We have studied the clinical and non-clinical pharmacology of the immunomodulatory drugs (IMiDs) for more than a decade. The IMiDs include thalidomide, lenalidomide and pomalidomide, and while they have very similar chemical structures, physicochemical properties, chemical stability, and aqueous solubility, and they all target the cereblon (CRBN) protein, they have significantly different pharmacokinetics and biodistribution properties. We have explored the potential for transporter-mediated drug-drug interactions and tumor resistance mechanisms with these agents. Our current funding has focused on the ability of AR-42 (REC-2282), a histone deacetylase inhibitor, to modulate IMiD resistance in myeloma through downregulation of the hyularonan receptor, CD44.

Publications related to this project:

1. Thangavadivel S, Zhao Q, Epperla N, Rike L, Mo X, Badawi M, Bystry DM, Phelps MA, Andritsos LA, Rogers KA, Jones J, Woyach JA, Byrd JC, Awan FT. Early Intervention with Lenalidomide in Patients with High-risk Chronic Lymphocytic Leukemia. Clin Cancer Res. 2020 Dec 1;26(23):6187-6195. doi: 10.1158/1078-0432.CCR-20-1280. Epub 2020 Sep 21. PubMed PMID: 32958702.
2. Saygin C, Larkin K, Blachly JS, Orwick S, Ngankeu A, Gregory CT, Phelps MA, Mani S, Walker A, Garzon R, Vasu S, Walsh KJ, Bhatnagar B, Klisovic RB, Grever MR, Marcucci G, Byrd JC, Blum W, Mims AS. A phase I study of lenalidomide plus chemotherapy with idarubicin and cytarabine in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome. Am J Hematol. 2020 Aug 10. PMID: 32777116. PMCID: PMC7821016 DOI: 10.1002/ajh.25958
3. Hughes JH, Upton RN, Reuter SE, Rozewski DM, Phelps MA, Foster DJR. Development of a physiologically based pharmacokinetic model for intravenous lenalidomide in mice. Cancer Chemother Pharmacol. 2019 Nov;84(5):1073-1087. Epub 2019 Sep 6. PMID: 31493176 PMCID: PMC7375688 DOI: 10.1007/s00280-019-03941-z
4. Hughes JH, Phelps MA, Upton RN, Reuter SE, Gao Y, Byrd JC, Grever MR, Hofmeister CC, Marcucci G, Blum W, Blum KA, Foster DJR. Population pharmacokinetics of lenalidomide in patients with B-cell malignancies. Br J Clin Pharmacol. 2019 May;85(5):924-934. Epub 2019 Feb 27. doi: 10.1111/bcp.13873; PMID: 30672004; PMCID: PMC6475687.
5. Sborov DW, Canella A, Hade EM, Mo X, Khountham S, Wang J, Ni W, Poi M, Coss C, Liu Z, Phelps MA, Mortazavi A, Andritsos L, Baiocchi RA, Christian BA, Benson DM, Flynn J, Porcu P, Byrd JC, Pichiorri F, Hofmeister CC. A phase 1 trial of the HDAC inhibitor AR-42 in patients with multiple myeloma and T- and B-cell lymphomas. Leuk Lymphoma. 2017 Oct;58(10):2310-2318. Epub 2017 Mar 7. doi: 10.1080/10428194.2017.1298751. PMID: 28270022. PMCID: PMC5489371.
6. Maly JJ, Christian BA, Zhu X, Wei L, Sexton JL, Jaglowski SM, Devine SM, Fehniger TA, Wagner-Johnston ND, Phelps MA, Bartlett NL, Blum KA. A Phase I/II Trial of Panobinostat in Combination with Lenalidomide in Patients with Relapsed or Refractory Hodgkin Lymphoma. Clin Lymphoma Myeloma Leuk. 2017 Jun;17(6):347-353. Epub 2017 May 22. doi: 10.1016/j.clml.2017.05.008. PMID: 28622959. PMCID: PMC6033275.
7. Harshman SW, Canella A, Ciarlariello PD, Agarwal K, Branson OE, Rocci A, Cordero H, Phelps MA, Hade EM, Dubovsky JA, Palumbo A, Rosko A, Byrd JC, Hofmeister CC, Benson DM Jr, Paulaitis ME, Freitas MA, Pichiorri F. Proteomic characterization of circulating extracellular vesicles identifies novel serum myeloma associated markers. J Proteomics. 2016 Mar 16;136:89-98. Epub 2016 Jan 13. doi: 10.1016/j.jprot.2015.12.016. PMID: 26775013. PMCID: PMC4783258.
