Publications by authors named "Howard Colman"

108 Publications

Impact of the COVID-19 pandemic on exercise habits among cancer patients.

Res Sq 2021 Sep 21. Epub 2021 Sep 21.

Purpose There is limited information on how the COVID-19 pandemic has changed health behaviors among cancer patients. We examined the impact of the pandemic on changes in exercise behaviors and identified characteristics associated with these changes among cancer patients. Methods Cancer patients (n   1,361) completed a survey from August-September 2020 to assess COVID-19 pandemic-related changes in health behaviors and psychosocial factors. Patients were categorized into 3 groups: exercising less, exercising did not change, and exercising more. Patient characteristics were compared by exercise groups. Results One-third of the patients reported a decreased amount of regular exercise, while 11% reported exercising more during the pandemic. Patients who exercised less were more likely to be unemployed/retired, undergoing active treatment, and had increased pandemic-related alcohol consumption and psychosocial stressors such as loneliness and financial stress (all  < 0.05). In contrast, patients who exercised more were younger, female, full-time employed, did not consume alcohol, and had good health status and more social interactions (all  < 0.05). Patients who were living in rural areas and did not experience changes in daily life, were also more likely not to experience changes in exercise habits (all  < 0.05). Conclusion Our results indicate that a significant proportion of cancer patients experienced changes in exercise habits during the first 6 months of the COVID-19 pandemic. Age, sex, employment status, health status, alcohol consumption, and psychosocial factors were associated with changes in exercise behaviors. Providers should monitor for changes in health behaviors, such as exercise, because of their importance in improving cancer survivorship.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21203/rs.3.rs-704646/v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8475966PMC
September 2021

Designing Clinical Trials for Combination Immunotherapy: A Framework for Glioblastoma.

Clin Cancer Res 2021 Sep 24. Epub 2021 Sep 24.

Duke University, Durham, North Carolina.

Immunotherapy has revolutionized treatment for many hard-to-treat cancers but has yet to produce significant improvement in outcomes for patients with glioblastoma. This reflects the multiple and unique mechanisms of immune evasion and escape in this highly heterogeneous tumor. Glioblastoma engenders profound local and systemic immunosuppression and is remarkably effective at inducing T-cell dysfunction, posing a challenge to any immunotherapy-based approach. To overcome these mechanisms, multiple disparate modes of immune-oriented therapy will be required. However, designing trials that can evaluate these combinatorial approaches requires careful consideration. In this review, we explore the immunotherapy resistance mechanisms that have been encountered to date and how combinatorial approaches may address these. We also describe the unique aspects of trial design in both preclinical and clinical settings and consider endpoints and markers of response best suited for an intervention involving multiple agents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-21-2681DOI Listing
September 2021

Caregiver burden by treatment and clinical characteristics of patients with glioblastoma.

Support Care Cancer 2022 Feb 11;30(2):1365-1375. Epub 2021 Sep 11.

Department of Pharmacotherapy, College of Pharmacy, University of Utah, Salt Lake City, UT, USA.

Background: Glioblastoma is an incurable disease with a poor prognosis. For caregivers of people with glioblastoma, the burden of care can be high. Patients often present with different clinical characteristics, which may impact caregiver burden in different ways. This study aimed to evaluate associations between patient clinical characteristics and caregiver burden/quality of life (QoL).

Methods: Caregiver-patient dyads were enrolled at 7 academic cancer centers in the United States. Eligible caregiver participants were self-reported as the primary caregiver of an adult living with glioblastoma and completed a caregiver burden survey. Eligible patients were age ≥ 18 years at glioblastoma diagnosis and alive when their respective caregiver entered the study, with the presence of cognitive dysfunction confirmed by the caregiver. Data were analyzed with descriptive statistics and multivariable analyses.

Results: The final cohort included 167 dyads. Poor patient performance status resulted in patient difficulty with mental tasks, more caregiving tasks, and increased caregiving time. Language problems were reported in patients with left-sided lesions. Patient confusion was negatively associated with all caregiver domains: emotional health, social health, general health, ability to work, confidence in finances, and overall QoL. Better caregiver QoL was observed in patients with frontal lobe lesions versus non-frontal lobe lesions.

Conclusion: This study reinforced that patient performance status is a critical clinical factor that significantly affects caregiver burden, caregiving tasks, and caregiver time. Additionally, patient confusion affects multiple facets of caregiver burden/QoL. These results could be used to support guided intervention for caregiver support, customized to the patient experience.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00520-021-06514-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8727395PMC
February 2022

Systematic review of combinations of targeted or immunotherapy in advanced solid tumors.

