Background: Marginal zone lymphoma (MZL) is a group of indolent B-cell lymphomas that accounts for ~10% of non-Hodgkin's lymphomas (NHLs) in the US. Ibrutinib (ibr) is a first-in-class, once-daily ...inhibitor of Bruton's tyrosine kinase (BTK), which is the only US FDA approved therapy for patients (pts) with MZL who require systemic therapy and have received ≥1 prior anti-CD20-based therapy. A first-in-human study of ibr in various B-cell malignancies demonstrated that a fixed continuous dose of 560 mg was well-tolerated and led to full target occupancy; this dose was, therefore, selected for phase 2 studies (Advani, JCO 2013). This phase 2 study of single-agent ibr in pts with relapsed/refractory (R/R) MZL reported (median follow-up of 19.4 mo) an overall response rate (ORR) of 48%, clinical benefit rate (CBR) of 83%, median progression-free survival (PFS) of 14.2 mo with median overall survival (OS) and duration of response (DOR) not reached (NR), and median time to initial response of 4.5 mo. ORRs did not significantly differ between MZL subtypes (splenic, 54%; nodal, 41%; extranodal, 50%; Noy, Blood 2017). Ibr was also found to be safe and well-tolerated by these pts with R/R MZL. Here, we report additional analyses of clinical outcomes by prior therapy, MZL subtype, as well as baseline mutation profiling.
Methods: This phase 2 study enrolled pts with R/R MZL receiving ≥1 prior treatment for MZL including ≥1 CD20-containing regimen. Pts received oral ibr 560 mg once daily for up to 3 years or until disease progression or unacceptable toxicity. The primary endpoint was ORR (by IRC), and secondary endpoints included DOR, PFS, and OS. We report clinical outcomes for 60 IRC-evaluable pts based on prior therapy (rituximab only RTX or RTX-based chemoimmunotherapy RTX-CIT) and MZL subtype. A cancer specific targeted gene panel was used to perform mutation profiling on baseline tumor samples. Correlations of gene mutations with known clinical relevance in MZL to DOR, PFS, OS, and maximum change from baseline in sum of product diameters (SPD) were analyzed.
Results: Median age of the 63 enrolled pts with R/R MZL was 66 y (range, 30-92). Pts had a median of 2 prior therapies (range, 1-9). For the 16 (25%) pts treated with prior RTX, median number of prior therapies was 1 (range, 1-4); 39 (62%) pts who received prior RTX-CIT had median 2 prior therapies (range 1-9). Of 14 pts refractory to their last prior therapy at enrollment, 8 (57%) were in the prior RTX group compared with 4 (29%) in the prior RTX-CIT group. Response rates for the 60 evaluable pts by prior therapy are summarized in Table 1. ORR for the prior RTX and RTX-CIT groups were 69% and 46%, respectively. The response rates for the prior RTX vs. prior RTX-CIT groups were CR: 6% vs 3%; PR: 63% vs 44%; SD: 25% vs 36%; and PD: 6% vs 13% with a CBR of 94% vs 82%. A waterfall plot of maximum change in tumor burden by prior therapy is presented in the Figure (median change: RTX, −69%; RTX-CIT, −59%). The median time to initial response was 2.8 mo for prior RTX and 5.6 mo for prior RTX-CIT. Median DOR was not reached in either subgroup; the estimated 18-mo DOR rate was 61% for prior RTX and 63% for prior RTX-CIT. The estimated18-mo PFS rate was 68% for prior RTX, and 35% for prior RTX-CIT. The estimated 18-mo OS was 86% for prior RTX, and 82% for prior RTX-CIT. The time to initial response, 18-mo DOR, and 18-mo PFS for pts by MZL subtypes are shown in Table 2.
Baseline gene mutation profiling of tumor tissues from 41 pts showed that mutations in the BCR-NFkB signaling pathway, MYD88 and TNFAIP3 (A20), positively correlated with response (MYD88 with PFS and TNFAIP3 with SPD). Mutations in NOTCH2 and KMT2D (MLL2), which are not involved in BCR-NFkB signaling, were negatively correlated with DOR.
Conclusions: Single-agent ibr showed a trend toward higher ORR and median PFS, and a faster response in R/R MZL pts who previously received RTX when compared with those who received RTX-CIT. These results could be influenced by the characteristics of pts in each subgroup. In all cases, continued treatment with ibr resulted in increased clinical benefit. Mutations in the BCR-NFkB signaling pathway, (MYD88 and TNFAIP3), were positively correlated with response and mutations in NOTCH2 and KMT2D were negatively correlated with response. These results provide evidence of the efficacy of single-agent ibr in pts previously exposed to RTX monotherapy and support the use of ibr as a chemo-free option for MZL.
