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  • 1
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 29, No. 27 ( 2011-09-20), p. 3611-3619
    Abstract: Despite aggressive therapies, median survival for malignant gliomas is less than 15 months. Patients with unmethylated O 6 -methylguanine–DNA methyltransferase (MGMT) fare worse, presumably because of temozolomide resistance. AdV-tk, an adenoviral vector containing the herpes simplex virus thymidine kinase gene, plus prodrug synergizes with surgery and chemoradiotherapy, kills tumor cells, has not shown MGMT dependency, and elicits an antitumor vaccine effect. Patients and Methods Patients with newly diagnosed malignant glioma received AdV-tk at 3 × 10 10 , 1 × 10 11 , or 3 × 10 11 vector particles (vp) via tumor bed injection at time of surgery followed by 14 days of valacyclovir. Radiation was initiated within 9 days after AdV-tk injection to overlap with AdV-tk activity. Temozolomide was administered after completing valacyclovir treatment. Results Accrual began December 2005 and was completed in 13 months. Thirteen patients were enrolled and 12 completed therapy, three at dose levels 1 and 2 and six at dose level 3. There were no dose-limiting or significant added toxicities. One patient withdrew before completing prodrug because of an unrelated surgical complication. Survival at 2 years was 33% and at 3 years was 25%. Patient-reported quality of life assessed with the Functional Assessment of Cancer Therapy-Brain (FACT-Br) was stable or improved after treatment. A significant CD3 + T-cell infiltrate was found in four of four tumors analyzed after treatment. Three patients with MGMT unmethylated glioblastoma multiforme survived 6.5, 8.7, and 46.4 months. Conclusion AdV-tk plus valacyclovir can be safely delivered with surgery and accelerated radiation in newly diagnosed malignant gliomas. Temozolomide did not prevent immune responses. Although not powered for efficacy, the survival and MGMT independence trends are encouraging. A phase II trial is ongoing.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2011
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  • 2
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 34, No. 3_suppl ( 2016-01-20), p. e287-e287
    Abstract: e287 Background: Growing evidence suggests that specific lifestyle practices (e.g., diet and exercise) may delay cancer progression among prostate cancer survivors (PCS) and restore post-treatment quality of life. However, there are limited efforts to translate this knowledge to sustainable behavior change among PCS at a population level. Methods: TrueNTH is an international partnership to develop innovative evidence-based interventions and care models to improve the physical and mental wellbeing of PCS. Within TrueNTH, four countries (U.S.A., Australia, Canada, U.K.) are developing solutions to improve lifestyle practices among PCS. Australia is implementing face-to-face and telehealth delivery of exercise and dietary programs facilitated by a web-based portal. Canada is implementing group-based exercise and yoga programs combined with a web-based portal to deliver exercise, nutrition and stress-reduction resources for PCS and caregivers. The U.K. is implementing a healthy living pharmacy approach to deliver tailored diet and exercise advice and support to men. The U.S. will implement a scalable web-based portal that reaches PCS, providers and partners and provides personalized exercise prescriptions and dietary advice, interactive guidance, and behavioral support via social media, tele-exercise, and face-to-face communities. Results: TrueNTH initiatives are in various phases of a three-year project. Australia has enrolled 30 of 80 men across 2 sites and via telehealth, and demonstrated acceptance of the portal. Canada has enrolled 30+ men in exercise programs and will soon add 4 sites and launch their portal. The UK has evaluated assessment protocols in 2 sites and will soon add a 3 rd site and implement the pharmacy-based program. The U.S. is building the portal and supportive tools and will begin a trial in Fall 2016. Conclusions: Each TrueNTH program shares common goals to improve lifestyle practices among PCS. Common metrics across initiatives will allow for a global comparison of implementation approaches and assessment of impact at a population level. TrueNTH will utilize this initiative to create a lifestyle survivorship program that improves the lives of PCS worldwide.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2016
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  • 3
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. 5018-5018
