intravenous decitabine (20 mg/m 2 per day by continuous 1-h intravenous infusion) in a 28-day treatment cycle, followed by 5 days of the other formulation in the next treatment cycle. Thereafter, all participants received oral decitabine-cedazuridine from the third cycle on until treatment discontinuation. The primary endpoint was total decitabine exposure over 5 days with oral decitabine-cedazuridine versus intravenous decitabine for cycles 1 and 2, measured as area under the curve in participants who received the full treatment dose in cycles 1 and 2 and had decitabine daily AUC 0-24 for both oral decitabine-cedazuridine and intravenous decitabine (ie, paired cycles). On completion of the study, all patients were rolled over to a maintenance study. This study is registered with ClinicalTrials.gov, NCT03306264., Findings: Between Feb 8, 2018, and June 7, 2021, 173 individuals were screened, 138 (80%) participants were randomly assigned to a treatment sequence, and 133 (96%) participants (87 [65%] men and 46 [35%] women; 121 [91%] White, four [3%] Black or African-American, three [2%] Asian, and five [4%] not reported) received treatment. Median follow-up was 966 days (IQR 917-1050). Primary endpoint of total exposure of oral decitabine-cedazuridine versus intravenous decitabine was 98·93% (90% CI 92·66-105·60), indicating equivalent pharmacokinetic exposure on the basis of area under the curve. The safety profiles of oral decitabine-cedazuridine and intravenous decitabine were similar. The most frequent adverse events of grade 3 or worse were thrombocytopenia (81 [61%] of 133 participants), neutropenia (76 [57%] participants), and anaemia (67 [50%] participants). The incidence of serious adverse events in cycles 1-2 was 31% (40 of 130 participants) with oral decitabine-cedazuridine and 18% (24 of 132 participants) with intravenous decitabine. There were five treatment-related deaths; two deemed related to oral therapy (sepsis and pneumonia) and three to intravenous treatment (septic shock [n=2] and pneumonia [n=1])., Interpretation: Oral decitabine-cedazuridine was pharmacologically and pharmacodynamically equivalent to intravenous decitabine. The results support use of oral decitabine-cedazuridine as a safe and effective alternative to intravenous decitabine for treatment of individuals with myelodysplastic syndromes or chronic myelomonocytic leukaemia., Funding: Astex Pharmaceuticals., Competing Interests: Declaration of interests GG-M has consulted for Acceleron; received honoraria and research funding from AbbVie, Astex, Bristol Myers Squibb, Curis, Genentech, and Novartis; received honoraria from Aprea; and received research funding from Gilead. JMc has received research funding from Astex; consulted for AbbVie, Apellis, BMS, CTI BioPharma, Novartis, Pfizer, and Takeda; received honoraria from BMS, Blueprint, Incyte, Jazz, Novartis, Stemline, and Takeda; and is an equity holder in COTA Healthcare. EAG has received research funding from Astex, Blueprint, and Celldex; received research funding from and consulted and served on advisory committees for Alexion and BMS/Celgene; consulted for and served on advisory committees for AbbVie, Apellis, AstraZeneca, CTI BioPharma, Genentech, Novartis, Taiho, and Takeda; and received honoraria from Aplastic Anemia and MDS International Foundation, Medicom, Physician Educational Resource, and Picnic Health. KWLY has consulted for BMS/Celgene, GSK, Jazz, Novartis, Pfizer, Shattuck, Taiho, and Takeda; received research funding from Astex, Forma, Genentech, Geron, Gilead, Janssen, Jazz, Novartis, Roche, Pfizer, and Treadwell; and received honoraria from AbbVie and Novartis. AMZ has received research funding from AbbVie, ADC Therapeutics, Amgen, Aprea, Astex, AstraZeneca, BMS, Boehringer-Ingelheim, Cardiff Oncology, Celgene, Incyte, Medimmune, Novartis, Otsuka, Pfizer, Takeda, and Trovagene; consulted for AbbVie, Acceleron, Agios, Amgen, Aprea, Astellas, BeyondSpring, BMS, Boehringer-Ingelheim, Cardiff, Cardinal Health, Celgene, Daiichi Sankyo, Epizyme, Geron, Gilead, Incyte, Ionis, Janssen, Jazz, Kura, Novartis, Pfizer, Seattle Genetics, Syndax, Taiho, Takeda, Trovagene, and Tyme; received honoraria from AbbVie, Acceleron, Agios, Amgen, Aprea, Astellas, BeyondSpring, BMS, Boehringer-Ingelheim, Cardiff, Cardinal, Celgene, Daiichi Sankyo, Epizyme, Geron, Gilead, Incyte, Ionis, Janssen, Jazz, Kura, Novartis, Otsuka, Pfizer, Seattle Genetics, Syndax, Taiho, Takeda, Trovagene, and Tyme; received travel expenses from Cardiff, Novartis, and Pfizer; and had leadership roles in boards or committees for AbbVie, BMS, Celgene, Geron, Gilead, Kura, and Novartis. AA-K's institution has received research support from Astex. HJD, NZ, NYG, JMa, HA, and JR declare no competing interests. PAP has served on an advisory committee for Agios. MS has served on advisory committees for AbbVie, BMS, Celgene, Jazz, Novartis, Pfizer, Roche, and Taiho and served on advisory committees for and received research funding from Actinium and Astellas. M-MK has served on advisory boards for AstraZeneca, BeiGene, BMS, Seattle Genetics, and Taiho. SF has consulted for and received honoraria from Blueprint, CTI, Gilead, GSK, Incyte, Janssen, Jazz, Karyopharm, Novartis, PharmaEssentia, Sanofi, Servier, Stemline, Taiho, and Takeda. OO has consulted for AbbVie, BMS/Celgene, CTI, Impact, Novartis, and Taiho and his institution has received research funding from AbbVie, Agios, Aprea, Astex, AstraZeneca, BMS/Celgene, CTI, Incyte, Janssen, Kartos, NS Pharma, and OncoTherapy. HK has received grants from AbbVie, Amgen, Ascentage, BMS, Daiichi-Sankyo, Immunogen, Jazz, and Novartis and received honoraria from AbbVie, Amgen, Amphista, Ascentage, Astellas, Biologix, Curis, Ipsen, KAHR, Labcorp, Novartis, Pfizer, Shenzhen Target Rx, Stemline, and Takeda. AED has consulted for Taiho; received honoraria from BMS, Novartis, and Gilead; served as chair of a data safety monitoring board for Geron; and is the 2023 American Society of Hematology Education Chair. CLO has received research funding from Astex and Genentech. GJR has consulted or served on advisory boards or data and safety monitoring committees for AbbVie, Actiunuim, Agios, Amgen, Astellas, AstraZeneca, Bluebird, Blueprint, Bluebird Bio, BMS, Catamaran, Celgene, Daiichi, GSK, Helsinn, Janssen, Jasper, Jazz, Mesoblast, Novartis, Pfizer, Roche, Syndax, Takeda, and Trovagene and received research support from Janssen. LB has consulted for Novartis. RB has received honoraria and research funding from BMS and Taiho; received research funding from Takeda; and received honoraria from AbbVie. BL has received honoraria and served on advisory committees and speakers bureaus for AbbVie, Amgen, and BMS and consulted for, received honoraria, and served on advisory committees and speakers bureaus for Novartis and Pfizer. AS has consulted for and received research funding from Kymera, consulted for Janssen and Rigel, and received honoraria from National Association for Continuing Education. K-HD, AO, and HNK are employed by Astex. YH and MA were employed in the past 24 months by and consult for Astex. MRS has consulted and served on advisory boards for and received travel expenses from BMS, CTI, Forma, Geron, GSK, and Taiho; received travel expenses from Astex; is an equity holder in and served on advisory committees for Karyopharm and Ryvu; and received research funding from ALX Oncology, Astex, Incyte, and Takeda., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Anemia is a common side effect of myelosuppressive chemotherapy; however, chemotherapy-induced anemia (CIA) management options are suboptimal. We evaluated the efficacy and safety of roxadustat in this setting. This open-label Phase 2 study included patients with non-myeloid malignancies and CIA (hemoglobin [Hb] ≤10 g/dL) who had planned concurrent myelosuppressive chemotherapy for ≥8 additional weeks. Oral roxadustat was administered for ≤16 weeks (starting dose 2.0 or 2.5 mg/kg, then titrated every 4 weeks). The primary efficacy endpoint was mean maximum change in Hb within 16 weeks of baseline without red blood cell (RBC) transfusion. Patients were assigned to roxadustat 2.0 (n = 31) or 2.5 mg/kg (n = 61) starting doses, and 89 were assessed for efficacy. The mean (standard deviation) maximum Hb change from baseline without RBC transfusion was 2.4 (1.5) and 2.5 (1.5) g/dL in the roxadustat 2.0 and 2.5 mg/kg groups, respectively. Median (range) time to Hb increase of ≥2 g/dL was 71 (57-92) days. Twelve patients (14.5%) had RBC transfusions (Week 5 to the end of treatment). Roxadustat was efficacious regardless of tumor type and chemotherapy regimen. Deep vein thrombosis (DVT) and pulmonary embolism (PE) occurred in 14 (15.2%) and nine (9.8%) patients, respectively, and three had serious adverse events attributed to roxadustat in the opinion of the investigators (PE: n = 2 [2.2%]; DVT: n = 1 [1.1%]). Roxadustat increased Hb in patients with CIA regardless of tumor type and chemotherapy regimen. Adverse events were consistent with observations in patients with advanced-stage malignancies., (© 2023 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Competing Interests: Conflict of Interest Disclosure James R. Berenson received consultant fees, speakers’ bureau honoraria, and research funding from Bristol Myers Squibb.

