Efficacy and safety of givosiran for acute hepatic porphyria: 24-month interim analysis of the randomized phase 3 ENVISION study.

BACKGROUND & AIMS: Upregulation of hepatic delta-aminolevulinic acid synthase 1 with accumulation of potentially toxic heme precursors delta-aminolevulinic acid and porphobilinogen is fundamental to the pathogenesis of acute hepatic porphyria. AIMS: evaluate long-term efficacy and safety of givosiran in acute hepatic porphyria. METHODS: Interim analysis of ongoing ENVISION study (NCT03338816), after all active patients completed their Month 24 visit. Patients with acute hepatic porphyria (≥12 years) with recurrent attacks received givosiran (2.5 mg/kg monthly) (n = 48) or placebo (n = 46) for 6 months (double-blind period); 93 received givosiran (2.5 mg or 1.25 mg/kg monthly) in the open-label extension (continuous givosiran, n = 47/48; placebo crossover, n = 46/46). Endpoints included annualized attack rate, urinary delta-aminolevulinic acid and porphobilinogen levels, hemin use, daily worst pain, quality of life, and adverse events. RESULTS: Patients receiving continuous givosiran had sustained annualized attack rate reduction (median 1.0 in double-blind period, 0.0 in open-label extension); in placebo crossover patients, median annualized attack rate decreased from 10.7 to 1.4. Median annualized days of hemin use were 0.0 (double-blind period) and 0.0 (open-label extension) for continuous givosiran patients and reduced from 14.98 to 0.71 for placebo crossover patients. Long-term givosiran led to sustained lowering of delta-aminolevulinic acid and porphobilinogen and improvements in daily worst pain and quality of life. Safety findings were consistent with the double-blind period. CONCLUSIONS: Long-term givosiran has an acceptable safety profile and significantly benefits acute hepatic porphyria patients with recurrent attacks by reducing attack frequency, hemin use, and severity of daily worst pain while improving quality of life.

Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial.

BACKGROUND: Based on the encouraging activity and manageable safety profile observed in a phase 1 study, the ECHELON-2 trial was initiated to compare the efficacy and safety of brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone (A+CHP) versus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for the treatment of CD30-positive peripheral T-cell lymphomas. METHODS: ECHELON-2 is a double-blind, double-dummy, randomised, placebo-controlled, active-comparator phase 3 study. Eligible adults from 132 sites in 17 countries with previously untreated CD30-positive peripheral T-cell lymphomas (targeting 75% with systemic anaplastic large cell lymphoma) were randomly assigned 1:1 to receive either A+CHP or CHOP for six or eight 21-day cycles. Randomisation was stratified by histological subtype according to local pathology assessment and by international prognostic index score. All patients received cyclophosphamide 750 mg/m2 and doxorubicin 50 mg/m2 on day 1 of each cycle intravenously and prednisone 100 mg once daily on days 1 to 5 of each cycle orally, followed by either brentuximab vedotin 1·8 mg/kg and a placebo form of vincristine intravenously (A+CHP group) or vincristine 1·4 mg/m2 and a placebo form of brentuximab vedotin intravenously (CHOP group) on day 1 of each cycle. The primary endpoint, progression-free survival according to blinded independent central review, was analysed by intent-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01777152. FINDINGS: Between Jan 24, 2013, and Nov 7, 2016, 601 patients assessed for eligibility, of whom 452 patients were enrolled and 226 were randomly assigned to both the A+CHP group and the CHOP group. Median progression-free survival was 48·2 months (95% CI 35·2-not evaluable) in the A+CHP group and 20·8 months (12·7-47·6) in the CHOP group (hazard ratio 0·71 [95% CI 0·54-0·93], p=0·0110). Adverse events, including incidence and severity of febrile neutropenia (41 [18%] patients in the A+CHP group and 33 [15%] in the CHOP group) and peripheral neuropathy (117 [52%] in the A+CHP group and 124 [55%] in the CHOP group), were similar between groups. Fatal adverse events occurred in seven (3%) patients in the A+CHP group and nine (4%) in the CHOP group. INTERPRETATION: Front-line treatment with A+CHP is superior to CHOP for patients with CD30-positive peripheral T-cell lymphomas as shown by a significant improvement in progression-free survival and overall survival with a manageable safety profile. FUNDING: Seattle Genetics Inc, Millennium Pharmaceuticals Inc, a wholly owned subsidiary of Takeda Pharmacuetical Company Limited, and National Institutes of Health National Cancer Institute Cancer Center.