    Abstract: 5018 Background: The PARP-inhibitor olaparib is approved for mCRPC patients (pts) with deleterious germline or somatic homologous recombination repair gene mutations (HRRm). PARP1 interacts with androgen signaling, and castration-resistant tumor cells exhibit increased PARP1 activity. Preclinically PARP1-inhibition synergizes with androgen receptor (AR) targeted therapy. BRCAAway is a biomarker selected, randomized, open-label, multicenter phase 2 trial evaluating efficacy of targeting AR vs PARP vs combination in first line mCRPC patients with germline and/or somatic HRRm in BRCA1, BRCA2, or ATM. Methods: Eligible mCRPC pts underwent tumor next generation sequencing and germline testing. Pts with inactivating BRCA1, BRCA2 and/or ATM alterations were randomized 1:1:1 to Arm 1 abiraterone (1000 mg daily) + prednisone (5mg bid) (Abi/pred), Arm 2 olaparib (300 mg bid) or Arm 3 olaparib + Abi/pred. The primary end point is progression-free survival (PFS) analyzed using Kaplan-Meier estimates and Cox regression. Secondary endpoints include measurable disease response rate (RR) by RECIST, PSA-RR, undetectable PSA (≤ 0.2 ng/ml) and toxicity. Arms 1 and 2 pts were allowed to cross over at progression. Pts with other HRRm were treated with olaparib; Arm 4 (ongoing). Results: 161 pts were registered and had NGS testing; 60 pts were randomized to Arms 1-3; to date 59 are evaluable for toxicity and 53 are evaluable for PFS. Baseline median age 67 (range 42-85) years; 54 pts were White, 6 were Black; sites of disease: bone only (n=31), soft tissue only (n=18), bone and soft tissue (n=10); median PSA 14.61 ng/ml (range 0.15-4036.8). Mutational status: BRCA1 only n = 2, BRCA2 only n = 39, ATM only n = 8, and 〉 1 HRRm n = 11. 34 pts had germline and 26 had somatic mutations. Median (range) follow-up time: 8.3 (0.8, 33.3), 12.2 (2.7, 21.8) and 16.8 (2.9, 41.7) months in Arms 1, 2 and 3. 43 pts had treatment-related adverse events; most common were fatigue (23 pts; 1 Grade (G) 3, 22 G1/2), nausea (17 pts, G1/2), and anemia (9 pts, 2 G3, 7 G1/2). ≥50% PSA decline was 79%, 67%, and 85% of pts in Arms 1, 2, and 3, respectively. Median PSA nadir (ng/mL) (95% CI) Arms 1-3: 2.17 (0.44, 49.27), 3.10 (0.83, 12.01), and 0.50 (0.10, 2.13), respectively. Undetectable PSA, median PFS, and 12-month PFS by Arm are listed in the table. Conclusions: In mCRPC pts with inactivating BRCA1, BRCA2 and/or ATM alterations Abi/pred + olaparib was well tolerated and resulted in longer PFS and better PSA response vs either agent alone. Clinical trial information: NCT03012321. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
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  • 4
    In: JCO Clinical Cancer Informatics, American Society of Clinical Oncology (ASCO), , No. 4 ( 2020-11), p. 691-699
    Abstract: As data-sharing projects become increasingly frequent, so does the need to map data elements between multiple classification systems. A generic, robust, shareable architecture will result in increased efficiency and transparency of the mapping process, while upholding the integrity of the data. MATERIALS AND METHODS The American Association for Cancer Research’s Genomics Evidence Neoplasia Information Exchange (GENIE) collects clinical and genomic data for precision cancer medicine. As part of its commitment to open science, GENIE has partnered with the National Cancer Institute’s Genomic Data Commons (GDC) as a secondary repository. After initial efforts to submit data from GENIE to GDC failed, we realized the need for a solution to allow for the iterative mapping of data elements between dynamic classification systems. We developed the Linked Entity Attribute Pair (LEAP) database framework to store and manage the term mappings used to submit data from GENIE to GDC. RESULTS After creating and populating the LEAP framework, we identified 195 mappings from GENIE to GDC requiring remediation and observed a 28% reduction in effort to resolve these issues, as well as a reduction in inadvertent errors. These results led to a decrease in the time to map between OncoTree, the cancer type ontology used by GENIE, and International Classification of Disease for Oncology, 3rd Edition, used by GDC, from several months to less than 1 week. CONCLUSION The LEAP framework provides a streamlined mapping process among various classification systems and allows for reusability so that efforts to create or adjust mappings are straightforward. The ability of the framework to track changes over time streamlines the process to map data elements across various dynamic classification systems.
