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  • 1
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 34, No. 15_suppl ( 2016-05-20), p. 9069-9069
    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
    detail.hit.zdb_id: 2005181-5
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  • 2
    In: Cancers, MDPI AG, Vol. 12, No. 9 ( 2020-09-16), p. 2636-
    Abstract: The pace of clinical trial data generation and publication is an area of interest within clinical oncology; however, little is known about the dynamics and covariates of time to reporting (TTR) of trial results. To assess these, ClinicalTrials.gov was queried for phase three clinical trials for patients with metastatic solid tumors, and the factors associated with TTR from enrollment completion to publication were analyzed. Based on the 319 included trials, cooperative-group-sponsored trials were reported at a slower rate than non-cooperative-group trials (median 37.5 vs. 31.0 months; p 〈 0.001), while industry-funded studies were reported at a faster rate than non-industry-supported trials (31.0 vs. 40.0 months; p = 0.005). Furthermore, successful trials (those meeting their primary endpoint) were reported at a faster rate than unsuccessful studies (27.5 vs. 36.0 months; p 〈 0.001). Multivariable analysis confirmed that industry funding was independently associated with a shorter TTR (p = 0.006), while cooperative group sponsorship was not associated with a statistically significant difference in TTR (p = 0.18). These data underscore an opportunity to improve cooperative group trial efficiency by reducing TTR.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2527080-1
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  • 3
    In: European Journal of Cancer, Elsevier BV, Vol. 136 ( 2020-09), p. 176-185
    Type of Medium: Online Resource
    ISSN: 0959-8049
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    Language: English
    Publisher: Elsevier BV
    Publication Date: 2020
    detail.hit.zdb_id: 1120460-6
    detail.hit.zdb_id: 1468190-0
    detail.hit.zdb_id: 82061-1
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  • 4
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 35, No. 15_suppl ( 2017-05-20), p. 10034-10034
    Abstract: 10034 Background: Senior adults ≥ 65 yrs remain underrepresented in early phase clinical trials in particular trials with novel immunotherapies. One general limitation to enrollment is the concern for immune-related toxicities in the context of older age and comorbidities. We analyzed the enrollment and incidence of toxicities of seniors in comparison to mid age and adolescent/young adult (AYA) pts enrolled in phase 1 immunotherapy trials. Methods: We identified 422 consecutive pts w advanced cancer treated on immunotherapy-based phase I trials bw 04/2009-09/2015. We divided pts into 3 cohorts based on age at start of trial (AYA 15-39y, mid age 40-64y, seniors 65y+) and collected pt/disease characteristics and immune-related adverse events (irAE) including endocrinopathies, diarrhea/colitis, pneumonitis, constitutional (eg fatigue, fever, anorexia), myalgia, and dermatitis. Results: Of 422 patients treated, 116 were seniors (27%, median 70y), 50 AYA (12%, median 30y), 256 mid age (61%, median 56y). Most common cancers were GI (n = 108, 26%), thoracic/head/neck (n = 84, 20%), GU (n = 54, 13%), and GYN (n = 47, 11%). Median PFS was comparable in all 3 cohorts (2.4m seniors, 2.1m AYA, 2.1m mid age). The incidence of irAE was higher in elderly than mid age or AYA (low grade [G1/2] 49% vs 34% vs 34%, p 0.02; high grade [G3/4] 19% vs 11% vs 12%. p 0.14). When comparing irAE rates of seniors to AYA and mid age pts, the odds ratio of high grade events was 1.81 (95% CI 1.01, 3.24; p 0.05) and low grade events was 1.85 (95% CI 1.20, 2.85; p 0.0055). Most common G1/2 irAE among all cohorts was fatigue (n = 76, 18%), dermatitis (n = 59, 14%), fever (n = 29, 7%) and anorexia (n = 28, 7%) with seniors having a greater incidence of low grade fatigue (25% vs 15%, OR 1.84, 95% CI 1.09, 3.10, p 0.025). Conclusions: Senior adults accounted for 〈 1/3 of pts on immunotherapy-based phase I trials. When compared to mid age and AYA pts, seniors had a higher likelihood of experiencing a toxicity. Early phase immunotherapy trials may be an option for older adults but with a particular vigilance for adverse events in this population.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2017
    detail.hit.zdb_id: 2005181-5
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  • 5
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 34, No. 15_suppl ( 2016-05-20), p. 9073-9073
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2016
    detail.hit.zdb_id: 2005181-5
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  • 6