Zmax test for delayed effect in immuno-oncology clinical trials.

Delayed separation in survival curves has been observed in immuno-oncology clinical trials. Under this situation, the classic log-rank test may confront high power loss. In this paper, we consider a Zmax test, which is the maximum of the log-rank test and a Fleming-Harrington test. Simulation studies indicate that the Zmax test not only controls the Type I error rate but also maintains good power under different delayed effect models. The asymptotic properties of the Zmax test are also established, which further supports its robustness. We apply the Zmax test to two data sets reported in recent immuno-oncology clinical trials, in which Zmax has exhibited remarkable improvement over the conventional log-rank test.

Pevonedistat (MLN4924), a First-in-Class NEDD8-activating enzyme inhibitor, in patients with acute myeloid leukaemia and myelodysplastic syndromes: a phase 1 study.

This trial was conducted to determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the first in class NEDD8-activating enzyme (NAE) inhibitor, pevonedistat, and to investigate pevonedistat pharmacokinetics and pharmacodynamics in patients with acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). Pevonedistat was administered via a 60-min intravenous infusion on days 1, 3 and 5 (schedule A, n = 27), or days 1, 4, 8 and 11 (schedule B, n = 26) every 21-days. Dose escalation proceeded using a standard '3 + 3' design. Responses were assessed according to published guidelines. The MTD for schedules A and B were 59 and 83 mg/m(2) , respectively. On schedule A, hepatotoxicity was dose limiting. Multi-organ failure (MOF) was dose limiting on schedule B. The overall complete (CR) and partial (PR) response rate in patients treated at or below the MTD was 17% (4/23, 2 CRs, 2 PRs) for schedule A and 10% (2/19, 2 PRs) for schedule B. Pevonedistat plasma concentrations peaked after infusion followed by elimination in a biphasic pattern. Pharmacodynamic studies of biological correlates of NAE inhibition demonstrated target-specific activity of pevonedistat. In conclusion, administration of the first-in-class agent, pevonedistat, was feasible in patients with MDS and AML and modest clinical activity was observed.

Pharmacokinetics/pharmacodynamics of ivosidenib in advanced IDH1-mutant cholangiocarcinoma: findings from the phase III ClarIDHy study.

PURPOSE: Report pharmacokinetic (PK)/pharmacodynamic (PD) findings from the phase III ClarIDHy study and any association between PK/PD parameters and treatment outcomes in this population. METHODS: Patients with mutant isocitrate dehydrogenase 1 (mIDH1) advanced cholangiocarcinoma were randomized at a 2:1 ratio to receive ivosidenib or matched placebo. Crossover from placebo to ivosidenib was permitted at radiographic disease progression. Blood samples for PK/PD analyses, a secondary endpoint, were collected pre-dose and up to 4 h post-dose on day (D) 1 of cycles (C) 1 - 2, pre-dose and 2 h post-dose on D15 of C1 - 2, and pre-dose on D1 from C3 onwards. Plasma ivosidenib and D-2-hydroxyglutarate (2-HG) were measured using liquid chromatography-tandem mass spectrometry. All clinical responses were centrally reviewed previously. RESULTS: PK/PD analysis was available for samples from 156 ivosidenib-treated patients. Ivosidenib was absorbed rapidly following single and multiple oral doses (time of maximum observed plasma concentration [Tmax] of 2.63 and 2.07 h, respectively). Ivosidenib exposure was higher at C2D1 than after a single dose, with low accumulation. In ivosidenib-treated patients, mean plasma 2-HG concentration was reduced from 1108 ng/mL at baseline to 97.7 ng/mL at C2D1, close to levels previously observed in healthy individuals. An average 2-HG inhibition of 75.0% was observed at steady state. No plasma 2-HG decreases were seen with placebo. Plasma 2-HG reductions were observed in ivosidenib-treated patients irrespective of best overall response (progressive disease, or partial response and stable disease). CONCLUSION: Once-daily ivosidenib 500 mg has a favorable PK/PD profile, attesting the 2-HG reduction mechanism of action and, thus, positive outcomes in treated patients with advanced mIDH1 cholangiocarcinoma. CLINICAL TRIAL REGISTRATION: NCT02989857 Registered February 20, 2017.

Semiparametric Bayesian local functional models for diffusion tensor tract statistics.