    Type of Medium: Online Resource
    ISSN: 2473-4276
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
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  • 5
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 33, No. 15_suppl ( 2015-05-20), p. 2010-2010
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2015
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  • 6
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 32, No. 15_suppl ( 2014-05-20), p. 3010-3010
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2014
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  • 7
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. 8583-8583
    Abstract: 8583 Background: Immunotherapy has shown efficacy in the treatment of recurrent, extensive-stage small cell lung cancer (ES-SCLC). In the Checkmate 032 trial, ipilimumab and nivolumab combination therapy resulted in a 21% objective response rate in relapsed SCLC. At present, there are no biomarkers used in clinical practice to predict treatment responsiveness in SCLC. Ipilimumab and nivolumab act by blocking key co-inhibitory immune pathways of CTLA-4 and PD-1/PD-L1, respectively, leading to reinvigoration of anti-tumor cytotoxic T cell responses and a decrease in immune suppressive tumor infiltrating leukocytes. The ratio of intratumor Teff (CD8+) cells to Treg (CD4+/Foxp3+) cells (Teff/Treg) could be a more reliable biomarker than effector cell infiltration alone. Methods: In this open-label, single arm trial, we enrolled patients with ES-SCLC who previously received platinum-based chemotherapy; prior anti-PD-1 /PD-L1 therapy was allowed. Patients were treated with nivolumab 1 mg/kg and ipilimumab 3 mg/kg, for a total of 4 doses each and received nivolumab 480 mg beginning with cycle 5, every 4 weeks until progression, unacceptable toxicity or study discontinuation. On-study biopsies were performed prior to initiation of therapy and during week 4 for the biomarker primary objective—to correlate disease response with intratumor Teff/Treg changes. Secondary objectives include determining ORR, DOR, PFS, and OS. Results: Twenty-two patients (median age 63.5 [range 54-80] years, ECOG 0/1/2 [41%/50%/9%], sex M/F [45%/55%] ) were enrolled and received treatment. Fourteen (64%) had paired biopsies while on treatment. Fifteen patients were evaluable per RECIST with an ORR of 13% (2/15, 2 partial responses [13%]) and DCR was 40% (6/15, 4 stable disease [27%] ). Grade 3 treatment-related adverse events (TRAEs) occurred in 9/22 [40%]. Grade 4 TRAEs occurred in 2/22 [9%] (elevated lipase and elevated bilirubin) and Grade 5 TRAEs occurred in 1/22 patients (hepatic failure). Out of the 9 patients previously treated with anti- PD-1/PD-L1 therapy, 1 had a partial response and 2 had stable disease. Multiplexed quantitative immunofluorescence analysis revealed changes of both CD8+ effector T cells and Tregs in the tumor micro-environment associated with clinical benefit to immunotherapy. Conclusions: Combination immunotherapy with ipilimumab and nivolumab shows clinical efficacy in relapsed extensive-stage SCLC, including those previously treated with anti-PD-1/PDL-1 therapy. Obtaining paired biopsies was shown to be successful in this prospective trial to study the tumor microenvironment in SCLC tumors treated with checkpoint inhibitors. Early biomarker evaluation during week 4 shows local immunomodulatory effect of treatment and supports exploration as predictive biomarker in this population. Clinical trial information: 03670056.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
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  • 8
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 35, No. 6_suppl ( 2017-02-20), p. 145-145
    Abstract: 145 Background: Abiraterone is a CYP17 inhibitor approved for treatment of men with mCRPC. The NCI 9012 trial evaluated abiraterone alone with or without the PARP inhibitor veliparib in mCRPC patients. We hypothesized that germline genetic variation in the androgen axis and other metabolic enzymes would predict response to veliparib + abiraterone vs. abiraterone alone. Methods: A randomized trial cohort of (148) men with advanced mCRPC treated with abiraterone with or without veliparib was genotyped for 120 DNA polymorphisms in genes involved in androgen metabolism using Lifetech Open array chips. Blood for pharmacogenomic SNP analysis were collected at pre-treatment from each subject into 10-mL EDTA tube. Polymorphisms were tested using Cox models without treatment for prognostic testing and with treatment arm for predictive testing. Results: Genotyping was completed in 143 of 148 men; all were treated with abiraterone; 72 without veliparib (Median PFS: 10.3m) and 71 with veliparib (Median PFS: 11.3m). Polymorphisms in separate genes (SLCO2B1, KIF3C CYP19A, ESR1) were significantly (P ≤ .025) associated with progression-free survival (PFS) during abiraterone (q-value 〈 0.69). Polymorphisms in (CYP11A1, HSD17B4, ABHD13;LIG4, CYP19A1, HSD17B4, TRMT11) were predictive for PFS in patients treated with combination of abiraterone/veliparib compared to abiraterone alone (p-value 〈 0.025; q-value 〈 0.28). Conclusions: This analysis examines the influence of inherited variations on the efficacy of abiraterone, establishing the importance of pharmacogenomics on individual’s response to this therapy. Genotyping patients at these loci could be predictive of improved PFS to valiparib in combination with abiraterone. Further analysis of the association of more than one polymorphisms compared to zero or one with PFS associated with improved TTP demonstrated a better response to therapy than individuals carrying zero or one is ongoing. Clinical trial information: NCT01576172.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2017