J Immunother Cancer 2021 07;9(7)

Duke Cancer Institute, Duke University, Durham, North Carolina, USA

With rapid advances in our understanding of cancer, there is an expanding number of potential novel combination therapies, including novel-novel combinations. Identifying which combinations are appropriate and in which subpopulations are among the most difficult questions in medical research. We conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-guided systematic review of trials of novel-novel combination therapies involving immunotherapies or molecular targeted therapies in advanced solid tumors. A MEDLINE search was conducted using a modified Cochrane Highly Sensitive Search Strategy for published clinical trials between July 1, 2017, and June 30, 2020, in the top-ranked medical and oncology journals. Trials were evaluated according to a criterion adapted from previously published Food and Drug Administration guidance and other key considerations in designing trials of combinations. This included the presence of a strong biological rationale, the use of a new established or emerging predictive biomarker prospectively incorporated into the clinical trial design, appropriate comparator arms of monotherapy or supportive external data sources and a primary endpoint demonstrating a clinically meaningful benefit. Of 32 identified trials, there were 11 (34%) trials of the novel-novel combination of anti-programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) and anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) therapy, and 10 (31%) trials of anti-PD-1/PD-L1 and anti-vascular endothelial growth factor (VEGF) combination therapy. 20 (62.5%) trials were phase II trials, while 12 (37.5%) were phase III trials. Most (72%) trials lacked significant preclinical evidence supporting the development of the combination in the given indication. A majority of trials (69%) were conducted in biomarker unselected populations or used pre-existing biomarkers within the given indication for patient selection. Most studies (66%) were considered to have appropriate comparator arms or had supportive external data sources such as prior studies of monotherapy. All studies were evaluated as selecting a clinically meaningful primary endpoint. In conclusion, designing trials to evaluate novel-novel combination therapies presents numerous challenges to demonstrate efficacy in a comprehensive manner. A greater understanding of biological rationale for combinations and incorporating predictive biomarkers may improve effective evaluation of combination therapies. Innovative statistical methods and increasing use of external data to support combination approaches are potential strategies that may improve the efficiency of trial design. Designing trials to evaluate novel-novel combination therapies presents numerous challenges to demonstrate efficacy in a comprehensive manner. A greater understanding of biological rationale for combinations and incorporating predictive biomarkers may improve effective evaluation of combination therapies. Innovative statistical methods and increasing use of external data to support combination approaches are potential strategies that may improve the efficiency of trial design.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jitc-2021-002459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256733PMC
July 2021

First line immunotherapy extends brain metastasis free survival, improves overall survival, and reduces the incidence of brain metastasis in patients with advanced melanoma.

Cancer Rep (Hoboken) 2021 12 17;4(6):e1419. Epub 2021 Jun 17.

Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, Utah, USA.

Background: Recent advances in targeted therapy and immunotherapy have improved the prognosis of melanoma patients but brain metastasis remains a major challenge. Currently, it is unclear how existing therapies can be best used to prevent or treat brain metastasis in melanoma patients.

Aims: We aimed to assess brain metastasis free survival (BMFS), overall survival (OS), incidence of brain metastases, and sequencing strategies of immunotherapy and targeted therapy in patients with BRAF-mutated advanced melanoma.

Methods And Results: We retrospectively analyzed 683 patients with BRAF-mutated advanced melanoma treated with first line (1L) immunotherapy (N = 266) or targeted therapy (N = 417). The primary outcome was BMFS. Secondary outcomes included OS of all patients and incidence of brain metastases in patients without documented brain metastases prior to 1L therapy. The median BMFS was 13.7 months [95% confidence interval (CI): 12.4-16.0] among all patients. The median BMFS for patients receiving 1L immunotherapy was 41.9 months [95% CI: 22.8-not reached (NR)] and targeted therapy was 11.0 months (95% CI: 8.8-12.5). Median OS results were qualitatively similar to BMFS results. The cumulative incidence of brain metastases for patients receiving 1L targeted therapy was higher than for patients receiving 1L immunotherapy (P < .001). Patients receiving 1L anti-CTLA4 plus anti-PD1 combination immunotherapy only or followed by second line (2L) targeted therapy had better BMFS (HR 0.40, 95% CI: 0.24-0.67, P = .001), improved OS (HR 0.49, 95% CI: 0.30-0.81, P = .005), and reduced incidence of brain metastases (HR 0.47, 95% CI: 0.24-0.67, P = .047) than patients receiving 1L combination BRAF and MEK targeted therapy followed by 2L immunotherapy.

Conclusion: Patients with advanced BRAF mutant melanoma treated with 1L immunotherapy have significantly longer BMFS and OS, and reduced incidence of brain metastases, compared with those treated with 1L targeted therapy. Further studies evaluating the ability of immunotherapy and targeted therapy to improve OS and prevent brain metastases are warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cnr2.1419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8714542PMC
December 2021

A first-in-human phase 0 clinical study of RNA interference-based spherical nucleic acids in patients with recurrent glioblastoma.

Sci Transl Med 2021 03;13(584)

Broom Street Associates, Wilmington, DE 19806, USA.

