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1.
Cancer Immunol Res ; 12(7): 921-943, 2024 Jul 02.
Article in English | MEDLINE | ID: mdl-38683145

ABSTRACT

The prognosis of patients with acute myeloid leukemia (AML) is limited, especially for elderly or unfit patients not eligible for hematopoietic stem cell (HSC) transplantation. The disease is driven by leukemic stem cells (LSCs), which are characterized by clonal heterogeneity and resistance to conventional therapy. These cells are therefore believed to be a major cause of progression and relapse. We designed MP0533, a multispecific CD3-engaging designed ankyrin repeat protein (DARPin) that can simultaneously bind to three antigens on AML cells (CD33, CD123, and CD70), aiming to enable avidity-driven T cell-mediated killing of AML cells coexpressing at least two of the antigens. In vitro, MP0533 induced selective T cell-mediated killing of AML cell lines, as well as patient-derived AML blasts and LSCs, expressing two or more target antigens, while sparing healthy HSCs, blood, and endothelial cells. The higher selectivity also resulted in markedly lower levels of cytokine release in normal human blood compared to single antigen-targeting T-cell engagers. In xenograft AML mice models, MP0533 induced tumor-localized T-cell activation and cytokine release, leading to complete eradication of the tumors while having no systemic adverse effects. These studies show that the multispecific-targeting strategy used with MP0533 holds promise for improved selectivity toward LSCs and efficacy against clonal heterogeneity, potentially bringing a new therapeutic option to this group of patients with a high unmet need. MP0533 is currently being evaluated in a dose-escalation phase 1 study in patients with relapsed or refractory AML (NCT05673057).


Subject(s)
Leukemia, Myeloid, Acute , Neoplastic Stem Cells , T-Lymphocytes , Humans , Leukemia, Myeloid, Acute/immunology , Leukemia, Myeloid, Acute/therapy , Leukemia, Myeloid, Acute/pathology , Animals , Mice , Neoplastic Stem Cells/immunology , Neoplastic Stem Cells/metabolism , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Interleukin-3 Receptor alpha Subunit/immunology , Interleukin-3 Receptor alpha Subunit/metabolism , Xenograft Model Antitumor Assays , Sialic Acid Binding Ig-like Lectin 3/metabolism , Sialic Acid Binding Ig-like Lectin 3/immunology , CD3 Complex/immunology , Cell Line, Tumor , Cytotoxicity, Immunologic
2.
Can Pharm J (Ott) ; 156(2): 85-93, 2023.
Article in English | MEDLINE | ID: mdl-36969304

ABSTRACT

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely prescribed for management of pain and inflammation. However, these medications are associated with adverse outcomes such as dyspepsia and acute myocardial infarction, especially with long-term uses. Objective: We sought to determine the effect of a pharmacist-led deprescribing intervention on oral NSAID use among patients in federal custody. Methods: Clinical pharmacists from Correctional Services Canada (CSC) conducted a prospective case series of adult patients with chronic noncancer pain who were on long-term NSAIDs (defined as >90 days supply in the past 120 days) in 3 CSC institutions in British Columbia, Canada. CSC clinical pharmacists met with patients to perform medication reviews and identify drug-related problems, with a focus on analgesic therapy. Pharmacist-led interventions were implemented in consultation with the primary care team to address these drug-related problems. Patient progress was monitored weekly for 3 months. Function, quality of life and pain severity scores (modified SPAASMS, Patient-Specific Functional Scale [PSFS] and visual analog scale [VAS] scores) were compared at baseline, 6 weeks and 3 months postintervention. Patient satisfaction survey results were also collected at 3 months. Results: A total of 53 patients received clinical pharmacist interventions. Modified SPAASMS, PSFS and VAS scores were collected at baseline, 6 weeks and 3 months from 38 patients (some were lost to follow-up when released back into the community). All 38 patients demonstrated clinically significant improvements to all 3 pain scales at 3 months (mean SPAASMS scores decreased by 7 points, mean PSFS scores increased by 2 points, mean VAS scores decreased by 2 points). Twenty-four of 31 patients who completed the patient satisfaction survey agreed that their overall health and well-being improved because of the visit they received from the pharmacist. Conclusion: Clinical pharmacist-led interventions in CSC have shown to reduce oral NSAID use as well as contribute positively to patient pain scores.