Background: Doublet combination therapies targeting immune checkpoints have shown promising efficacy in patients with advanced solid tumors, but it is unknown if rational triplet combinations will be well tolerated and associated with improved antitumor activity. The objective of this trial was to determine the recommended phase 2 doses (RP2Ds) and to assess the safety and efficacy of the programmed cell death protein 1 (PD-1) inhibitor dostarlimab in combination with (1) the poly(ADP-ribose) polymerase inhibitor niraparib with or without vascular endothelial growth factor inhibitor bevacizumab or (2) carboplatin-paclitaxel chemotherapy with or without bevacizumab, in patients with advanced cancer., Methods: IOLite is a multicenter, open-label, multi-arm clinical trial. Patients with advanced solid tumors were enrolled. Patients received dostarlimab in combination with niraparib with or without bevacizumab or in combination with carboplatin-paclitaxel with or without bevacizumab until disease progression, unacceptable toxicity, or withdrawal from the study. Prespecified endpoints in all parts were to evaluate the dose-limiting toxicities (DLTs), RP2Ds, pharmacokinetics (PKs), and preliminary efficacy for each combination., Results: A total of 55 patients were enrolled; patients received dostarlimab and: (1) niraparib in part A (n=22); (2) carboplatin-paclitaxel in part B (n=14); (3) niraparib plus bevacizumab in part C (n=13); (4) carboplatin-paclitaxel plus bevacizumab in part D (n=6). The RP2Ds of all combinations were determined. All combinations were safe and tolerable, with no new safety signals observed. DLTs were reported in 2, 1, 2, and 0 patients, in parts A-D, respectively. Preliminary antitumor activity was observed, with confirmed Response Evaluation Criteria in Solid Tumors v1.1 complete/partial responses reported in 4 of 22 patients (18.2%), 6 of 14 patients (42.9%), 4 of 13 patients (30.8%), and 3 of 6 (50.0%) patients, in parts A-D, respectively. Disease control rates were 40.9%, 57.1%, 84.6%, and 83.3%, in parts A-D, respectively. Dostarlimab PK was unaffected by any combinations tested. Coadministration of bevacizumab showed no impact on niraparib PKs. The overall mean PD-1 receptor occupancy was 99.0%., Conclusions: Dostarlimab was well tolerated in both doublet and triplet regimens tested, with promising antitumor activity observed with all combinations. We observed higher disease control rates in the triplet regimens than in doublet regimens., Trial Registration Number: NCT03307785., Competing Interests: Competing interests: TAY has received research support to the institution from Artios, AstraZeneca, Bayer, Clovis, Constellation, Cyteir, Eli Lilly, EMD Serono, Forbius, F-Star, Genentech, GlaxoSmithKline, ImmuneSensor, Ipsen, Jounce, Karyopharm, Kyowa, Merck, Novartis, Pfizer, Regeneron, Repare, Ribon Therapeutics, Sanofi, Scholar Rock, Seattle Genetics, Tesaro, and Vertex Pharmaceuticals; and has served as a consultant for Aduro, Almac, AstraZeneca, Atrin, Axiom, Bayer, Bristol Myers Squibb, Calithera, Clovis, Cybrexa, EMD Serono, F-Star, Guidepoint, Ignyta, I-Mab, Janssen, Merck, Pfizer, Repare, Roche, Rubius, Schrodinger, Seattle Genetics, Varian, and Zai Labs. AB has nothing to disclose. EPH reports institutional research or clinical trial support from Seattle Genetics, Puma, AstraZeneca, Hutchinson MediPharma, OncoMed, MedImmune, StemCentrx, Genentech/Roche, Curis, Verastem, Zymeworks, Syndax, Lycera, Rgenix, Novartis, Mersana, Millenium, TapImmune, Lilly, BerGenBio, Medivation, Pfizer, Tesaro, Boehringer Ingelheim, Eisai, H3 Biomedicine, Radius Health, Acerta, Takeda, Macrogenics, AbbVie, Immunomedics, FujiFilm, Effector, Merus, Nucana, Regeneron, Leap Therapeutics, Taiho Pharmaceutical, EMD Serono, Daiichi Sankyo, ArQule, Syros, Clovis, Cytomx, InventisBio, Deciphera, Unum Therapeutics, Sermonix Pharmaceuticals, Sutro, Aravive, Zenith Epigenetics, Arvinas, Torque, Harpoon, Fochon, Black Diamond, Orinove, Molecular Templates, Silverback Therapeutics, Compugen, G1Therapeutics, Karyopharm Therapeutics and Torque Therapeutics, outside the submitted work. JS reports grants from Pfizer, Celgene, Genentech; personal fees from Celgene, PUMA, TTC Oncology, Pfizer, Novartis, TapImmune, Ipsen, Tempus, and AstraZeneca; and honoraria from Ipsen, Celgene, PUMA, Novartis, Pfizer, Tempus, and AstraZeneca; institutional research support from Pfizer, AbbVie, AstraZeneca, Verastem, Leap therapeutics, Endocyte, Cleave, Merck, Bayer, Exelixis, Medivation, Biomarin, Tesaro, TTC-Oncology, Genentech/Roche, Arqule, Syros, Sermonix, Black Diamond, Fujifilm, Arcus, Corcept, ImmuneSensor, Aduro, Agenus, Five Prime, Gilead, CytRx, Merrimack, Ipsen, Plexxikon, Proacta, Esanex, MiRNA, and BIND outside the submitted work. MRP reports funding from Tesaro/GSK during the conduct of the study; consulting fees from Janssen, EMD serono, Pfizer, Pharmacyclics, Bayer, and Genentech outside the submitted work. JRA reports personal fees from Novartis, Eli Lilly, Orion Pharmaceuticals, Servier Pharmaceuticals, Peptomyc, Merck Sharp & Dohme, Kelun Pharmaceuticals/Klus Pharma, Spectrum Pharmaceuticals, Pfizer, Roche Pharmaceuticals, Ellipses Pharma, Certera, Bayer, Molecular Partners, NovellusDX, IONCTURA SA; grants from Bayer, Novartis, Blueprint Pharmaceuticals, Spectrum Pharmaceuticals, Tocagen, Symphogen, BioAlta, Pfizer, GenMab, CytomX, Kelun-Biotech, Takeda-Millenium, GlaxoSmithKline, Ipsen; travel reimbursement from ESMO, Department of Defense, Merck Sharp & Dohme, Louisiana State University, Kelun Pharmaceuticals/Klus Pharma, Huntsman Cancer Institute, Cancer Core Europe, Karolinska Cancer Institute, King Abdullah International Medical Research Center, Bayer, WIN Consortium, Jansen, Molecular Partners; and other compensation from European Journal of Cancer, VHIO/Ministero De Empleo Y Seguridad Social, Chinese University of Hong Kong, SOLTI, Elsevier, GlaxoSmithKline, outside the submitted work. LE was an employee of GSK at the time the study was done. MD was an employee of GSK at the time the study was done. WG was an employee of GSK at the time the study was done. SK was an employee of GSK at the time the study was done. SL was an employee of GSK at the time the study was done. BJD was an employee of GSK at the time the study was done. NG has nothing to disclose., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Many patients with advanced melanoma are resistant to immune checkpoint inhibition. In the ILLUMINATE-204 phase I/II trial, we assessed intratumoral tilsotolimod, an investigational Toll-like receptor 9 agonist, with systemic ipilimumab in patients with anti-PD-1- resistant advanced melanoma. In all patients, 48.4% experienced grade 3/4 treatment-emergent adverse events. The overall response rate at the recommended phase II dose of 8 mg was 22.4%, and an additional 49% of patients had stable disease. Responses in noninjected lesions and in patients expected to be resistant to ipilimumab monotherapy were observed. Rapid induction of a local IFNα gene signature, dendritic cell maturation and enhanced markers of antigen presentation, and T-cell clonal expansion correlated with clinical response. A phase III clinical trial with this combination (NCT03445533) is ongoing. SIGNIFICANCE: Despite recent developments in advanced melanoma therapies, most patients do not experience durable responses. Intratumoral tilsotolimod injection elicits a rapid, local type 1 IFN response and, in combination with ipilimumab, activates T cells to promote clinical activity, including in distant lesions and patients not expected to respond to ipilimumab alone. This article is highlighted in the In This Issue feature, p. 1861 ., (©2021 American Association for Cancer Research.)

Purpose: The CLASSICAL-Lung clinical trial tested the combination of pepinemab, an IgG4 humanized mAb targeting semaphorin 4D, with the PD-L1 inhibitor avelumab to assess the effects of coupling increased T-cell infiltration and reversal of immune suppression via pepinemab with sustained T-cell activation via checkpoint inhibition., Patients and Methods: This phase Ib/II, single-arm study was designed to evaluate the safety, tolerability, and efficacy of pepinemab in combination with avelumab in 62 patients with advanced non-small cell lung cancer (NSCLC), including immunotherapy-naïve (ION) patients and patients whose tumors progressed following anti-PD-1/L1 monotherapy (IOF). The main objectives were to evaluate safety/tolerability, establish a recommended phase 2 dose (RP2D), obtain a preliminary evaluation of antitumor activity, and investigate candidate biomarker activity., Results: The combination was well tolerated with no major safety signals identified. Pepinemab, 10 mg/kg with avelumab, 10 mg/kg, every 2 weeks, was selected as the RP2D. Among 21 evaluable ION patients, 5 patients experienced partial responses (PR), 4 patients evidenced clinical benefit ≥1 year, and the disease control rate (DCR) was 81%. Notably, overall response rate with the combination therapy was higher than previously reported for single-agent avelumab in the PD-L1-negative/low population. Among 29 evaluable IOF patients, the combination resulted in a DCR of 59%, including 2 PR and 7 patients with durable clinical benefit of ≥23 weeks. Biomarker analysis of biopsies demonstrated increased CD8 T-cell density correlating with RECIST response criteria., Conclusions: The combination of pepinemab with avelumab was well tolerated in NSCLC and showed signs of antitumor activity in immunotherapy-resistant and PD-L1-negative/low tumors., (©2021 American Association for Cancer Research.)

Aim: To evaluate real-world effectiveness of guideline-recommended palonosetron-containing antiemetic regimens in patients receiving highly (HEC) or moderately emetogenic (MEC) chemotherapy. Patients & methods: This retrospective analysis used records of adults receiving first-line chemotherapy and a three-drug palonosetron-containing antiemetic regimen for HEC or palonosetron-containing antiemetic regimen for MEC (carboplatin). Results: A total of 1587 records were evaluated. For HEC and MEC, respectively, chemotherapy-induced nausea and vomiting (CINV) occurred in 40 versus 44% of patient cycles (p = 0.01), and unscheduled iv. antiemetics in 41 versus 35% (p < 0.05). A total of 48% of HEC patients versus 42% of MEC patients had CINV-related clinic visits (p = 0.05). Conclusion: Palonosetron-containing antiemetic regimens may provide insufficient CINV control. Alternative regimens may improve patient quality of life and reduce healthcare resource utilization.

