Browsing by Author "Fleming, Gini F."

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    Effects of Slide Storage on Detection of Molecular Markers by IHC and FISH in Endometrial Cancer Tissues From a Clinical Trial: An NRG Oncology/GOG Pilot Study
    (Wolters Kluwer, 2022) Grushko, Tatyana A.; Filiaci, Virginia L.; Montag, Anthony G.; Apushkin, Marsha; Gomez, Maria J.; Monovich, Laura; Ramirez, Nilsa C.; Schwab, Carlton; Kesterson, Joshua P.; Seward, Shelly M.; Method, Michael W.; Olopade, Olufunmilayo I.; Fleming, Gini F.; Birrer, Michael J.; Medicine, School of Medicine
    We performed a pilot study in anticipation of using long-aged precut formalin fixed paraffin embedded (FFPE) tissue sections stored in real-world conditions for translational biomarker studies of TOP2A, Ki67, and HER2 in endometrial cancer. FFPE tissue blocks or unstained slides or both from GOG-0177 were collected centrally (1999-2000) and stored at room temperature. During 2004-2011 specimens were stored at 4°C. Matched pairs of stored slides and freshly cut slides from stored blocks were analyzed for TOP2A (KiS1), Ki67 (MIB1) and HER2 (Herceptest™) proteins. To assess DNA stability (HER2 PathVision), FISH was repeated on stored slides from 21 cases previously shown to be HER2-amplified. IHC staining intensity and extent, mean FISH copies/cell, and copy number ratios were compared using the kappa statistic for concordance or signed rank test for differences in old cut versus new cut slides. IHC results reflected some protein degradation in stored slides. The proportion of cells with TOP2A staining was lower on average by 12% in older sections (p=.03). The proportion of Ki67 positive cells was lower in stored slides by an average of 10% (p<.01). Too few cases in the IHC cohort were FISH positive for any conclusions. HER2 amplification by FISH was unaffected by slide storage. We conclude that use of aged stored slides for proliferation markers TOP2A and Ki67 is feasible but may modestly underestimate true values in endometrial cancer. Pilot studies for particular storage conditions/durations/antigens to be used in translational studies are warranted.
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    A pharmacodynamic study of sirolimus and metformin in patients with advanced solid tumors
    (Springer, 2018-08) Sehdev, Amikar; Karrison, Theodore; Zha, Yuanyuan; Janisch, Linda; Turcich, Michelle; Cohen, Ezra E. W.; Maitland, Michael; Polite, Blase N.; Gajewski, Thomas F.; Salgia, Ravi; Pinto, Navin; Bissonnette, Marc B.; Fleming, Gini F.; Ratain, Mark J.; Sharma, Manish R.; Medicine, School of Medicine
    Background Sirolimus is a mammalian target of rapamycin (mTOR) inhibitor. Metformin may potentiate mTOR inhibition by sirolimus while mitigating its adverse effects. We conducted a pilot study to test this hypothesis. Methods Patients with advanced solid tumor were treated with sirolimus for 7 days followed by randomization to either sirolimus with metformin (Arm A) or sirolimus (Arm B) until day 21. From day 22 onwards, all patients received sirolimus and metformin. The primary aim was to compare the change in phospho-p70S6K (pp70S6K) in peripheral blood mononuclear cells (PBMC) from day 8 to day 22 using a two-sample t test. Secondary aims were objective response rate, toxicity, and other serum pharmacodynamic biomarkers (e.g., fasting glucose, triglycerides, insulin, C-peptide, IGF-1, IGF-1R, IGF-BP, and leptin). Results 24 patients were enrolled, with 18 evaluable for the primary endpoint. There was no significant difference in mean change in pp70S6K in arm A vs. arm B (− 0.12 vs. − 0.16; P = 0.64). Similarly, there were no significant differences in other serum pharmacodynamic biomarkers. There were no partial responses. There were no dose-limiting or unexpected toxicities. Conclusions Adding metformin to sirolimus, although well tolerated, was not associated with significant changes in pp70S6K in PBMC or other serum pharmacodynamic biomarkers. Impact: Combining metformin with sirolimus did not improve mTOR inhibition.
