Daniel George

Positions:

Professor of Medicine

Medicine, Medical Oncology
School of Medicine

Professor in Surgery

Surgery
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1992

Duke University

Medical Resident, Medicine

Johns Hopkins University

Fellow in Medical Oncology, Medicine

Johns Hopkins University

Grants:

Plasma Angiome and Serum Androgens as Predictors of Overall Survival in Metastatic Prostate Cancer

Administered By
Medicine, Medical Oncology
Awarded By
Department of Defense
Role
Collaborator
Start Date
End Date

Alternative splicing and epithelial-mesenchymal plasticity in prostate tumors

Administered By
Molecular Genetics and Microbiology
Awarded By
National Institutes of Health
Role
Collaborating Investigator
Start Date
End Date

Disparities in the Use of Oral Anticancer Agents in Kidney Cancer

Administered By
Population Health Sciences
Awarded By
National Institutes of Health
Role
Investigator
Start Date
End Date

Calithera CX-839-008

Administered By
Duke Cancer Institute
Role
Principal Investigator
Start Date
End Date

A Phase II open-label, Multicenter study of Apalutamide, Abiraterone Acetate and Prednisone in African American and Caucasian men with metastatic castrate-resistant prostate cancer

Administered By
Duke Cancer Institute
Role
Principal Investigator
Start Date
End Date

Publications:

Patterns of response and progression in bone and soft tissue during and after treatment with radium-223 for metastatic castrate-resistant prostate cancer.

BACKGROUND: Radium-223 improves survival and time to first symptomatic skeletal event in symptomatic bone predominant metastatic castrate-resistant prostate cancer (mCRPC). The imaging response to radium-223 has not been well characterized. METHODS: To describe patterns of response and progression with radium-223, we performed a retrospective review of all mCPRC patients who received radium-223 at Duke from 1 June 2013 to 1 June 2015. Radionuclide bone scans obtained at baseline, during, and after treatment were reviewed by two radiologists. The automated bone scan index (aBSI) was generated at each time point using EXINI boneBSI version 2.4. Computed tomography (CT) and magnetic resonance imaging (MRI) clinical radiology reports were reviewed to evaluate for soft tissue, visceral, epidural, and bone progression. Clinical data were abstracted from the electronic health record. RESULTS: We identified 61 men who received at least one dose of radium-223 at Duke during the study period (median, 5 doses; range, 1-6). Among men with imaging during treatment, 2 of 14 (14.3%) had resolution of greater than or equal to 1 lesion on bone scan, 4 of 14 (28.6%) had zero new bone lesions, 10 of 14 (71.4%) had greater than or equal to 1 new bone lesion, 14 of 26 (53.9%) progressed on CT. After radium-223, 6 of 39 (15.4%) had resolution of 1 to 4 bone lesions, 15 of 39 (38.5%) demonstrated zero new bone lesions, 24 of 39 (61.5%) progressed on bone scan, 15 of 37 (40.5%) progressed on CT, and 10 of 34 (29.4%) progressed on both bone scan and CT. No men with zero new bone lesions after radium-223 ultimately progressed in bone alone and only 3 of 15 eventually demonstrated any progression in the bone. aBSI decreased significantly from baseline to after radium-223 among men with zero new bone lesions (median change in aBSI -0.23 [IQR, -1.5, 0.02]) and increased significantly for men with greater than or equal to 1 new postradium bone lesions (median change in aBSI 1.41 [IQR, -0.05, 3.63] [P = 0.018]). CONCLUSIONS: Bone and soft tissue progression during and following radium-223 is common in heavily pretreated men with mCRPC. However, stable disease and responses were observed in a subset of patients and may be associated with durable treatment response in the bone. Prospective studies are needed to further investigate the change in aBSI as a biomarker of bone scan response/stabilization and progression following treatment with radium-223.
Authors
McNamara, MA; Oyekunle, T; Chin, BB; Oldan, J; Anand, A; Ritz, M; Shantzer, L; Anand, M; Armstrong, AJ; George, DJ
MLA Citation
McNamara, Megan Ann, et al. “Patterns of response and progression in bone and soft tissue during and after treatment with radium-223 for metastatic castrate-resistant prostate cancer..” Prostate, vol. 79, no. 10, July 2019, pp. 1106–16. Pubmed, doi:10.1002/pros.23822.
URI
https://scholars.duke.edu/individual/pub1383740
PMID
31045266
Source
pubmed
Published In
Prostate
Volume
79
Published Date
Start Page
1106
End Page
1116
DOI
10.1002/pros.23822

Pharmacodynamic study of radium-223 in men with bone metastatic castration resistant prostate cancer.