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Chen:Merck: Consultancy, Other: travel expenses ; Genentech/Roche: Consultancy, Honoraria, Other: travel expenses, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: travel expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Research Funding; Millennium: Honoraria, Research Funding, Speakers Bureau. Thieblemont:Roche: Consultancy, Honoraria, Research Funding; Janssen: Consultancy; Bayer: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Cellectis: Speakers Bureau; Sanofi: Other: travel expenses. Martin:Teva: Research Funding; Janssen: Consultancy, Honoraria, Other: travel expenses; Celgene: Consultancy; Genentech: Consultancy; Novartis: Consultancy; Gilead: Consultancy, Other: travel expenses. Flowers:National Institutes Of Health: Research Funding; Spectrum: Consultancy; Bayer: Consultancy; OptumRx: Consultancy; Prime Oncology: Research Funding; V Foundation: Research Funding; Clinical Care Options: Research Funding; Gilead: Consultancy; Eastern Cooperative Oncology Group: Research Funding; Janssen Pharmaceutical: Research Funding; Research to Practice: Research Funding; Celgene: Consultancy, Research Funding; Millennium/Takeda: Research Funding; Genentech/Roche: Consultancy, Research Funding; Onyx: Research Funding; National Cancer Institute: Research Funding; Acerta: Research Funding; Abbvie: Consultancy, Research Funding; TG Therapeutics: Research Funding; Burroughs Welcome Fund: Research Funding; Educational Concepts: Research Funding; Infinity: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Seattle Genetics: Consultancy. Morschhauser:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Servier: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria; Gilead: Consultancy; Roche: Consultancy, Honoraria. Collins:Celleron: Consultancy; Roche: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb: Research Funding; ADC Therapeutics: Research Funding; Takeda: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria; Amgen: Research Funding; Celgene: Research Funding; Pfizer: Consultancy, Honoraria. Ma:Novartis: Consultancy, Research Funding; Genentech: Consultancy, Speakers Bureau; AbbVie: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding, Speakers Bureau; Acerta: Research Funding; Gilead: Consultancy, Research Funding, Speakers Bureau. Coleman:Gilead: Consultancy, Research Funding, Speakers Bureau; Merck: Research Funding; AbbVie: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Millenium: Research Funding; Janssen Oncology: Research Funding. Peles:Onyx: Honoraria, Other: travel expenses, Speakers Bureau; Novartis: Honoraria, Other: travel expenses, Speakers Bureau; Celgene: Honoraria, Other: travel expenses, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: travel expenses, Speakers Bureau; SGN: Honoraria, Other: travel expenses, Speakers Bureau; Florida Cancer Specialists: Employment, Equity Ownership. Smith:Sharp: Research Funding; Seattle Genetics: Research Funding; Portola Pharmaceuticals: Research Funding; Merck: Research Funding; Acerta: Research Funding; Genentech: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Dohme Corp: Research Funding; Janssen: Research Funding. Barrientos:Gilead: Consultancy, Research Funding; Janssen: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding. Smith:AbbVie: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Employment, Other: travel expenses. Munneke:AbbVie: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Employment, Other: travel expenses. Wu:Pharmacyclics LLC, an AbbVie Company: Employment, Patents & Royalties; AbbVie: Equity Ownership. Cheung:AbbVie: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Employment, Patents & Royalties; Eli Lilly: Equity Ownership. Kwei:Pharmacyclics LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership; Gilead Sciences: Employment, Equity Ownership. Samakoglu:Pharmacyclics LLC, an AbbVie Company: Employment. Arango-Hisijara:Pharmacyclics LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Dimery:AbbVie: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Employment. Noy:Pharmacyclics LLC, an AbbVie Company: Honoraria, Other: Travel, Accommodation, Expenses, Research Funding, Speakers Bureau.
Sensory neurons provide organisms with data about the world in which they live, for the purpose of successfully exploiting their environment. The consequences of sensory perception are not simply ...limited to decision-making behaviors; evidence suggests that sensory perception directly influences physiology and aging, a phenomenon that has been observed in animals across taxa. Therefore, understanding the neural mechanisms by which sensory input influences aging may uncover novel therapeutic targets for aging-related physiologies. In this review, we examine different perceptive experiences that have been most clearly linked to aging or age-related disease: food perception, social perception, time perception, and threat perception. For each, the sensory cues, receptors, and or pathways that influence aging as well as the individual or groups of neurons involved, if known, are discussed. We conclude with general thoughts about the potential impact of this line of research on human health and aging.
