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Background This phase 1 study evaluated safety, pharmacokinetics (PK), maximum tolerated dose (MTD), and antitumour activity of regorafenib in paediatric patients with solid tumours. Patients and methods Patients (aged 6 months to Results Forty-one patients (median age 13 years) received regorafenib (four cohorts: 60–93 mg/m2). Five of 23 evaluable patients experienced dose-limiting toxicities (Grade 4 thrombocytopenia, Grade 3 maculopapular rash, pyrexia, hypertension, and exfoliative dermatitis [each n = 1]). The MTD was defined as 82 mg/m2. The most common Grade ≥3 drug-related TEAE was thrombocytopenia (10%). The incidence and severity of hypertension, diarrhoea, fatigue, hypothyroidism, and hand–foot skin reaction were lower than reported in adults. Regorafenib exposure increased with dose, with substantial overlap because of moderate-to-high interpatient variability. One patient with rhabdomyosarcoma experienced an unconfirmed partial response; 15 patients had stable disease, five for >16 weeks. Conclusions The recommended phase 2 dose of single-agent regorafenib in paediatric patients with solid malignancies is 82 mg/m2. Regorafenib demonstrated acceptable tolerability and preliminary antitumour activity, supporting further investigation in paediatric patients. Clinical trial number NCT02085148.

Recombinant granulocyte colony-stimulating factors (rG-CSFs), such as filgrastim, are administered to prevent complications in patients receiving chemotherapy. In Europe, a biosimilar to filgrastim, tevagrastim/ratiograstim/biograstim, was approved in 2008. In the USA, the same product was approved as tbo-filgrastim under a 351(a) biologic license application in 2012 with the brand name Granix®. Postmarket surveillance remains a priority for monitoring the safety of biologics and biosimilars to identify rare and immunogenicity-related events. We report the global and US pharmacovigilance data for tevagrastim/ratiograstim/biograstim and tbo-filgrastim, respectively. Cumulative exposure and adverse event data from initial approval in Europe to December 31, 2016, were collected globally from spontaneous reports submitted by healthcare professionals and consumers, scientific literature, competent authorities, and solicited case reports from non-interventional studies. A separate search was conducted on the global data set to identify reports originating from the USA and Puerto Rico to describe the US experience. Overall, the global safety profile of tevagrastim/ratiograstim/biograstim in the postmarket, real-world setting was comparable to clinical trial experience. Postmarket safety experience of tbo-filgrastim in the USA was consistent with global data. The most common SAEs were febrile neutropenia and decreased white blood cell count. The most common non-serious event was bone pain. There was no evidence of immunogenicity. This pharmacovigilance analysis indicates that postmarket experience of tevagrastim/ratiograstim/biograstim and tbo-filgrastim is consistent with clinical trials. Adverse reactions associated with the originator rG-CSF (capillary leak syndrome and glomerulonephritis) have not been observed with tevagrastim/ratiograstim/biograstim or tbo-filgrastim during the postmarket period.

4078 Background: REG, a multikinase inhibitor, and PEMBRO, an anti-PD-1 mAb, are approved as monotherapies in advanced HCC after progression on sorafenib. This phase 1b dose-finding study investigated first-line REG plus PEMBRO in advanced HCC. Methods: Patients (pts) in the first cohort received a starting REG dose of 120 mg/day orally for 3 weeks (wks) on/1 wk off, which could be escalated (160 mg) or reduced (80 mg) in later cohorts, plus a fixed dose of PEMBRO 200 mg IV every 3 wks. Due to a high dose modification rate in the REG 120 mg cohort, an exploratory REG 80 mg cohort was introduced. Primary objective was safety and tolerability; secondary aims were to assess the maximum tolerated dose (MTD), recommended phase 2 dose, and anti-tumor activity. Results: 35 pts started on REG 120 mg/day and 22 on REG 80 mg/day. Median age was 66 yrs (range 29–81), 84% of pts were male, 70%/30% had ECOG PS 0/1, 26%/74% were BCLC stage B/C, 100% were C–P A, 46% had extrahepatic spread, and 32% had macrovascular invasion. MTD of REG was 120 mg/day. Grade (Gr) 3/4 treatment-emergent adverse events (TEAE) occurred in 86% of pts on REG 120 mg and 50% on REG 80 mg (Table). Most common Gr 3/4 TEAE for REG 120 mg/80 mg were AST increased (23%/9%), lipase increased (20%/5%), ALT increased (17%/9%), and hypertension (17%/9%). TEAE led to REG/PEMBRO dose reductions or interruptions in 71%/57% of pts on REG 120 mg and 59%/45% on REG 80 mg. Median treatment duration (range) was 3.0 months (mo; 0.2–20.5) for REG 120 mg and 3.5 mo (0.03–24.4) for PEMBRO, and 3.5 mo (0.7–10.8) for REG 80 mg and 3.5 mo (0.8–11.3) for PEMBRO. Of 32 evaluable pts on REG 120 mg, 10 (31%) had a partial response (PR) and 18 (56%) had stable disease (SD); disease control rate (DCR) was 88% (RECIST v1.1). Of 22 pts on REG 80 mg, 4 (18%) had a PR and 16 (73%) had SD; DCR was 91%. As of 17 Dec 2020, 16 pts remain on treatment (REG 120 mg n = 5; REG 80 mg n = 11); median follow up was 11.7 mo and 6.9 mo, respectively. REG pharmacokinetic exposure was as expected for 80 mg and 120 mg doses. Flow cytometry analysis of sequential peripheral blood showed changes in subsets of T-cells and monocytes, which may contribute to clinical benefit. Conclusions: First-line REG plus PEMBRO in advanced HCC showed no new safety signals and encouraging anti-tumor activity (DCR ̃90%). The REG 80 mg cohort appeared to have lower rates of dose reductions and interruptions due to TEAE vs REG 120 mg. Efficacy data for the REG 80 mg cohort are preliminary due to short follow-up. Clinical trial information: NCT03347292. [Table: see text]