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 35, No. 31_suppl ( 2017-11-01), p. 152-152
    Abstract: 152 Background: Older adults (65y+) with cancer are underrepresented in trials of novel drugs notably in phase I clinical trials with immunotherapies. The trepidation over immune-related toxicities in the context of older age and associated comorbidities may function as a barrier to participation. To that end, we investigated the enrollment and incidence of immune related adverse events of older adults enrolled in phase 1 immunotherapy trials. Methods: We identified 422 consecutive pts w advanced cancer treated on immunotherapy-based phase I trials bw 04/2009-09/2015, and collected pt/disease characteristics and immune-related adverse events (irAE) such as endocrinopathies, diarrhea/colitis, pneumonitis, constitutional (fatigue, fever, anorexia), myalgia, and dermatitis. Results: Older adults comprised 27% of trial participants (116 of 422 pts, median age 70y) while 256 pts were mid age (61%, median 56y). Most common cancers were GI (n = 108, 26%), thoracic/head/neck (n = 84, 20%), GU (n = 54, 13%), and GYN (n = 47, 11%). Median PFS was comparable among older pts (2.4m) and mid age (2.1m). Older adults had a higher incidence of irAE than mid age (low grade [G1/2] 49% vs 34%, p 0.02; high grade [G3/4] 19% vs 11%. p 0.14). The odds ratio of high grade events among older adults vs mid age pts was 1.81 (95% CI 1.01, 3.24; p 0.05) and low grade events was 1.85 (95% CI 1.20, 2.85; p 0.0055). Most common G1/2 irAE among all patients was fatigue (n = 76, 18%), dermatitis (n = 59, 14%), fever (n = 29, 7%) and anorexia (n = 28, 7%) with older adults having a greater incidence of low grade fatigue (25% vs 15%, OR 1.84, 95% CI 1.09, 3.10, p 0.025). Conclusions: Older adult participation remained under 30% for immunotherapy-based phase I trials. This early analysis suggests a higher incidence of toxicities among older adults, which calls for the urgent integration of comprehensive supportive care strategy to guide seniors through therapy. This work lays the foundation for future studies investigating the early involvement of supportive care through treatment on early phase clinical trials with immunotherapeutic agents.
    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
    detail.hit.zdb_id: 2005181-5
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  • 7
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 3997-3997
    Abstract: Background: Despite the rising incidence of sarcoma in the geriatric population, there is a paucity of older adults enrolled on clinical trials. Whether older sarcoma patients treated on early phase clinical trials have any meaningful differences in clinical benefit or survival outcomes compared to younger patients remains unknown. Methods: We analyzed clinical and next generation sequencing data from sarcoma patients treated on phase 1 trials at MD Anderson Cancer Center (MDACC) and performed logistic and Cox proportional hazards regression analyses to compare response rate (RR), median time to progression (mTTP), clinical benefit rate (CBR; defined as CR, PR, or SD & gt; 6 months), and median overall survival (mOS) between patients younger and older than 65 years of age. Results: Among the 406 patients with advanced sarcomas (321 soft tissue sarcoma, 85 bone sarcomas) treated on phase 1 trials at MDACC from May 2006 to May 2018, median age was 53 (range 11-84), 48% were female, and patients had a median 3 prior lines of therapy (range 0-9). The most commonly treated soft tissue sarcoma subtypes included leiomyosarcoma (n=66; 16%), liposarcoma (n=52; 13%), GIST (n=44; 11%), UPS (n=14; 3%), and synovial sarcoma (n=11; 3%) and most commonly treated bone sarcomas included osteosarcoma (n=34; 8%), chondrosarcoma (n=28; 7%), and Ewing’s sarcoma (n=25; 6%). 25% (n=102) of sarcoma patients treated on phase 1 protocols were age 65 or older. RR in patients younger than 65 years was 7% compared to 8% in those 65 or older, odds ratio 1.21 (95% CI 0.52, 2.83), p=0.66. mTTP for patients younger than 65 was 2.7 months compared to 3.7 months in those 65 or older, hazard ratio 0.90 (95% CI 0.72, 1.14), p=0.39. CBR in patients younger than 65 years was 22% compared to 31% in those 65 or older, odds ratio 1.65 (95% CI 1.00, 2.72), p=0.05. mOS in patients younger than 65 years was 16.1 months compared to 20.0 months in those 65 years or older, hazard ratio 1.08 (95% CI 0.80, 1.46), p=0.61. Conclusion: Heavily pretreated, metastatic sarcoma patients aged 65 or older enrolled on phase 1 studies at MDACC had no significant differences in response rate, time to progression, and overall survival compared to their younger counterparts. In fact, older sarcoma patients demonstrated an improved clinical benefit rate compared to younger patients. Older patients should be encouraged to enroll on early phase clinical trials when clinically appropriate and broad eligibility criteria for such studies are needed to ensure older sarcoma patients are not excluded from these trials. Citation Format: Shiraj Sen, Roberto C. Pestana, Kenneth Hess, David S. Hong, Ishwaria M. Subbiah, Anthony Conley, Gerald S. Falchook, Robert S. Benjamin, Shreyas Patel, Funda Meric-Bernstam, Vivek Subbiah. Outcomes of geriatric sarcoma patients enrolled in phase 1 clinical trials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3997.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 8