We propose a semiparametric Bayesian local functional model (BFM) for the analysis of multiple diffusion properties (e.g., fractional anisotropy) along white matter fiber bundles with a set of covariates of interest, such as age and gender. BFM accounts for heterogeneity in the shape of the fiber bundle diffusion properties among subjects, while allowing the impact of the covariates to vary across subjects. A nonparametric Bayesian LPP2 prior facilitates global and local borrowings of information among subjects, while an infinite factor model flexibly represents low-dimensional structure. Local hypothesis testing and credible bands are developed to identify fiber segments, along which multiple diffusion properties are significantly associated with covariates of interest, while controlling for multiple comparisons. Moreover, BFM naturally group subjects into more homogeneous clusters. Posterior computation proceeds via an efficient Markov chain Monte Carlo algorithm. A simulation study is performed to evaluate the finite sample performance of BFM. We apply BFM to investigate the development of white matter diffusivities along the splenium of the corpus callosum tract and the right internal capsule tract in a clinical study of neurodevelopment in new born infants.

Asia-inclusive global development of pevonedistat: Clinical pharmacology and translational research enabling a phase 3 multiregional clinical trial.

The investigational NEDD8-activating enzyme inhibitor pevonedistat is being evaluated in combination with azacitidine versus single-agent azacitidine in patients with higher-risk myelodysplastic syndrome (higher-risk MDS), higher-risk chronic myelomonocytic leukemia (higher-risk CMML), or low-blast acute myeloid leukemia (AML) in a Phase 3 trial PANTHER. To support Asia-inclusive global development, we applied multiregional clinical trial (MRCT) principles of the International Conference on Harmonisation E17 guidelines by evaluating similarity in drug-related and disease-related intrinsic and extrinsic factors. A PubMed literature review (January 2000-November 2019) supported similarity in epidemiology of higher-risk MDS, AML, and CMML in Western and East Asian populations. Furthermore, the treatment of MDS/AML was similar in both East Asian and Western regions, with the same dose of azacitidine being the standard of care. Median overall survival in MDS following azacitidine treatment was generally comparable across regions, and the types and frequencies of molecular alterations in AML and MDS were comparable. Dose-escalation studies established the same maximum tolerated dose of pevonedistat in combination with azacitidine in Western and East Asian populations. Pevonedistat clearance was similar across races. Taken together, conservation of drug-related and disease-related intrinsic and extrinsic factors supported design of an Asia-inclusive Phase 3 trial and a pooled East Asian region. A sample size of ~ 30 East Asian patients (of ~ 450 randomized) was estimated as needed to demonstrate consistency in efficacy relative to the global population. This analysis is presented as an exemplar to illustrate application of clinical pharmacology and translational science principles in designing Asia-inclusive MRCTs. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Azacitidine is the standard of care for myelodysplastic syndromes/low-blast acute myeloid leukemia (AML) across Western and East Asian patients. The first-in-class small-molecule inhibitor of NEDD8-activating enzyme, pevonedistat, has been investigated as a single agent in multiple studies of hematologic and nonhematologic malignancies and in combination with azacitidine in elderly patients with untreated AML. WHAT QUESTION DID THIS STUDY ADDRESS? By applying clinical pharmacology and translational science and International Conference on Harmonisation E17 principles, this study designed an East Asian-inclusive global pivotal Phase 3 trial of pevonedistat, taking into consideration drug-related and disease-related intrinsic and extrinsic factors. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? These analyses provide scientific rationale for Asia-inclusive globalization of the pivotal, Phase 3 PANTHER trial and for pooling clinical data across the East Asian region for assessing consistency in efficacy. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? We developed a framework to facilitate efficient global clinical development of investigational therapies for rare cancers and orphan diseases in Asia-inclusive multiregional clinical trials.

Model-Based Meta-Analysis for Multiple Myeloma: A Quantitative Drug-Independent Framework for Efficient Decisions in Oncology Drug Development.

The failure rate for phase III trials in oncology is high; quantitative predictive approaches are needed. We developed a model-based meta-analysis (MBMA) framework to predict progression-free survival (PFS) from overall response rates (ORR) in relapsed/refractory multiple myeloma (RRMM), using data from seven phase III trials. A Bayesian analysis was used to predict the probability of technical success (PTS) for achieving desired phase III PFS targets based on phase II ORR data. The model demonstrated a strongly correlated (R2 = 0.84) linear relationship between ORR and median PFS. As a representative application of the framework, MBMA predicted that an ORR of ∼66% would be needed in a phase II study of 50 patients to achieve a target median PFS of 13.5 months in a phase III study. This model can be used to help estimate PTS to achieve gold-standard targets in a target product profile, thereby enabling objectively informed decision-making.

