Richard Riedel

Overview:

Novel therapies for soft tissue and bone sarcomas

Positions:

Associate Professor of Medicine

Medicine, Medical Oncology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 2000

Thomas Jefferson University

Resident in Medicine, Medicine

Duke University

Fellow in Hematology-Oncology, Medicine

Duke University

Fellow in Hematology-Oncology, Medicine

Duke University

Grants:

BLU-285-1303

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

Dissecting Mechanisms of Metastasis Through Comparative Systems Genetics

Administered By
Radiation Oncology
Awarded By
National Institutes of Health
Role
Investigator
Start Date
End Date

NIR-DT-301 -1702

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

DCC-2618-03-002 (Intrigue)

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

IMDZ-04-1702

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

Publications:

Co-occurrence of targetable mutations in Non-small cell lung cancer (NSCLC) patients harboring MAP2K1 mutations

© 2020 Background: MAP2K1 mutations are rare in non-small cell lung cancer (NSCLC) and considered to be mutually exclusive from known driver mutations. Activation of the MEK1-cascade is considered pivotal in resistance to targeted therapy approaches, and MAP2K1 K57 N mutation could be linked to resistance in preclinical models. We set out this study to detect MAP2K1 mutations and potentially targetable co-mutations using a molecular multiplex approach. Methods: Between 2012 and 2018, we routinely analyzed 14.512 NSCLC patients with two next-generation sequencing (NGS) panels. In a subset of patients, fluorescence in-situ hybridization was performed to detect rearrangements or amplifications. We assessed clinical parameters and co-occurring mutations and compared treatment outcomes of different forms of systemic therapy. Results: We identified 66 (0.5%) patients with MAP2K1 mutations. Both adenocarcinoma (n = 62) and squamous cell carcinoma (n = 4) histology. The presence of the mutations was linked to smoking, and transversions were more common than transitions. K57 N was the most frequent MAP2K1 mutation (n = 25). Additional mutations were found in 57 patients (86.4%). Mutations of TP53 were detected in 33 patients, followed by KEAP1 mutations in 28.1%. 24 patients (36.4%) had either MAP2K1-only or a co-occurring aberration considered targetable, including EGFR mutations, a BRAF V600E mutation and ROS1 rearrangements. Outcome analyses revealed a trend toward benefit from pemetrexed treatment. Conclusion: Our analysis shows that MAP2K1-mutated NSCLC patients might frequently present with potentially targetable aberrations. Their role in providing resistance in these subtypes and the possible therapeutic opportunities justify further analyses of this rare NSCLC subgroup.
Authors
Scheffler, M; Holzem, A; Kron, A; Nogova, L; Ihle, MA; von Levetzow, C; Fassunke, J; Wömpner, C; Bitter, E; Koleczko, S; Abdulla, DSY; Michels, S; Fischer, R; Riedel, R; Weber, JP; Westphal, T; Gerigk, U; Kern, J; Kaminsky, B; Randerath, W; Kambartel, KO; Merkelbach-Bruse, S; Büttner, R; Wolf, J
MLA Citation
Scheffler, M., et al. “Co-occurrence of targetable mutations in Non-small cell lung cancer (NSCLC) patients harboring MAP2K1 mutations.” Lung Cancer, vol. 144, June 2020, pp. 40–48. Scopus, doi:10.1016/j.lungcan.2020.04.020.
URI
https://scholars.duke.edu/individual/pub1440388
Source
scopus
Published In
Lung Cancer (Amsterdam, Netherlands)
Volume
144
Published Date
Start Page
40
End Page
48
DOI
10.1016/j.lungcan.2020.04.020

A Phase 1b Dose-Escalation Trial of NC-6300 (Nanoparticle Epirubicin) in Patients with Advanced Solid Tumors or Advanced, Metastatic, or Unresectable Soft Tissue Sarcoma.

PURPOSE:NC-6300 is a novel nanoparticle formulation of epirubicin that has a pH sensitive linker conjugated to epirubicin. It exhibits selective tumor accumulation owing to enhanced permeability and retention effect. We conducted a phase 1b trial to determine maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of NC-6300 monotherapy in advanced, metastatic, or unresectable solid tumors, including soft tissue sarcomas. EXPERIMENTAL DESIGN:This Phase 1b dose escalation trial of NC-6300 monotherapy employed a Bayesian continuous reassessment method design. NC-6300 was administered on Day 1 of every 21-day cycle, with epirubicin-equivalent dose increments from 125 mg/m2 to 215 mg/m2. Safety, efficacy, quality-of-life, and pharmacokinetic profile of NC-6300 monotherapy were evaluated. RESULTS:Twenty-nine subjects (16 male) were enrolled: 17 with soft tissue sarcoma, 1 with osteosarcoma and 11 with other solid tumors. Observed dose‑limiting toxicities included thrombocytopenia, stomatitis, lung infection and febrile neutropenia. The most common grade 3/4 adverse events were neutropenia (59%), anemia (24%), thrombocytopenia (24%) and febrile neutropenia (21%). MTD and RP2D were determined to be 185 mg/m2 and 150 mg/m2, respectively. The objective response rate in the evaluable population was 11%. Partial response was observed in angiosarcoma and endometrial stromal sarcoma. A dose-dependent increase was observed in both total and released epirubicin concentrations. CONCLUSIONS:NC-6300 was well tolerated with a manageable side effect profile, despite the MTD and RP2D being higher than conventional epirubicin doses. A signal of preliminary activity was observed in angiosarcoma. NC-6300 warrants further investigation in patients with advanced solid tumors, including sarcoma.
Authors
Chawla, SP; Goel, S; Chow, W; Braiteh, F; Singh, AS; Grilley Olson, JE; Osada, A; Bobe, I; Riedel, RF
MLA Citation
Chawla, Sant P., et al. “A Phase 1b Dose-Escalation Trial of NC-6300 (Nanoparticle Epirubicin) in Patients with Advanced Solid Tumors or Advanced, Metastatic, or Unresectable Soft Tissue Sarcoma.Clinical Cancer Research : An Official Journal of the American Association for Cancer Research, May 2020. Epmc, doi:10.1158/1078-0432.ccr-20-0591.
URI
https://scholars.duke.edu/individual/pub1441859
PMID
32381487
Source
epmc
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Published Date
DOI
10.1158/1078-0432.ccr-20-0591

Correlative Analyses of the SARC028 Trial Reveal an Association Between Sarcoma-Associated Immune Infiltrate and Response to Pembrolizumab.