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 604-604
    Abstract: Background: Patients with advanced carcinoma of unknown primary (CUP) have limited effective therapeutic options given the challenges of phenotypic and genotypic diversity. To identify future novel therapeutic strategies we conduct an ongoing exploratory analysis of next-generation sequencing (NGS) of relapsed, refractory CUP. Methods: We identified CUP patients referred to our phase I clinic with adequate FFPE sections from archival tissue for a targeted CLIA-certified NGS assay (Foundation One, MA). Over 2000 exons of 186 cancer-related genes plus over 30 introns from 14 genes often rearranged in cancer were fully sequenced for point mutations, insertions/deletions, copy number alterations (CNAs) and select gene fusions. Results: Of 19 patients seen (10 male, 9 female; median age at diagnosis 49 years), 17 demonstrated genomic alterations (median 3 aberrations/tumor, range 0 - 10); two patients had no reportable genomic alterations. Of the 71 detected aberrations, 17 (24%) have been implicated in impaired cell cycle regulation and arrest; specifically in genes which encode the cyclin-dependent kinases (CDK12 Q570*, CDKN2A/B loss, CDKN2A p16INK4a loss and p14ARF exon 2-3 loss) or their associated proteins including amplification of CCND1 and CCNE1 (n = 3). Of these 8 patients with impaired cell cycle regulation, 5 (63%) demonstrated concurrent mutations associated with epigenetic deregulation and impaired DNA methylation, most commonly ARID1A Y1211fs*5 and S1929fs*25, which encodes the AT-rich interactive domain-containing protein 1A, Arid1a, a member of the SWI/SNF chromatin remodeling complex); other mutations observed are CREBBP S893L (encoding a ubiquitously expressed transcriptional coregulatory protein controlling chromatin remodeling via its histone acetyltransferase activity); MLL2 R4904* (encoding an H3K4-specific histone methyltransferase) and KDM6A S466* (encoding the histone H3 lysine 27 demethylase UTX). Overall 5 of 19 (26%) patients with advanced relapsed CUP demonstrated a profile of aberrations that concurrently impact cell cycle arrest and epigenetic regulation. Conclusion: Through NGS-based molecular profiling, we can a subset of patients with advanced carcinoma of unknown primary with coexisting mutations leading to impaired cell cycle arrest and epigenetic deregulation, highlighting a therapeutic combination with a cell cycle inhibitor (such as Cdk4/6 inhibitors currently in clinical trial) and histone deacetylase inhibitors. Note: This abstract was not presented at the meeting. Citation Format: Ishwaria M. Subbiah, Gauri Varadhachary, Apostolia M. Tsimberidou, Jennifer J. Wheler, Vivek Subbiah, Filip Janku, Sinchita Roy Chowdhuri, Ralph Zinner, David S. Hong. Impaired cell cycle arrest with concurrent epigenetic deregulation identified through next generation sequencing in patients with advanced carcinoma of unknown primary: Implications for personalized medicine. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 604. doi:10.1158/1538-7445.AM2015-604
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 9
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 4263-4263
    Abstract: Background: Relapsed refractory colorectal adenocarcinoma (CRC) is evolving as a disease with distinct molecular subsets rather than a singular histology. Given the varied outcomes of CRC patients treated on clinical trials particularly with targeted therapies, we aimed to identify a molecular phenotype for future therapeutic targeting. Methods: We identified CRC patients referred to our Phase I clinic with adequate tissue for next generation sequencing (NGS) on a commercially available platform (FoundationOne, Boston, MA). Over 2000 exons of 186 cancer-related genes plus over 30 introns from 14 genes often rearranged in cancer were fully sequenced for point mutations, insertions/deletions, copy number alterations (CNAs) and select gene fusions. Results: Overall, 60 relapsed CRC patients (31 male, 29 female; median age 55 years; 56 colon primary, 4 rectum primary). 