Glioblastoma (GBM) is one of the most difficult cancers to effectively treat, in part because of the lack of precision therapies and limited therapeutic access to intracranial tumor sites due to the presence of the blood-brain and blood-tumor barriers. We have developed a precision medicine approach for GBM treatment that involves the use of brain-penetrant RNA interference-based spherical nucleic acids (SNAs), which consist of gold nanoparticle cores covalently conjugated with radially oriented and densely packed small interfering RNA (siRNA) oligonucleotides. On the basis of previous preclinical evaluation, we conducted toxicology and toxicokinetic studies in nonhuman primates and a single-arm, open-label phase 0 first-in-human trial (NCT03020017) to determine safety, pharmacokinetics, intratumoral accumulation and gene-suppressive activity of systemically administered SNAs carrying siRNA specific for the GBM oncogene Bcl2Like12 (Bcl2L12). Patients with recurrent GBM were treated with intravenous administration of siBcl2L12-SNAs (drug moniker: NU-0129), at a dose corresponding to 1/50th of the no-observed-adverse-event level, followed by tumor resection. Safety assessment revealed no grade 4 or 5 treatment-related toxicities. Inductively coupled plasma mass spectrometry, x-ray fluorescence microscopy, and silver staining of resected GBM tissue demonstrated that intravenously administered SNAs reached patient tumors, with gold enrichment observed in the tumor-associated endothelium, macrophages, and tumor cells. NU-0129 uptake into glioma cells correlated with a reduction in tumor-associated Bcl2L12 protein expression, as indicated by comparison of matched primary tumor and NU-0129-treated recurrent tumor. Our results establish SNA nanoconjugates as a potential brain-penetrant precision medicine approach for the systemic treatment of GBM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/scitranslmed.abb3945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8272521PMC
March 2021

Adult Gliomas.

Authors:
Howard Colman

Continuum (Minneap Minn) 2020 12;26(6):1452-1475

Purpose Of Review: This article highlights important aspects of the evaluation, diagnosis, and treatment of adult gliomas, including lower-grade astrocytomas and oligodendrogliomas, glioblastomas, and ependymomas.

Recent Findings: The appropriate initial evaluation and accurate diagnosis of gliomas require an understanding of the spectrum of clinical and radiographic presentations. Recent advances in the understanding of distinct molecular prognostic subtypes have led to major revisions in the diagnostic classification of gliomas. Integration of these new diagnostic and molecular classifications is an important part of the modern management of gliomas and facilitates better understanding and interpretation of the efficacy of different therapies in specific glioma subtypes.

Summary: The management of adult gliomas is a multidisciplinary endeavor. However, despite recent molecular and treatment advances, the majority of diffuse gliomas remain incurable, and efforts aimed at the development and testing of new therapies in clinical trials are ongoing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/CON.0000000000000935DOI Listing
December 2020

Randomized Phase II and Biomarker Study of Pembrolizumab plus Bevacizumab versus Pembrolizumab Alone for Patients with Recurrent Glioblastoma.

Clin Cancer Res 2021 02 16;27(4):1048-1057. Epub 2020 Nov 16.

Dana-Farber Cancer Institute, Boston, Massachusetts.

Purpose: VEGF is upregulated in glioblastoma and may contribute to immunosuppression. We performed a phase II study of pembrolizumab alone or with bevacizumab in recurrent glioblastoma.

Patients And Methods: Eighty bevacizumab-naïve patients with recurrent glioblastoma were randomized to pembrolizumab with bevacizumab (cohort A, = 50) or pembrolizumab monotherapy (cohort B, = 30). The primary endpoint was 6-month progression-free survival (PFS-6). Assessed biomarkers included evaluation of tumor programmed death-ligand 1 expression, tumor-infiltrating lymphocyte density, immune activation gene expression signature, and plasma cytokines. The neurologic assessment in neuro-oncology (NANO) scale was used to prospectively assess neurologic function.

Results: Pembrolizumab alone or with bevacizumab was well tolerated but of limited benefit. For cohort A, PFS-6 was 26.0% [95% confidence interval (CI), 16.3-41.5], median overall survival (OS) was 8.8 months (95% CI, 7.7-14.2), objective response rate (ORR) was 20%, and median duration of response was 48 weeks. For cohort B, PFS-6 was 6.7% (95% CI, 1.7-25.4), median OS was 10.3 months (95% CI, 8.5-12.5), and ORR was 0%. Tumor immune markers were not associated with OS, but worsened OS correlated with baseline dexamethasone use and increased posttherapy plasma VEGF (cohort A) and mutant , unmethylated , and increased baseline PlGF and sVEGFR1 levels (cohort B). The NANO scale contributed to overall outcome assessment.

Conclusions: Pembrolizumab was ineffective as monotherapy and with bevacizumab for recurrent glioblastoma. The infrequent radiographic responses to combinatorial therapy were durable. Tumor immune biomarkers did not predict outcome. Baseline dexamethasone use and tumor MGMT warrant further study as potential biomarkers in glioblastoma immunotherapy trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-20-2500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284901PMC
February 2021

Radiographic read paradigms and the roles of the central imaging laboratory in neuro-oncology clinical trials.