Purpose: This study examined safety, pharmacokinetics, and efficacy of veliparib, a PARP inhibitor, combined with carboplatin and etoposide in patients with extensive-stage (ED) small cell lung cancer (SCLC) and other solid tumors., Patients and Methods: The 3 + 3 design was used for dose escalation of oral veliparib in combination with carboplatin (AUC 5 on day 1) and etoposide (100 mg/m 2 on days 1-3) in 21-day cycles. Veliparib dose was explored from 80 to 240 mg b.i.d. on 7-day, 14-day, or continuous schedules. Patients without disease progression continued on maintenance monotherapy (veliparib 400 mg b.i.d.) until disease progression or unacceptable toxicity., Results: Thirty-nine patients were enrolled to determine the recommended phase II dose of 240 mg veliparib for 14 days combined with carboplatin and etoposide based on long-term tolerability. Dose-limiting toxicity occurred in 1 patient (grade 2 toxic motor polyneuropathy) at veliparib 240 mg b.i.d. for 7 days. Most common adverse events related to veliparib were nausea (39%), fatigue (39%), and hematologic toxicities. Continuous dosing of veliparib 240 mg b.i.d. with carboplatin and etoposide resulted in excessive chemotherapy dose delays due to hematologic toxicity (grade 3/4 neutropenia/thrombocytopenia). Etoposide pharmacokinetics was not affected by veliparib. Confirmed responses occurred in 17 of 39 (44%) and 16 of 25 (64%) of all enrolled and ED SCLC patients, respectively. At the RP2D, confirmed responses occurred in 6 of 13 (46%) and 5 of 6 (83%) of all enrolled and ED SCLC patients, respectively., Conclusions: Veliparib (240 mg b.i.d. 14 days) plus carboplatin/etoposide can be safely combined. Phase II of this study is ongoing in first-line patients with ED SCLC., (©2018 American Association for Cancer Research.)

Objectives: Tissue factor overexpression is associated with tumor progression, venous thromboembolism, and worsened survival in patients with cancer. Tissue factor and activated factor VII (FVIIa) complex may contribute to tumor invasiveness by promoting cell migration and angiogenesis. The study objective was to evaluate safety, pharmacokinetics, and efficacy of PCI-27483, a selective FVIIa inhibitor., Methods: This was an open-label, multicenter phase 2 trial of patients with advanced pancreatic cancer. Part A of the study was an intrapatient dose escalation lead-in portion in patients concurrently receiving gemcitabine, and in part B, patients were randomized 1: 1 to the recommended phase 2 dose combination PCI-27483-gemcitabine versus gemcitabine alone., Results: Target international normalized ratio (between 2.0-3.0) was achieved following PCI-27483 treatment. Overall safety of PCI-27483-gemcitabine (n = 26) was similar to gemcitabine alone (n = 16), with a higher incidence of mostly low-grade bleeding events (65% vs. 19%). Progression-free survival (PFS) and overall survival (OS) were not significantly different between patients treated with PCI-27483-gemcitabine (PFS: 3.7 months, OS: 5.7 months) and those treated with gemcitabine alone (PFS: 1.9 months, OS: 5.6 months)., Conclusions: Targeted inhibition of the coagulation cascade was achieved by administering PCI-27483. PCI-27483-gemcitabine was well tolerated, but superiority to single agent gemcitabine was not demonstrated., (The Author(s). Published by S. Karger AG, Basel.)

Neoantigens, which are expressed on tumor cells, are one of the main targets of an effective antitumor T-cell response. Cancer immunotherapies to target neoantigens are of growing interest and are in early human trials, but methods to identify neoantigens either require invasive or difficult-to-obtain clinical specimens, require the screening of hundreds to thousands of synthetic peptides or tandem minigenes, or are only relevant to specific human leukocyte antigen (HLA) alleles. We apply deep learning to a large (N = 74 patients) HLA peptide and genomic dataset from various human tumors to create a computational model of antigen presentation for neoantigen prediction. We show that our model, named EDGE, increases the positive predictive value of HLA antigen prediction by up to ninefold. We apply EDGE to enable identification of neoantigens and neoantigen-reactive T cells using routine clinical specimens and small numbers of synthetic peptides for most common HLA alleles. EDGE could enable an improved ability to develop neoantigen-targeted immunotherapies for cancer patients.

Aim: Real-world palonosetron effectiveness was evaluated in an antiemetic regimen with highly emetogenic chemotherapy (HEC)., Patients & Methods: In this Phase IV, prospective, multicenter observational study, HEC-treated cancer patients received palonosetron, a neurokinin 1 receptor antagonist, and dexamethasone. Primary objective was to assess complete response (CR) for acute (≤24 h), delayed and overall (≤120 h) chemotherapy-induced nausea and vomiting., Results: Of 159 patients, 65.4% had breast cancer, 64.8% received anthracycline (doxorubicin)-plus-cyclophosphamide-containing chemotherapy; 155 completed one HEC cycle. CR was 60.0% acute, 39.4% delayed and 34.8% overall, and then increased (all phases) in 69 patients completing four HEC cycles. Anthracycline (doxorubicin) plus cyclophosphamide-receiving patients had especially low CR., Conclusion: Even within a recommended three-drug antiemetic regimen, palonosetron may provide suboptimal chemotherapy-induced nausea and vomiting control with HEC in real-world settings.

Purpose: Seviteronel (INO-464) is an oral, selective cytochrome P450c17a (CYP17) 17,20-lyase (lyase) and androgen receptor inhibitor with in vitro and in vivo anti-tumor activity. This open-label phase 1 clinical study evaluated safety, tolerability, pharmacokinetics (PK), and activity of once-daily (QD) seviteronel in women with locally advanced or metastatic TNBC or ER+ breast cancer., Methods: Seviteronel was administered in de-escalating 750, 600, and 450 mg QD 6-subject cohorts. The 750 mg QD start dose was a phase 2 dose determined for men with castration-resistant prostate cancer in (Shore et al. J Clin Oncol 34, 2016). Enrollment at lower doses was initiated in the presence of dose-limiting toxicities (DLTs). The primary objective of this study was to determine seviteronel safety, tolerability, and MTD. The secondary objectives included description of its PK in women and its initial activity, including clinical benefit rate at 4 (CBR16) and 6 months (CBR24)., Results: Nineteen women were enrolled. A majority of adverse events (AEs) were Grade (Gr) 1/2, independent of relationship; the most common were tremor (42%), nausea (42%), vomiting (37%), and fatigue (37%). Four Gr 3/4 AEs (anemia, delirium, mental status change, and confusional state) deemed possibly related to seviteronel occurred in four subjects. DLTs were observed at 750 mg (Gr 3 confusional state with paranoia) and 600 mg (Gr 3 mental status change and Gr 3 delirium) QD, with none at 450 mg QD. The recommended phase 2 dose (RP2D) was 450 mg QD, and at the RP2D, 4 of 7 subjects reached at least CBR16 (2 TNBC subjects and 2 ER+ subjects achieved CBR16 and CBR24, respectively); no objective tumor responses were reported., Conclusions: Once-daily seviteronel was generally well tolerated in women with and 450 mg QD was chosen as the RP2D.

Background: Patients with relapsed or refractory lymphoma or chronic lymphocytic leukaemia have a poor prognosis. Therapies targeting more than one isoform of PI3K, as well as mTOR, might increase antitumour activity. We aimed to investigate the efficacy and safety of voxtalisib (also known as XL765 or SAR245409), a pan-PI3K/mTOR inhibitor, in patients with relapsed or refractory lymphoma, or chronic lymphocytic leukaemia/small lymphocytic lymphoma., Methods: We did a non-randomised, open-label, phase 2 trial at 30 oncology clinics in the USA, Belgium, Germany, France, the Netherlands, and Australia. Patients aged 18 years or older with Eastern Cooperative Oncology Group (EGOG) performance status score of 2 or lower and relapsed or refractory mantle cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, or chronic lymphocytic leukaemia/small lymphocytic lymphoma were enrolled and treated with voxtalisib 50 mg orally twice daily in 28-day continuous dosing cycles until progression or unacceptable toxicity. The primary endpoint was the proportion of patients in each disease-specific cohort who achieved an overall response, defined as a complete response or partial response. All patients who received more than 4 weeks of treatment and who completed a baseline and at least one post-baseline tumour assessment were analysed for efficacy and all patients were analysed for safety. This study is registered with ClinicalTrials.gov, number NCT01403636, and has been completed., Findings: Between Oct 19, 2011, and July 24, 2013, 167 patients were enrolled (42 with mantle cell lymphoma, 47 with follicular lymphoma, 42 with diffuse large B-cell lymphoma, and 36 with chronic lymphocytic leukaemia/small lymphocytic lymphoma. The median number of previous anticancer regimens was three (IQR 2-4) for patients with lymphoma and four (2-5) for patients with chronic lymphocytic leukaemia/small lymphocytic lymphoma. Of 164 patients evaluable for efficacy, 30 (18·3%) achieved an overall response (partial, n=22; complete, n=8); 19 (41·3%) of 46 with follicular lymphoma, five (11·9%) of 42 with mantle cell lymphoma, two (4·9%) of 41 with diffuse large B-cell lymphoma, and four (11·4%) of 35 with chronic lymphocytic leukaemia/small lymphocytic lymphoma. The safety profile was consistent with that of previous studies of voxtalisib. The most frequently reported adverse events were diarrhoea (in 59 [35%] of 167 patients), fatigue (in 53 [32%]), nausea (in 45 [27%]), pyrexia (in 44 [26%,]), cough (in 40 [24%]), and decreased appetite (in 35 [21%]). The most frequently reported grade 3 or worse adverse events were anaemia (in 20 [12%] of 167 patients), pneumonia (in 14 [8%]), and thrombocytopenia (in 13 [8%]). Serious adverse events occurred in 97 (58·1%) of 167 patients., Interpretation: Voxtalisib 50 mg given orally twice daily had an acceptable safety profile, with promising efficacy in patients with follicular lymphoma but limited efficacy in patients with mantle cell lymphoma, diffuse large B-cell lymphoma, or chronic lymphocytic leukaemia/small lymphocytic lymphoma., Funding: Sanofi., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Novel therapies are needed for patients with relapsed or refractory multiple myeloma (MM). We conducted a multicenter, phase 1 study in advanced hematological malignancies to assess the safety, efficacy, and recommended phase 2 dose (RP2D) of oral selinexor, a selective inhibitor of the nuclear export protein XPO1. In the dose-escalation phase, 25 patients with heavily pretreated MM (22) or Waldenstrom macroglobulinemia (3) were administered selinexor (3-60 mg/m 2 ) in 8 or 10 doses per 28-day cycle. In the dose-expansion phase, 59 patients with MM received selinexor at 45 or 60 mg/m 2 with 20 mg dexamethasone, twice weekly in 28-day cycles, or selinexor (40 or 60 mg flat dose) without corticosteroids in 21-day cycles. The most common nonhematologic adverse events (AEs) were nausea (75%), fatigue (70%), anorexia (64%), vomiting (43%), weight loss (32%), and diarrhea (32%), which were primarily grade 1 or 2. The most common grade 3 or 4 AEs were hematologic, particularly thrombocytopenia (45%). Single-agent selinexor showed modest efficacy with an objective response rate (ORR) of 4% and clinical benefit rate of 21%. In contrast, the addition of dexamethasone increased the ORR with all responses of ≥partial response occurring in the 45 mg/m 2 selinexor plus 20 mg dexamethasone twice weekly cohort (ORR = 50%). Furthermore, 46% of all patients showed a reduction in MM markers from baseline. Based on these findings, we conclude that selinexor in combination with dexamethasone is active in heavily pretreated MM and propose a RP2D of 45 mg/m 2 (80 mg) plus 20 mg dexamethasone given twice weekly. This trial was registered at clinicaltrials.gov as #NCT01607892., (© 2018 by The American Society of Hematology.)