323 Background: In a phase Ib study, REG 120 mg/day plus PEMBRO for first-line treatment of advanced HCC showed no unexpected safety signals and encouraging anti-tumor activity. At the maximum tolerated dose (MTD) of REG (120 mg/day), approximately three-quarters of patients (pts) had a REG dose reduction or interruption due to a treatment-emergent adverse event (TEAE). Here, we present preliminary data for the REG 80 mg/day cohort. Methods: This is an ongoing, dose-finding study in pts who had no prior systemic therapy. In the first cohort, pts received REG 120 mg/day orally for 3 weeks on/1 week off plus PEMBRO 200 mg intravenously q 3 weeks. In later cohorts, the REG dose could be escalated (160 mg/day) or reduced (80 mg/day); the PEMBRO dose is fixed. The primary objective is safety and tolerability. Secondary objectives are to define the MTD and recommended phase II dose and assess anti-tumor activity. Results: By July 24, 2020, 16 pts were treated with REG 80 mg/day. Median age was 67 years (range 56–79), 25%/75% were Barcelona Clinic Liver Cancer stage B/C, 100% Child–Pugh A, and 69%/31% had Eastern Cooperative Oncology Group performance status 0/1. Grade (Gr) 3 TEAEs occurred in 8/16 pts (50%) and there were no Gr 4 TEAEs (Table); one pt experienced Gr 5 pneumonitis (not drug related). There were no reports of Gr 3 hand–foot skin reaction or Gr 3 maculopapular rash, and one report (6%) of Gr 3 rash. TEAEs led to a REG dose reduction or interruption in 50% of pts and to a PEMBRO dose interruption in 25% of pts. Median treatment duration (range) including pts ongoing was 4.1 months (0.4–7.1) for REG and 3.8 months (0.03–7.2) for PEMBRO. Of 13 evaluable pts, 2 (15%) had a partial response and 9 (69%) had stable disease (Response Evaluation Criteria in Solid Tumors v1.1); disease control rate was 85%. Conclusions: These preliminary results for the combination of REG 80 mg/day plus PEMBRO for first-line treatment of advanced HCC were consistent with the REG 120 mg/day cohort. The combination showed no unexpected safety signals and encouraging anti-tumor activity. Assessment of REG 80 mg/day plus PEMBRO is ongoing. Clinical trial information: NCT03347292. [Table: see text]

10507 Background: In pediatric patients with solid tumors, regorafenib demonstrated acceptable tolerability and preliminary anti-tumor activity. This phase 1 study evaluated regorafenib in combination with vincristine/irinotecan in pediatric patients with rhabdomyosarcoma (RMS) and other solid tumors. Methods: Patients with relapsed/refractory tumors received intravenous vincristine (1.5 mg/m2, Days 1 and 8) and irinotecan (50 mg/m2/day, Days 1–5) plus once-daily oral regorafenib (patients 6– < 24 months: 60 mg/m2 escalating to 65 mg/m2; patients 2– < 18 years: 72 mg/m2 escalating to 82 mg/m2) on either Days 1–14 (concomitant dosing) or Days 8–21 (sequential dosing) during each 21-day cycle. As per protocol, at least 50% of patients were required to have RMS. Results: At the time of the cut-off, of 21 treated patients (RMS, n = 12; Ewing sarcoma, n = 5; neuroblastoma, n = 3; Wilms tumor, n = 1), two had concomitant (72 mg/m2) and 19 had sequential (72 mg/m2, n = 6; 82 mg/m2, n = 13) dosing. Median age was 10 years (1.5–17.0). Patients received a median of 3 cycles (1–17); dose reductions of irinotecan occurred in 62% of patients. Grade 3 dose-limiting toxicities were reported in both patients receiving concomitant dosing (peripheral neuropathy and liver injury; pain, vomiting, febrile aplasia) and one patient each in the sequential groups (rash and elevated AST; thrombocytopenia). Concomitant dosing was discontinued. The maximum tolerated dose and recommended phase 2 dose (RP2D) of regorafenib in the sequential combination was 82 mg/m2. The most common grade ≥3 treatment-emergent adverse events were neutropenia (71%), thrombocytopenia (33%), leukopenia (29%), anemia (24%), and ALT increased (24%). The response rate was 38%, including 1 complete (RMS) and 7 partial responders (5 RMS, 2 Ewing sarcoma); 3 of whom had prior irinotecan. Six (4 with alveolar subtype) of 12 patients with RMS had a response. Nine patients (43%) had stable disease (maximum duration 17 cycles). After the cut-off, partial response was reported for two additional patients (1 RMS, 1 Ewing sarcoma). Conclusions: Regorafenib can be combined at its single agent RP2D of 82 mg/m2 with standard-dose vincristine/irinotecan (with appropriate dose modifications) in pediatric patients with refractory/relapsed solid tumors in a sequential dosing schedule. Clinical activity was observed in patients with sarcoma. Clinical trial information: NCT02085148.