Neuro Oncol 2021 02;23(2):189-198

UCLA Brain Tumor Imaging Laboratory (BTIL), Center for Computer Vision and Imaging Biomarkers, University of California Los Angeles, Los Angeles, California, USA.

Determination of therapeutic benefit in intracranial tumors is intimately dependent on serial assessment of radiographic images. The Response Assessment in Neuro-Oncology (RANO) criteria were established in 2010 to provide an updated framework to better characterize tumor response to contemporary treatments. Since this initial update a number of RANO criteria have provided some basic principles for the interpretation of changes on MR images; however, the details of how to operationalize RANO and other criteria for use in clinical trials are ambiguous and not standardized. In this review article designed for the neuro-oncologist or treating clinician, we outline essential steps for performing radiographic assessments by highlighting primary features of the Imaging Charter (referred to as the Charter for the remainder of this article), a document that describes the clinical trial imaging methodology and methods to ensure operationalization of the Charter into the workings of a clinical trial. Lastly, we provide recommendations for specific changes to optimize this methodology for neuro-oncology, including image registration, requirement of growing tumor for eligibility in trials of recurrent tumor, standardized image acquisition guidelines, and hybrid reader paradigms that allow for both unbiased measurements and more comprehensive interpretation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/neuonc/noaa253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906061PMC
February 2021

Expression of the Androgen Receptor Governs Radiation Resistance in a Subset of Glioblastomas Vulnerable to Antiandrogen Therapy.

Mol Cancer Ther 2020 10 12;19(10):2163-2174. Epub 2020 Aug 12.

Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.

New approaches are needed to overcome intrinsic therapy resistance in glioblastoma (GBM). Because GBMs exhibit sexual dimorphism and are reported to express steroid hormone receptors, we reasoned that signaling through the androgen receptor (AR) could mediate therapy resistance in GBM, much as it does in AR-positive prostate and breast cancers. We found that nearly half of GBM cell lines, patient-derived xenografts (PDX), and human tumors expressed AR at the transcript and protein level-with expression levels overlapping those of primary prostate cancer. Analysis of gene expression datasets also revealed that AR expression is higher in GBM patient samples than normal brain tissue. Multiple clinical-grade antiandrogens slowed the growth of and radiosensitized AR-positive GBM cell lines and PDXs and Antiandrogens blocked the ability of AR-positive GBM PDXs to engage adaptive transcriptional programs following radiation and slowed the repair of radiation-induced DNA damage. These results suggest that combining blood-brain barrier permeable antiandrogens with radiation may have promise for patients with AR-positive GBMs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-20-0095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7842184PMC
October 2020

Diabetes, Body Fatness, and Insulin Prescription Among Adolescents and Young Adults with Cancer.

J Adolesc Young Adult Oncol 2021 04 29;10(2):217-225. Epub 2020 Jul 29.

Huntsman Cancer Institute, Salt Lake City, Utah, USA.

Rates of obesity and obesity-related health consequences, including type 2 diabetes (T2D) and cancer, continue to rise. While cancer patients are at an increased risk of developing T2D, the prevalence of T2D and insulin prescription among young patients with cancer remains unknown. Using the Total Cancer Care Study cohort at Huntsman Cancer Institute (Salt Lake City, UT), we identified individuals age 18-39 years at cancer diagnosis between 2009 and 2019. Multivariable logistic regression was used to investigate associations between body mass index (BMI) with insulin prescription within 1 year of cancer diagnosis. In total, 344 adolescents and young adults (AYAs) were diagnosed with primary invasive cancer. Within this cohort, 19 patients (5.5%) were ever diagnosed with T2D, 48 AYAs ever received an insulin prescription (14.0%), and 197 were overweight or obese (BMI: 25+ kg/m) at cancer diagnosis. Each kg/m unit increase in BMI was associated with 6% increased odds of first insulin prescription within 1 year of cancer diagnosis among AYAs, even after adjustment for age, sex, smoking history, marital status, glucocorticoid prescription, and cancer treatments (odds ratio = 1.06, 95% confidence interval 1.02-1.11;  = 0.005). One in every 18 AYAs with cancer ever had T2D, 1 in 7 AYA patients with cancer ever received an insulin prescription, and higher BMI was associated with increased risk of insulin prescription within a year of cancer diagnosis among AYAs. Understanding the incidence of T2D and insulin prescription/use is critical for short-term and long-term clinical management of AYAs with cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/jayao.2020.0071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064923PMC
April 2021

Repeat radiation with bevacizumab and minocycline in bevacizumab-refractory high grade gliomas: a prospective phase 1 trial.

J Neurooncol 2020 Jul 6;148(3):577-585. Epub 2020 Jun 6.

Huntsman Cancer Institute, Salt Lake City, UT, USA.

Introduction: There are no effective treatments for gliomas after progression on radiation, temozolomide, and bevacizumab. Microglia activation may be involved in radiation resistance and can be inhibited by the brain penetrating antibiotic minocycline. In this phase 1 trial, we examined the safety and effect on survival, symptom burden, and neurocognitive function of reirradiation, minocycline, and bevacizumab.