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  • 9
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 8597-8597
    Abstract: 8597 Background: Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma with poor prognosis. In extensive stage patients, frontline treatment with chemoimmunotherapy shows modest clinical benefit. However, the biological impact of immunotherapy in SCLC is poorly understood with no clear predictive biomarkers to guide patient selection in this setting. Methods: We collected paired baseline (pre-treatment), on-treatment (week 4), and progression biopsies from patients with relapsed advanced-stage SCLC treated with combination nivolumab (nivo) and ipilimumab (ipi) in a single-arm, phase 2 clinical trial (NCT03670056). Nivo 1 mg/kg and ipi 3 mg/kg were administered every 3 weeks for 4 cycles, followed by nivo maintenance until progressive disease (PD) by RECIST 1.1 or treatment-limiting toxicity. Paired pre/on-treatment samples were available from 16/22 patients, as well as 3 biopsies at progression. The tumor samples were studied using whole exome DNA sequencing (including germline DNA) and RNA-sequencing coupled to Ocean Genomics TxomeAI data analysis pipeline. Results: 6/11 evaluable patients had PD; 5 patients showed clinical activity of treatment (3 with stable disease, 2 with partial response). The frequency of deleterious mutations in TP53 and RB1 was 91% and 64%, respectively. Mutations in HLA-A were more common in baseline samples from patients with PD than those with clinical activity. New TP53 and PLEC mutations were found 4 of 6 patients with PD in week 4 samples vs baseline. The baseline tumor mutational burden was not associated with treatment sensitivity and prominently increased in week 4 biopsies of PD patients. All four molecular SCLC transcriptomic subtypes based on the expression of ASCL1, NEUROD1, and POU2F3 were present in the trial with SCLC-A being the most common (9/16 cases). All patients with clinical activity to ipi/nivo were of SCLC-A subtype. 2/16 of cases showed a different molecular subtype after 4 weeks of treatment: one case with SCLC-N switched to SCLC-A and another case converted from SCLC-A to SCLC-N. Comparison of baseline and on-treatment samples showed upregulation of transcripts associated with T-cell activation and PD-1 signaling. In the 3 biopsies at progression, transcriptomic changes included reduction of neutrophil degranulation, type 1/2 interferon and signatures, as well as down-regulation of β-2 microglobulin, while cell cycle and mitotic prophase pathways were overexpressed. Conclusions: Dual checkpoint blockade using nivo/ipi has a prominent immunomodulatory role in extensive stage SCLC characterized by increased local adaptive immune responses, reduced HLA class-I antigen presentation and change in the molecular subtype in a subset of cases. We identified genomic features associated with treatment sensitivity/resistance. Clinical trial information: NCT03670056 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
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  • 10
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 36, No. 7_suppl ( 2018-03-01), p. 104-104
    Abstract: 104 Background: Fatigue is a common and disabling complaint in patients with cancer and can be reduced by exercise. To further personalize exercise prescriptions, moderators of exercise effects on fatigue should be investigated. However, most randomized controlled trials (RCTs) are not adequately powered to identify heterogeneity in responses to exercise. Therefore, we conducted a meta-analysis using individual patient data (IPD) of exercise RCTs to investigate the effect and moderators of exercise on cancer-related fatigue. Methods: Within the Predicting OptimaL cAncer RehabIlitation and Supportive care (POLARIS) consortium, principal investigators of 34 exercise RCTs worldwide have shared their IPD, including in total 4366 cancer patients. A 1-step IPD meta-analysis, using a linear mixed-effect model with a random intercept on study was undertaken to investigate effect on fatigue. The result, a between-group difference in standardized z-scores, corresponds to a Cohen’s d effect size. An interaction term was included in the model to assess potential moderators including demographic (sex, age, marital status, education), clinical (body mass index, distant metastasis), intervention-related (timing, delivery mode, duration) and exercise-related (type, frequency, intensity, duration) characteristics. Results: Exercise significantly reduced fatigue (β = -0.17, 95% CI -0.22;-0.12). The effect was not moderated by demographic, clinical or exercise-related characteristics. Supervised exercise had significantly larger effects on fatigue than unsupervised exercise (β difference = -0.18, 95%CI -0.28;-0.08). Compared to the control group, supervised exercise significantly improved fatigue (β = -0.23, 95%CI = -0.29;-0.17), while unsupervised exercise did not (β = -0.04, 95%CI = -0.13;0.04). Conclusions: Exercise significantly reduces cancer-related fatigue across subgroups formed on the basis of demographic and clinical characteristics. The effect of exercise is significantly larger when performed under supervision. Hence, exercise, and preferably supervised exercise, represents a viable intervention for the prevention and treatment of fatigue among patients with cancer.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2018
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