Background: Granulocyte colony-stimulating factors are effective at reducing the risk and duration of neutropenia. The current meta-analysis compared the neutropenia-related efficacy and safety of lipegfilgrastim to those of pegfilgrastim and filgrastim. Methods: Embase was searched for trials examining the efficacy/safety of lipegfilgrastim, pegfilgrastim, or filgrastim. Outcomes included febrile neutropenia, severe neutropenia, duration of severe neutropenia, time to recovery of absolute neutrophil count, and incidence of bone pain. Direct comparisons were made using random-effects models. No trials directly compared lipegfilgrastim and filgrastim. Indirect comparisons were made between lipegfilgrastim and filgrastim with pegfilgrastim as the common comparator. Results: This meta-analysis included a total of 5769 patients from 24 studies. Over all cycles, lipegfilgrastim showed a lower, nonsignificant risk of febrile neutropenia compared with pegfilgrastim. Lipegfilgrastim has a lower risk of febrile neutropenia versus filgrastim but was also not statistically significant. The risk ratio for severe neutropenia in cycle 1 was 0.80, a 20% reduction in favor of lipegfilgrastim. For cycles 2–4, the risk ratio was 0.53 (0.35, 0.79) for lipegfilgrastim versus pegfilgrastim. The risk of severe neutropenia in cycles 2–4 was also significantly lower for lipegfilgrastim (risk ratio 0.45, 0.27, 0.75, respectively). No significant differences were found for febrile neutropenia and severe neutropenia in cycle 1. However, in cycles 2–4, lipegfilgrastim was associated with significant and clinically meaningful reductions in risk of severe neutropenia versus either pegfilgrastim or filgrastim. Conclusions: Compared with pegfilgrastim or filgrastim, lipegfilgrastim has a statistically significantly lower absolute neutrophil count recovery time; however, differences in duration of severe neutropenia and bone pain were nonsignificant., SCOPUS: ar.j, info:eu-repo/semantics/published

Objective The prospective non-interventional study (NIS) NADIR was designed to evaluate both effectiveness and safety of prophylactic use of lipegfilgrastim (Lonquex® ), a glycopegylated granulocyte colony-stimulating factor, in cancer patients with different tumor entities undergoing chemotherapy in routine clinical practice. The primary objective was incidence of severe neutropenia, febrile neutropenia (FN), and neutropenia-associated complications. Method NADIR was a national, multicenter, prospective NIS. Results Here, we present the data on patients with non-Hodgkin lymphoma (NHL). Final analysis comprised 337 NHL patients having received ≥1 administration of lipegfilgrastim. Primary prophylaxis with lipegfilgrastim was documented in 78.7% of patients with high risk to develop FN. In total, ≥1 severe neutropenia (grade 3/4) was reported in 115 (34.1%) patients and ≥1 event of FN documented in 15 (4.5%) patients. Grade 3/4 infections were reported in 22 (6.5%) patients overall. Most frequently reported adverse events (AEs) related to lipegfilgrastim in total were bone pain (5.4%), leukocytosis (2.1%), back pain (1.8%), platelet count decreased (1.2%), and myalgia (1.2%). Fatal serious AEs were documented in 9 (2.7%) patients; none were attributable to lipegfilgrastim. Conclusion Prophylaxis or therapeutic intention with lipegfilgrastim in NHL patients in routine clinical practice showed similar effectiveness and safety as demonstrated in the pivotal trials.