Methods: The trial used a 3 + 3 design for dose escalation followed by a ten person dose expansion. Patients received reirradiation with dosing based on radiation oncologist judgment, bevacizumab 10 mg/kg IV every two weeks, and oral minocycline twice a day. Symptom burden was measured using MDASI-BT. Neurocognitive function was measured using the COGSTATE battery.

Results: The maximum tolerated dose of minocycline was 400 mg twice a day with no unexpected toxicities. The PFS3 was 64.6%, and median overall survival was 6.4 months. Symptom burden and neurocognitive function did not decline in the interval between treatment completion and tumor progression.

Conclusions: Minocycline 400 mg orally twice a day with bevacizumab and reirradiation is well tolerated by physician and patient reported outcomes in people with gliomas that progress on bevacizumab.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11060-020-03551-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438283PMC
July 2020

A Bayesian adaptive randomized phase II multicenter trial of bevacizumab with or without vorinostat in adults with recurrent glioblastoma.

Neuro Oncol 2020 10;22(10):1505-1515

Neuro-Oncology Branch, National Institute of Health, Bethesda, Maryland.

Background: Bevacizumab has promising activity against recurrent glioblastoma (GBM). However, acquired resistance to this agent results in tumor recurrence. We hypothesized that vorinostat, a histone deacetylase (HDAC) inhibitor with anti-angiogenic effects, would prevent acquired resistance to bevacizumab.

Methods: This multicenter phase II trial used a Bayesian adaptive design to randomize patients with recurrent GBM to bevacizumab alone or bevacizumab plus vorinostat with the primary endpoint of progression-free survival (PFS) and secondary endpoints of overall survival (OS) and clinical outcomes assessment (MD Anderson Symptom Inventory Brain Tumor module [MDASI-BT]). Eligible patients were adults (≥18 y) with histologically confirmed GBM recurrent after prior radiation therapy, with adequate organ function, KPS ≥60, and no prior bevacizumab or HDAC inhibitors.

Results: Ninety patients (bevacizumab + vorinostat: 49, bevacizumab: 41) were enrolled, of whom 74 were evaluable for PFS (bevacizumab + vorinostat: 44, bevacizumab: 30). Median PFS (3.7 vs 3.9 mo, P = 0.94, hazard ratio [HR] 0.63 [95% CI: 0.38, 1.06, P = 0.08]), median OS (7.8 vs 9.3 mo, P = 0.64, HR 0.93 [95% CI: 0.5, 1.6, P = 0.79]) and clinical benefit were similar between the 2 arms. Toxicity (grade ≥3) in 85 evaluable patients included hypertension (n = 37), neurological changes (n = 2), anorexia (n = 2), infections (n = 9), wound dehiscence (n = 2), deep vein thrombosis/pulmonary embolism (n = 2), and colonic perforation (n = 1).

Conclusions: Bevacizumab combined with vorinostat did not yield improvement in PFS or OS or clinical benefit compared with bevacizumab alone or a clinical benefit in adults with recurrent GBM. This trial is the first to test a Bayesian adaptive design with adaptive randomization and Bayesian continuous monitoring in patients with primary brain tumor and demonstrates the feasibility of using complex Bayesian adaptive design in a multicenter setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/neuonc/noaa062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686463PMC
October 2020

Challenges of targeting V600E mutations in adult primary brain tumor patients: a report of two cases.

CNS Oncol 2019 12 10;8(4):CNS48. Epub 2019 Dec 10.

Division of Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.

Therapeutic targeting of alterations in primary brain tumor patients has demonstrated clinical activity in case reports and early trials; however, there is limited high-level evidence of the efficacy. Targeting V600E mutations with concurrent dabrafenib and trametinib in anaplastic pleomorphic xanthoastrocytoma resulted in a transient radiographic and clinical response and no therapeutic benefit in a patient with an epithelioid glioblastoma. / inhibition did not produce a durable treatment effect in glioblastoma or pleomorphic xanthoastrocytoma with alterations. Heterogenicity of related cases in the literature makes an evaluation of efficacy targeting therapies in gliomas difficult and requires additional investigation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/cns-2019-0018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912849PMC
December 2019

Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT): A Bayesian Adaptive Platform Trial to Develop Precision Medicines for Patients With Glioblastoma.

JCO Precis Oncol 2019 27;3. Epub 2019 Mar 27.

Dana-Farber Cancer Institute, Boston, MA.

Purpose: Adequately prioritizing the numerous therapies and biomarkers available in late-stage testing for patients with glioblastoma (GBM) requires an efficient clinical testing platform. We developed and implemented INSIGhT (Individualized Screening Trial of Innovative Glioblastoma Therapy) as a novel adaptive platform trial (APT) to develop precision medicine approaches in GBM.

