Matrix metalloproteinase-9 deficiency confers resilience in fibrodysplasia ossificans progressiva in a man and mice.

Single case studies of extraordinary disease resilience may provide therapeutic insight into conditions for which no definitive treatments exist. An otherwise healthy 35-year-old man (patient-R) with the canonical pathogenic ACVR1R206H variant and the classic congenital great toe malformation of fibrodysplasia ossificans progressiva (FOP) had extreme paucity of post-natal heterotopic ossification (HO) and nearly normal mobility. We hypothesized that patient-R lacked a sufficient post-natal inflammatory trigger for HO.

Testosterone propionate and treatment modulated D-galactose induced reproductive alterations in male Wistar rats: An experimental study.

Background: The male reproductive system undergoes several adverse age-related changes like decreased hormone synthesis, sperm count, and testicular alteration that can impact on fertility.

Objective: The study aims to investigate the effects of testosterone propionate (TP), and ayurvedic formulation (SB) on D-galactose (D-gal) induced reproductive aging in male Wistar rats.

Materials And Methods: 60 male Wistar rats were divided into 10 groups of 6 animals.

Randomized, open-label, phase 2 study of andecaliximab plus nivolumab versus nivolumab alone in advanced gastric cancer identifies biomarkers associated with survival.

Background: Matrix metalloproteinase-9 (MMP9) selectively cleaves extracellular matrix proteins contributing to tumor growth and an immunosuppressive microenvironment. This study evaluated andecaliximab (ADX), an inhibitor of MMP9, in combination with nivolumab (NIVO), for the treatment of advanced gastric cancer.

Methods: Phase 2, open-label, randomized multicenter study evaluating the efficacy, safety, and pharmacodynamics of ADX+NIVO versus NIVO in patients with pretreated metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma.

Phase III Study to Evaluate Efficacy and Safety of Andecaliximab With mFOLFOX6 as First-Line Treatment in Patients With Advanced Gastric or GEJ Adenocarcinoma (GAMMA-1).

Purpose: Andecaliximab (ADX) is a monoclonal antibody that inhibits matrix metalloproteinase 9, an extracellular enzyme involved in matrix remodeling, tumor growth, and metastases. A phase I and Ib study of modified oxaliplatin, leucovorin, and fluorouracil (mFOLFOX6) with ADX revealed encouraging antitumor activity in patients with gastric or gastroesophageal junction (GEJ) adenocarcinoma.

Materials And Methods: This phase III, randomized, double-blinded, placebo (PBO)-controlled multicenter study investigated the efficacy and safety of mFOLFOX6 with and without ADX in patients with untreated human epidermal growth factor receptor 2-negative gastric or GEJ adenocarcinoma.

No increased bleeding events in patients with relapsed chronic lymphocytic leukemia and indolent non-Hodgkin lymphoma treated with idelalisib.

The advent of novel B-cell receptor pathway targeting agents like ibrutinib dramatically changed management of B-cell malignancies. However, with concomitant anticoagulation (AC) and antiplatelet (AP) therapy, ibrutinib is associated with increased bleeding. This analysis aimed to determine the role of AC/AP therapy in patients with idelalisib-treated B-cell malignancies and to establish if it contributes to increased bleeding events.

Phase 1b study to investigate the safety and tolerability of idelalisib in Japanese patients with relapsed/refractory follicular lymphoma and chronic lymphocytic leukemia.

Objective: Idelalisib is an orally administered, highly selective inhibitor of phosphatidylinositol 3-kinase-δ. In this phase 1b study, the safety, tolerability and pharmacokinetics of idelalisib, an oral inhibitor of phosphatidylinositol 3-kinase-δ, were evaluated in Japanese patients with relapsed or refractory indolent B-cell non-Hodgkin lymphoma.

Methods: In total, six patients (follicular lymphoma: n = 3, chronic lymphocytic leukemia: n = 3) were enrolled to receive idelalisib 150 mg twice daily.

Safety and Efficacy of Andecaliximab (GS-5745) Plus Gemcitabine and Nab-Paclitaxel in Patients with Advanced Pancreatic Adenocarcinoma: Results from a Phase I Study.

Background: Matrix metalloproteinase 9 (MMP9) expression in the tumor microenvironment is implicated in multiple protumorigenic processes. Andecaliximab (GS-5745), a monoclonal antibody targeting MMP9 with high affinity and selectivity, was evaluated in combination with gemcitabine and nab-paclitaxel in patients with advanced pancreatic adenocarcinoma.