PURPOSE: We recently reported a 17.5% objective RECIST 1.1 response rate in a phase II study of pembrolizumab in patients with advanced sarcoma (SARC028). The majority of responses occurred in undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated liposarcoma (DDLPS). We sought to determine whether we can identify immune features that correlate with clinical outcomes from tumor tissues obtained pre- and on-treatment. PATIENTS AND METHODS: Pretreatment (n = 78) and 8-week on-treatment (n = 68) tumor biopsies were stained for PD-L1 and multiplex immunofluorescence panels. The density of positive cells was quantified to determine associations with anti-PD-1 response. RESULTS: Patients that responded to pembrolizumab were more likely to have higher densities of activated T cells (CD8+ CD3+ PD-1+) and increased percentage of tumor-associated macrophages (TAM) expressing PD-L1 pre-treatment compared with non-responders. Pre-treatment tumors from responders also exhibited higher densities of effector memory cytotoxic T cells and regulatory T cells compared with non-responders. In addition, higher density of cytotoxic tumor-infiltrating T cells at baseline correlated with a better progression-free survival (PFS). CONCLUSIONS: We show that quantitative assessments of CD8+ CD3+ PD-1+ T cells, percentage of TAMs expressing PD-L1, and other T-cell densities correlate with sarcoma response to pembrolizumab and improved PFS. Our findings support that multiple cell types present at the start of treatment may enhance tumor regression following anti-PD-1 therapy in specific advanced sarcomas. Efforts to confirm the activity of pembrolizumab in an expansion cohort of patients with UPS/DDLPS are underway.
Authors
Keung, EZ; Burgess, M; Salazar, R; Parra, ER; Rodrigues-Canales, J; Bolejack, V; Van Tine, BA; Schuetze, SM; Attia, S; Riedel, RF; Hu, J; Okuno, SH; Priebat, DA; Movva, S; Davis, LE; Reed, DR; Reuben, A; Roland, CL; Reinke, D; Lazar, AJ; Wang, W-L; Wargo, JA; Tawbi, HA
MLA Citation
Keung, Emily Z., et al. “Correlative Analyses of the SARC028 Trial Reveal an Association Between Sarcoma-Associated Immune Infiltrate and Response to Pembrolizumab.Clin Cancer Res, vol. 26, no. 6, Mar. 2020, pp. 1258–66. Pubmed, doi:10.1158/1078-0432.CCR-19-1824.
URI
https://scholars.duke.edu/individual/pub1427273
PMID
31900276
Source
pubmed
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
26
Published Date
Start Page
1258
End Page
1266
DOI
10.1158/1078-0432.CCR-19-1824

SU2C-SARC032: A phase II randomized controlled trial of neoadjuvant pembrolizumab with radiotherapy and adjuvant pembrolizumab for high-risk soft tissue sarcoma.

Authors
Mowery, YM; Ballman, KV; Riedel, RF; Brigman, BE; Attia, S; Meyer, CF; Schuetze, S; Burgess, MA; Chmielowski, B; Dickson, MA; Hartner, LP; Milhem, MM; Tinoco, G; Van Tine, BA; Wagner, AJ; Reinke, DK; Kirsch, DG
MLA Citation
Mowery, Yvonne Marie, et al. “SU2C-SARC032: A phase II randomized controlled trial of neoadjuvant pembrolizumab with radiotherapy and adjuvant pembrolizumab for high-risk soft tissue sarcoma.Journal of Clinical Oncology, vol. 36, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2018, pp. TPS11588–TPS11588. Crossref, doi:10.1200/jco.2018.36.15_suppl.tps11588.
URI
https://scholars.duke.edu/individual/pub1441415
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
36
Published Date
Start Page
TPS11588
End Page
TPS11588
DOI
10.1200/jco.2018.36.15_suppl.tps11588

Detection of endoglin-expressing CTCs in patients enrolled in an adaptive enrichment phase 3 trial of TRC105 and pazopanib versus pazopanib alone in patients with advanced angiosarcoma (TAPPAS).

Authors
Ravi, V; Brohl, AS; Chawla, SP; Attia, S; Riedel, RF; Liebner, DA; Thornton, KA; Basu Mallick, A; Davis, DW; Cervantes, M; Liu, W; Zhu, K; Alvarez, D; Theuer, CP; Robinson, SI; Penel, N; Stacchiotti, S; Tap, WD; Jones, RL; Maki, RG
MLA Citation
Ravi, Vinod, et al. “Detection of endoglin-expressing CTCs in patients enrolled in an adaptive enrichment phase 3 trial of TRC105 and pazopanib versus pazopanib alone in patients with advanced angiosarcoma (TAPPAS).Journal of Clinical Oncology, vol. 36, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2018, pp. e23570–e23570. Crossref, doi:10.1200/jco.2018.36.15_suppl.e23570.
URI
https://scholars.duke.edu/individual/pub1441793
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
36
Published Date
Start Page
e23570
End Page
e23570
DOI
10.1200/jco.2018.36.15_suppl.e23570