This study estimated the cost-effectiveness of arsenic trioxide (ATO) added to all-trans retinoic acid (ATRA) when used in first-line acute promyelocytic leukemia (APL) treatment.A Markov cohort model was developed with 3 states: stable disease (during first- or second-line treatment), disease event, and death. Newly diagnosed patients with low- to intermediate-risk APL were included and each month could remain in their current health state or move to another. Treatment consisted of ATO + ATRA, ATRA + idarubicin (IDA), or ATRA + cytarabine (AraC) + additional chemotherapy. After an initial disease event, patients discontinued first-line therapy and switched to a second-line ATO regimen. Efficacy and safety data were obtained from published trials; quality of life/utility estimates were obtained from the literature; costs were obtained from US data sources. Costs and outcomes over time were used to calculate incremental cost-effectiveness ratios (ICERs). Deterministic and probabilistic sensitivity analyses were conducted.Compared to ATRA + AraC + additional chemotherapy, ATRA + IDA treatment had ICERs of $2933 per life-year (LY) saved and $3122 per quality-adjusted life-year (QALY) gained. Compared to the ATRA + IDA regimen, first-line ATO + ATRA treatment had ICERs of $4512 per LY saved and $5614 per QALY gained. Results were sensitive to changes in pharmacy costs of the ATO + ATRA regimen during consolidation.The ATO + ATRA regimen is highly cost-effective compared to ATRA + AraC + additional chemotherapy or ATRA + IDA in the treatment of newly diagnosed low- to intermediate-risk APL patients.

Plasma amino acid level changes occur in mild, moderate and severe stages of liver injury in human patients. In animal models, however, data are mainly restricted to severe liver injury models in rats. Here we present the characterization of a rat model of moderate liver dysfunction secondary to alpha-napthylisothiocyanate (ANIT)-induced cholestasis. Rats treated with 30 mg/kg/day ANIT for 3 weeks exhibited a time-dependent increase in plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin levels and a decrease in albumin concentration. According to a liver dysfunction evaluation based on the human Child-Pugh-Score, animals developed a moderate liver dysfunction in the first two weeks of ANIT treatment, while only a mild dysfunction was observed at the end of week 3 despite ongoing ANIT administration. Univariate analysis of branched-chain amino acid plasma levels indicated that reduced levels of branched chain amino acids were associated with the ANIT treatment. These data may set the stage for further research of amino acid disturbances and requirements in non-severe cholestasis.

The objective of this study was to estimate the net cost of arsenic trioxide (ATO) added to all-trans retinoic acid (ATRA) compared to ATRA plus chemotherapy when used in first-line acute promyelocytic leukemia (APL) treatment for low to intermediate risk patients from the perspective of the overall Italian healthcare systemA Markov model was developed with 3 health states: stable disease, disease event and death. Each month, patients could move from stable to disease event or die from either state. After a disease event, patients discontinued initial treatment and switched to the other regimen as second-line therapy. Treatment regimens, efficacy and adverse events were derived from published sources and expert opinion; unit costs were collected from standard Italian sources. Clinical outcomes and costs for pre-ATO and post-ATO scenarios were combined with population and product utilization information to calculate the total budgetary impact using a 3-year time horizon; one-way sensitivity analyses were conducted. Three-year cumulative pharmacy costs for ATO+ATRA were €46,700 per-patient versus €6,500 for ATRA+chemotherapy; however, medical costs for ATO+ATRA were €12,300 per-patient versus €30,200 for ATRA+chemotherapy. The total budgetary impact was estimated to be an additional €127,300, €312,500 and €477,800 in the first, second and third years, respectively. The model was most sensitive to changes in the cost of the ATO+ATRA regimen during the consolidation phase. Budgetary impact models are valuable to payers making formulary decisions regarding the access and affordability of new medicines. The cost of treatment analysis showed that pharmacy costs for ATO+ATRA were higher than for ATRA+chemotherapy, while all other evaluated costs were lower for ATO+ATRA treated patients. The average budgetary impact was €305,900 per year overall, representing a 3.5% increase. Further research is needed to determine the cost-effectiveness of ATO+ATRA compared to the current first-line standard of care in APL.