Patients And Methods: This phase I study was completed in two parts: part A was a dose-finding, monotherapy phase that enrolled patients with advanced solid tumors, and part B examined andecaliximab in combination with chemotherapy in specific patient cohorts.

Medical comorbidities in patients with chronic lymphocytic leukaemia treated with idelalisib: analysis of two large randomised clinical trials.

Comorbidities influence survival in patients with chronic lymphocytic leukaemia (CLL) treated with chemo-immunotherapy or ibrutinib. While idelalisib has been studied in patients with comorbidities, their impact has not been investigated. We analysed 481 patients treated with idelalisib on two randomised trials (NCT01659021 and NCT01539512).

Phase Ib Study of Tirabrutinib in Combination with Idelalisib or Entospletinib in Previously Treated Chronic Lymphocytic Leukemia.

Purpose: Bruton tyrosine kinase (BTK) inhibition alone leads to incomplete responses in chronic lymphocytic leukemia (CLL). Combination therapy may reduce activation of escape pathways and deepen responses. This open-label, phase Ib, sequential dose-escalation and dose-expansion study evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of the selective BTK inhibitor tirabrutinib alone, in combination with the PI3K delta (PI3Kδ) inhibitor idelalisib, or with the spleen tyrosine kinase (SYK) inhibitor entospletinib in patients with relapsed/refractory CLL.

Prognostic risk score for patients with relapsed or refractory chronic lymphocytic leukaemia treated with targeted therapies or chemoimmunotherapy: a retrospective, pooled cohort study with external validations.

Background: Clinically validated prognostic models for overall survival do not exist for patients with relapsed or refractory chronic lymphocytic leukaemia (CLL) who are on targeted therapies. We aimed to create a prognostic model to identify high-risk individuals who do not achieve a good outcome with available targeted therapies.

Methods: In this retrospective, pooled cohort study, 2475 patients with CLL treated between June 22, 2012, and Sept 23, 2015, in six randomised trials of ibrutinib, idelalisib, and venetoclax, or at the Mayo Clinic CLL Database (MCCD) were included.

ACCELERATE and European Medicine Agency Paediatric Strategy Forum for medicinal product development for mature B-cell malignancies in children.

Paediatric Strategy Forums have been created by the multistakeholder organisation, ACCELERATE, and the European Medicines Agency to facilitate dialogue between all relevant stakeholders and suggest strategies in critical areas of paediatric oncology drug development. As there are many medicines being developed for B-cell malignancies in adults but comparatively few in children with these malignancies, a Paediatric Strategy Forum was held to discuss the best approach to develop these products for children. It was concluded that as current frontline therapy is highly successful, despite associated acute toxicity, de-escalation of this or substitution of presently used drugs with new medicines can only be undertaken when there is an effective salvage regimen, which is currently not available.

Time course of safety and efficacy of aflibercept in combination with FOLFIRI in patients with metastatic colorectal cancer who progressed on previous oxaliplatin-based therapy.

Background: Patients with metastatic colorectal cancer (mCRC) previously-treated with oxaliplatin benefit significantly from the addition of aflibercept to FOLFIRI in relation to overall survival, progression-free survival and response rate.

Patients And Methods: The results for efficacy and safety over the time course of the VEGF Trap (aflibercept) with irinotecan in colorectal cancer after failure of oxaliplatin regimen trial were analysed based on data from 1226 patients randomised to receive FOLFIRI plus either aflibercept (n=612) or placebo (n=614). Hazard ratios (HR) by 6-month time period were estimated using a piecewise Cox proportional hazard model.

Multicenter phase II study of tivozanib (AV-951) and everolimus (RAD001) for patients with refractory, metastatic colorectal cancer.

Background: Treatments that target the vascular endothelial growth factor (VEGF) pathway have efficacy in colorectal cancer. We evaluated tolerability and efficacy of tivozanib (an oral VEGF receptor-1, -2, -3 inhibitor) plus everolimus (an oral mammalian target of rapamycin inhibitor).

Methods: The phase Ib study followed a 3 + 3 dose-escalation design with three dose levels.

Efficacy, safety, pharmacokinetics, and biomarkers of cediranib monotherapy in advanced hepatocellular carcinoma: a phase II study.

Purpose: We conducted a single-arm phase II study of cediranib, a pan-VEGFR tyrosine kinase inhibitor, in patients with advanced hepatocellular carcinoma (HCC).

Experimental Design: Patients with histologically confirmed measurable advanced HCC and adequate hematologic, hepatic, and renal functions received cediranib 30-mg orally once daily (4 weeks/cycle). The primary endpoint was progression-free survival (PFS) rate at 3 months.

Prospective study of bevacizumab plus temozolomide in patients with advanced neuroendocrine tumors.