4.
PLoS One ; 17(1): e0262151, 2022.
Article in English | MEDLINE | ID: mdl-35030185

ABSTRACT

BACKGROUND: Limited information is available regarding real-world treatment patterns and their effectiveness and safety in patients with locally advanced basal cell carcinoma, including patients not typically represented in clinical trials. The purpose of the current study was to describe how clinicians diagnose and treat locally advanced basal cell carcinoma in the United States. METHODS: This prospective, multicenter, observational registry study included patients with newly diagnosed, Hedgehog pathway inhibitor-naive locally advanced basal cell carcinoma without basal cell carcinoma nevus syndrome (n = 433) treated at 75 US academic and community practices, including dermatology, Mohs surgery, and medical oncology sites. The main outcomes of this study were treatment patterns and associated effectiveness and safety for patients with locally advanced basal cell carcinoma in real-world settings. RESULTS: Determination of locally advanced basal cell carcinoma was mainly based on lesion size (79.6% of patients), histopathology (54.3%), extent of involvement (49.0%), and location (46.2%). Within 90 days of determination of locally advanced disease, 115 patients (26.6%) received vismodegib, 251 (58.0%) received surgery/other (non-vismodegib) treatment, and 67 (15.5%) had not yet received treatment (observation). Vismodegib-treated patients had a higher prevalence of high-risk clinical features predictive for locoregional recurrence than those with non-vismodegib treatment or observation. Clinical response rate was 85.1% with vismodegib and 94.9% with non-vismodegib treatment (primarily surgery). The most common adverse events with vismodegib were ageusia/dysgeusia, muscle spasms, alopecia, and weight loss. Rates of cutaneous squamous cell cancers were comparable between vismodegib and non-vismodegib treatment. CONCLUSIONS: This prospective observational study offers insight on real-world practice, treatment selection, and outcomes for a nationally representative sample of US patients with locally advanced basal cell carcinoma. For patients with lesions that were not amenable to surgery, vismodegib treatment was associated with effectiveness and safety that was consistent with that observed in clinical trials.


Subject(s)
Anilides/therapeutic use , Antineoplastic Agents/therapeutic use , Carcinoma, Basal Cell/drug therapy , Pyridines/therapeutic use , Adult , Aged , Aged, 80 and over , Ageusia/etiology , Anilides/adverse effects , Antineoplastic Agents/adverse effects , Carcinoma, Basal Cell/pathology , Female , Humans , Male , Middle Aged , Neoplasm Recurrence, Local , Neoplasm Staging , Prospective Studies , Pyridines/adverse effects , Registries , Treatment Outcome , Young Adult
5.
J Manag Care Spec Pharm ; 27(5): 615-624, 2021 May.
Article in English | MEDLINE | ID: mdl-33586513

