Jeffrey Clarke

Positions:

Assistant Professor of Medicine

Medicine, Medical Oncology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 2008

Indiana University, School of Medicine

Categorical Internal Medicine Residency, Medicine

Duke University School of Medicine

Hematology and Medical Oncology Fellowship, Medicine

Duke University School of Medicine

Internal Medicine Chief Resident, Medicine

Duke University School of Medicine

Grants:

A Phase II Clinical Trial of Combination Nivolumab (Opdivo), Ipilimumab (Yervoy), and Taxane in Patients with Untreated Metastatic Non-Small Cell Lung Cancer (NSCLC) (The OPTIMAL Trial)

Administered By
Duke Cancer Institute
Awarded By
Bristol-Myers Squibb Company
Role
Principal Investigator
Start Date
End Date

A Phase 2 Study of Poziotinib in Patients with Non-Small Cell Lung Cancer, Locally Advanced or Metastatic, with EGFR or HER2 Exon 20 Insertion Mutation (POZITIVE20-1)

Administered By
Duke Cancer Institute
Awarded By
Spectrum Pharmaceuticals, Inc
Role
Principal Investigator
Start Date
End Date

A Phase 1 Dose Escalation and Phase 2 Randomized, Open-Label Study of Nivolumab and Veliparib in Combination with Platinum Doublet Chemotherapy in Subjects with Metastatic or Advanced Non-Small Cell Lung Cancer (NSCLC)

Administered By
Duke Cancer Institute
Awarded By
AbbVie Inc.
Role
Principal Investigator
Start Date
End Date

An open-label Phase I dose-escalation study to evaluate the safety, tolerability, max. tolerated dose, pharmacokinetics,and pharmacodynamics of the anti-C4.4a antibody drug conjugate BAY 1129980 in subjects w/ advanced solid tumors known to expressC4

Administered By
Duke Cancer Institute
Awarded By
Bayer HealthCare AG
Role
Principal Investigator
Start Date
End Date

A screening protocol to determine tumor antigen expression and HLA sub-type ofr eligibility determination for clinical trials evaluating the safety and efficacy of Autologous T Cell expressing enhance

Administered By
Duke Cancer Institute
Awarded By
Adaptimmune Limited
Role
Principal Investigator
Start Date
End Date

Publications:

Potentially functional genetic variants in PLIN2, SULT2A1 and UGT1A9 genes of the ketone pathway and survival of nonsmall cell lung cancer.

The ketone metabolism pathway is a principle procedure in physiological homeostasis and induces cancer cells to switch between glycolysis and oxidative phosphorylation for energy production. We conducted a two-phase analysis for associations between genetic variants in the ketone metabolism pathway genes and survival of nonsmall cell lung cancer (NSCLC) by analyzing genotyping data from two published genome-wide association studies (GWASs). In the discovery, we used a genotyping dataset from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial in the multivariable Cox proportional hazards regression analysis. We used Bayesian false discovery probability (≤0.80) for multiple testing correction to evaluate associations between 25,819 (2,176 genotyped and 23,643 imputed) single-nucleotide polymorphisms (SNPs) in 162 genes and survival of 1,185 NSCLC patients. Subsequently, we validated the identified significant SNPs with an additional 984 NSCLC patients from the Harvard Lung Cancer Susceptibility GWAS study. Finally, we found that three independent and potentially functional SNPs in three different genes (i.e., PLIN2 rs7867814 G>A, SULT2A1 rs2547235 C>T and UGT1A9 rs2011404 C>T) were independently associated with risk of death from NSCLC, with a combined hazards ratio of 1.22 [95% confidence interval = 1.09-1.36 and p = 0.0003], 0.82 (0.74-0.91 and p = 0.0002) and 1.21 (1.10-1.33 and p = 0.0001), respectively. Additional expression quantitative trait loci analysis found that the survival-associated PLIN2 rs7867814 GA + AA genotypes, but not the genotypes of other two SNPs, were significantly associated with increased mRNA expression levels (p = 0.005). These results indicated that PLIN2 variants may be potential predictors of NSCLC survival through regulating the PLIN2 expression.
Authors
Tang, D; Zhao, YC; Liu, H; Luo, S; Clarke, JM; Glass, C; Su, L; Shen, S; Christiani, DC; Gao, W; Wei, Q
MLA Citation
Tang, Dongfang, et al. “Potentially functional genetic variants in PLIN2, SULT2A1 and UGT1A9 genes of the ketone pathway and survival of nonsmall cell lung cancer.Int J Cancer, vol. 147, no. 6, Sept. 2020, pp. 1559–70. Pubmed, doi:10.1002/ijc.32932.
URI
https://scholars.duke.edu/individual/pub1432699
PMID
32072637
Source
pubmed
Published In
Int J Cancer
Volume
147
Published Date
Start Page
1559
End Page
1570
DOI
10.1002/ijc.32932

Molecular Landscape of BRAF-Mutant NSCLC Reveals an Association Between Clonality and Driver Mutations and Identifies Targetable Non-V600 Driver Mutations.