Purpose: To evaluate the safety and efficacy of mocetinostat (a Class I/IV HDAC inhibitor) in combination with gemcitabine in patients with solid tumors, including pancreatic cancer., Methods: In this open-label, non-randomized Phase I/II study (NCT00372437) sequential cohorts of patients with solid tumors received gemcitabine (1000 mg/m 2 , day 1 of three consecutive weeks, 4-week cycles) and oral mocetinostat [50-110 mg, three times per week (TIW)]. The maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) was determined based on dose-limiting toxicities in Cycle 1 (Phase I study). The MTD/RP2D was further evaluated in patients with advanced pancreatic cancer (Phase II study) using a two-stage design. The Phase II primary endpoint was overall response rate (ORR)., Results: Forty-eight patients were enrolled into the Phase I (n = 25) and Phase II (n = 23) studies. In the Phase I study, the MTD/RP2D was mocetinostat 90 mg TIW + gemcitabine 1000 mg/m 2 . Grade ≥ 3 treatment-related adverse events (AEs) were reported by 81% of all patients, the most frequent being fatigue (38%) and thrombocytopenia (19%). The ORR was 11% in the Phase I study (n = 2 patients with pancreatic cancer, responses lasting for 16.8 and 4.0 months, respectively). As no responses were seen in the Phase II cohort, the study was terminated., Conclusions: Mocetinostat TIW in combination with gemcitabine was associated with significant toxicities in patients with advanced pancreatic cancer. The level of clinical activity of this treatment combination was not considered high enough to merit further testing in this setting.

Selinexor is a novel, first-in-class, selective inhibitor of nuclear export compound, which blocks exportin 1 (XPO1) function, leads to nuclear accumulation of tumor suppressor proteins, and induces cancer cell death. A phase 1 dose-escalation study was initiated to examine the safety and efficacy of selinexor in patients with advanced hematological malignancies. Ninety-five patients with relapsed or refractory acute myeloid leukemia (AML) were enrolled between January 2013 and June 2014 to receive 4, 8, or 10 doses of selinexor in a 21- or 28-day cycle. The most frequently reported adverse events (AEs) in patients with AML were grade 1 or 2 constitutional and gastrointestinal toxicities, which were generally manageable with supportive care. The only nonhematological grade 3/4 AE, occurring in >5% of the patient population, was fatigue (14%). There were no reported dose-limiting toxicities or evidence of cumulative toxicity. The recommended phase 2 dose was established at 60 mg (∼35 mg/m 2 ) given twice weekly in a 4-week cycle based on the totality of safety and efficacy data. Overall, 14% of the 81 evaluable patients achieved an objective response (OR) and 31% percent showed ≥50% decrease in bone marrow blasts from baseline. Patients achieving an OR had a significant improvement in median progression-free survival (PFS) (5.1 vs 1.3 months; P = .008; hazard ratio [HR], 3.1) and overall survival (9.7 vs 2.7 months; P = .01; HR, 3.1) compared with nonresponders. These findings suggest that selinexor is safe as a monotherapy in patients with relapsed or refractory AML and have informed subsequent phase 2 clinical development. This trial was registered at www.clinicaltrials.gov as #NCT01607892., (© 2017 by The American Society of Hematology.)

Patients with relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL) have a poor prognosis and limited treatment options. We evaluated selinexor, an orally bioavailable, first-in-class inhibitor of the nuclear export protein XPO1, in this phase 1 trial to assess safety and determine a recommended phase 2 dose (RP2D). Seventy-nine patients with various NHL histologies, including diffuse large B-cell lymphoma, Richter's transformation, mantle cell lymphoma, follicular lymphoma, and chronic lymphocytic leukemia, were enrolled. In the dose-escalation phase, patients received 3 to 80 mg/m 2 of selinexor in 3- or 4-week cycles and were assessed for toxicities, pharmacokinetics, and antitumor activity. In the dose-expansion phase, patients were treated with selinexor at 35 or 60 mg/m 2 The most common grade 3 to 4 drug-related adverse events were thrombocytopenia (47%), neutropenia (32%), anemia (27%), leukopenia (16%), fatigue (11%), and hyponatremia (10%). Tumor biopsies showed decreases in cell-signaling pathways (Bcl-2, Bcl-6, c-Myc), reduced proliferation (Ki67), nuclear localization of XPO1 cargos (p53, PTEN), and increased apoptosis after treatment. Twenty-two (31%) of the 70 evaluable patients had an objective responses, including 4 complete responses and 18 partial responses, which were observed across a spectrum of NHL subtypes. A dose of 35 mg/m 2 (60 mg) was identified as the RP2D. These findings suggest that inhibition of XPO1 with oral selinexor at 35 mg/m 2 is a safe therapy with encouraging and durable anticancer activity in patients with R/R NHL. The trial was registered at www.clinicaltrials.gov as #NCT01607892., (© 2017 by The American Society of Hematology.)

Background: APF530, a novel extended-release granisetron injection, was superior to ondansetron in a guideline-recommended three-drug regimen in preventing delayed-phase chemotherapy-induced nausea and vomiting (CINV) among patients receiving highly emetogenic chemotherapy (HEC) in the double-blind Phase III Modified Absorption of Granisetron In the prevention of CINV (MAGIC) trial., Patients and Methods: This MAGIC post hoc analysis evaluated CINV prevention efficacy and safety of APF530 versus ondansetron, each with fosaprepitant and dexamethasone, in patient subgroup receiving an anthracycline plus cyclophosphamide (AC) regimen. Patients were randomized 1:1 to APF530 500 mg subcutaneously (granisetron 10 mg) or ondansetron 0.15 mg/kg intravenously (IV) (≤16 mg); stratification was by planned cisplatin ≥50 mg/m 2 (yes/no). Patients were to receive fosaprepitant 150 mg IV and dexamethasone 12 mg IV on day 1, then dexamethasone 8 mg orally once daily on day 2 and twice daily on days 3 and 4. Patients were mostly younger females (APF530 arm, mean age 54.1 years, female, 99.3%; ondansetron arm, 53.8 years, female 98.3%). The primary end point was delayed-phase (>24-120 hours) complete response (CR)., Results: APF530 versus ondansetron regimens achieved numerically better CINV control in delayed and overall (0-120 hours) phases for CR, complete control, total response, rescue medication use, and proportion with no nausea. APF530 trends are consistent with the overall population, although not statistically superior given the underpowered AC subgroup analysis. The APF530 regimen in this population was generally well tolerated, with safety comparable to that of the overall population., Conclusion: APF530 plus fosaprepitant and dexamethasone effectively prevented CINV among patients receiving AC-based HEC, a large subgroup in whom CINV control has traditionally been challenging., Competing Interests: Disclosure IDS, LS, and NV have acted in consultant/advisory roles for Heron Therapeutics, Inc. EB has received research funding and honoraria from Heron Therapeutics, Inc. MCM has received honoraria from EMB Statistical Solutions, LLC. RBG is employed by and has ownership interests in Heron Therapeutics, Inc. The other authors report no conflicts of interest in this work.

Purpose: The high fatality-to-case ratio of ovarian cancer is directly related to platinum resistance. Exportin-1 (XPO1) is a nuclear exporter that mediates nuclear export of multiple tumor suppressors. We investigated possible clinicopathologic correlations of XPO1 expression levels and evaluated the efficacy of XPO1 inhibition as a therapeutic strategy in platinum-sensitive and -resistant ovarian cancer. Experimental Design: XPO1 expression levels were analyzed to define clinicopathologic correlates using both TCGA/GEO datasets and tissue microarrays (TMA). The effect of XPO1 inhibition, using the small-molecule inhibitors KPT-185 and KPT-330 (selinexor) alone or in combination with a platinum agent on cell viability, apoptosis, and the transcriptome was tested in immortalized and patient-derived ovarian cancer cell lines (PDCL) and platinum-resistant mice (PDX). Seven patients with late-stage, recurrent, and heavily pretreated ovarian cancer were treated with an oral XPO1 inhibitor. Results: XPO1 RNA overexpression and protein nuclear localization were correlated with decreased survival and platinum resistance in ovarian cancer. Targeted XPO1 inhibition decreased cell viability and synergistically restored platinum sensitivity in both immortalized ovarian cancer cells and PDCL. The XPO1 inhibitor-mediated apoptosis occurred through both p53-dependent and p53-independent signaling pathways. Selinexor treatment, alone and in combination with platinum, markedly decreased tumor growth and prolonged survival in platinum-resistant PDX and mice. In selinexor-treated patients, tumor growth was halted in 3 of 5 patients, including one with a partial response, and was safely tolerated by all. Conclusions: Taken together, these results provide evidence that XPO1 inhibition represents a new therapeutic strategy for overcoming platinum resistance in women with ovarian cancer. Clin Cancer Res; 23(6); 1552-63. ©2016 AACR ., (©2016 American Association for Cancer Research.)

