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Plinabulin following radiation enhances dendritic cell maturation and checkpoint inhibitor retreatment of relapsed/refractory cancers
Lin, Steven H; Subbiah, Vivek; Cohen, Evan N; Li, Ziyi; Lu, Yingjuan June; Son, Ye Lin; Lyu, Yue; Gao, Hui; Jayachandran, Gitanjali; Neri, Shinya; Sharma, Amrish; Fang, Penny; Karp, Daniel; Hong, David; Rodon, Jordi; Yu, Hao; Peng, Jing; Lloyd, G Kenneth; Tonra, James R; Reuben, James M; Huang, Lan; Fu, Siqing
BACKGROUND:Plinabulin exerts immunomodulatory activity through guanine nucleotide exchange factor (GEF)-H1 release from depolymerizing tubulin in the cytoskeleton, leading to dendritic cell (DC) activation. Preclinical studies demonstrated that irradiation potentiates plinabulin-induced DC maturation and, when combined with immune checkpoint inhibitors (ICIs), triggers an abscopal antitumor response via increased tumor-infiltrating DCs and T cells. METHODS:A phase 1 translational study (NCT04902040) of plinabulin plus ICIs after radiation therapy (RT) initiation was conducted in ICI-relapsed/refractory cancers with primary (safety, tolerability, and objective tumor response rate) and secondary (disease control rate [DCR]) endpoints. FINDINGS/RESULTS:This triple regimen was safe and achieved a DCR of 54% (3/13 partial response [PR] and 4/13 stable disease [SD]) in mostly heavily pretreated patients. Responding tumors included non-small cell lung cancer (2/2 PR + SD), head-and-neck squamous cell carcinoma (2/3 PR + SD), and Hodgkin's lymphoma (2/2 PR in patients after 12 or 16 prior lines of therapy). PR + SD patients had significantly higher GEF-H1 immune-activation scores in peripheral blood and intratumorally at pretreatment/baseline and DC activation/T cell clonal expansion post-treatment compared with progressive disease patients. CONCLUSIONS:These preliminary results provide a rationale for testing RT/plinabulin/ICI combination in future post-ICI-failure confirmatory trials. FUNDING/BACKGROUND:This study was funded by BeyondSpring Pharmaceuticals, Inc.
PMID: 40580957
ISSN: 2666-6340
CID: 5881742
Digital biobanks are underutilized in dermatology and create opportunities to reduce the burden of skin disease
Jumonville, Ghislaine; Hong, David; Khan, Atlas; DeWan, Andrew; Leal, Suzanne M; Weng, Chunhua; Petukhova, Lynn
Digital biobanks that integrate genetic data with health data captured by digital sources are used routinely to discover genes, biomarkers, gene–environment interactions and pharmacogenetic relationships across many clinical areas. There remain many opportunities in dermatology to further use biobank data to increase our knowledge about the genetic architecture of skin disease, to resolve disease mechanisms that can be modulated by medical interventions and to discover genetically derived disease relationships that inform on drug repurposing and adverse events. Such knowledge promises to reduce the global burden of skin disease and facilitates the development of tailored medical care.
PMCID:10941321
PMID: 37936310
ISSN: 1365-2133
CID: 5710672
Analysis of protein-coding variation in a national electronic biorepository generates new hypotheses about the genetic basis of various skin disorders [Meeting Abstract]
Hong, D.; Weng, C.; Petukhova, L.