ABSTRACT

BACKGROUND: In the randomized phase 3 GALLIUM trial, first-line treatment with obinutuzumab (GA101; G) plus chemotherapy (G + chemo) resulted in superior progression-free survival (PFS) compared with rituximab plus chemotherapy (R + chemo) for patients with follicular lymphoma (FL). G + chemo was found to be cost-effective when compared with R + chemo (incremental cost-effectiveness ratio [ICER] of approximately $2,300 per quality-adjusted life-year [QALY] gained). Two rituximab biosimilars, rituximab-abbs (Ra) and rituximab-pvvr (Rp), have been approved by the FDA for use in this setting. However, the cost-effectiveness of G + chemo versus Ra + chemo and Rp + chemo has not yet been estimated. OBJECTIVE: To evaluate the cost-effectiveness of G + chemo versus Ra + chemo and Rp + chemo in the first-line treatment of FL. METHODS: We adapted an existing Markov model that compared G + chemo with R + chemo, using investigator-assessed PFS and postprogression survival data from the GALLIUM trial to model overall survival. All patients in the study received induction chemoimmunotherapy with either G + chemo or R + chemo, with responders then receiving obinutuzumab or rituximab maintenance therapy for 2 years or until disease progression. We assumed that the efficacy and safety of the rituximab biosimilars plus chemotherapy were the same as the R + chemo arm of the GALLIUM study. Drug utilization and treatment duration were also derived from GALLIUM. Health care costs were based on Medicare reimbursements, and drug costs were average sale prices for intravenous therapies or wholesale acquisition costs for oral therapies used after progression. Utility estimates were based on the GALLIUM trial data and published literature. Sensitivity analyses were conducted to assess the key drivers of the model and uncertainty in the results. Results: Treatment with G + chemo led to an increase of 0.93 QALYs relative to rituximab biosimilars plus chemotherapy (95% credible range [CR] = 0.36-1.46). The total cost of G + chemo was $191,317, whereas the total costs of Ra + chemo and Rp + chemo were $164,340 (Δ14.1%) and $169,755 (Δ11.3%), respectively, with G + chemo resulting in incremental costs of $26,978 (95% CR = $19,781-$33,119) and $21,562 (95% CR = $14,473-$28,389), respectively. The incremental total drug and administration costs were $32,678 (Δ25.4%) and $27,263 (Δ21.2%) for G + chemo versus Ra + chemo and G + chemo versus Rp + chemo, respectively. There were cost savings of $7,050 (Δ-12.4%) related to disease progression for G + chemo ($56,727) compared with Ra + chemo and Rp + chemo ($63,777). ICERs were $28,879 and $23,082 per QALY gained for G + chemo versus Ra + chemo and Rp + chemo, respectively. In probabilistic sensitivity analyses, G + chemo was cost-effective at the $50,000 and $100,000 per QALY thresholds versus both Ra + chemo (88% and 98% probabilities of cost-effectiveness, respectively) and Rp + chemo (93% and 98%, respectively). CONCLUSIONS: G + chemo is projected to be cost-effective versus rituximab biosimilars plus chemotherapy in the United States as first-line treatment for FL, driven by increased QALYs for G + chemo and cost savings from delayed disease progression. DISCLOSURES: This study was funded by Genentech, a member of the Roche Group. The study sponsor was involved in study design, data interpretation, and writing of the report. All authors approved the decision to submit the report for publication. Spencer and Guzauskas report fees from Genentech during the conduct of the study. Felizzi was employed by F. Hoffmann-La Roche at the time this study was conducted; Launonen is an employees of F. Hoffmann-La Roche. Felizzi and Launonen previously had share ownership in Novartis. Dawson and Masaquel are employees of Genentech, and they have stock options in F. Hoffmann-La Roche. Veenstra reports fees from Genentech, during the conduct of this study and outside of the submitted work. This work was presented, in part, at the AACR Virtual Meeting Advances in Malignant Lymphoma meeting (virtual; August 17-19, 2020) and the SOHO annual meeting (virtual; September 9-12, 2020).


Subject(s)
Antibodies, Monoclonal, Humanized/economics , Antineoplastic Agents, Immunological/economics , Biosimilar Pharmaceuticals/economics , Lymphoma, Follicular/drug therapy , Rituximab/economics , Cost-Benefit Analysis , Drug Costs , Humans , Markov Chains , Quality-Adjusted Life Years , United States
6.
Oncology (Williston Park) ; 35(12): 804-811, 2021 12 22.
Article in English | MEDLINE | ID: mdl-35089000

ABSTRACT

INTRODUCTION: A subcutaneous (SC) formulation of the anti-CD20 monoclonal antibody, rituximab (Rituxan), is approved in diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and chronic lymphocytic leukemia (CLL). Rituximab-SC (R-SC) has been associated with time and clinic resource savings vs the original intravenous formulation (R-IV). Insight into the resource implications of widening R-SC adoption in a US oncology setting is needed. METHODS: A single-institution, retrospective observational analysis was conducted in adult patients with DLBCL, FL, or CLL. The primary outcome measure was chair occupancy time (difference between patient room-in and room-out times). Prescribing patterns were a secondary outcome. RESULTS: Overall, 1190 patients were analyzed (treatment time frame: pre-R-SC adoption: n = 490 [41%], pre- and post R-SC adoption: n = 189 [16%], post R-SC adoption: n = 511 [43%]). Of the patients in the post-R-SC period, 374 (73%) received R-IV, 52 (10%) received R-IV and R-SC, and 85 (17%) received R-SC. When administered, R-SC reduced combination therapy chair time vs R-IV by a mean 37% (93.2 minutes; P < .001). Monotherapy (any route) reduced chair time vs combination by a mean 35.2 minutes (P < .001), with a further 40.2-minute reduction with R-SC (P < .001), a 62% (133.4-minute) total chair time savings vs R-IV. Doctors were more likely to prescribe R-SC to patients with FL than DLBCL. CONCLUSIONS: R-SC is associated with significantly reduced chair time vs R-IV in a US oncology setting. Widespread adoption would be expected to improve practice efficiency and patient access to care, and to reduce health care resource burden.