Abstract Falls in Parkinson's disease (PD) are common and frequently devastating. Falls prevention is an urgent priority, but there is no accepted program that specifically addresses the risk profile ...in PD. Therefore, we aimed to provide consensus-based clinical practice recommendations that systematically address potential fall risk factors in PD. We developed an overview of both generic (age-related) and PD-specific factors. For each factor, we specified: best method of ascertainment; disciplines that should be involved in assessment and treatment; and which interventions could be engaged. Using a web-based tool, we asked 27 clinically active professionals from multiple relevant disciplines to evaluate this overview. The revised version was subsequently reviewed by 12 experts. Risk factors and their associated interventions were included in the final set of recommendations when at least 66% of reviewing experts agreed. These recommendations included 31 risk factors. Nearly all required a multidisciplinary team approach, usually involving a neurologist and PD-nurse specialist. Finally, the expert panel proposed to first identify the specific fall type and to tailor screening and treatment accordingly. A routine evaluation of all risk factors remains reserved for high-risk patients without prior falls, or for patients with seemingly unexplained falls. In conclusion, this project produced a set of consensus-based clinical practice recommendations for the examination and management of falls in PD. These may be used in two ways: for pragmatic use in current clinical practice, pending further evidence; and as the active intervention in clinical trials, aiming to evaluate the effectiveness and cost-effectiveness of large scale implementation.
To assess the safety and tolerability of a vandetanib-eluting radiopaque embolic (BTG-002814) for transarterial chemoembolization (TACE) in patients with resectable liver malignancies.
The VEROnA ...clinical trial was a first-in-human, phase 0, single-arm, window-of-opportunity study. Eligible patients were aged ≥18 years and had resectable hepatocellular carcinoma (HCC) (Child-Pugh A) or metastatic colorectal cancer (mCRC). Patients received 1 mL of BTG-002814 transarterially (containing 100 mg of vandetanib) 7-21 days prior to surgery. The primary objectives were to establish the safety and tolerability of BTG-002814 and determine the concentrations of vandetanib and the N-desmethyl vandetanib metabolite in the plasma and resected liver after treatment. Biomarker studies included circulating proangiogenic factors, perfusion computed tomography, and dynamic contrast-enhanced magnetic resonance imaging.
Eight patients were enrolled: 2 with HCC and 6 with mCRC. There was 1 grade 3 adverse event (AE) before surgery and 18 after surgery; 6 AEs were deemed to be related to BTG-002814. Surgical resection was not delayed. Vandetanib was present in the plasma of all patients 12 days after treatment, with a mean maximum concentration of 24.3 ng/mL (standard deviation ± 13.94 ng/mL), and in resected liver tissue up to 32 days after treatment (441-404,000 ng/g). The median percentage of tumor necrosis was 92.5% (range, 5%-100%). There were no significant changes in perfusion imaging parameters after TACE.
BTG-002814 has an acceptable safety profile in patients before surgery. The presence of vandetanib in the tumor specimens up to 32 days after treatment suggests sustained anticancer activity, while the low vandetanib levels in the plasma suggest minimal release into the systemic circulation. Further evaluation of this TACE combination is warranted in dose-finding and efficacy studies.
Transarterial chemoembolization (TACE) is the current standard of care for patients with intermediate-stage hepatocellular carcinoma (HCC) and is also a treatment option for patients with liver ...metastases from colorectal cancer. However, TACE is not a curative treatment, and tumor progression occurs in more than half of the patients treated. Despite advances and technical refinements of TACE, including the introduction of drug-eluting beads-TACE, the clinical efficacy of TACE has not been optimized, and improved arterial therapies are required.
The primary objectives of the VEROnA study are to evaluate the safety and tolerability of vandetanib-eluting radiopaque embolic beads (BTG-002814) in patients with resectable liver malignancies and to determine concentrations of vandetanib and the N-desmethyl metabolite in plasma and resected liver following treatment with BTG-002814.
The VEROnA study is a first-in-human, open-label, single-arm, phase 0, window-of-opportunity study of BTG-002814 (containing 100 mg vandetanib) delivered transarterially, 7 to 21 days before surgery in patients with resectable liver malignancies. Eligible patients have a diagnosis of colorectal liver metastases, or HCC (Childs Pugh A), diagnosed histologically or radiologically, and are candidates for liver surgery. All patients are followed up for 28 days following surgery. Secondary objectives of this study are to evaluate the anatomical distribution of BTG-002814 on noncontrast-enhanced imaging, to evaluate histopathological features in the surgical specimen, and to assess changes in blood flow on dynamic contrast-enhanced magnetic resonance imaging following treatment with BTG-002814. Exploratory objectives of this study are to study blood biomarkers with the potential to identify patients likely to respond to treatment and to correlate the distribution of BTG-002814 on imaging with pathology by 3-dimensional modeling.
Enrollment for the study was completed in February 2019. Results of a planned interim analysis were reviewed by a safety committee after the first 3 patients completed follow-up. The recommendation of the committee was to continue the study without any changes to the dose or trial design, as there were no significant unexpected toxicities related to BTG-002814.
The VEROnA study is studying the feasibility of administering BTG-002814 to optimize the use of this novel technology as liver-directed therapy for patients with primary and secondary liver cancer.
ClinicalTrial.gov NCT03291379; https://clinicaltrials.gov/ct2/show/NCT03291379.
DERR1-10.2196/13696.
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