INTRODUCTION: Approximately 4% of NSCLC harbor BRAF mutations, and approximately 50% of these are non-V600 mutations. Treatment of tumors harboring non-V600 mutations is challenging because of functional heterogeneity and lack of knowledge regarding their clinical significance and response to targeted agents. METHODS: We conducted an integrative analysis of BRAF non-V600 mutations using genomic profiles of BRAF-mutant NSCLC from the Guardant360 database. BRAF mutations were categorized by clonality and class (1 and 2: RAS-independent; 3: RAS-dependent). Cell viability assays were performed in Ba/F3 models. Drug screens were performed in NSCLC cell lines. RESULTS: A total of 305 unique BRAF mutations were identified. Missense mutations were most common (276, 90%), and 45% were variants of unknown significance. F468S and N581Y were identified as novel activating mutations. Class 1 to 3 mutations had higher clonality than mutations of unknown class (p < 0.01). Three patients were treated with MEK with or without BRAF inhibitors. Patients harboring G469V and D594G mutations did not respond, whereas a patient with the L597R mutation had a durable response. Trametinib with or without dabrafenib, LXH254, and lifirafenib had more potent inhibition of BRAF non-V600-mutant NSCLC cell lines than other MEK, BRAF, and ERK inhibitors, comparable with the inhibition of BRAF V600E cell line. CONCLUSIONS: In BRAF-mutant NSCLC, clonality is higher in known functional mutations and may allow identification of variants of unknown significance that are more likely to be oncogenic drivers. Our data indicate that certain non-V600 mutations are responsive to MEK and BRAF inhibitors. This integration of genomic profiling and drug sensitivity may guide the treatment for BRAF-mutant NSCLC.
Authors
Negrao, MV; Raymond, VM; Lanman, RB; Robichaux, JP; He, J; Nilsson, MB; Ng, PKS; Amador, BE; Roarty, EB; Nagy, RJ; Banks, KC; Zhu, VW; Ng, C; Chae, YK; Clarke, JM; Crawford, JA; Meric-Bernstam, F; Ou, S-H; Gandara, DR; Heymach, JV; Bivona, TG; McCoach, CE
MLA Citation
URI
https://scholars.duke.edu/individual/pub1447965
PMID
32540409
Source
pubmed
Published In
J Thorac Oncol
Published Date
DOI
10.1016/j.jtho.2020.05.021

Current multidisciplinary management of brain metastases.

Brain metastasis (BM), the most common adult brain tumor, develops in 20% to 40% of patients with late-stage cancer and traditionally are associated with a poor prognosis. The management of patients with BM has become increasingly complex because of new and emerging systemic therapies and advancements in radiation oncology and neurosurgery. Current therapies include stereotactic radiosurgery, whole-brain radiation therapy, surgical resection, laser-interstitial thermal therapy, systemic cytotoxic chemotherapy, targeted agents, and immune-checkpoint inhibitors. Determining the optimal treatment for a specific patient has become increasingly individualized, emphasizing the need for multidisciplinary discussions of patients with BM. Recognizing and addressing the sequelae of BMs and their treatment while maintaining quality of life and neurocognition is especially important because survival for patients with BMs has improved. The authors present current and emerging treatment options for patients with BM and suggest approaches for managing sequelae and disease recurrence.
Authors
MLA Citation
Moravan, Michael J., et al. “Current multidisciplinary management of brain metastases.Cancer, vol. 126, no. 7, Apr. 2020, pp. 1390–406. Pubmed, doi:10.1002/cncr.32714.
URI
https://scholars.duke.edu/individual/pub1428070
PMID
31971613
Source
pubmed
Published In
Cancer
Volume
126
Published Date
Start Page
1390
End Page
1406
DOI
10.1002/cncr.32714

APOB Genotypes and CDH13 Haplotypes in the Cholesterol-Related Pathway Genes Predict Non-Small Cell Lung Cancer Survival.