Subject(s)
Antineoplastic Agents, Immunological/administration & dosage , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Lymphoma, Follicular/drug therapy , Rituximab/administration & dosage , Humans , Immunologic Factors , Injections, Subcutaneous , Patient Care/methods , Retrospective Studies
7.
J Clin Oncol ; 39(2): 145-154, 2021 01 10.
Article in English | MEDLINE | ID: mdl-33301375

ABSTRACT

PURPOSE: A first-in-human study was performed with MP0250, a DARPin drug candidate. MP0250 specifically inhibits both vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) with the aim of disrupting the tumor microenvironment. PATIENTS AND METHODS: A multicenter, open-label, repeated-dose, phase I study was conducted to assess the safety, tolerability, and pharmacokinetics of MP0250 in 45 patients with advanced solid tumors. In the dose-escalation part, 24 patients received MP0250 as a 3-hour infusion once every 2 weeks at five different dose levels (0.5-12 mg/kg). Once the maximum tolerated dose (MTD) was established, 21 patients were treated with a 1-hour infusion (n = 13, 8 mg/kg, once every 2 weeks and n = 8, 12 mg/kg, once every 3 weeks) of MP0250 in the dose confirmation cohorts. RESULTS: In the dose-escalation cohort, patients treated with 12 mg/kg MP0250 once every 2 weeks experienced dose-limiting toxicities. Therefore, MTD was 8 mg/kg once every 2 weeks or 12 mg/kg once every 3 weeks. The most common adverse events (AEs) were hypertension (69%), proteinuria (51%), and diarrhea and nausea (both 36%); hypoalbuminemia was reported in 24% of patients. Most AEs were consistent with inhibition of the VEGF and HGF pathways. Exposure was dose-proportional and sustained throughout the dosing period for all patients (up to 15 months). The half-life was about 2 weeks. Signs of single-agent antitumor activity were observed: 1 unconfirmed partial response with a time to progression of 23 weeks and 24 patients with stable disease, with the longest duration of 72 weeks and a median duration of 18 weeks. CONCLUSION: MP0250 is a first-in-class DARPin drug candidate with suitable tolerability and appropriate pharmacokinetic properties for further development in combination with other anticancer therapies.


Subject(s)
Hepatocyte Growth Factor/antagonists & inhibitors , Neoplasms/drug therapy , Recombinant Fusion Proteins/administration & dosage , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Adult , Aged , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Cohort Studies , Dose-Response Relationship, Drug , Female , Hepatocyte Growth Factor/metabolism , Humans , Infusions, Intravenous , Male , Middle Aged , Molecular Targeted Therapy , Neoplasms/metabolism , Neoplasms/pathology , Recombinant Fusion Proteins/adverse effects , Recombinant Fusion Proteins/pharmacokinetics , Tumor Microenvironment , Vascular Endothelial Growth Factor A/metabolism , Young Adult
8.
Can J Diabetes ; 45(1): 89-95, 2021 Feb.
Article in English | MEDLINE | ID: mdl-33011131

ABSTRACT

OBJECTIVES: Our aim in this study was to assess the impact of the Mobile Diabetes Telemedicine Clinic, which serves First Nations communities in British Columbia, on clients' with diabetes condition and management. METHODS: A travelling team visits approximately 120 sites annually. Assessment of persons with diabetes includes interview, physical exam, point-of-care laboratory (glycated hemoglobin, blood glucose, lipid profile, kidney profile) and retinal fundus photographs. Nurses provide education and lifestyle, medication and wellness recommendations. The endocrinologist reviews records and provides further recommendations to primary care providers. To assess the impact at second and later visits, compared with the immediately preceding visit, we measured mean changes in body weight, glycated hemoglobin, urinary albumin:creatinine ratio and estimated glomerular filtration rate, as well as changes in proportions of clients meeting targets for blood pressure, low-density lipoprotein cholesterol, medications, smoking and physical activity. RESULTS: From 2012 to 2018, a total of 3,045 visits were completed by 1,056 clients with diabetes who attended on at least 2 occasions. Mean time since the preceding visit was 1.6 years. Mean change (after vs before) in glycated hemoglobin was 0.06 (95% confidence limit, -0.03 to 0.14), body weight 0.0 kg (-0.2 to 0.2), albumin:creatinine ratio 1.31 mg/mmol (0.27 to 2.35) and estimated glomerular filtration rate -4.8 mL/min (-6.2 to -3.4). The proportion of clients meeting both blood pressure targets (systolic <130 mmHg and diastolic <80 mmHg) increased from 25% at first visit to 33% at the second and 32% at the third or later visits (p<0.001, chi-square test). The proportion of those with low-density lipoprotein cholesterol of <2.0 mmol/L increased from 56% to 62% at the second visit and 69% at the third or later visits (p<0.001). The proportion of those taking renin-angiotensin-aldosterone system inhibitors or other antihypertensive agents and statins increased (p<0.001), and proportions decreased for smoking (p<0.001) and exercising ≥60 min/week (p=0.002). CONCLUSIONS: Weight and diabetic control were stabilized. Most management practices showed improvement.