Purpose: Both tyrosine kinase inhibitors targeting the vascular endothelial growth factor (VEGF) receptor and bevacizumab, a monoclonal antibody targeting VEGF, have antitumor activity in neuroendocrine tumors (NETs). Temozolomide, an oral analog of dacarbazine, also has activity against NETs when administered alone or in combination with other agents. We performed a phase II study to evaluate the efficacy of temozolomide in combination with bevacizumab in patients with locally advanced or metastatic NETs.

Antitumor activity and safety of tivozanib (AV-951) in a phase II randomized discontinuation trial in patients with renal cell carcinoma.

Purpose: The antitumor activity and safety of tivozanib, which is a potent and selective vascular endothelial growth factor receptor-1, -2, and -3 inhibitor, was assessed in patients with advanced/metastatic renal cell carcinoma (RCC).

Patients And Methods: In this phase II, randomized discontinuation trial, 272 patients received open-label tivozanib 1.5 mg/d (one cycle equaled three treatment weeks followed by a 1-week break) orally for 16 weeks.

Biologic and clinical activity of tivozanib (AV-951, KRN-951), a selective inhibitor of VEGF receptor-1, -2, and -3 tyrosine kinases, in a 4-week-on, 2-week-off schedule in patients with advanced solid tumors.

Purpose: To assess the maximum tolerated dose (MTD)/dose-limiting toxicities (DLT), safety, pharmacokinetics, and pharmacodynamics of tivozanib, a potent and selective oral VEGF receptor (VEGFR) tyrosine kinase inhibitor.

Experimental Design: Dose levels of 1.0, 1.

Development of second-generation VEGFR tyrosine kinase inhibitors: current status.

The vascular endothelial growth factor (VEGF) signaling pathway appears to be the dominant pathway involved in tumor angiogenesis, providing a rationale for targeting the VEGF receptors (VEGFR-1, -2, and -3) in the treatment of cancers. In particular, VEGF signaling is thought to be important in renal cell carcinoma (RCC) because of the deregulation of the pathway through nearly uniform loss of the von Hippel Lindau protein. The tyrosine kinase inhibitors (TKIs) sorafenib, sunitinib, and pazopanib are approved by the US Food and Drug Administration for the treatment of advanced RCC; however, these multitargeted agents inhibit a wide range of kinase targets in addition to the VEGFRs, resulting in a range of adverse effects unrelated to efficient VEGF blockade.

Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B (CALGB 80303).

Purpose: The combination of gemcitabine plus bevacizumab produced a 21% response rate and a median survival of 8.8 months in a multicenter phase II trial in patients with metastatic pancreatic cancer. These encouraging data led Cancer and Leukemia Group B (CALGB) to conduct a double-blind, placebo-controlled, randomized phase III trial of gemcitabine/bevacizumab versus gemcitabine/placebo in advanced pancreatic cancer patients.

Phase II study of pemetrexed in patients with advanced neuroendocrine tumors.

Purpose: In some reports, 5-fluorouracil has been associated with modest activity in patients with neuroendocrine tumors. Pemetrexed is a multitargeted antifolate with activity in tumor types not significantly responsive to other antifolates. We evaluated the efficacy of pemetrexed in a phase II study of patients with advanced neuroendocrine tumors.

Efficacy and safety of gemcitabine, oxaliplatin, and bevacizumab in advanced biliary-tract cancers and correlation of changes in 18-fluorodeoxyglucose PET with clinical outcome: a phase 2 study.

Background: Previous phase 2 studies have shown antitumour activity with gemcitabine and oxaliplatin (GEMOX) in patients with advanced biliary-tract cancers (BTCs). In this phase 2 study, we assessed the efficacy and safety of combined bevacizumab with GEMOX (GEMOX-B) in patients with advanced BTCs, and investigated how changes in 18-fluorodeoxyglucose ([(18)F]FDG)-PET correlate with clinical outcome.

Methods: Patients with advanced measurable BTCs were given the following treatment on days 1 and 15 of a 28-day cycle: bevacizumab 10 mg/kg, followed by gemcitabine 1000 mg/m(2) (10 mg/m(2) per min) and oxaliplatin 85 mg/m(2) (2-h infusion).

Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: a phase II study.

Purpose: To assess the safety and efficacy of sunitinib in patients with advanced hepatocellular carcinoma (HCC) and explore biomarkers for sunitinib response.

Patients And Methods: We conducted a multidisciplinary phase II study of sunitinib, an antivascular endothelial growth factor receptor tyrosine kinase inhibitor, in advanced HCC. Patients received sunitinib 37.