Methods: INSIGhT compares experimental arms with a common control of standard concurrent temozolomide and radiation therapy followed by adjuvant temozolomide. The primary end point is overall survival. Patients with newly diagnosed unmethylated GBM who are R132H mutation negative and with genomic data available for biomarker grouping are eligible. At the initiation of INSIGhT, three experimental arms (neratinib, abemaciclib, and CC-115), each with a proposed genomic biomarker, are tested simultaneously. Initial randomization is equal across arms. As the trial progresses, randomization probabilities adapt on the basis of accumulating results using Bayesian estimation of the biomarker-specific probability of treatment impact on progression-free survival. Treatment arms may drop because of low probability of treatment impact on overall survival, and new arms may be added. Detailed information on the statistical model and randomization algorithm is provided to stimulate discussion on trial design choices more generally and provide an example for other investigators developing APTs.

Conclusion: INSIGhT (NCT02977780) is an ongoing novel biomarker-based, Bayesian APT for patients with newly diagnosed unmethylated GBM. Our goal is to dramatically shorten trial execution timelines while increasing scientific power of results and biomarker discovery using adaptive randomization. We anticipate that trial execution efficiency will also be improved by using the APT format, which allows for the collaborative addition of new experimental arms while retaining the overall trial structure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/PO.18.00071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448806PMC
March 2019

The contribution of the rs55705857 G allele to familial cancer risk as estimated in the Utah population database.

BMC Cancer 2019 Mar 1;19(1):190. Epub 2019 Mar 1.

Division of Oncology, University of Utah School of Medicine, Huntsman Cancer Institute, Salt Lake City, Utah, USA.

Background: IDH1/2 mutated glioma has been associated with a germline risk variant, the rs55705857 G allele. The Utah Population Database (UPDB), a computerized genealogy of people in Utah, is a unique resource to evaluate cancer risk in related individuals.

Methods: One hundred and two individuals with IDH1/2 mutant or 1p/19q co-deleted glioma were genotyped and linked to the UPDB. DNA came from blood (21), tumor tissue (43), or both (38). We determined congruence between somatic and germline samples and estimated the relative risk for developing cancer to first and second-degree relatives of G and A allele carriers at rs55705857.

Results: Somatic (glioma) DNA had 85.7% sensitivity (CI 57.2-98.2%) and 95.8% specificity (CI 78.9-99.89%) for germline rs55705857 G allele. Forty-one patients were linked to pedigrees in the UPDB with at least three generations of data. First-degree relatives of rs55705857 G allele carriers were at significantly increased risk for developing cancer (RR = 1.72, p = 0.045, CI 1.02-2.94), and specifically for oligodendroglioma (RR = 57.61, p = 0.017, CI 2.96-320.98) or prostate cancer (RR = 4.10, p = 0.008, CI 1.62-9.58); relatives of individuals without the G allele were not at increased risk. Second-degree relatives of G allele carriers also had significantly increased risk for developing cancer (RR = 1.50, p = 0.007, CI 1.15-2.01).

Conclusions: Tumor DNA may approximate genotype at the rs55705857 locus. We confirmed this locus confers an increased risk of all cancers and especially of oligodendroglioma. No increased cancer or brain tumor risk is seen in family members of individuals without the high-risk G allele.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12885-019-5381-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397494PMC
March 2019

VHA Practice Guideline Recommendations for Diffuse Gliomas.

Fed Pract 2018 Aug;35(Suppl 5):S28-S35

is the Acting Chief of Pathology and Laboratory Medicine Service at VA Pittsburgh Healthcare System and member of the Division of Neuropathology at University of Pittsburgh Department of Pathology, is an Otolaryngologist at VA Pittsburgh Healthcare System, and is the Section Chief of Hematology\Oncology at VA Pittsburgh Healthcare System in Pennsylvania. is an Oncologist at VA-New York Harbor Healthcare System. is a Pathologist at University of Pittsburgh Department of Pathology in Pennsylvania. is Chief of Pathology and Laboratory Medicine Services at the South Texas Veterans Healthcare System in San Antonio. is the former Chief of Pathology and Laboratory Medicine Service at VA Pittsburgh Healthcare System. is a Pathologist at St. Louis VA Medical Center in Missouri. is the VA National Director of Pathology and Laboratory Medicine Services. is a Pathologist at Bay Pine Health Care System in Florida. is an Investigator at VA Salt Lake Health Care System Informatics and Computing Infrastructure. is an Oncologist at VA Puget Sound Health Care System, in Seattle, Washington. is the Director of Genomic Medicine Implementation and Associate Director of Genomic Medicine for the VA. is a Neuro-Oncologist at George E. Wahlen VA Medical Center and the Director of Medical Neuro-Oncology at the Huntsman Cancer Institute, Salt Lake City, Utah.

Although histology still plays a critical role in diagnosing diffuse gliomas, additional ancillary testing is an essential tool for VA pathology laboratories.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6248149PMC
August 2018

Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma.

Nat Med 2019 03 11;25(3):477-486. Epub 2019 Feb 11.