Purpose This trial evaluated the safety, pharmacokinetics, pharmacodynamics, and efficacy of selinexor (KPT-330), a novel, oral small-molecule inhibitor of exportin 1 (XPO1/CRM1), and determined the recommended phase II dose. Patients and Methods In total, 189 patients with advanced solid tumors received selinexor (3 to 85 mg/m 2 ) in 21- or 28-day cycles. Pre- and post-treatment levels of XPO1 mRNA in patient-derived leukocytes were determined by reverse transcriptase quantitative polymerase chain reaction, and tumor biopsies were examined by immunohistochemistry for changes in markers consistent with XPO1 inhibition. Antitumor response was assessed according Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 guidelines. Results The most common treatment-related adverse events included fatigue (70%), nausea (70%), anorexia (66%), and vomiting (49%), which were generally grade 1 or 2. Most commonly reported grade 3 or 4 toxicities were thrombocytopenia (16%), fatigue (15%), and hyponatremia (13%). Clinically significant major organ or cumulative toxicities were rare. The maximum-tolerated dose was defined at 65 mg/m 2 using a twice-a-week (days 1 and 3) dosing schedule. The recommended phase II dose of 35 mg/m 2 given twice a week was chosen based on better patient tolerability and no demonstrable improvement in radiologic response or disease stabilization compared with higher doses. Pharmacokinetics were dose proportional, with no evidence of drug accumulation. Dose-dependent elevations in XPO1 mRNA in leukocytes were demonstrated up to a dose level of 28 mg/m 2 before plateauing, and paired tumor biopsies showed nuclear accumulation of key tumor-suppressor proteins, reduction of cell proliferation, and induction of apoptosis. Among 157 patients evaluable for response, one complete and six partial responses were observed (n = 7, 4%), with 27 patients (17%) achieving stable disease for ≥ 4 months. Conclusion Selinexor is a novel and safe therapeutic with broad antitumor activity. Further interrogation into this class of therapy is warranted.

Introduction: Combretastatin A4-phosphate, fosbretabulin tromethamine (CA4P) is a vascular disrupting agent that targets tumor vasculature. This study evaluated the safety of CA4P when combined with carboplatin, paclitaxel, and bevacizumab in chemotherapy-naïve subjects with advanced nonsquamous, non-small-cell lung cancer., Methods: Adult subjects with confirmed American Joint Committee on Cancer six stage IIIB/IV non-small-cell lung cancer and an Eastern Cooperative Oncology Group performance score of 0 or 1 were randomized to receive six cycles (treatment phase) of paclitaxel (200 mg/m 2 ), carboplatin (area under the concentration versus time curve 6), and bevacizumab (15 mg/kg) on day 1 and repeated every 21 days, or this regimen plus CA4P (60 mg/m 2 ) on days 7, 14, and 21 of each cycle. Subjects could then receive additional maintenance treatment (excluding carboplatin and paclitaxel) for up to 1 year., Results: Sixty-three subjects were randomized, 31 to control and 32 to CA4P, and 19 (61.3%) and 17 (53.1%), respectively, completed the treatment phase. Exposure to study treatment and dose modifications were comparable between the randomized groups. The overall incidence of treatment-emergent adverse events was similar between groups, with increased neutropenia, leukopenia, and hypertension in the CA4P group. Deaths, serious adverse events, and early discontinuations from treatment were comparable between the randomized treatment groups. The overall tumor response rate with CA4P was 50% versus 32% in controls. Overall and progression-free survival rates were comparable between the groups., Conclusion: CA4P plus carboplatin, paclitaxel, and bevacizumab appears to be a tolerable regimen with an acceptable toxicity profile in subjects with advanced non-small-cell lung cancer., Competing Interests: JB was employed by OXiGENE, Inc at the time of conducting the study. The authors report no other conflicts of interest in this work.

Purpose: Pralatrexate is a folate analogue indicated for the treatment of relapsed or refractory peripheral T-cell lymphoma. It has not been formally tested in patients with renal impairment. This study evaluated the pharmacokinetic (PK) profile of pralatrexate in patients with renal impairment and with relapsed/refractory advanced solid tumors and lymphoma., Methods: This was an open-label, nonrandomized, phase 1 study. Eligible patients received pralatrexate administered as an IV push over 3-5 min once weekly for 6 weeks in 7-week cycles until progressive disease or intolerable toxicity. Four cohorts of 6 patients were planned for a total of 24 patients. Patients with normal renal function (Cohort A), mild (Cohort B), and moderate renal impairment (Cohort C) received 30 mg/m 2 pralatrexate once weekly for 6 weeks in 7-week cycles, and patients with severe renal impairment (Cohort D) were to be administered 20 mg/m 2 once weekly for 6 weeks. Plasma and urine samples were collected at pre-specified time points to determine the PK profile of pralatrexate in each treatment cohort. Patients were followed for safety and tolerability., Results: A total of 29 patients were enrolled and 27 patients (14 male) received at least 1 dose of pralatrexate. Because of a qualifying toxicity in Cohort C, the starting dose for Cohort D was reduced to 15 mg/m 2 . Chronic renal impairment led to a decrease in renal clearance of the pralatrexate diastereomers, PDX-10a and PDX-10b, but systemic exposure to these diastereomers was not dramatically affected by renal impairment. Pralatrexate exposure in Cohort D (15 mg/m 2 ) was similar to the exposure in other cohorts (30 mg/m 2 ). No apparent difference in toxicity between the four treatment cohorts was observed, except for an increase in cytopenias in patients with severe renal impairment., Conclusion: Pralatrexate exposure, at a dose of 30 mg/m 2 , in patients with mild or moderate renal impairment was similar to the exposure in patients with normal renal function. For patients with severe renal impairment only, a pralatrexate dose of 15 mg/m 2 is recommended.

Aim: APF530, extended-release granisetron, provides sustained release for ≥5 days for acute- and delayed-phase chemotherapy-induced nausea and vomiting (CINV). We compared efficacy and safety of APF530 versus ondansetron for delayed CINV after highly emetogenic chemotherapy (HEC), following a guideline-recommended three-drug regimen., Methods: HEC patients received APF530 500 mg subcutaneously or ondansetron 0.15 mg/kg intravenously, with dexamethasone and fosaprepitant. Primary end point was delayed-phase complete response (no emesis or rescue medication)., Results: A higher percentage of APF530 versus ondansetron patients had delayed-phase complete response (p = 0.014). APF530 was generally well tolerated; treatment-emergent adverse event incidence was similar across arms, mostly mild-to-moderate injection-site reactions., Conclusion: APF530 versus the standard three-drug regimen provided superior control of delayed-phase CINV following HEC. ClinicalTrials.gov : NCT02106494.

Purpose: Sotatercept may represent a novel approach to the treatment of chemotherapy-induced anemia (CIA). We report the results from two phase 2 randomized studies examining the use of sotatercept for the treatment of CIA in patients with metastatic cancer., Methods: In study A011-08, patients with metastatic breast cancer were randomized to 2:2:2:1 to receive sotatercept 0.1, 0.3, or 0.5 mg/kg, or placebo, respectively, every 28 days. In study ACE-011-NSCL-001, patients with solid tumors treated with platinum-based chemotherapy received sotatercept 15 or 30 mg every 42 days. The primary endpoint for both studies was hematopoietic response, defined as a hemoglobin (Hb) increase of ≥1 g/dL from baseline., Results: Both studies were terminated early due to slow patient accrual. Among patients treated with sotatercept in the A011-08 and ACE-011-NSCL-001 studies, more patients achieved a mean Hb increase of ≥1 g/dL in the combined sotatercept 0.3 mg/kg and 15 mg (66.7 %) group and sotatercept 0.5 mg/kg and 30 mg (38.9 %) group versus the sotatercept 0.1 mg/kg (0 %) group. No patients achieved a mean Hb increase of ≥1 g/dL in the placebo group. The incidence of treatment-related adverse events (AEs) was low in both studies, and treatment discontinuations due to AEs were uncommon., Conclusions: Although both studies were terminated early, these results indicate that sotatercept is active and has an acceptable safety profile in the treatment of CIA.

Purpose: The US community-based, phase IIIB UPFRONT trial was designed to compare three frontline bortezomib-based regimens in transplantation-ineligible patients with myeloma., Patients and Methods: Patients (N = 502) were randomly assigned 1:1:1 to 24 weeks (eight 21-day cycles) of induction with bortezomib-dexamethasone (VD; n = 168; intravenous bortezomib 1.3 mg/m(2), days 1, 4, 8, and 11 plus oral dexamethasone 20 mg, days 1, 2, 4, 5, 8, 9, 11, and 12 [cycles 1 to 4], or 1, 2, 4, and 5 [cycles 5 to 8]), bortezomib-thalidomide-dexamethasone (VTD; n = 167; bortezomib and dexamethasone as before plus oral thalidomide 100 mg, days 1 to 21), or bortezomib-melphalan-prednisone (VMP; n = 167; bortezomib as before plus oral melphalan 9 mg/m(2) and oral prednisone 60 mg/m(2), days 1 to 4, every other cycle), followed by 25 weeks (five 35-day cycles) of bortezomib maintenance (1.6 mg/m(2), days 1, 8, 15, and 22). The primary end point was progression-free survival., Results: After 42.7 months' median follow-up, median progression-free survival with VD, VTD, and VMP was 14.7, 15.4, and 17.3 months, respectively; median overall survival was 49.8, 51.5, and 53.1 months, with no significant differences among treatments for either end point (global P = .46 and P = .79, respectively, Wald test). Overall response rates were 73% (VD), 80% (VTD), and 70% (VMP). Adverse events were more common with VTD than VD or VMP. Bortezomib maintenance was feasible without producing cumulative toxicity., Conclusion: Although all bortezomib-containing regimens produced good outcomes, VTD and VMP did not appear to offer an advantage over VD in transplantation-ineligible patients with myeloma treated in US community practice., (© 2015 by American Society of Clinical Oncology.)

Background: Despite advances with new therapies, a significant proportion of patients (>30%) suffer delayed-onset chemotherapy-induced nausea and vomiting (CINV) despite use of antiemetics. APF530 is a sustained-release subcutaneous (SC) formulation of granisetron for preventing CINV. APF530 pharmacokinetics, safety, and efficacy were studied in two open-label, single-dose Phase II trials (C2005-01 and C2007-01, respectively) in patients receiving moderately emetogenic chemotherapy or highly emetogenic chemotherapy., Methods: In C2005-01, 45 patients received APF530 250, 500, or 750 mg SC (granisetron 5, 10, or 15 mg, respectively). In C2007-01, 35 patients were randomized to APF530 250 or 500 mg SC. Injections were given 30 to 60 minutes before single-day moderately emetogenic chemotherapy or highly emetogenic chemotherapy. Plasma granisetron was measured from predose to 168 hours after study drug administration. Safety and efficacy were also evaluated., Results: APF530 pharmacokinetics were dose proportional, with slow absorption and elimination of granisetron after a single SC dose. Median time to maximum plasma concentration and half-life were similar for APF530 250 and 500 mg in both trials, with no differences between the groups receiving moderately and highly emetogenic chemotherapy. Exposure to granisetron was maintained at a therapeutic level over the delayed-onset phase, at least 168 hours. Adverse events in both trials were as expected for granisetron; injection site reactions (eg, erythema and induration) were predominantly mild and seen in ≤20% of patients. Complete responses (no emesis, with no rescue medication) were obtained in the acute, delayed, and overall phases in ≥80% and ≥75% of patients in both trials with the 250 and 500 mg doses, respectively., Conclusion: After a single injection of APF530, there were dose-proportional pharmacokinetics and sustained concentrations of granisetron over 168 hours. The 250 and 500 mg doses were well tolerated and maintained therapeutic granisetron levels for ≥5 days.