Introduction: The addition of rituximab to chemotherapy has been associated with substantial responses in patients with indolent NHL, but patients usually relapse. Bendamustine hydrochloride (bendamustine; Treanda®) is an alkylating agent approved globally for multiple indications including chronic lymphocytic leukemia, indolent B-cell NHL, mantel cell lymphoma, and multiple myeloma. This open-label, single-arm, multicenter study in China aims to determine the overall response rate (ORR) to bendamustine treatment in patients with indolent B-cell NHL refractory to a rituximab-containing regimen. Methods: Patients with documented relapse from indolent B-cell NHL after rituximab treatment and 1-3 previous chemotherapy regimens were included. Patients received bendamustine intravenous 120 mg/m2 infusion (over 60 minutes) on day 1 and 2 of each 21-day cycle for at least 6 cycles and were allowed to continue treatment for up to 8 cycles. Primary endpoint was response rate based on the modified International Workshop Response Criteria; secondary endpoints were duration of response (DOR), progression-free survival (PFS), and safety. Results: A total of 102 patients from 20 centers were enrolled. All enrolled patients were analyzed for safety and efficacy. The ORR was 73% (95% CI: 62.82-80.92) per independent review committee (IRC) including 19% complete response (CR) and 54% partial response (PR). The ORR per investigator assessment was 78% (30% CR and 48% PR). Among 31 patients with disease refractory to last alkylator therapy, the ORR was 68% (95% CI: 48.63-83.32). The median DOR was 16.5 months (95% CI: 10.9-NA) per IRC and 12.5 months per investigator. Durable responses were observed across all baseline patient and disease characteristics. Median DOR was not reached in patients refractory to last alkylator or chemotherapy treatment. The median PFS was 18.6 months and was similar across baseline characteristics. Disease characteristics did not significantly impact PFS. The overall safety profile was consistent with known adverse events (AEs). The most common AEs (≥40%) were white blood cell count decreased (54%), neutrophil count decreased (47%), neutropenia (46%), leukopenia (45%), nausea (44%), and platelet count decreased (40%). Most patients completed planned treatment; the mean relative dose intensity was 82%. Neutropenia was the most common reason for dose reductions. Four patients died during the study, three of which were attributed to bendamustine. At least one serious AE was experienced by 29 patients, and AEs that resulted in discontinued treatment occurred in 25 patients. Conclusions: Single-agent bendamustine is effective in the treatment of Chinese patients with rituximab-refractory, relapsed indolent B-cell NHL including those with previous alkylator exposure, with a safety profile consistent with known AEs. Sponsor: Teva Branded Pharmaceutical Products R&D Disclosures Mueller: Teva Pharmaceuticals, Inc.: Employment, Equity Ownership.

Introduction: Marketed therapeutic products are subject to periodic benefit-risk evaluation reports (PBRERs), which provide comprehensive worldwide safety assessments and benefit-risk analyses. The short-acting recombinant human granulocyte colony-stimulating factor (rG-CSF) is known as filgrastim (Tevagrastim®, Ratiograstim®, Biograstim®) in Europe (approved in 2008) and tbo-filgrastim (Granix®) in the United States (approved in 2012). In the United States, Granix is indicated for reducing the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. Here, we present the accumulated safety data from the PBRER for the rG-CSFs collected in a 3-year period from the 52 countries in which the product was registered. Methods: Cumulative data were collected since initial approval in 2008. This PBRER period includes data captured from September 16, 2012, to September 15, 2015. Data were collected from spontaneous reports submitted by healthcare professionals and consumers, the scientific literature, competent authorities, and solicited case reports. Adverse reactions were categorized by system organ class (SOC), source, and seriousness. Pharmacovigilance in Europe requires screening of all adverse reaction reports and antibody assessment for cases of suspected immunogenicity. Safety concerns identified by the originator during the use of filgrastim were described in the risk management plan (RMP; version 8; dated 14 May 2012). Results: During this PBRER period, the estimated exposure to the rG-CSFs was ~4,314,994 patient-days. As of September 15, 2015, the estimated cumulative exposure to the rG-CSFs was ~8,741,835 patient-days over 7 years. Estimated cumulative exposure to the rG-CSFs in clinical trials were 190 patient-days in healthy subjects and 22,099 patient-days in patients with cancer. The global safety database processed 561 rG-CSFs case reports from initial product approval through September 15, 2015 (~9 years), including 339 (60%) from this PBRER period (~3 years). Postmarketing data sources cumulatively reported 1133 adverse reactions, 702 (62%) from this PBRER period. The most common adverse events (AEs) reported during this PBRER period per SOC are summarized in the figure. The most frequently reported serious AEs associate with general disorders and administration site conditions during this period were pyrexia (11 reports) and ineffective drug (8). Reports of serious bone pain (3 reports), back pain (2), muscular weakness (2), musculoskeletal pain (2), and myalgia (2) were also received during this period. The most common AEs associated with serious skin conditions were pruritus and urticarial (5 reports each). Two additional safety concerns (capillary leak syndrome [CLS] and cytokine release syndrome [CRS]) were identified by the originator during the use of filgrastim and were subsequently added to the RMP based on recommendations from the Pharmacovigilance Risk Assessment Committee. As of September 15, 2015, one report of CLS and no reports of CRS have been received. Overall, reported cases of immunogenicity showed no impact on efficacy or pharmacokinetics/ pharmacodynamics of the rG-CSFs. Updated data will be presented at the conference as available. Conclusions: No significant changes in the safety or risk-benefit profiles were identified for the rG-CSFs relative to other filgrastim products during this reporting period, and reported cases of immunogenicity showed no clinically relevant impact. Figure Adverse reactions per SOC reported from September 16, 2012, to September 15, 2015. Sponsor: Teva Branded Pharmaceutical Products R&D Figure. Adverse reactions per SOC reported from September 16, 2012, to September 15, 2015. / Sponsor: Teva Branded Pharmaceutical Products R&D Disclosures Abboud: Teva: Speakers Bureau; Alexion, Baxalta, Pharmacyclics, Takeda, Cardinal Health: Honoraria; Merck, Teva, Novartis, Pfizer, Seattle Genetics: Research Funding; Gerson and Lehman Group (GLG): Consultancy. Lang:Teva ratiopharm: Employment. Lammerich:Teva ratiopharm/Teva Pharmaceuticals, Inc.: Employment. Buchner:Merckle GmbH member of TEVA Group: Employment; Teva Pharmaceuticals, Inc.: Equity Ownership. Liu:Teva Pharmaceuticals, Inc.: Employment. Mueller:Teva Pharmaceuticals, Inc.: Employment, Equity Ownership. Pathak:Teva Pharmaceuticals: Employment, Equity Ownership.