Randomized, double-blind, placebo-controlled phase III study of ixazomib plus lenalidomide-dexamethasone in patients with relapsed/refractory multiple myeloma: China Continuation study.

BACKGROUND: The China Continuation study was a separate regional expansion of the global, double-blind, placebo-controlled, randomized phase III TOURMALINE-MM1 study of ixazomib plus lenalidomide-dexamethasone (Rd) in patients with relapsed/refractory multiple myeloma (RRMM) following one to three prior therapies. METHODS: Patients were randomized (1:1) to receive ixazomib 4.0 mg or placebo on days 1, 8, and 15, plus lenalidomide 25 mg on days 1-21 and dexamethasone 40 mg on days 1, 8, 15, and 22, in 28-day cycles. Randomization was stratified according to number of prior therapies, disease stage, and prior proteasome inhibitor exposure. The primary endpoint was progression-free survival (PFS). In total, 115 Chinese patients were randomized (57 ixazomib-Rd, 58 placebo-Rd). RESULTS: At the preplanned final analysis for PFS, after median PFS follow-up of 7.4 and 6.9 months, respectively, PFS was improved with ixazomib-Rd versus placebo-Rd (median 6.7 vs 4.0 months; HR 0.598; p = 0.035). At the preplanned final analysis of overall survival (OS), after median follow-up of 20.2 and 19.1 months, respectively, OS was improved with ixazomib-Rd versus placebo-Rd (median 25.8 vs 15.8 months; HR 0.419; p = 0.001). On the ixazomib-Rd and placebo-Rd arms, respectively, 38 (67%) and 43 (74%) patients reported grade ≥3 adverse events (AEs), 19 (33%) and 18 (31%) reported serious AEs, and 4 (7%) and 5 (9%) died on-study. The most frequent grade 3/4 AEs were thrombocytopenia (18%/7% vs 14%/5%), neutropenia (19%/5% vs 19%/2%), and anemia (12%/0 vs 26%/2%). CONCLUSIONS: This study demonstrated that PFS and OS were significantly improved with ixazomib-Rd versus placebo-Rd, with limited additional toxicity, in patients with RRMM. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01564537.

Phase I Study of the Novel Investigational NEDD8-Activating Enzyme Inhibitor Pevonedistat (MLN4924) in Patients with Relapsed/Refractory Multiple Myeloma or Lymphoma.

PURPOSE: Evaluate the safety, pharmacokinetic profile, pharmacodynamic effects, and antitumor activity of the first-in-class investigational NEDD8-activating enzyme (NAE) inhibitor pevonedistat (TAK-924/MLN4924) in patients with relapsed/refractory lymphoma or multiple myeloma. EXPERIMENTAL DESIGN: Patients with relapsed/refractory myeloma (n = 17) or lymphoma (n = 27) received intravenous pevonedistat 25 to 147 mg/m(2) on days 1, 2, 8, 9 (schedule A; n = 27) or 100 to 261 mg/m(2) on days 1, 4, 8, 11 (schedule B; n = 17) of 21-day cycles. RESULTS: Maximum tolerated doses were 110 mg/m(2) (schedule A) and 196 mg/m(2) (schedule B). Dose-limiting toxicities included febrile neutropenia, transaminase elevations, muscle cramps (schedule A), and thrombocytopenia (schedule B). Common adverse events included fatigue and nausea. Common grade ≥3 events were anemia (19%; schedule A), and neutropenia and pneumonia (12%; schedule B). Clinically significant myelosuppression was uncommon. There were no treatment-related deaths. Pevonedistat pharmacokinetics exhibited a biphasic disposition phase and approximate dose-proportional increases in systemic exposure. Consistent with the short mean elimination half-life of approximately 8.5 hours, little-to-no drug accumulation in plasma was seen after multiple dosing. Pharmacodynamic evidence of NAE inhibition included increased skin levels of CDT-1 and NRF-2 (substrates of NAE-dependent ubiquitin ligases), and increased NRF-2-regulated gene transcript levels in whole blood. Pevonedistat-NEDD8 adduct was detected in bone marrow aspirates, indicating pevonedistat target engagement in the bone marrow compartment. Three lymphoma patients had partial responses; 30 patients achieved stable disease. CONCLUSIONS: Pevonedistat demonstrated anticipated pharmacodynamic effects in the clinical setting, a tolerable safety profile, and some preliminary evidence that may be suggestive of the potential for activity in relapsed/refractory lymphoma.