Purpose: Subcutaneous APF530 provides controlled sustained release of granisetron to prevent acute (0-24 h) and delayed (24-120 h) chemotherapy-induced nausea and vomiting (CINV). This randomized, double-blind phase 3 trial compared APF530 and palonosetron in preventing acute and delayed CINV after moderately (MEC) or highly emetogenic chemotherapy (HEC)., Methods: Patients receiving single-day MEC or HEC received single-dose APF530 250 or 500 mg subcutaneously (SC) (granisetron 5 or 10 mg) or intravenous palonosetron 0.25 mg. Primary objectives were to establish APF530 noninferiority to palonosetron for preventing acute CINV following MEC or HEC and delayed CINV following MEC and to determine APF530 superiority to palonosetron for preventing delayed CINV following HEC. The primary efficacy end point was complete response (CR [using CI difference for APF530-palonosetron]). A lower confidence bound greater than -15 % indicated noninferiority., Results: In the modified intent-to-treat population (MEC = 634; HEC = 707), both APF530 doses were noninferior to palonosetron in preventing acute CINV after MEC (CRs 74.8 % [-9.8, 9.3] and 76.9 % [-7.5, 11.4], respectively, vs. 75.0 % palonosetron) and after HEC (CRs 77.7 % [-11.5, 5.5] and 81.3 % [-7.7, 8.7], respectively, vs. 80.7 % palonosetron). APF530 500 mg was noninferior to palonosetron in preventing delayed CINV after MEC (CR 58.5 % [-9.5, 12.1] vs. 57.2 % palonosetron) but not superior in preventing delayed CINV after HEC. Adverse events were generally mild and unrelated to treatment, the most common (excluding injection-site reactions) being constipation., Conclusions: A single subcutaneous APF530 injection offers a convenient alternative to palonosetron for preventing acute and delayed CINV after MEC or HEC.

Study Objective: To assess the dose proportionality of azacitidine pharmacokinetics (PK) after single subcutaneous (SC) doses of 25-100 mg/m2, and determine the effect of renal impairment on PK after single and multiple 75 mg/m2 SC azacitidine doses., Design: Multicenter, phase I, open-label, parallel group study., Setting: Community clinics and major academic centers., Patients: Twenty-seven patients with solid or hematologic malignancies., Interventions: Part 1 evaluated azacitidine dose proportionality in patients with normal renal function randomized to single 25, 50, 75, or 100 mg/m2 SC doses. The 75 mg/m2 dosing group received 4 additional days of SC azacitidine. In Part 2, patients with severe renal impairment (creatinine clearance < 30 ml/min/1.73 m2 Cockcroft-Gault adjusted) received azacitidine 75 mg/m2 for 5 consecutive days., Measurements and Main Results: PK parameters were determined using noncompartmental methods. In patients with normal renal function (n=21), azacitidine area under the plasma-time curve (AUC0-∞) and maximum observed plasma concentration (Cmax) were dose proportional within the 25-100 mg/m2 range. Concentration versus time profiles after single and multiple azacitidine 75 mg/m2 doses were similar in shape for patients with normal (n=6) or impaired renal function (n=6), with higher mean concentrations in the latter group. Higher mean exposures (AUC0-∞ and Cmax) in renally impaired patients were observed; however, individual exposure values were, with few exceptions, within the same range in both groups. No drug accumulation after multiple doses was observed in either group. Terminal half-life and time to maximum plasma concentration were comparable between groups. Azacitidine tolerability was similar in patients with normal or impaired renal function., Conclusion: Azacitidine is dose proportional over the 25-100 mg/m2 dosing range. Overall, renal impairment had no important effect on azacitidine PK. Therefore, no initial azacitidine dose adjustment in patients with renal impairment is required.

Purpose: Vintafolide (EC145) is a folic acid-desacetylvinblastine conjugate that binds to the folate receptor (FR), which is expressed on the majority of epithelial ovarian cancers. This randomized phase II trial evaluated vintafolide combined with pegylated liposomal doxorubicin (PLD) compared with PLD alone. The utility of an FR-targeted imaging agent, (99m)Tc-etarfolatide (EC20), in selecting patients likely to benefit from vintafolide was also examined., Patients and Methods: Women with recurrent platinum-resistant ovarian cancer who had undergone ≤ two prior cytotoxic regimens were randomly assigned at a 2:1 ratio to PLD (50 mg/m(2) intravenously [IV] once every 28 days) with or without vintafolide (2.5 mg IV three times per week during weeks 1 and 3). Etarfolatide scanning was optional. The primary objective was to compare progression-free survival (PFS) between the groups., Results: The intent-to-treat population comprised 149 patients. Median PFS was 5.0 and 2.7 months for the vintafolide plus PLD and PLD-alone arms, respectively (hazard ratio [HR], 0.63; 95% CI, 0.41 to 0.96; P = .031). The greatest benefit was observed in patients with 100% of lesions positive for FR, with median PFS of 5.5 compared with 1.5 months for PLD alone (HR, 0.38; 95% CI, 0.17 to 0.85; P = .013). The group of patients with FR-positive disease (10% to 90%) experienced some PFS improvement (HR, 0.873), whereas patients with disease that did not express FR experienced no PFS benefit (HR, 1.806)., Conclusion: Vintafolide plus PLD is the first combination to demonstrate an improvement over standard therapy in a randomized trial of patients with platinum-resistant ovarian cancer. Etarfolatide can identify patients likely to benefit from vintafolide.

The attenuated vaccinia virus, modified vaccinia Ankara, has been engineered to deliver the tumor antigen 5T4 (TroVax®). Here, we report results from a randomized open-label phase II trial in castration-resistant prostate cancer patients in which TroVax was administered in combination with docetaxel and compared against docetaxel alone. The aim was to recruit 80 patients (40 per arm), but the study was terminated early due to recruitment challenges. Therefore, this paper reports the comparative safety and immunological and clinical efficacy in 25 patients, 12 of whom were treated with TroVax plus docetaxel and 13 with docetaxel alone. 5T4-specific immune responses were monitored throughout the study. Clinical responses were assessed by measuring changes in tumor burden by CT and bone scan and by quantifying PSA concentrations. TroVax was well tolerated in all patients. Of 10 immunologically evaluable patients, 6 mounted 5T4-specific antibody responses. Patients treated with TroVax plus docetaxel showed a greater median progression-free survival of 9.67 months compared with 5.10 months for patients on the docetaxel alone arm (P = 0.097; HR = 0.31; 95% CI 0.08-1.24). Importantly, a pre-treatment biomarker previously demonstrated to predict 5T4 immune response and treatment benefit showed a strong association with 5T4 antibody response and a statistically significant association with progression-free survival in patients treated with TroVax plus docetaxel, but not docetaxel alone.

Purpose: This open-label, randomized phase II trial assessed efficacy and tolerability of two low-dose regimens of subcutaneous (SC) decitabine in patients with low- or intermediate-1-risk myelodysplastic syndrome (MDS)., Patients and Methods: Patients received decitabine 20 mg/m(2) SC per day for 3 consecutive days on days 1, 2, and 3 every 28 days (schedule A) or 20 mg/m(2) SC per day once every 7 days on days 1, 8, and 15 every 28 days (schedule B) for up to 1 year. Primary efficacy end point was overall improvement rate (OIR: complete remission [CR], partial remission [PR], marrow CR [mCR], or hematologic improvement [HI]). Secondary end points were HI, transfusion independence, cytogenetic response, overall survival (OS), and time to acute myeloid leukemia or death., Results: Efficacy and safety populations were identical: schedule A, n = 43; schedule B, n = 22. Median time from MDS diagnosis to treatment was 3.6 months; 89% had de novo MDS. The trial was terminated early on achievement of protocol-defined OIR superiority of schedule A over schedule B; OIR was 23% for schedule A (seven CRs, three HIs) and 23% for schedule B (one mCR, one PR, three HIs). No differences were observed in secondary end points. Median OS was not reached; approximately 70% of patients were alive at 500 days. Patients in schedule A (67%) and schedule B (59%) were RBC/platelet independent on study. The most frequent drug-related adverse events overall were neutropenia (28% v 36%), anemia (23% v 18%), and thrombocytopenia (16% v 32%)., Conclusion: In this phase II study, low-dose decitabine showed promising results in patients with low- or intermediate-1-risk MDS.