BACKGROUND: Radium-223 is a targeted alpha-particle therapy that improves survival in men with metastatic castration resistant prostate cancer (mCRPC), particularly in men with elevated serum levels of bone alkaline phosphatase (B-ALP). We hypothesized that osteomimicry, a form of epithelial plasticity leading to an osteoblastic phenotype, may contribute to intralesional deposition of radium-223 and subsequent irradiation of the tumor microenvironment. METHODS: We conducted a pharmacodynamic study (NCT02204943) of radium-223 in men with bone mCRPC. Prior to and three and six months after radium-223 treatment initiation, we collected CTCs and metastatic biopsies for phenotypic characterization and CTC genomic analysis. The primary objective was to describe the impact of radium-223 on the prevalence of CTC B-ALP over time. We measured radium-223 decay products in tumor and surrounding normal bone during treatment. We validated genomic findings in a separate independent study of men with bone metastatic mCRPC (n = 45) and publicly accessible data of metastatic CRPC tissues. RESULTS: We enrolled 20 men with symptomatic bone predominant mCRPC and treated with radium-223. We observed greater radium-223 radioactivity levels in metastatic bone tumor containing biopsies compared with adjacent normal bone. We found evidence of persistent Cellsearch CTCs and B-ALP (+) CTCs in the majority of men over time during radium-223 therapy despite serum B-ALP normalization. We identified genomic gains in osteoblast mimicry genes including gains of ALPL, osteopontin, SPARC, OB-cadherin and loss of RUNX2, and validated genomic alterations or increased expression at the DNA and RNA level in an independent cohort of 45 men with bone-metastatic CRPC and in 150 metastatic biopsies from men with mCRPC. CONCLUSIONS: Osteomimicry may contribute in part to the uptake of radium-223 within bone metastases and may thereby enhance the therapeutic benefit of this bone targeting radiotherapy.
Authors
Armstrong, AJ; Gupta, S; Healy, P; Kemeny, G; Leith, B; Zalutsky, MR; Spritzer, C; Davies, C; Rothwell, C; Ware, K; Somarelli, JA; Wood, K; Ribar, T; Giannakakou, P; Zhang, J; Gerber, D; Anand, M; Foo, W-C; Halabi, S; Gregory, SG; George, DJ
MLA Citation
Armstrong, Andrew J., et al. “Pharmacodynamic study of radium-223 in men with bone metastatic castration resistant prostate cancer..” Plos One, vol. 14, no. 5, 2019. Pubmed, doi:10.1371/journal.pone.0216934.
URI
https://scholars.duke.edu/individual/pub1386208
PMID
31136607
Source
pubmed
Published In
Plos One
Volume
14
Published Date
Start Page
e0216934
DOI
10.1371/journal.pone.0216934

Cabozantinib versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate or poor risk (Alliance A031203 CABOSUN randomised trial): Progression-free survival by independent review and overall survival update.

BACKGROUND: The randomised phase 2 CABOSUN trial comparing cabozantinib with sunitinib as initial therapy for advanced renal cell carcinoma (RCC) of intermediate or poor risk met the primary end-point of improving progression-free survival (PFS) as assessed by investigator. We report PFS by independent radiology review committee (IRC) assessment, ORR per IRC and updated overall survival (OS). PATIENTS AND METHODS: Previously untreated patients with advanced RCC of intermediate or poor risk by IMDC criteria were randomised 1:1 to cabozantinib 60 mg daily or sunitinib 50 mg daily (4 weeks on/2 weeks off). Stratification was by risk group and presence of bone metastases. RESULTS: A total of 157 patients were randomised 1:1 to cabozantinib (n = 79) or sunitinib (n = 78). Median PFS per IRC was 8.6 months (95% confidence interval [CI] 6.8-14.0) versus 5.3 months (95% CI 3.0-8.2) for cabozantinib versus sunitinib (hazard ratio [HR] 0.48 [95% CI 0.31-0.74]; two-sided p = 0.0008), and ORR per IRC was 20% (95% CI 12.0-30.8) versus 9% (95% CI 3.7-17.6), respectively. Subgroup analyses of PFS by stratification factors and MET tumour expression were consistent with results for the overall population. With a median follow-up of 34.5 months, median OS was 26.6 months (95% CI 14.6-not estimable) with cabozantinib and 21.2 months (95% CI 16.3-27.4) with sunitinib (HR 0.80 [95% CI 0.53-1.21]. The incidence of grade 3 or 4 adverse events was 68% for cabozantinib and 65% for sunitinib. CONCLUSIONS: In this phase 2 trial, cabozantinib treatment significantly prolonged PFS per IRC compared with sunitinib as initial systemic therapy for advanced RCC of poor or intermediate risk. TRIAL REGISTRATION NUMBER: NCT01835158.
Authors
Choueiri, TK; Hessel, C; Halabi, S; Sanford, B; Michaelson, MD; Hahn, O; Walsh, M; Olencki, T; Picus, J; Small, EJ; Dakhil, S; Feldman, DR; Mangeshkar, M; Scheffold, C; George, D; Morris, MJ
URI
https://scholars.duke.edu/individual/pub1308253
PMID
29550566
Source
pubmed
Published In
Eur J Cancer
Volume
94
Published Date
Start Page
115
End Page
125
DOI
10.1016/j.ejca.2018.02.012

Biomarkers of immunotherapy in urothelial and renal cell carcinoma: PD-L1, tumor mutational burden, and beyond.