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    A Randomized Phase II Trial of Epigenetic Priming with Guadecitabine and Carboplatin in Platinum-resistant, Recurrent Ovarian CancerA Randomized Phase II Trial of Epigenetic Priming with Guadecitabine and Carboplatin in Platinum-resistant, Recurrent Ovarian Cancer
    (American Association for Cancer Research, 2020-03-01) Oza, Amit M.; Matulonis, Ursula A.; Secord, Angeles Alvarez; Nemunaitis, John; Roman, Lynda D.; Blagden, Sarah P.; Banerjee, Susana; McGuire, William P.; Ghamande, Sharad; Birrer, Michael J.; Fleming, Gini F.; Markham, Merry Jennifer; Hirte, Hal W.; Provencher, Diane M.; Basu, Bristi; Kristeleit, Rebecca; Armstrong, Deborah K.; Schwartz, Benjamin; Braly, Patricia; Hall, Geoff D.; Nephew, Kenneth P.; Jueliger, Simone; Oganesian, Aram; Naim, Sue; Hao, Yong; Keer, Harold; Azab, Mohammad; Matei, Daniela; Anatomy and Cell Biology, School of Medicine
    PURPOSE: Platinum resistance in ovarian cancer (OC) is associated with epigenetic modifications. Hypomethylating agents (HMAs) have been studied as carboplatin re-sensitizing agents in OC. This randomized phase 2 trial compared guadecitabine, a second generation HMA, and carboplatin (G+C) against second-line chemotherapy in women with measurable or detectable platinum-resistant OC. PATIENTS AND METHODS: Patients received either G+C (guadecitabine 30 mg/m2 SC once-daily for 5 days and carboplatin) or treatment of choice (TC; topotecan, pegylated liposomal doxorubicin, paclitaxel, or gemcitabine) in 28-day cycles until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints were RECIST v1.1 and CA-125 response rate, 6-month PFS, and overall survival (OS). RESULTS: Of 100 patients treated, 51 received G+C and 49 received TC, of which 27 crossed over to G+C. The study did not meet its primary endpoint as the median PFS was not statistically different between arms (16.3 weeks vs 9.1 weeks in the G+C and TC groups, respectively; P = 0.07). However, the 6-month PFS rate was significantly higher in the G+C group (37% vs. 11% in TC group; P = 0.003). The incidence of grade 3 or higher toxicity was similar in G+C and TC groups (51% and 49%, respectively), with neutropenia and leukopenia being more frequent in the G+C group. CONCLUSIONS: Although this trial did not show superiority for PFS of G+C versus TC, the 6-month PFS increased in G+C treated patients. Further refinement of this strategy should focus on identification of predictive markers for patient selection.
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    Translational randomized phase II trial of cabozantinib in combination with nivolumab in advanced, recurrent, or metastatic endometrial cancer
    (BMJ, 2022-03) Lheureux, Stephanie; Matei, Daniela E.; Konstantinopoulos, Panagiotis A.; Wang, Ben X.; Gadalla, Ramy; Block, Matthew S.; Jewell, Andrea; Gaillard, Stephanie L.; McHale, Michael; McCourt, Carolyn; Temkin, Sarah; Girda, Eugenia; Backes, Floor J.; Werner, Theresa L.; Duska, Linda; Kehoe, Siobhan; Colombo, Ilaria; Wang, Lisa; Li, Xuan; Wildman, Rachel; Soleimani, Shirin; Lien, Scott; Wright, John; Pugh, Trevor; Ohashi, Pamela S.; Brooks, David G.; Fleming, Gini F.; Obstetrics and Gynecology, School of Medicine
    Background Combining immunotherapy and antiangiogenic agents is a promising treatment strategy in endometrial cancer. To date, no biomarkers for response have been identified and data on post-immunotherapy progression are lacking. We explored the combination of a checkpoint inhibitor (nivolumab) and an antiangiogenic agent (cabozantinib) in immunotherapy-naïve endometrial cancer and in patients whose disease progressed on previous immunotherapy with baseline biopsy for immune profiling. Patients and methods In this phase II trial (ClinicalTrials.gov NCT03367741, registered December 11, 2017), women with recurrent endometrial cancer were randomized 2:1 to nivolumab with cabozantinib (Arm A) or nivolumab alone (Arm B). The primary endpoint was Response Evaluation Criteria in Solid Tumors-defined progression-free survival (PFS). Patients with carcinosarcoma or prior immune checkpoint inhibitor received combination treatment (Arm C). Baseline biopsy and serial peripheral blood mononuclear cell (PBMC) samples were analyzed and associations between patient outcome and immune data from cytometry by time of flight (CyTOF) and PBMCs were explored. Results Median PFS was 5.3 (90% CI 3.5 to 9.2) months in Arm A (n=36) and 1.9 (90% CI 1.6 to 3.4) months in Arm B (n=18) (HR=0.59, 90% CI 0.35 to 0.98; log-rank p=0.09, meeting the prespecified statistical significance criteria). The most common treatment-related adverse events in Arm A were diarrhea (50%) and elevated liver enzymes (aspartate aminotransferase 47%, alanine aminotransferase 42%). In-depth baseline CyTOF analysis across treatment arms (n=40) identified 35 immune-cell subsets. Among immunotherapy-pretreated patients in Arm C, non-progressors had significantly higher proportions of activated tissue-resident (CD103+CD69+) ɣδ T cells than progressors (adjusted p=0.009). Conclusions Adding cabozantinib to nivolumab significantly improved outcomes in heavily pretreated endometrial cancer. A subgroup of immunotherapy-pretreated patients identified by baseline immune profile and potentially benefiting from combination with antiangiogenics requires further investigation.