Subject(s)
Diabetes Mellitus/therapy , Health Services, Indigenous/standards , Indigenous Peoples/statistics & numerical data , Mobile Health Units/standards , Practice Guidelines as Topic/standards , Telemedicine/methods , British Columbia/epidemiology , Diabetes Mellitus/epidemiology , Humans , Prognosis
9.
Cancer Med ; 9(20): 7537-7547, 2020 10.
Article in English | MEDLINE | ID: mdl-32860335

ABSTRACT

Real-world practice patterns and clinical outcomes in patients with follicular lymphoma (FL), including the adoption of maintenance rituximab (MR) therapy in the United States (US), have been reported in few studies since the release of the National LymphoCare Study almost a decade ago. We analyzed data from the largest integrated healthcare system in the United States, the Veterans Health Administration (VHA), to identify rates of adoption and effectiveness of MR in FL patients after first-line (1L) treatment. We identified previously untreated patients with FL in the VHA between 2006 and 2014 who achieved at least stable disease after chemoimmunotherapy or immunotherapy. Among these patients, those who initiated MR within 238 days of 1L composed the MR group, whereas those who did not were classified as the non-MR group. We examined the effect of MR on progression-free survival (PFS) and overall survival (OS). A total of 676 patients met our inclusion criteria, of whom 300 received MR. MR was associated with significant PFS (hazard ratio [HR]=0.55, P < .001) and OS (HR = 0.53, P = .005) compared to the non-MR group, after adjusting by age, sex, ethnicity, geographic region, diagnosis period, stage, grade at diagnosis, hemoglobin, lactate dehydrogenase (LDH), Charlson comorbidity index (CCI), 1L treatment regimen, and response to 1L treatment. These results suggest that in FL patients who do not experience disease progression after 1L treatment in real-world settings, MR is associated with a significant improvement in both PFS and OS. Maintenance therapy should be considered in FL patients who successfully complete and respond to 1L therapy.


Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , Lymphoma, Follicular/drug therapy , Lymphoma, Follicular/epidemiology , Rituximab/therapeutic use , Veterans Health/statistics & numerical data , Veterans , Aged , Aged, 80 and over , Antineoplastic Agents, Immunological/administration & dosage , Antineoplastic Agents, Immunological/adverse effects , Female , Humans , Kaplan-Meier Estimate , Lymphoma, Follicular/diagnosis , Lymphoma, Follicular/mortality , Maintenance Chemotherapy , Male , Middle Aged , Neoplasm Grading , Neoplasm Staging , Prognosis , Rituximab/administration & dosage , Rituximab/adverse effects , SEER Program , Treatment Outcome
10.
BioDrugs ; 34(4): 423-433, 2020 Aug.
Article in English | MEDLINE | ID: mdl-32583318

ABSTRACT

The DARPin® drug platform was established with a vision to expand the medical use of biologics beyond what was possible with monoclonal antibodies. It is based on naturally occurring ankyrin repeat domains that are typically building blocks of multifunctional human proteins. The platform allows for the generation of diverse, well-behaved, multifunctional drug candidates. Recent clinical data illustrate the favorable safety profile of the first DARPin® molecules tested in patients. With the positive phase III results of the most advanced DARPin® drug candidate, abicipar, the DARPin® drug platform is potentially about to achieve its first marketing approval. This review highlights some of the key milestones and decisions encountered when transforming the DARPin® platform from an academic concept to a biotech drug pipeline engine.


Subject(s)
Ankyrin Repeat , Antibodies, Monoclonal/chemistry , Pharmaceutical Preparations , Antibodies, Monoclonal/immunology , Humans
11.
Leuk Lymphoma ; 60(7): 1668-1676, 2019 07.
Article in English | MEDLINE | ID: mdl-30632837