Interleukin-1beta induces beta-calcitonin gene-related peptide secretion in human type II alveolar epithelial cells.

Calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide mainly present in sensory nerve fibers, which is present in almost all organs, but it is also found in cultured rat type II alveolar epithelial cells (AEII). Our data have previously shown that CGRP may play an important role in inflammation as an immunomodulator. Proinflammatory factor IL-1beta induces CGRP release from neuron-derived sources. However, whether IL-1beta can induce CGRP secretion from a nonneural source, AEII cells, is not known. In the present study, we demonstrated that human AEII A549 cells expressed beta-CGRP, and IL-1beta (0.001-50 ng/ml) directly increased CGRP secretion from these cells in a time- and concentration-dependent manner. The mRNA level of beta-CGRP was also elevated by IL-1beta (1 ng/ml). In addition, we found that IL-1beta-induced CGRP production was mediated through the PKC-p38 mitogen-activated protein (MAP) kinase-NF-kappaB signaling pathway. Furthermore, IL-1beta-induced chemokines MCP-1 and IL-8 were partially inhibited by exogenous hCGRP (0.1-10 nM) and potentiated by hCGRP8-37 (0.1-10 nM), a CGRP1-receptor antagonist. In addition, the CGRP-inhibited chemokine effect was partially reduced by Rp-cAMP, a cAMP-PK inhibitor. These results suggest that AEII-derived CGRP may act in an autocrine/paracrine mode and play an important inhibitory role in the local area in lung inflammatory diseases.

Semiparametric Bayes local additive models for longitudinal data.

In longitudinal data analysis, there is great interest in assessing the impact of predictors on the time-varying trajectory in a response variable. In such settings, an important issue is to account for heterogeneity in the shape of the trajectory among subjects, while allowing the impact of the predictors to vary across subjects. We propose a flexible semiparametric Bayes approach for addressing this issue relying on a local partition process prior, which allows flexible local borrowing of information across subjects. Local hypothesis testing and credible bands are developed for the identification of time windows across which a predictor has a significant impact, while adjusting for multiple comparisons. Posterior computation proceeds via an efficient MCMC algorithm using the exact block Gibbs sampler. The methods are assessed using simulation studies and applied to a yeast cell-cycle gene expression data set.

Neuroinflammation, hyperphosphorylated tau, diffuse amyloid plaques, and down-regulation of the cellular prion protein in air pollution exposed children and young adults.

Air pollution exposures have been linked to neuroinflammation and neuropathology. Autopsy samples of the frontal cortex from control (n = 8) and pollution-exposed (n = 35) children and young adults were analyzed by RT-PCR (n = 43) and microarray analysis (n = 12) for gene expression changes in oxidative stress, DNA damage signaling, NFκB signaling, inflammation, and neurodegeneration pathways. The effect of apolipoprotein E (APOE) genotype on the presence of protein aggregates associated with Alzheimer's disease (AD) pathology was also explored. Exposed urbanites displayed differential (>2-fold) regulation of 134 genes. Forty percent exhibited tau hyperphosphorylation with pre-tangle material and 51% had amyloid-ß (Aß) diffuse plaques compared with 0% in controls. APOE4 carriers had greater hyperphosphorylated tau and diffuse Aß plaques versus E3 carriers (Q = 7.82, p = 0.005). Upregulated gene network clusters included IL1, NFκB, TNF, IFN, and TLRs. A 15-fold frontal down-regulation of the prion-related protein (PrP(C)) was seen in highly exposed subjects. The down-regulation of the PrP(C) is critical given its important roles for neuroprotection, neurodegeneration, and mood disorder states. Elevation of indices of neuroinflammation and oxidative stress, down-regulation of the PrP(C) and AD-associated pathology are present in young megacity residents. The inducible regulation of gene expression suggests they are evolving different mechanisms in an attempt to cope with the constant state of inflammation and oxidative stress related to their environmental exposures. Together, these data support a role for air pollution in CNS damage and its impact upon the developing brain and the potential etiology of AD and mood disorders.