8. Cheng H, Xie Z, Jones WP, Wei XT, Liu Z, Wang D, Kulp SK, Wang J, Coss CC, Chen CS, Marcucci G, Garzon R, Covey JM, Phelps MA, Chan KK. Preclinical Pharmacokinetics Study of R- and S-Enantiomers of the Histone Deacetylase Inhibitor, AR-42 (NSC 731438), in Rodents. AAPS J. 2016 May;18(3):737-45. Epub 2016 Mar 4. doi: 10.1208/s12248-016-9876-3. PMID: 26943915. PMCID: PMC5256597.
9. Maddocks K, Wei L, Rozewski D, Jiang Y, Zhao Y, Adusumilli M, Pierceall WE, Doykan C, Cardone MH, Jones JA, Flynn J, Andritsos LA, Grever MR, Byrd JC, Johnson AJ, Phelps MA, Blum KA. Reduced occurrence of tumor flare with flavopiridol followed by combined flavopiridol and lenalidomide in patients with relapsed chronic lymphocytic leukemia (CLL). Am J Hematol. 2015 Apr;90(4):327-33. Epub 2015 Feb 25. doi: 10.1002/ajh.23946. PMID: 25639448. PMCID: PMC4552311.
10. Maddocks K, Ruppert AS, Browning R, Jones J, Flynn J, Kefauver C, Gao Y, Jiang Y, Rozewski DM, Poi M, Phelps MA, Harper E, Johnson AJ, Byrd JC, Andritsos LA. A dose escalation feasibility study of lenalidomide for treatment of symptomatic, relapsed chronic lymphocytic leukemia. Leuk Res. 2014 Sep;38(9):1025-9. Epub 2014 May 29. doi: 10.1016/j.leukres.2014.05.011. PMID: 25082342. PMCID: PMC4312491.
11. Jiang Y, Wang J, Rozewski DM, Kolli S, Wu CH, Chen CS, Yang X, Hofmeister CC, Byrd JC, Johnson AJ, Phelps MA. Sensitive liquid chromatography/mass spectrometry methods for quantification of pomalidomide in mouse plasma and brain tissue. J Pharm Biomed Anal. 2014 Jan;88:262-8. Epub 2013 Sep 2. doi: 10.1016/j.jpba.2013.08.036. PMID: 24095801. PMCID: PMC3860284.
12. Rozewski DM, Herman SE, Towns WH 2nd, Mahoney E, Stefanovski MR, Shin JD, Yang X, Gao Y, Li X, Jarjoura D, Byrd JC, Johnson AJ, Phelps MA. Pharmacokinetics and tissue disposition of lenalidomide in mice. AAPS J. 2012 Dec;14(4):872-82. Epub 2012 Sep 7. doi: 10.1208/s12248-012-9401-2. PMID: 22956478. PMCID: PMC3475844.
13. Hofmeister CC, Yang X, Pichiorri F, Chen P, Rozewski DM, Johnson AJ, Lee S, Liu Z, Garr CL, Hade EM, Ji J, Schaaf LJ, Benson DM Jr, Kraut EH, Hicks WJ, Chan KK, Chen C-S, Farag SS, Grever MR, Byrd JC, Phelps MA. Phase I trial of lenalidomide and CCI‐779 in patients with relapsed multiple myeloma: evidence for lenalidomide-CCI-779 interaction via P-glycoprotein. J Clin Oncol. 2011 Sept 1;29(25):3427-34. Epub 2011 Aug 8. doi: 10.1200/JCO.2010.32.4962. PMID: 21825263. PMCID: PMC3164245.
14. Blum W, Klisovic RB, Becker H, Yang X, Rozewski DM, Phelps MA, Garzon R, Walker A, Chandler JC, Whitman SP, Curfman J, Liu S, Schaaf L, Mickle J, Kefauver C, Devine SM, Grever MR, Marcucci G, Byrd JC. Dose escalation of lenalidomide in relapsed or refractory acute leukemias. J of Clin Oncol. 2010 Nov 20;28(33):4919-25. Epub 2010 Oct 18. doi: 10.1200/JCO.2010.30.3339. PMID: 20956622. PMCID: PMC3020696.
15. Liu Q, Farley KL, Johnson AJ, Muthusamy N, Hofmeister CC, Blum KA, Schaaf LJ, Grever MR, Byrd JC, Dalton JT, Phelps MA*. Development and validation of a highly sensitive liquid chromatography/mass spectrometry method for simultaneous quantification of lenalidomide and flavopiridol in human plasma. Ther Drug Monit. 2008 Oct;30(5):620-7. doi: 10.1097/FTD.0b013e318185813d. PMID: 18708993. PMCID: PMC3740534.