ABSTRACT

The GALLIUM trial compared obinutuzumab (GA101, G)-based chemotherapy followed by G monotherapy (G + chemo) for up to two years to rituximab (R)-based chemotherapy followed by R monotherapy (R + chemo) for up to two years in previously untreated follicular lymphoma (FL) patients. We estimated the cost-effectiveness of G + chemo versus R + chemo utilizing GALLIUM trial data and published literature. G + chemo had increased drug costs (undiscounted: $135,200 versus $127,700 for R + chemo), representing a relative increase of 5.9%. However, this was offset by a $6,400 lower cost for disease progression. G + chemo led to increased quality-adjusted life years (QALYs) relative to R + chemo of 0.81 (95% credible range, [CR]: 0.22-1.37), and the overall discounted incremental cost was $1,900 (95% CR: -$7,400 to $8,900). The incremental cost-effectiveness ratio was ∼$2,300 per QALY gained, and the results were highly robust to sensitivity analyses. Treatment with G + chemo compared to R + chemo is cost-effective in previously untreated FL patients in the US.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/economics , Drug Costs/statistics & numerical data , Lymphoma, Follicular/drug therapy , Lymphoma, Follicular/economics , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bendamustine Hydrochloride/administration & dosage , Cyclophosphamide/administration & dosage , Doxorubicin/administration & dosage , Female , Follow-Up Studies , Humans , Lymphoma, Follicular/pathology , Male , Middle Aged , Prednisone/administration & dosage , Prognosis , Quality-Adjusted Life Years , Rituximab/administration & dosage , Survival Rate , United States , Vincristine/administration & dosage , Young Adult
13.
J Drugs Dermatol ; 17(2): 143-148, 2018 Feb 01.
Article in English | MEDLINE | ID: mdl-29462221

ABSTRACT

BACKGROUND: Information is limited on the use of vismodegib for treatment of advanced basal cell carcinoma beyond the setting of clinical trials. OBJECTIVE: To investigate the treatment patterns and characteristics of patients treated with vismodegib in clinical practice. METHODS: A longitudinal, retrospective cohort study was undertaken using data from a US commercial insurance claims (Truven Health Analytics MarketScan) database. Eligible patients were ≥18 years of age, with ≥1 claim for vismodegib from January 2012 to December 2015. RESULTS: A total of 321 patients were included in the analysis. Approximately 20% of the patients took 1 or more treatment breaks of ≥ 30 days each before treatment discontinuation. Median duration of vismodegib treatment before the first treatment break and discontinuation was 4.0 and 5.5 months, respectively. Older age ( > 65 years) and absence of Gorlin syndrome were associated with increased risk for treatment interruption or discontinuation. Overall, 47% and 36% of patients underwent surgery or radiotherapy within the 6 months before and after vismodegib initiation, respectively. CONCLUSIONS: Real-world evidence indicates that vismodegib is being used in clinical practice as part of combination treatment strategies. J Drugs Dermatol. 2018;17(2):143-148.


Subject(s)
Anilides/therapeutic use , Carcinoma, Basal Cell/drug therapy , Databases, Factual/statistics & numerical data , Insurance Claim Reporting/statistics & numerical data , Pyridines/therapeutic use , Skin Neoplasms/drug therapy , Aged , Carcinoma, Basal Cell/epidemiology , Cohort Studies , Female , Humans , Male , Middle Aged , Retrospective Studies , Skin Neoplasms/epidemiology , United States/epidemiology
14.
Oncotarget ; 8(58): 98371-98383, 2017 Nov 17.
Article in English | MEDLINE | ID: mdl-29228696

ABSTRACT

BACKGROUND: The VEGF/VEGFR and the HGF/cMET pathways are key mediators of the interplay of tumor cells and their microenvironment. However, inhibition of VEGF has been shown to produce only limited clinical benefit and inhibition of the activation of cMET by HGF has not translated into clinical benefit in pivotal trials. MP0250, a DARPin® molecule that specifically inhibits both VEGF and HGF has been developed to explore the clinical potential of dual inhibition of these pathways. RESULTS: MP0250 binding to VEGF and HGF inhibited downstream signalling through VEGFR2 and cMET resulting in inhibition of proliferation of VEGF- and HGF-dependent cells. Antitumor activity was demonstrated in VEGF- and HGF-dependent xenograft and syngeneic models with activity superior to that of individual VEGF- and HGF-blocking DARPin® molecules. Combination therapy studies showed potentiation of the antitumor activity of chemotherapy and immunotherapy agents, including an anti-PD1 antibody. MATERIALS AND METHODS: Potency of MP0250 was assessed in cellular models and in a variety of xenograft models as monotherapy or in combination with standard-of-care drugs. CONCLUSIONS: Dual inhibition of VEGF and HGF by MP0250 produced powerful single agent and combination antitumor activity. This, together with increasing understanding of the role of the HGF/cMET pathway in resistance to VEGF (and other agents), supports testing of MP0250 in the clinic.