Immune checkpoint inhibitors targeting the PD-1 pathway have greatly changed clinical management of metastatic urothelial carcinoma and metastatic renal cell carcinoma. However, response rates are low, and biomarkers are needed to predict for treatment response. Immunohistochemical quantification of PD-L1 was developed as a promising biomarker in early clinical trials, but many shortcomings of the four different assays (different antibodies, disparate cellular populations, and different thresholds of positivity) have limited its clinical utility. Further limitations include the use of archival specimens to measure this dynamic biomarker. Indeed, until PD-L1 testing is standardized and can consistently predict treatment outcome, the currently available PD-L1 assays are not clinically useful in urothelial and renal cell carcinoma. Other more promising biomarkers include tumor mutational burden, profiles of tumor infiltrating lymphocytes, molecular subtypes, and PD-L2. Potentially, a composite biomarker may be best but will need prospective testing to validate such a biomarker.
Authors
Zhu, J; Armstrong, AJ; Friedlander, TW; Kim, W; Pal, SK; George, DJ; Zhang, T
MLA Citation
Zhu, Jason, et al. “Biomarkers of immunotherapy in urothelial and renal cell carcinoma: PD-L1, tumor mutational burden, and beyond..” J Immunother Cancer, vol. 6, no. 1, Jan. 2018. Pubmed, doi:10.1186/s40425-018-0314-1.
URI
https://scholars.duke.edu/individual/pub1300103
PMID
29368638
Source
pubmed
Published In
Journal for Immunotherapy of Cancer
Volume
6
Published Date
Start Page
4
DOI
10.1186/s40425-018-0314-1

Phase Ib Trial of Cabazitaxel and Tasquinimod in Men With Heavily Pretreated Metastatic Castration Resistant Prostate Cancer (mCRPC): The CATCH Trial.

BACKGROUND: Tasquinimod is an immunomodulating and anti-antiangiogenic oral agent with anti-prostate cancer activity in preclinical studies and in clinical trials of men with metastatic castration resistant prostate cancer (mCRPC), including single agent activity and in combination with taxanes. We sought to identify the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of tasquinimod in combination with cabazitaxel and prednisone in men with chemorefractory mCRPC. METHODS: Men with mCRPC who had failed prior docetaxel chemotherapy received cabazitaxel 25 mg/m2 every 3 weeks with oral tasquinimod at 1 of 3 escalating dose levels (0.25, 0.5, and 1.0 mg once daily) with prednisone and PEG-filgastrim support, using a 3 + 3 dose escalation design. Treatment continued until progressive disease or unacceptable toxicity. RESULTS: We enrolled 25 men with chemorefractory mCRPC. The RP2D was 0.5 mg tasquinimod based on excess DLTs (two of three men) observed at dose level 3 (1.0 mg) including grade 3 sensory neuropathy and grade 3 atrial fibrillation. Dose level 2 was expanded to 14 men, where 3 DLTs were observed: grade 3 fatigue, grade 4 febrile neutropenia, and grade 3 liver function abnormalities. The proportion of men with a ≥30% PSA decline was 63% and the median composite progression-free survival (PFS) was 8.5 months (95% CI 4.2-16.4 months) based on 12 PFS events. The median number of cycles of cabazitaxel was 6 (range 1-13), with six men receiving >10 cycles. Best overall RECIST responses (CR + PR) were observed in three men (12%), with stable disease in 12 (48%). No pharmacokinetic interactions were observed. CONCLUSIONS: We determined the RP2D of tasquinimod combined with cabazitaxel to be 0.5 mg daily following a 3 week lead-in of tasquinimod 0.25 mg with growth factor support. No unexpected toxicities occurred. Prostate 77: 385-395, 2017. © 2016 Wiley Periodicals, Inc.
Authors
Armstrong, AJ; Humeniuk, MS; Healy, P; Szmulewitz, R; Winters, C; Kephart, J; Harrison, MR; Martinez, E; Mundy, K; Halabi, S; George, D
MLA Citation
Armstrong, Andrew J., et al. “Phase Ib Trial of Cabazitaxel and Tasquinimod in Men With Heavily Pretreated Metastatic Castration Resistant Prostate Cancer (mCRPC): The CATCH Trial..” Prostate, vol. 77, no. 4, 2017, pp. 385–95. Pubmed, doi:10.1002/pros.23277.
URI
https://scholars.duke.edu/individual/pub1149185
PMID
27862097
Source
pubmed
Published In
Prostate
Volume
77
Published Date
Start Page
385
End Page
395
DOI
10.1002/pros.23277