BACKGROUND: Several oncogenic signals are involved in the synthesis, metabolism, transportation, and modulation of cholesterol. However, the roles of genetic variants of the cholesterol pathway genes in cancer survival remain unclear. METHODS: We investigated associations between 26,781 common SNPs in 209 genes of the cholesterol pathway and non-small cell lung cancer (NSCLC) survival by utilizing genotyping data from two published genome-wide association studies. We used multivariate Cox proportional hazards regression and expression quantitative trait loci analyses to identify survival-associated SNPs and their correlations with the corresponding mRNA expression, respectively. We also used the Kaplan-Meier survival analysis and bioinformatics functional prediction to further evaluate the identified independent SNPs. RESULTS: We found five independent SNPs (APOB rs1801701C>T; CDH13 rs35859010 C>T, rs1833970 T>A, rs254315 T>C, and rs425904 T>C) to be significantly associated with NSCLC survival in both discovery and replication datasets. When the unfavorable genotype (APOB rs1801701CC) and haplotypes (CDH13 rs35859010-rs1833970-rs254315-rs425904 C-A-T-C and T-T-T-T) were combined into a genetic score as the number of unfavorable genotypes/haplotypes (NUGH) in the multivariate analysis, an increased NUGH was associated with worse survival (Ptrend < 0.0001). In addition, both APOB rs1801701T<C and CDH13 rs425904C<T were correlated with mRNA expression of the genes in normal lung tissues from the genotype-tissue expression project. CONCLUSIONS: Genetic variants of APOB and CDH13 in the cholesterol pathway were associated with NSCLC survival, possibly by affecting their gene expression. IMPACT: Genetic variants of APOB and CDH13 in the cholesterol pathway may provide new scientific insights into NSCLC prognosis.
Authors
Deng, W; Liu, H; Luo, S; Clarke, J; Glass, C; Su, L; Lin, L; Christiani, DC; Wei, Q
MLA Citation
Deng, Wei, et al. “APOB Genotypes and CDH13 Haplotypes in the Cholesterol-Related Pathway Genes Predict Non-Small Cell Lung Cancer Survival.Cancer Epidemiol Biomarkers Prev, vol. 29, no. 6, June 2020, pp. 1204–13. Pubmed, doi:10.1158/1055-9965.EPI-19-1262.
URI
https://scholars.duke.edu/individual/pub1436653
PMID
32238407
Source
pubmed
Published In
Cancer Epidemiol Biomarkers Prev
Volume
29
Published Date
Start Page
1204
End Page
1213
DOI
10.1158/1055-9965.EPI-19-1262

Use of low-frequency driver mutations detected by cell-free circulating tumor DNA to guide targeted therapy in non-small-cell lung cancer: A multicenter case series

© 2019 American Society of Clinical Oncology. Purpose To evaluate the clinical outcome of patients with non-small-cell lung cancer treated by targeting low variant allelic frequency (VAF) driver mutations identified through cell-free DNA (cfDNA) next-generation sequencing (NGS). Detection of driver mutations in cancer is critically important in the age of targeted therapy, where both tumor-based as well as cfDNA sequencing methods have been used for therapeutic decision making. We hypothesized that VAF should not be predictive of response and that low VAF alterations detected by cfDNA NGS can respond to targeted therapy. Patients and Methods A multicenter retrospective case review was performed to identify patients with non-small-cell lung cancer who received targeted molecular therapy on the basis of findings of low VAF alterations in cfDNA NGS. Mutations at low VAF were defined as < 0.2% mutated cfDNA molecules in a background of wild-type cfDNA. Results One hundred seventy-two patients underwent cfDNA NGS testing. Of the 172 patients, 12 were identified as having low VAF driver alterations and were considered for targeted therapy. The median progression-free survival (PFS) for all patients was 52 weeks (range, 17 to 88 weeks). For patients with EGFR exon 19 deletion (n = 7), the median PFS was 52 weeks (range, 17 to 60.5 weeks). For patients with EML4-ALK fusions (n = 3), the median PFS was 60 weeks (range, 18 to 88 weeks). The median overall survival for all patients after diagnosis was 57.6 weeks. Conclusion Targeted treatment response for driver mutations detected by cfDNA may be independent of VAF, even in relation to other higher VAF aberrations in plasma, and directly dependent on the underlying disease biology and ability to treat the patient with appropriate targeted therapy.
Authors
Jacobs, MT; Mohindra, NA; Shantzer, L; Chen, IL; Phull, H; Mitchell, W; Raymond, VM; Banks, KC; Nagy, RJ; Lanman, RB; Christensen, J; Patel, JD; Clarke, J; Patel, SP
MLA Citation
URI
https://scholars.duke.edu/individual/pub1428069
Source
scopus
Published In
Jco Precision Oncology
Volume
2
Published Date
DOI
10.1200/PO.17.00318