Background: Cancer-induced muscle wasting begins early in the course of a patient's malignant disease, resulting in declining physical function and other detrimental clinical consequences. This randomised, double-blind, placebo-controlled phase 2 trial assessed the efficacy and safety of enobosarm, a selective androgen receptor modulator, in patients with cancer., Methods: We enrolled male (>45 years) and female (postmenopausal) patients with cancer who were not obese and who had at least 2% weight loss in the previous 6 months. Participants were randomly assigned (1:1:1 ratio, by computer generated list, block size three, stratified by cancer type) to receive once-daily oral enobosarm 1 mg, 3 mg, or placebo for up to 113 days at US and Argentinian oncology clinics. The sponsor, study personnel, and participants were masked to assignment. The primary endpoint was change in total lean body mass from baseline, assessed by dual-energy x-ray absorptiometry. Efficacy analyses were done only in patients who had a baseline and an on-treatment assessment in the protocol-specified window of within 10 days before baseline or first study drug, and within 10 days of day 113 or end of study (evaluable efficacy population). Adverse events and other safety measurements were assessed in the intention-to-treat (safety) population. This trial is registered with ClinicalTrials.gov, number NCT00467844., Findings: Enrolment started on July 3, 2007, and the last patient completed the trial on Aug 1, 2008. 159 patients were analysed for safety (placebo, n=52; enobosarm 1 mg, n=53; enobosarm 3 mg, n=54). The evaluable efficacy population included 100 participants (placebo, n=34; enobosarm 1 mg, n=32; enobosarm 3 mg, n=34). Compared with baseline, significant increases in total lean body mass by day 113 or end of study were noted in both enobosarm groups (enobosarm 1 mg median 1·5 kg, range -2·1 to 12·6, p=0·0012; enodosarm 3 mg 1·0 kg, -4·8 to 11·5, p=0·046). Change in total lean body mass within the placebo group (median 0·02 kg, range -5·8 to 6·7) was not significant (p=0·88). The most common serious adverse events were malignant neoplasm progression (eight of 52 [15%] with placebo vs five of 53 [9%] with enobosarm 1 mg vs seven of 54 [13%] with enobosarm 3 mg), pneumonia (two [4%] vs two [4%] vs three [6%]), and febrile neutropenia (three [6%vs one [2%] vs none). None of these events were deemed related to study drug., Interpretation: Cancer cachexia is an unmet medical need and our data suggest that use of enobosarm might lead to improvements in lean body mass, without the toxic effects associated with androgens and progestational agents., Funding: GTx., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Carfilzomib is a selective proteasome inhibitor that binds irreversibly to its target. In phase 1 studies, carfilzomib elicited promising responses and an acceptable toxicity profile in patients with relapsed and/or refractory multiple myeloma (R/R MM). In the present phase 2, multicenter, open-label study, 129 bortezomib-naive patients with R/R MM (median of 2 prior therapies) were separated into Cohort 1, scheduled to receive intravenous carfilzomib 20 mg/m(2) for all treatment cycles, and Cohort 2, scheduled to receive 20 mg/m(2) for cycle 1 and then 27 mg/m(2) for all subsequent cycles. The primary end point was an overall response rate (≥ partial response) of 42.4% in Cohort 1 and 52.2% in Cohort 2. The clinical benefit response (overall response rate + minimal response) was 59.3% and 64.2% in Cohorts 1 and 2, respectively. Median duration of response was 13.1 months and not reached, and median time to progression was 8.3 months and not reached, respectively. The most common treatment-emergent adverse events were fatigue (62.0%) and nausea (48.8%). Single-agent carfilzomib elicited a low incidence of peripheral neuropathy-17.1% overall (1 grade 3; no grade 4)-in these pretreated bortezomib-naive patients. The results of the present study support the use of carfilzomib in R/R MM patients. This trial is registered at www.clinicaltrials.gov as NCT00530816.

Introduction: This open-label phase II study assessed the efficacy and tolerability of eribulin, a non-taxane microtubule dynamics inhibitor with novel mechanism of action, as monotherapy in patients who have advanced non-small-cell lung cancer (NSCLC)., Patients and Methods: Enrolled patients had progressed during or after platinum-based doublet chemotherapy. Initially, two patient cohorts (taxane-pre-treated and taxane-naïve) received eribulin mesylate (1.4 mg/m(2)) as a 2- to 5-minute intravenous infusion on days 1, 8, and 15 of a 28-day cycle. To assess tolerability of a second dosing schedule, a cohort of taxane-pre-treated patients received eribulin on days 1 and 8 of a 21-day cycle. The primary endpoint was objective response rate (ORR) evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) by independent radiographic review., Results: One hundred three patients received eribulin. The ORR was 9.7% (all partial responses [PR]). Overall disease control rate (PR + stable disease) was 55.3%. Median duration of response, progression-free survival, and overall survival were 5.8, 3.4, and 9.4 months, respectively. The most common drug-related adverse events were neutropenia (54%; 49% grade 3/4); fatigue (49%; 11% grade 3, no grade 4); nausea (38%; 1% grade 3, no grade 4); alopecia (32%); anemia (29%, 4% grade 3/4) and neuropathy (23%; 2% grade 3, no grade 4). The 28-day schedule was associated with many dose delays, interruptions, or omissions due to neutropenia (day 15). The 21-day cycle was well-tolerated., Conclusions: Eribulin monotherapy administered on days 1 and 8 of a 21-day cycle is active and tolerated as second- or later-line chemotherapy for NSCLC., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the efficacy and safety of the thrombolytic tenecteplase, a fibrin-specific recombinant tissue plasminogen activator, for restoring function to dysfunctional central venous catheters (CVCs)., Materials and Methods: In this double-blind, placebo-controlled study, eligible patients with dysfunctional nonhemodialysis CVCs were randomly assigned to two treatment arms. In the first arm (TNK-TNK-PBO), patients received an initial dose of intraluminal tenecteplase (TNK) (up to 2 mg), a second dose of tenecteplase if indicated, and a third placebo (PBO) dose. In the PBO-TNK-TNK arm, placebo was instilled first followed by up to two doses of tenecteplase, if needed, for restoration of catheter function. After administration of each dose, CVC function was assessed at 15, 30, and 120 minutes., Results: There were 97 patients who received either TNK-TNK-PBO (n = 50) or PBO-TNK-TNK (n = 47). Within 120 minutes of initial study drug instillation, catheter function was restored to 30 patients (60%) in the TNK-TNK-PBO arm and 11 patients (23%) in the PBO-TNK-TNK arm, for a treatment difference of 37 percentage points (95% confidence interval 18-55; P = .0002). Cumulative restoration rates for CVC function increased to 87% after the second dose of tenecteplase in both study arms combined. Two patients developed a deep vein thrombosis (DVT) after exposure to tenecteplase; one DVT was considered to be drug related. No cases of intracranial hemorrhage, major bleeding, embolic events, catheter-related bloodstream infections, or catheter-related complications were reported., Conclusions: Tenecteplase was efficacious for restoration of catheter function in these study patients with dysfunctional CVCs., (Copyright © 2010 SIR. Published by Elsevier Inc. All rights reserved.)

This randomized, double-blind, crossover study assessed the efficacy and tolerability of a new rapid onset nasal fentanyl formulation (Fentanyl Pectin Nasal Spray; FPNS) for breakthrough cancer pain (BTCP). Eighty-three of 114 patients experiencing one to four BTCP episodes/day while taking ≥60 mg/day of oral morphine or equivalent successfully identified an effective dose of FPNS during a titration phase and entered a double-blind phase in which 10 BTCP episodes were treated with this effective dose (7) or placebo (3). Compared with placebo, FPNS significantly improved mean summed pain intensity difference (SPID) from 10 min (P<0.05) until 60 min (P<0.0001), including the primary endpoint at 30 min (P<0.0001). FPNS significantly improved pain intensity (PI) scores as early as 5 min (P<0.05); pain intensity difference (PID) from 10 min (P<0.01); and pain relief (PR) scores from 10 min (P<0.001). More patients showed a clinically meaningful (≥ 2-point reduction in PI) pain reduction from 10 min onward (P ≤ 0.01) and 90.6% of the FPNS-treated versus 80.0% of placebo-treated BTCP episodes did not require rescue medication (P<0.001). Approximately 70% of patients were satisfied or very satisfied with the convenience and ease of use of FPNS. Only 5.3% of patients withdrew from treatment due to adverse events, no significant nasal effects were reported, and 87% of patients elected to continue open-label treatment post-study. In this short-term study, FPNS was safe, well tolerated, and rapidly efficacious for BTCP., (Copyright © 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Introduction: Aflibercept (vascular endothelial growth factor [VEGF] trap), a recombinant fusion protein, blocks the activity of VEGF-A and placental growth factor and has demonstrated activity in pretreated patients with lung cancer in a phase I trial. This study evaluated the efficacy and safety of intravenous aflibercept in patients with platinum- and erlotinib-resistant lung adenocarcinoma., Methods: An open-label, single arm, multicenter trial was conducted, with the primary end point of response rate (modified RECIST). Additional endpoints included safety, duration of response, progression-free survival, and overall survival. Patients with platinum- and erlotinib-resistant lung adenocarcinoma were eligible. Aflibercept 4.0 mg/kg intravenous every 2 weeks was administered until progression of disease or intolerable toxicity., Results: Ninety-eight patients were enrolled; 89 were evaluable for response. Median age was 60 years, 41% were men with Eastern Cooperative Oncology Group performance status 0/1/2 in 35/55/9% of patients. The overall response rate was 2.0%, (95% confidence interval, 0.2-7.2%). Median progression-free survival was 2.7 months, and overall was survival 6.2 months. Six- and 12-month survival rates were 54 and 29%, respectively. A median of four cycles was administered (range 1-22). Common grade 3/4 toxicities included dyspnea (21%), hypertension (23%), and proteinuria (10%). Two cases of grade 5 hemoptysis were reported, and one case each of tracheoesophageal fistula, decreased cardiac ejection fraction, cerebral ischemia, and reversible posterior leukoencephalopathy., Conclusions: Aflibercept has minor single agent activity in heavily pretreated lung adenocarcinoma, and is well tolerated, with no unexpected toxicities. Further studies evaluating aflibercept in lung cancer, in combination with chemotherapy and other targeted therapies, are ongoing.

Background and Objective: Bortezomib, an antineoplastic for the treatment of relapsed multiple myeloma and mantle cell lymphoma, undergoes metabolism through oxidative deboronation by cytochrome P450 (CYP) enzymes, primarily CYP3A4 and CYP2C19. Omeprazole, a proton-pump inhibitor, is primarily metabolized by and demonstrates high affinity for CYP2C19. This study investigated whether coadministration of omeprazole affected the pharmacokinetics, pharmacodynamics and safety profile of bortezomib in patients with advanced cancer. The variability of bortezomib pharmacokinetics with CYP enzyme polymorphism was also investigated., Patients and Methods: This open-label, crossover, pharmacokinetic drug-drug interaction study was conducted at seven institutions in the US and Europe between January 2005 and August 2006. Patients who had advanced solid tumours, non-Hodgkin's lymphoma or multiple myeloma, were aged >/=18 years, weighed >/=50 kg and had a life expectancy of >/=3 months were eligible. Patients received bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11 for two 21-day cycles, plus omeprazole 40 mg in the morning of days 6-10 and in the evening of day 8 in either cycle 1 (sequence 1) or cycle 2 (sequence 2). On day 21 of cycle 2, patients benefiting from therapy could continue to receive bortezomib for six additional cycles. Blood samples for pharmacokinetic/pharmacodynamic evaluation were collected prior to and at various timepoints after bortezomib administration on day 8 of cycles 1 and 2. Blood samples for pharmacogenomics were also collected. Pharmacokinetic parameters were calculated by noncompartmental analysis of plasma concentration-time data for bortezomib administration on day 8 of cycles 1 and 2, using WinNonlin version 4.0.1.a software. The pharmacodynamic profile was assessed using a whole-blood 20S proteasome inhibition assay., Results: Twenty-seven patients (median age 64 years) were enrolled, 12 in sequence 1 and 15 in sequence 2, including eight and nine pharmacokinetic-evaluable patients, respectively. Bortezomib pharmacokinetic parameters were similar when bortezomib was administered alone or with omeprazole (maximum plasma concentration 120 vs 123 ng/mL; area under the plasma concentration-time curve from 0 to 72 hours 129 vs 135 ng . h/mL). The pharmacodynamic parameters were also similar (maximum effect 85.8% vs 93.7%; area under the percent inhibition-time curve over 72 hours 4052 vs 3910 % x h); the differences were not statistically significant. Pharmacogenomic analysis revealed no meaningful relationships between CYP enzyme polymorphisms and pharmacokinetic/pharmacodynamic parameters. Toxicities were generally similar between patients in sequence 1 and sequence 2, and between cycle 1 and cycle 2 in both treatment sequences. Among 26 evaluable patients, 13 (50%) were assessed as benefiting from bortezomib at the end of cycle 2 and continued to receive treatment., Conclusion: No impact on the pharmacokinetics, pharmacodynamics and safety profile of bortezomib was seen with coadministration of omeprazole. Concomitant administration of bortezomib and omeprazole is unlikely to cause clinically significant drug-drug interactions and is unlikely to have an impact on the efficacy or safety of bortezomib.