48 (80%) patients had a mutation linked to aberrant Wnt pathway signaling (most commonly, APC 43 pts, 90%). Of these 48 patients, over half (n = 26, 54%) demonstrated a concurrent mutation affecting the PI3K cascade (PIK3CA in 12 patients [4 E545K, 3 Q546K, 2 E542K, 1 H1047Y, 1 E453K, 1 R38C]). Of these 26 pts with concurrent aberrant Wnt and PI3K pathways, 22 also demonstrated a concomitant MAPK pathway mutation (17 KRAS and 3 BRAF). Of the 60 CRC pts overall, 22 (37%) patients had coexisting aberrations linked to in all three (Wnt, PI3K, and MAPK) cascades. Conclusions: Concomitant mutations in three pathways (Wnt, MAPK, PI3K) implicated in cancer occur frequently in patients with advanced CRC, emphasizing the need for a combinatorial therapeutic strategy ideally targeting all three cascades. Note: This abstract was not presented at the meeting. Citation Format: Ishwaria M. Subbiah, Filip Janku, Apostolia M. Tsimberidou, Aung Naing, Vivek Subbiah, Jennifer J. Wheler, Ralph Zinner, Cathy Eng, Michael J. Overman, Scott Kopetz, David S. Hong. Concurrent aberrations in the Wnt, MAPK and PI3K pathways identified through next generation sequencing of relapsed refractory colorectal adenocarcinoma (CRC): Implications for future therapeutic trials. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4263. doi:10.1158/1538-7445.AM2015-4263
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 10
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 48-48
    Abstract: Background: Fibrolamellar hepatocellular carcinoma (FLHCC) is an extremely rare malignancy predominantly affecting adolescents and young adults without underlying chronic liver disease. Its molecular profile is poorly defined. Given limited effective therapeutic options, we characterized the molecular profiles of patients with advanced FLHCC treated with novel targeted therapies on phase I clinical trials. Methods: Of over 3400 pts with advanced malignancies seen in the Phase I clinic, we identified 12 FLHCC pts (0.4 %). We performed single gene-PCR based testing for oncogenic mutations in KRAS, NRAS, BRAF, CKIT, EGFR, PIK3CA, MET, GNAQ, TP53, IHC for PTEN loss, ALK-1, estrogen receptor (ER) and FISH for her2/neu, cMET amplification and ALK-1 rearrangement on patients with adequate available tissue in the MD Anderson CLIA-certified lab. Additionally next-generation sequencing from FFPE sections using a targeted NGS assay in a CLIA laboratory (Foundation One, MA) was completed on two patients. Over 2000 exons of 186 cancer-related genes plus over 30 introns from 14 genes often rearranged in cancer were fully sequenced for point mutations, insertions/deletions, copy number alterations (CNAs) and select gene fusions. Results: Abnormal expression of the tumor suppressor gene PTEN was shown in 2 of 4 (50%) tested pt's tumors. The first patient's tumor shows overt PTEN loss on IHC while the second pt's tumor showed very weak cytoplasmic staining for PTEN. Interruptions of PTEN functions result in loss of negative regulation of AKT and its downstream components including mTOR. Single gene-based PCR sequencing for oncogenic mutations and the remainder of the tests using IHC and FISH were negative. Next generation sequencing of two pts revealed a missense mutation in FBXW7-E192A in one pt. The second pt's NGS profile did not reveal any actionable mutations. E192A is a missense mutation that occurs prior to the F-box domain and the highly conserved WD40 repeat region, which plays a role in substrate recognition. Mao et al (Science 2008) have reported that FBXW7 targets mTOR for degradation and cooperates with PTEN in tumor suppression and tumor cell lines harboring mutations in FBXW7 demonstrated particular sensitivity to rapamycin. . Conclusion: With thorough comprehensive molecular profiling, we can identify potential actionable aberrations in a subset of advanced FL-HCC patients. Herein we identified activation of the PI3K/AKT/MTOR pathway by PTEN loss and missense mutation in FBXW7. Further matching patients to these actionable aberrations is underway, thereby translating these therapeutic targets to the bedside with the development of novel targeted therapies. Citation Format: Ishwaria M. Subbiah, Filip Janku, Aung Naing, Siqing Fu, David S. Hong, Ahmed O. Kaseb, Cynthia Herzog, Razelle Kurzrock, Robert A. Wolff, Robert A. Wolff, Vivek Subbiah. Theranostic profiling of adolescents and young adults (AYA) with advanced fibrolamellar hepatocellular carcinoma identifies aberrant activation of the PI3K/AKT/MTOR signaling cascade. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 48. doi:10.1158/1538-7445.AM2013-48 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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