Search

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.

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

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.

We conducted our study to determine the pharmacokinetics (PK) and clinical efficacy of oral mesna in patients receiving ifosfamide for soft tissue sarcoma.Seventeen patients were enrolled in a randomized prospective Phase I/II study. Seventeen patients were exposed to study medication. Ifosfamide was given at a dose of 2 g/m2/day for 5 days on a 21-day cycle. Before the first cycle, all patients were randomized onto a crossover design and received either the approved i.v. or i.v./oral mesna regimen, with crossover for the second cycle of chemotherapy. The i.v. mesna regimen consisted of dosings (20% ifosfamide dose) at 0, 4, and 8 h. The i.v./oral arm consisted of an i.v. mesna dosing (20% ifosfamide dose) at 0 h, followed by oral tablet dosing (40% ifosfamide dose) at 2 and 6 h. In-patient clinical monitoring and phlebotomy and urine sampling for mesna, dimesna, and ifosfamide PK were performed on all chemotherapy days.Thirteen patients were evaluable for PK and 17 for efficacy and toxicity. No significant differences were detected in the plasma PK of the concomitantly infused ifosfamide. Rates of hemorrhagic cystitis were similar across mesna schedules. Four of 10 evaluable patients demonstrated objective response.On the basis of our study, an i.v./oral mesna regimen is at least as uroprotective as the approved i.v. regimen. The i.v./oral regimen will improve patient tolerance and convenience, allow for a reduction in elective hospitalizations for ifosfamide chemotherapy, reduce the potential morbidity associated with inpatient administration of chemotherapy, and likely result in decreased costs of care.