Purpose: As treatment options expand for metastatic colorectal cancer (mCRC), a blood marker with a prognostic and predictive role could guide treatment. We tested the hypothesis that circulating tumor cells (CTCs) could predict clinical outcome in patients with mCRC., Patients and Methods: In a prospective multicenter study, CTCs were enumerated in the peripheral blood of 430 patients with mCRC at baseline and after starting first-, second-, or third-line therapy. CTCs were measured using an immunomagnetic separation technique., Results: Patients were stratified into unfavorable and favorable prognostic groups based on CTC levels of three or more or less than three CTCs/7.5 mL, respectively. Patients with unfavorable compared with favorable baseline CTCs had shorter median progression-free survival (PFS; 4.5 v 7.9 months; P = .0002) and overall survival (OS; 9.4 v 18.5 months; P < .0001). Differences persisted at 1 to 2, 3 to 5, 6 to 12, and 13 to 20 weeks after therapy. Conversion of baseline unfavorable CTCs to favorable at 3 to 5 weeks was associated with significantly longer PFS and OS compared with patients with unfavorable CTCs at both time points (PFS, 6.2 v 1.6 months; P = .02; OS, 11.0 v 3.7 months; P = .0002). Among nonprogressing patients, favorable compared with unfavorable CTCs within 1 month of imaging was associated with longer survival (18.8 v 7.1 months; P < .0001). Baseline and follow-up CTC levels remained strong predictors of PFS and OS after adjustment for clinically significant factors., Conclusion: The number of CTCs before and during treatment is an independent predictor of PFS and OS in patients with metastatic colorectal cancer. CTCs provide prognostic information in addition to that of imaging studies.

Purpose: Deforolimus (AP23573), a novel non-prodrug rapamycin analogue, inhibits the mammalian target of rapamycin, a downstream effector of the phosphatidylinositol 3-kinase/Akt and nutrient-sensing pathways. A phase 2 trial was conducted to determine the efficacy and safety of single-agent deforolimus in patients with relapsed or refractory hematologic malignancies., Experimental Design: Eligible patients were assigned to one of five disease-specific, parallel cohorts and given 12.5 mg deforolimus as a 30-minute infusion once daily for 5 days every 2 weeks. A Simon two-stage design was used for each cohort. Safety, pharmacokinetics, pharmacodynamics, and antitumor response were assessed., Results: Fifty-five patients received deforolimus as follows: cohort 1 23 acute myelogenous leukemia, two myelodysplastic syndrome and one chronic myelogenous leukemia in nonlymphoid blast phase; cohort 2, one acute lymphocytic leukemia; cohort 3, nine agnogenic myeloid metaplasia; cohort 4, eight chronic lymphocytic leukemia; cohort 5, nine mantle cell lymphoma and two T-cell leukemia/lymphoma. Most patients were heavily pretreated. Of the 52 evaluable patients, partial responses were noted in five (10%), two of seven agnogenic myeloid metaplasia and three of nine mantle cell lymphoma. Hematologic improvement/stable disease was observed in 21 (40%). Common treatment-related adverse events, which were generally mild and reversible, were mouth sores, fatigue, nausea, and thrombocytopenia. Decreased levels of phosphorylated 4E-BP1 in 9 of 11 acute myelogenous leukemia/myelodysplastic syndrome patients after therapy showed mammalian target of rapamycin inhibition by deforolimus., Conclusions: Deforolimus was well-tolerated in patients with heavily pretreated hematologic malignancies, and antitumor activity was observed. Further investigation of deforolimus alone and in combination with other therapeutic agents is warranted in patients with selected hematologic malignancies.

Diarrhea is a well-recognized side effect of chemotherapy and can result in chemotherapy delay and/or dose reduction, potentially reducing the therapeutic benefit of treatment. Octreotide has been shown to be effective in controlling chemotherapy-induced diarrhea (CID). In this open-label, randomized, multicenter study, designed to asses the effects of two dose levels of octreotide long-acting release (LAR), patients with active or prior CID and scheduled for chemotherapy were randomized to receive up to six doses of either 30 or 40 mg of octreotide LAR. The primary endpoint was the proportion of patients experiencing severe diarrhea during the trial. Secondary endpoints included the proportion of patients requiring IV fluids due to diarrhea, unscheduled visits to healthcare professionals due to diarrhea, and changes in primary therapy, as well as treatment satisfaction and quality of life. In total, 147 patients were randomized and received at least 1 dose; 124 patients were efficacy-evaluable. Baseline characters were balanced in the 30-mg and 40-mg groups with the exception of gender. Fewer patients in the 40-mg group compared with those in the 30-mg group experienced severe diarrhea (61.7% vs 48.4%; P = 0.14), required IV fluid (31.7% vs 18.8%; P = 0.10), and had diarrhea-related unscheduled healthcare visits (41.7% vs. 28.1 %; P = 0.11); however, these differences were not statistically significant. No significant differences were observed between the treatment groups in either measured quality of life or treatment satisfaction. Adverse events were balanced between the two groups. No specific recommendations can be made from this trial regarding the use of 30 mg versus 40 mg of octreotide LAR for CID.

Background: Current chemotherapy regimens for breast cancer result in high incidences of anemia, which can be treated with erythropoietic agents. The relative efficacy of darbepoetin alfa and epoetin alfa was explored in this phase II, open-label, randomized, multicenter trial in anemic patients with breast cancer receiving chemotherapy., Patients and Methods: Patients were randomized at a 1:1 ratio to receive darbepoetin alfa 200 microg every 2 weeks (n = 72) or epoetin alfa 40,000 U weekly (n = 69) for < or = 16 weeks. Clinical and hematologic endpoints and validation of a novel patient satisfaction questionnaire for anemia treatment were evaluated for all patients randomized to receive > or = 1 dose of study drug., Results: Baseline characteristics were generally similar between treatment groups. Mean changes in hemoglobin (Hb) level from baseline were similar at 1.9 g/dL for darbepoetin alfa and 1.7 g/dL for epoetin alfa. Hematopoietic responses (> or = 2 g/dL increase in Hb level from baseline or Hb level > or = 12 g/dL) were also similar between groups (88% for darbepoetin alfa and 81% for epoetin alfa). The proportions of patients who received a transfusion during treatment were 6% (95% CI, 0-11%) for darbepoetin alfa and 16% (95% CI, 7%-25%) for epoetin alfa. Most patients (67 patients receiving darbepoetin alfa [93%]; 61 patients receiving epoetin alfa [90%]) exhibited a clinically meaningful target Hb level > or = 11 g/dL. No differences in safety were observed., Conclusion: These results suggest that, in patients with breast cancer, darbepoetin alfa 200 microg every 2 weeks and epoetin alfa 40,000 U weekly result in comparable clinical outcomes for the treatment of chemotherapy-induced anemia.

Diarrhea is a common, often dose-limiting toxicity associated with cancer chemotherapy treatment. However, the problem is not well recognized and frequently is not managed appropriately. The primary objectives of the current study were to describe the sociodemographic and clinical characteristics of cancer patients with chemotherapy-induced diarrhea (CID) and describe the clinical consequences of CID on treatment changes. This was a retrospective review of medical records from 378 cancer patients who experienced diarrhea while receiving chemotherapy at 25 geographically dispersed US cancer clinics. Severe diarrhea (National Cancer Institute-Common Toxicity Criteria grades 3 or 4) was experienced by about one third of patients during their chemotherapy. Patients who experienced CID underwent changes in their chemotherapy treatment, including dose reductions (45%), delays in therapy (71%), reduction in dose intensity (64%), and discontinuation of therapy (3%). Dose reductions were statistically significant. Although the majority of diarrhea was grade 1, almost one half of all patients required dosing reductions, and more than one half of these patients experienced dosing delays. Changes to chemotherapy treatment resulting from CID may ultimately impact patient clinical outcomes.

Objective: To compare the analgesic efficacy and safety of oxymorphone extended release (ER) and oxycodone controlled release (CR) in patients with moderate to severe cancer pain., Research Design and Methods: This randomized, multicenter, double-blind, 2-period crossover study included adult outpatients (>or= 18 years of age) with moderate or severe cancer pain who were first titrated for 3-10 days with open-label oxymorphone or oxycodone to achieve a stable dose that provided and other efficacy parameters were comparable for adequate analgesia with tolerable adverse events and no requirement for more than 2 doses of rescue medication per day. The subsequent double-blind treatment phase was a 7- to 10-day period of oxycodone CR or oxymorphone ER treatment followed by crossing over to the alternate medication for another 7-10 days. During the treatment phase, up to 2 doses per day of morphine sulfate 15-mg tablets were allowed as rescue., Main Outcomes and Measures: Assessments included the Brief Pain Inventory, global evaluations, Karnofsky performance status, and clinical laboratory evaluations (serum chemistry profile, complete blood count, urinalysis). Efficacy variables were analyzed using a mixed-effects model with treatment, sequence, and period as fixed effects and subject as a random effect., Results: Forty-seven patients entered the titration/stabilization phase, 44 received at least 1 dose of study drug, 42 completed the first double-blind phase, and 40 completed the second double-blind phase. Mean pain intensity scores the 2 groups. The mean daily dosage of oxycodone CR (91.9 mg) was twice that of oxymorphone ER (45.9 mg), an equianalgesic dose ratio of 2:1. Rescue medication use was low in both groups (approximately 1 tablet of morphine sulfate 15 mg/day). No significant differences in opioid adverse events were observed between the groups., Conclusions: Adult patients with cancer who were taking oxycodone CR were readily converted to oxymorphone ER and required half the milligram dose to stabilize their pain. Within 72 h, most patients achieved a stable dose that provided adequate relief with similar opioid adverse events.