Department of Medical and Molecular Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.

Glioblastoma is the most common primary malignant brain tumor in adults and is associated with poor survival. The Ivy Foundation Early Phase Clinical Trials Consortium conducted a randomized, multi-institution clinical trial to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab in 35 patients with recurrent, surgically resectable glioblastoma. Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomized to receive adjuvant, post-surgical programmed cell death protein 1 (PD-1) blockade alone. Neoadjuvant PD-1 blockade was associated with upregulation of T cell- and interferon-γ-related gene expression, but downregulation of cell-cycle-related gene expression within the tumor, which was not seen in patients that received adjuvant therapy alone. Focal induction of programmed death-ligand 1 in the tumor microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells and a decreasing monocytic population was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41591-018-0337-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6408961PMC
March 2019

Buparlisib in Patients With Recurrent Glioblastoma Harboring Phosphatidylinositol 3-Kinase Pathway Activation: An Open-Label, Multicenter, Multi-Arm, Phase II Trial.

J Clin Oncol 2019 03 4;37(9):741-750. Epub 2019 Feb 4.

1 Dana-Farber Cancer Institute, Boston, MA.

Purpose: Phosphatidylinositol 3-kinase (PI3K) signaling is highly active in glioblastomas. We assessed pharmacokinetics, pharmacodynamics, and efficacy of the pan-PI3K inhibitor buparlisib in patients with recurrent glioblastoma with PI3K pathway activation.

Methods: This study was a multicenter, open-label, multi-arm, phase II trial in patients with PI3K pathway-activated glioblastoma at first or second recurrence. In cohort 1, patients scheduled for re-operation after progression received buparlisib for 7 to 13 days before surgery to evaluate brain penetration and modulation of the PI3K pathway in resected tumor tissue. In cohort 2, patients not eligible for re-operation received buparlisib until progression or unacceptable toxicity. Once daily oral buparlisib 100 mg was administered on a continuous 28-day schedule. Primary end points were PI3K pathway inhibition in tumor tissue and buparlisib pharmacokinetics in cohort 1 and 6-month progression-free survival (PFS6) in cohort 2.

Results: Sixty-five patients were treated (cohort 1, n = 15; cohort 2, n = 50). In cohort 1, reduction of phosphorylated AKT immunohistochemistry score was achieved in six (42.8%) of 14 patients, but effects on phosphoribosomal protein S6 and proliferation were not significant. Tumor-to-plasma drug level was 1.0. In cohort 2, four (8%) of 50 patients reached 6-month PFS6, and the median PFS was 1.7 months (95% CI, 1.4 to 1.8 months). The most common grade 3 or greater adverse events related to treatment were lipase elevation (n = 7 [10.8%]), fatigue (n = 4 [6.2%]), hyperglycemia (n = 3 [4.6%]), and elevated ALT (n = 3 [4.6%]).

Conclusion: Buparlisib had minimal single-agent efficacy in patients with PI3K-activated recurrent glioblastoma. Although buparlisib achieved significant brain penetration, the lack of clinical efficacy was explained by incomplete blockade of the PI3K pathway in tumor tissue. Integrative results suggest that additional study of PI3K inhibitors that achieve more-complete pathway inhibition may still be warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.18.01207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6553812PMC
March 2019

A platform for efficient early evaluation of biomarker-associated therapies in newly diagnosed IDH wild-type, MGMT unmethylated glioblastoma.

Authors:
Howard Colman

Neuro Oncol 2019 01;21(1):6-7

Huntsman Cancer Institute and Department of Neurosurgery, University of Utah, Salt Lake City, Utah.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/neuonc/noy190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6303428PMC
January 2019

Precision Medicine for Primary Central Nervous System Tumors: Are We There Yet?

Am Soc Clin Oncol Educ Book 2018 May;38:158-167

From the Massachusetts General Hospital, Harvard Medical School, Boston, MA; Departments of Neurosurgery, Neurology, and Internal Medicine (Oncology), Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; Department of Neurology, The Brain Tumor Center at Erasmus MC Cancer Institute, Rotterdam, Netherlands; Division of Neuro-Oncology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.

In recent years, technologic advances have increased tremendously our understanding of the molecular characteristics and genetic drivers of a variety of brain tumors. These discoveries have led to paradigm shifts in the treatment of these tumor entities and may therefore have a considerable impact on the outcome of affected patients in the near future. Here, we provide a broad overview of recently discovered clinically actionable mutations that have been identified in three different primary brain tumors: gliomas, meningiomas, and craniopharyngiomas. We furthermore highlight the diagnostic and therapeutic implications of these findings and summarize recently published and ongoing trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/EDBK_199247DOI Listing
May 2018

Introduction. Update on adult neuro-oncology.

Neurosurg Focus 2018 06;44(6):E1

3Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3171/2018.3.FOCUS18149DOI Listing
June 2018

Mutant IDH1 Promotes Glioma Formation In Vivo.