16.
Leuk Lymphoma ; 58(4): 809-815, 2017 04.
Article in English | MEDLINE | ID: mdl-27562750

ABSTRACT

Positron emission tomography (PET) after induction therapy in follicular lymphoma (FL) is predictive of survival in clinical trials. We describe use of PET and computed tomography (CT) after rituximab-based induction therapy in FL patients followed by the National LymphoCare Study and explore the association between imaging response assessment and survival. Among 1289 patients, imaging consisted of: PET ± CT (35%), CT alone (42%), other/no imaging (24%). Median follow-up was 7.6 years. In unadjusted analyses, positive PET ± CT and CT were prognostic of inferior OS (HR 1.78; 95% CI: 1.16-2.72 and HR 1.61, 95% CI: 1.13-2.29, respectively) and PFS (HR 1.63, 95% CI: 1.21-2.20 and HR 1.45, 95% CI: 1.12-1.89, respectively). Adjusting for FL International Prognostic Index, PET remained predictive of OS (HR 1.54, 95% CI: 1.01-2.36) and PFS (HR 1.54, 95% CI: 1.14-2.07). Residual disease via PET in FL is prognostic of survival in clinical practice.


Subject(s)
Fluorodeoxyglucose F18 , Lymphoma, Follicular/diagnostic imaging , Lymphoma, Follicular/mortality , Positron-Emission Tomography , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Female , Humans , Lymphoma, Follicular/drug therapy , Lymphoma, Follicular/pathology , Male , Middle Aged , Neoplasm Metastasis , Neoplasm Staging , Positron-Emission Tomography/methods , Prognosis , Rituximab/administration & dosage , Survival Analysis , Tomography, X-Ray Computed , Treatment Outcome
17.
Am J Hematol ; 91(8): 770-5, 2016 08.
Article in English | MEDLINE | ID: mdl-27124800

ABSTRACT

We aimed to comprehensively study sex differences in disease and patients' characteristics, treatment and outcomes in patients with follicular lymphoma (FL) in the United States (USA) utilizing the National LymphoCare Study registry (2004-2014). Among evaluable males (n = 1277) and females (n = 1375) with FL, females less commonly received anthracyclines and were more likely to receive rituximab monotherapy. Overall response rates were comparable between sex groups. With a median follow-up of 8.1 years, male sex emerged as an adverse factor for PFS (HR, 0.84, 95% CI, 0.72-0.97). Lymphoma-related mortality (HR, 0.46; 0.23-0.93) and overall survival (HR, 0.63; 0.41-0.97) favored females aged ≤60 years. There are subtle differences in outcomes between male and female FL patients diagnosed and treated in the contemporary era. These data represent the largest prospective analysis of FL patients in the USA based on sex and can aid design of clinical trials for this disease. Am. J. Hematol. 91:770-775, 2016. © 2016 Wiley Periodicals, Inc.


Subject(s)
Lymphoma, Follicular/drug therapy , Lymphoma, Follicular/mortality , Adult , Aged , Aged, 80 and over , Anthracyclines/therapeutic use , Antineoplastic Agents/therapeutic use , Disease-Free Survival , Female , Humans , Lymphoma, Follicular/diagnosis , Male , Middle Aged , Registries , Rituximab/therapeutic use , Sex Factors , Survival Rate , Treatment Outcome , United States , Young Adult
18.
Clin J Oncol Nurs ; 20(2): E41-8, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26991722

ABSTRACT

BACKGROUND: In patients with previously untreated chronic lymphocytic leukemia (CLL) and comorbidities, treatment with the glycoengineered, type II anti-CD20 monoclonal antibody obinutuzumab (Gazyva®) (GA101) plus chlorambucil (Leukeran®) was associated with superior outcomes to rituximab (Rituxan®) plus chlorambucil, with a similar safety profile. However, a higher occurrence of infusion-related reactions (IRRs) was reported with obinutuzumab. These reactions typically require additional management. OBJECTIVES: The focus of this article is to provide oncology nurses and physicians with advice for obinutuzumab IRR management based on clinical trial data and nursing experience. METHODS: The authors reviewed the published management strategies for IRRs with obinutuzumab that were identified during the phase III CLL11 trial and an expanded access phase IIb study (ML28979). Practical advice for obinutuzumab IRR management was developed based on available clinical trial information and nursing experience. FINDINGS: IRRs with obinutuzumab are generally manageable. Most IRRs (all grades), and all grade 3-4 IRRs, occurred during the first infusion. Therefore, IRR management could be improved substantially with extra vigilance at this early stage.