e14072Background: Recombinant granulocyte-colony stimulating factors (G-CSFs) reduce the risk of chemotherapy-induced neutropenia. Lipegfilgrastim (LIP) is a novel, long-acting, once-per-cycle G-CS...

10542Background: Regorafenib, a multikinase inhibitor targeting VEGFR1-3, PDGFR, TIE-2, RET, c-KIT, is approved for the treatment of adults with advanced CRC and GIST. This study assessed its safet...

7040 Background: All-trans retinoic acid (ATRA) and arsenic trioxide (ATO) have dramatically improved treatment outcomes in Acute Promyelocytic Leukemia (APL). To address the question regarding the...

Amino acids represent basic elements of proteins, which as a main source of nutrition themselves serve as a major reserve for maintaining essential functions of humans as well as animals. Taking the recent state of scientific knowledge into account, the industrial sector of amino acids is a priori “suitable” to a specific kind of an ecologically sound way of production, which is based on biotechnology. The following article may point out characteristics of this particular industrial sector and illustrates the applicability of the latest economic methods, founded on development of the discipline of bionics in order to describe economic aspects of amino acids markets. The several biochemical and technological fields of application of amino acids lead to specific market structures in high developed and permanently evolving systems. The Harvard tradition of industrial economics explains how market structures mould the behaviour of the participants and influences market results beyond that. A global increase in intensity of competition confirms the notion that the supply-side is characterised by asymmetric information in contrast to Kantzenbachs concept of “narrow oligopoly” with symmetrical shared knowledge about market information. Departing from this point, certain strategies of companies in this market form shall be derived. The importance of Research and Development increases rapidly and leads to innovative manufacturing methods which replace more polluting manufacturing processes like acid hydrolysis. In addition to these modifications within the production processes the article deals furthermore with the pricing based on product life cycle concept and introduces specific applications of tools like activity based costing and target costing to the field of amino acid production. The authors come to the conclusion that based on a good transferability of latest findings in bionics and ecological compatibility competitors in amino acids manufacturing are well advised to exercise concepts of the management of complex systems in order to choose the right strategy towards gaining market leadership.

e17540 Background: Medical products registered in the European Union (EU) are subject to Periodic Safety Update Reports (PSURs), which provide comprehensive worldwide safety data assessments and benefit-risk analyses. Methods: The present PSUR for tbo-filgrastim-containing products within the TEVA group (Tevagrastim, Biograstim, Ratiograstim [marketed in the US as Granix]) analyzed safety data accumulated between April 1, 2012 and March 31, 2013 in 38 countries. Cumulative data were collected from clinical trials and post-marketing sources from September 15, 2008 (initial approval) to the end of the current PSUR period, March 31, 2013. Data were collected from spontaneous reports from healthcare professionals, consumers, scientific literature, competent authorities, and solicited case reports. Adverse reactions were categorized by system organ class (SOC), source, and seriousness. Teva pharmacovigilance requires screening of all adverse reaction reports and antibody assessment for cases of suspected immun...