ISI:001276879001186
ISSN: 0022-202x
CID: 5713722
A phase I trial of imexon, a pro-oxidant, in combination with docetaxel for the treatment of patients with advanced breast, non-small cell lung and prostate cancer
Moulder, Stacy; Dhillon, Navneet; Ng, Chaan; Hong, David; Wheler, Jennifer; Naing, Aung; Tse, Susan; La Paglia, Amy; Dorr, Robert; Hersh, Evan; Boytim, Michelle; Kurzrock, Razelle
PURPOSE/OBJECTIVE:Imexon is an iminopyrrolidone that induces apoptosis and has synergistic activity with docetaxel in preclinical models. This trial was designed to establish the maximum tolerated dose (MTD) of imexon given with docetaxel in breast, prostate and non-small cell lung cancer (NSCLC). PATIENTS AND METHODS/METHODS:34 patients received protocol therapy. 26 patients received escalating doses of imexon given intravenously over 60 min on days 1-5 every 21 days. Docetaxel was administered intravenously at a fixed dose of 75 mg/m(2) immediately following imexon on day 1 every 21 days. A 3+3 design was used with eight additional patients treated at MTD. Response was measured using RECIST. RESULTS:Seven dose levels of imexon were evaluated (390 mg/m(2) to 1,700 mg/m(2)). The MTD was imexon 1,300 mg/m(2) IV on days 1-5 in combination with docetaxel. Dose limiting toxicities were grade 3 non-cardiac chest pain and grade 3 diarrhea. Activity was seen in 4 patients [2 partial responses (NSCLC (PR=1), prostate cancer (PR=1)), 2 minor responses (MR=breast, NSCLC)]. Eleven patients had stable disease by RECIST (including the patients with MR; prostate cancer=6, NSCLC=3). Six (one with breast cancer, two with prostate cancer and three with NSCLC) demonstrated stable disease (SD) for > or = 3 months. CONCLUSION/CONCLUSIONS:The MTD of combination therapy is imexon 1,300 mg/m(2) IV on days 1-5 with docetaxel 75 mg/m(2) IV on day 1 of a 21 day treatment cycle. Demonstrated responses warrant further investigation in phase II trials of which a phase II trial in NSCLC is planned.
PMID: 19499186
ISSN: 1573-0646
CID: 5449412
Clinical outcomes and factors predicting development of venous thromboembolic complications in patients with advanced refractory cancer in a Phase I Clinic: the M. D. Anderson Cancer Center experience
Vemulapalli, Sushma; Chintala, Lakshmi; Tsimberidou, Apostolia-Maria; Dhillon, Navjot; Lei, Xiudong; Hong, David; Kurzrock, Razelle
Venous thromboembolism (VTE) is common in patients with advanced cancer and may influence patient eligibility for clinical studies, quality of life, and survival. We reviewed the medical records of 220 consecutive patients seen in the Phase I Clinical Trials Program at M. D. Anderson Cancer Center to determine the frequency of VTE, associated characteristics, and clinical outcomes. Twenty-three (10.5%) patients presenting to the Phase I Clinic had a history of VTE; 26 (11.8%) patients subsequently developed VTE, with a median follow-up of 8.4 months. These included nine (39%) patients with and 17 (8.6%) without a history of VTE (P < 0.0001). The most common events were deep venous thromboses of the extremities and pulmonary emboli. The median survival of patients with and without a history of VTE was 4.7 and 10.9 months, respectively (P = 0.0002). Multivariate analysis demonstrated that a history of VTE (P < 0.0001), pancreatic cancer (P = 0.007), and platelet count >440 x 10(9)/L (P = 0.026) predicted new VTE episodes. In conclusion, this retrospective analysis demonstrated that a history or new development of VTE was noted in 40 (18%) of 220 patients seen in our Phase I Clinic. A prognostic score that can be used to predict time to development of and frequency of VTE is proposed. Am. J. Hematol. 2009. (c) 2009 Wiley-Liss, Inc.
PMID: 19437507
ISSN: 1096-8652
CID: 5449382
Age-stratified phase I trial of a combination of bortezomib, gemcitabine, and liposomal doxorubicin in patients with advanced malignancies [Meeting Abstract]
Falchook, G. S.; Dhillon, N.; Moulder, S.; Duvic, M.; Ng, C.; Hong, D.; Camacho, L.; Lim, J.; Wang, M.; Fayad, L.; Kurzrock, R.
ISI:000455043703380
ISSN: 0732-183x
CID: 5449432