Cell Rep 2018 05;23(5):1553-1564

Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA; Department of Surgery, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA; Department of Oncological Sciences, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA. Electronic address:

Isocitrate dehydrogenase 1 (IDH1) is the most commonly mutated gene in grade II-III glioma and secondary glioblastoma (GBM). A causal role for IDH1 in gliomagenesis has been proposed, but functional validation in vivo has not been demonstrated. In this study, we assessed the role of IDH1 in glioma development in the context of clinically relevant cooperating genetic alterations in vitro and in vivo. Immortal astrocytes expressing IDH1 exhibited elevated (R)-2-hydroxyglutarate levels, reduced NADPH, increased proliferation, and anchorage-independent growth. Although not sufficient on its own, IDH1 cooperated with PDGFA and loss of Cdkn2a, Atrx, and Pten to promote glioma development in vivo. These tumors resembled proneural human mutant IDH1 GBM genetically, histologically, and functionally. Our findings support the hypothesis that IDH1 promotes glioma development. This model enhances our understanding of the biology of IDH1-driven gliomas and facilitates testing of therapeutic strategies designed to combat this deadly disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2018.03.133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6032974PMC
May 2018

Validation of postoperative residual contrast-enhancing tumor volume as an independent prognostic factor for overall survival in newly diagnosed glioblastoma.

Neuro Oncol 2018 08;20(9):1240-1250

Department of Molecular Medicine, Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota, USA.

Background: In the current study, we pooled imaging data in newly diagnosed glioblastoma (GBM) patients from international multicenter clinical trials, single institution databases, and multicenter clinical trial consortiums to identify the relationship between postoperative residual enhancing tumor volume and overall survival (OS).

Methods: Data from 1511 newly diagnosed GBM patients from 5 data sources were included in the current study: (i) a single institution database from UCLA (N = 398; Discovery); (ii) patients from the Ben and Cathy Ivy Foundation for Early Phase Clinical Trials Network Radiogenomics Database (N = 262 from 8 centers; Confirmation); (iii) the chemoradiation placebo arm from an international phase III trial (AVAglio; N = 394 from 120 locations in 23 countries; Validation); (iv) the experimental arm from AVAglio examining chemoradiation plus bevacizumab (N = 404 from 120 locations in 23 countries; Exploratory Set 1); and (v) an Alliance (N0874) phase I/II trial of vorinostat plus chemoradiation (N = 53; Exploratory Set 2). Postsurgical, residual enhancing disease was quantified using T1 subtraction maps. Multivariate Cox regression models were used to determine influence of clinical variables, O6-methylguanine-DNA methyltransferase (MGMT) status, and residual tumor volume on OS.

Results: A log-linear relationship was observed between postoperative, residual enhancing tumor volume and OS in newly diagnosed GBM treated with standard chemoradiation. Postoperative tumor volume is a prognostic factor for OS (P < 0.01), regardless of therapy, age, and MGMT promoter methylation status.

Conclusion: Postsurgical, residual contrast-enhancing disease significantly negatively influences survival in patients with newly diagnosed GBM treated with chemoradiation with or without concomitant experimental therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/neuonc/noy053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071654PMC
August 2018

Prospective Feasibility Trial for Genomics-Informed Treatment in Recurrent and Progressive Glioblastoma.

Clin Cancer Res 2018 01 26;24(2):295-305. Epub 2017 Oct 26.

Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.

Glioblastoma is an aggressive and molecularly heterogeneous cancer with few effective treatment options. We hypothesized that next-generation sequencing can be used to guide treatment recommendations within a clinically acceptable time frame following surgery for patients with recurrent glioblastoma. We conducted a prospective genomics-informed feasibility trial in adults with recurrent and progressive glioblastoma. Following surgical resection, genome-wide tumor/normal exome sequencing and tumor RNA sequencing were performed to identify molecular targets for potential matched therapy. A multidisciplinary molecular tumor board issued treatment recommendations based on the genomic results, blood-brain barrier penetration of the indicated therapies, drug-drug interactions, and drug safety profiles. Feasibility of generating genomics-informed treatment recommendations within 35 days of surgery was assessed. Of the 20 patients enrolled in the study, 16 patients had sufficient tumor tissue for analysis. Exome sequencing was completed for all patients, and RNA sequencing was completed for 14 patients. Treatment recommendations were provided within the study's feasibility time frame for 15 of 16 (94%) patients. Seven patients received treatment based on the tumor board recommendations. Two patients reached 12-month progression-free survival, both adhering to treatments based on the molecular profiling results. One patient remained on treatment and progression free 21 months after surgery, 3 times longer than the patient's previous time to progression. Analysis of matched nonenhancing tissue from 12 patients revealed overlapping as well as novel putatively actionable genomic alterations. Use of genome-wide molecular profiling is feasible and can be informative for guiding real-time, central nervous system-penetrant, genomics-informed treatment recommendations for patients with recurrent glioblastoma. .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-17-0963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7516926PMC
January 2018
-->