e13555 Background: Tbo-filgrastim is a G-CSF approved in the US as a biologic under the BLA 351(a) pathway, for reducing duration of severe neutropenia (DSN) in patients with non-myeloid malignancies receiving chemotherapy (CTx) associated with a clinically significant incidence of febrile neutropenia (FN). Here, we summarize data from the development program (16 preclinical studies; 2 Phase I and 3 Phase III clinical studies). Methods: Preclinical: The PK, safety pharmacology, PD, and toxicology of tbo-filgrastim vs reference filgrastim were investigated in 3 in vitro studies and 13 animal model studies. Clinical: The PK/PD of tbo-filgrastim and filgrastim were compared in 2 Phase I studies in 200 healthy volunteers. The safety and efficacy of tbo-filgrastim were compared with filgrastim in 3 Phase III studies in 677 patients receiving CTx for breast cancer (BC), lung cancer (LC) and non-Hodgkin lymphoma (NHL). The BC study, in which DSN was the primary parameter, was placebo controlled. Results: Preclinical: Binding affinity to the human G-CSF receptor and growth-promoting activity were comparable between tbo-filgrastim and filgrastim in vitro. In vivo, no relevant differences were seen between tbo-filgrastim and reference filgrastim in PK, PD, safety, or tolerability in animal models. Clinical and laboratory findings, gross pathology and histopathology in animal models were similar to filgrastim. Clinical: tbo-Filgrastim was safe, effective, and comparable to filgrastim in the prevention of FN. DSN, absolute neutrophil count (ANC) nadir, and time to ANC recovery were comparable. The incidence of FN was low (mean of 12.1%, 15.0%, and 11.1% in Cycle 1 of the BC, LC, and NHL studies, respectively), with no significant differences between agents. In the BC study, in Cycle 1, DSN was 1.1 vs 3.9 days for tbo-filgrastim and placebo, respectively. The efficacy of tbo-filgrastim was independent of the myelotoxic potential of CTx. Immunogenicity and incidence of binding and neutralizing antibodies were low and comparable. Conclusions: The safety profiles of tbo-filgrastim and filgrastim were similar and characteristic of filgrastims. Tbo-filgrastim was superior to placebo and equivalent to filgrastim in reducing DSN after myelotoxic CTx. Clinical trial information: 2004-001452-36, 2004-001450-84, 2004-001449-13.

e13548 Background: Lipegfilgrastim is a once-per-cycle fixed-dose glycoPEGylated granulocyte-colony stimulating factor (G-CSF) under development for the prevention of severe neutropenia in cancer patients receiving chemotherapy (CTx). PEGylation of a molecule extends its half-life in the body, requiring less frequent dosing and allowing for administration of G-CSF once per CTx cycle, making treatment potentially less expensive and enhancing patient compliance and safety. Briefly, traditional PEGylation methods use chemical conjugation through reactive groups on amino acids, which may reduce protein activity and result in non-uniform chemical and pharmaceutical properties. Here, we describe a highly site-specific GlycoPEGylation technology for site-directed PEGylation and summarize preclinical findings compared with pegfilgrastim (Neulasta). Methods: Glycosylation sequon scanning was used to identify the glycoPEGylation site with least impact on protein activity. E. coli-expressed G-CSF was selectively glycosylated at natural O-glycosylation sites and a polyethylene glycol (PEG) sialic acid derivative attached using a sialyltransferase (glycoPEGylation technology). Ligand binding affinity was assessed using the BIACORE 3000 system. Biologic activity of lipegfilgrastim was assessed in an NFS-60 cell line proliferation assay vs filgrastim and pegfilgrastim. PK and PD properties were studied in healthy and neutropenic animal models. Results: GlycoPEGylation produces long-acting G-CSF with improved PK profiles. In vitro, lipegfilgrastim had binding affinity and specific activity comparable to pegfilgrastim, and both were lower than non-PEGylated filgrastim. Comparable increases in leukocytes, neutrophilic granulocytes, and monocytes were seen with lipegfilgrastim and pegfilgrastim in rats and monkeys and were consistent with the effects expected for a long-lasting G-CSF. Conclusions: GlycoPEGylation technology platform is used to produce lipegfilgrastim – a novel, biologically active G-CSF with greater structural homogeneity and comparable pharmacologic properties to conventionally PEGylated G-CSFs.

e13552 Background: Tbo-filgrastim is a granulocyte colony-stimulating factor (G-CSF) approved for use in the US as a biologic under BLA 351(a) for reducing duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive chemotherapy (CTx) associated with a clinically significant incidence of febrile neutropenia. Here, we report an integrated analysis of clinical safety data from three Phase III studies. Methods: Safety results from three Phase III studies in breast cancer (placebo-controlled), non-small cell lung cancer, and non-Hodgkin lymphoma were integrated. All safety variables were analyzed using descriptive statistics. The incidence of treatment-emergent adverse events (TEAEs) was compared between treatment groups using Fisher's exact test (2-sided P-values). Changes in laboratory parameters from baseline were compared between the tbo-filgrastim and filgrastim treatment groups using the Wilcoxon test. Results: In the integrated analysis of CTx Cycle 1, 80.2% of 677 patients experienced a TEAE; 16.7% of these were related to study drug. The most commonly reported TEAEs were nausea, alopecia, neutropenia, diarrhea, asthenia, and vomiting, and most due to concomitant CTx. The most commonly reported drug-related TEAEs were bone pain (3.4%), diarrhea (2.2%), asthenia (2.2%), myalgia (1.9%), arthralgia (1.5%), headache (1.2%), and pyrexia (1.0%), all of which are characteristic of G-CSFs. Five patients had serious drug-related TEAEs; none caused reductions in the dose of study drug or scheduled CTx. There were 11 deaths across studies; none was considered drug related. There were no clinically significant differences between tbo-filgrastim and filgrastim in the overall incidence of deaths, serious or severe TEAEs, discontinuations due to TEAEs, or in laboratory safety variables. In all cycles of CTx, the most commonly reported TEAEs in patients treated with tbo-filgrastim correlated with those of the reference filgrastim. Conclusions: Tbo-filgrastim is safe and well tolerated in breast cancer, non-small cell lung cancer, and non-Hodgkin lymphoma patients undergoing CTx, with a safety profile similar to that of the reference filgrastim. Clinical trial information: 2004-001452-36, 2004-001450-84, 2004-001449-13.