Subject(s)
Antibodies, Monoclonal, Humanized/adverse effects , Drug-Related Side Effects and Adverse Reactions/nursing , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/mortality , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/administration & dosage , Clinical Trials, Phase III as Topic , Disease Management , Dose-Response Relationship, Drug , Drug Administration Schedule , Drug-Related Side Effects and Adverse Reactions/physiopathology , Evidence-Based Medicine , Female , Humans , Infusions, Intravenous , Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis , Male , Middle Aged , Oncology Nursing , Prognosis , Severity of Illness Index , Survival Analysis , Treatment Outcome
19.
Can J Diabetes ; 40(3): 242-6, 2016 Jun.
Article in English | MEDLINE | ID: mdl-27026222

ABSTRACT

OBJECTIVES: 1) How closely do capillary glycated hemoglobin (A1C) levels agree with venous A1C levels? 2) How well do venous A1C levels agree with plasma glucose for diagnosis of diabetes in this population? METHODS: The Seabird Island mobile diabetes clinic screened people not known to have diabetes by using finger-prick capillary A1C levels with point-of-care analysis according to the Siemens/Bayer DCA 2000 system. Clients then went to a clinical laboratory for confirmatory testing for venous A1C levels, fasting plasma glucose (FPG) and plasma glucose 2 hours after 75 g oral glucose load (2hPG). A reference laboratory compared the DCA 2000 and the clinical laboratory's Roche Integra 800CTS system to the National Glycohemoglobin Standardization Program Diabetes Control and Complications Trial (DCCT) reference. RESULTS: 1) In the reference laboratory, DCA 2000 and Integra 800CTS both agreed very closely with the DCCT standard. In the field, capillary glycated hemoglobin percent (A1C) % was biased, underestimating venous A1C % by a mean of 0.19 (p<0.001). The margin of error of bias-adjusted capillary A1C % was ±0.36 for 95% of the time, compared to ±0.27 for venous A1C%. 2) By linear regression, we found FPG 7.0 mmol/L and 2hPG 11.1 mmol/L predicted mean venous A1C levels very close to 6.5%, with no significant bias. CONCLUSIONS: Point-of-care capillary A1C did not perform as well in the field as in the laboratory, but the bias is correctible, and the margin of error is small enough that the test is clinically useful. In this population, venous A1C levels ≥6.5% agree closely with the FPG and 2hPG thresholds to diagnose diabetes; ethnic-specific adjustment of the venous A1C threshold is not necessary.


Subject(s)
Diabetes Mellitus/diagnosis , Hemoglobins/metabolism , Point-of-Care Testing , Blood Glucose , Canada , Glycated Hemoglobin/metabolism , Humans , Indians, North American , Mass Screening/methods , Predictive Value of Tests
20.
Br J Haematol ; 172(5): 724-34, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26729445

ABSTRACT

To examine the effectiveness of an initial management strategy of watchful waiting for follicular lymphoma (FL) in clinical practice, we compared outcomes for patients diagnosed 2004-2007 in the United States initially managed with watchful waiting with outcomes following initial rituximab monotherapy and chemoimmunotherapy. In total, 1754 stage II-IV patients in the National LymphoCare Study underwent watchful waiting (n = 386), rituximab monotherapy (n = 296) or rituximab plus chemotherapy (n = 1072) as initial management strategy. Female patients and those who received treatment in the Northeast or in an academic setting more commonly underwent watchful waiting versus initial chemoimmunotherapy; whereas patients with grade 3 histology, anaemia, elevated lactate dehydrogenase, extranodal involvement, B symptoms or performance status ≥1 more commonly received chemoimmunotherapy. Although time to new treatment and progression-free survival following first- and second-line therapy were improved with chemoimmunotherapy, and time to chemotherapy was improved with rituximab monotherapy, there were no differences in overall survival between watchful waiting and chemoimmunotherapy or rituximab monotherapy. With 8-year overall survival estimates of 74%, initial management with watchful waiting in the context of sequential therapy remains a viable option for FL patients in the modern era. This trial was registered at www.clinicaltrials.gov (NCT00097565).


Subject(s)
Lymphoma, Follicular/therapy , Watchful Waiting , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Female , Humans , Kaplan-Meier Estimate , Lymphoma, Follicular/drug therapy , Lymphoma, Follicular/pathology , Male , Middle Aged , Neoplasm Staging , Prospective Studies , Rituximab/administration & dosage , Rituximab/therapeutic use , Treatment Outcome
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