e13551 Background: Balugrastim is a once-per-cycle fixed-dose genetic fusion protein composed of human serum albumin (HSA) and granulocyte colony-stimulating factor (G-CSF) in development for prevention of severe neutropenia in cancer patients receiving chemotherapy. Albumin fusion is a clinically validated technology that extends product half-life, allowing for infrequent dosing, better tolerability, lower cost, and improves drug design, potentially lowering immunogenicity risk. Here, we describe the technology used to produce balugrastim and summarize preclinical findings compared with pegfilgrastim (Neulasta). Methods: Design and production of balugrastim was described previously (Halpern et al. Pharmaceut Res 2002;19:1720−1729). Biologic activity of balugrastim was assessed in an NFS-60 cell line proliferation assay vs filgrastim and pegfilgrastim. PK and PD properties were studied in healthy and neutropenic animal models. Results: Albumin fusion produces a long-acting G-CSF with comparable pharmacologic properties to pegfilgrastim. In vitro, balugrastim had binding affinity and cell proliferation activity comparable to pegfilgrastim, and both were lower than non-PEGylated filgrastim on a molar basis. Overall increases in leukocytes, neutrophilic granulocytes, and monocytes were dose dependent and consistent with the effects expected for a long-acting G-CSF with some variation based on the specific animal model used. A single balugrastim dose in BDF1 mice elicited a dose-dependent increase in peripheral granulocytes and mobilized hematopoietic progenitor cells. In cynomolgus monkeys, balugrastim caused an increase in peripheral neutrophils similar to pegfilgrastim, with higher responses after 2nd, 3rd, and 4th doses. In mice, balugrastim had shorter terminal half-life and mean residence time, and faster clearance than pegfilgrastim. In monkeys, terminal half-life of balugrastim was slightly longer than pegfilgrastim. Conclusions: An albumin fusion technology platform was used to produce balugrastim – a novel, biologically active albumin G-CSF fusion protein with greater structural homogeneity and comparable pharmacologic properties to conventionally PEGylated G-CSFs.

e17572 Background: Balugrastim is a recombinant fusion protein composed of human serum albumin and human granulocyte colony-stimulating factor, which allows for once-per-chemotherapy cycle administration. We present a combined analysis of two double-blind, randomized Phase III studies comparing efficacy and safety of balugrastim vs pegfilgrastim in breast cancer patients receiving myelosuppressive chemotherapy (CTx). Methods: All patients were treated with doxorubicin 60 mg/m2 followed by docetaxel 75 mg/m2 administered by i.v. infusion on Day 1 of a 21-day cycle for up to 4 cycles. For each cycle, patients received a single s.c. injection of balugrastim approximately 24 hours after administration of CTx. The primary endpoint for both studies was duration of severe neutropenia (DSN) in Cycle 1. Safety of balugrastim was assessed by evaluating the type, frequency, and severity of adverse events (AEs); changes in laboratory parameters and vital signs, and immunogenicity over time. Analyses were performed in the per-protocol population. Results: A total of 469 patients were randomized to receive balugrastim 40 mg (N=235) or pegfilgrastim 6 mg (N=234). Mean DSN in Cycle 1 was 1.1±1.11 days in patients receiving balugrastim (n=236) and 1.0±1.14 days in patients receiving pegfilgrastim (n=234). Non-inferiority was demonstrated by statistical analysis for balugrastim vs pegfilgrastim for reduction in DSN across studies. Patients treated with balugrastim had a significantly shorter time to ANC recovery in Cycle 1 vs pegfilgrastim (2.0 vs 2.3 days; P=0.015). No other significant differences were seen between treatment groups in either study for any other secondary endpoints in Cycles 1–4. The safety profile was similar for both drugs, with the incidence of AEs consistent with the underlying medical condition and administration of myelosuppressive CTx. Conclusions: In both Phase III studies, non-inferiority was clearly demonstrated for balugrastim 40 mg vs pegfilgrastim 6 mg. Balugrastim is a safe and effective alternative to long-acting pegfilgrastim for reducing DSN in breast cancer patients receiving myelosuppressive chemotherapy. Clinical trial information: 2010-019001-42.