Current and Past Funding for This Project:

1. 08/01/2016 – 07/31/2021. Overcoming IMiD resistance in Myeloma. National Cancer Institute/National Institute of Health. R01CA201382. Role: MPI (MPIs: Phelps, Hofmeister, Pichiorri). Goal: This project evaluates the mechanisms of IMiD resistance in multiple myeloma and evaluate the ability of AR-42 to overcome resistance in a phase 1/2 clinical trial.
2. 08/01/2019 – 07/31/2021. Diversity Supplement–A. Castillo: Overcoming IMiD resistance in myeloma. National Cancer Institute. R01CA201382 (Supplement) Role: MPI (Pichiorri/Hofmeister/Phelps). Goal: The proposed studies will investigate the mechanisms of IMID-induced resistance by assessing: (a) the functional role of CD44 in IMiD cellular uptake; (b) the role of small-non-coding-RNA (miRNA) in regulating CRBN and IRF4 and their significance in IMiD treatment; (c) if resistance can be overcome by combining AR-42 with an IMiD in a Phase 1 clinical trial.

Hematopoietic stem cell transplant (HSCT) is used broadly in patients with blood malignancies, including leukemia, lymphoma, and myeloma. Cytotoxic chemotherapy ablates diseased tumor cells residing in bone marrow and lymphoid tissues, and when followed immediately by HSCT, hematopoiesis within bone marrow and circulating blood cell counts can recover more quickly. In myeloma, the DNA alkylating and crosslinking agent, melphalan, is given in one or two high doses, and autologous HSCT follows. Our lab is working to understand the relationships between melphalan exposure, the rate of recovery of circulating blood cells, and longer-term survival outcomes in myeloma patients. We achieve this by developing semi-mechanistic models of hematopoiesis and linking these to pharmacokinetic models of melphalan drug exposure. We then use these models to explore potential factors that impact melphalan exposure and the rate of recovery of neutrophils and platelets in individual patients. Current work on this project involves collaborations with investigators at the University of Illinois Chicago and Emory University where we are conducting real-time pharmacokinetics to inform individualized patient melphalan dosing and evaluating our ability to achieve specific AUC targets and how these targets might improve efficacy and safety of this high-dose melphalan, autologous HSCT regimen.

Clinical protocols related to this project:

1.  2011-2015. A randomized study to compare the effect of short- and long-term schedules of cryotherapy on the incidence and severity of mucositis in high-dose melphalan. PI: Hofmeister, CC; Co-Is and Key Personnel: Benson SM, Tackett KA, Devine,SM, Lamprecht MS, Lester JL, Efebera YA, Phelps MA, Hummel HL, Meheran KM, Gill JS, Duda JE. 2011C0080.

Publications related to this project:

1. Li J, Seligson N, Zhang X, Johnson J, Vangundy Z, Wang D, Phelps M, Hofmeister C, Sadee W, Poi MJ. Association of ANRIL Polymorphism With Overall Survival in Adult Patients With Hematologic Malignancies After Allogeneic Hematopoietic Stem Cell Transplantation. Anticancer Res. 2020 Oct;40(10):5707-5713. doi: 10.21873/anticanres.14585. PubMed PMID: 32988896.
2. Persaud AK, Li J, Johnson JA, Seligson N, Sborov DW, Duah E, Cho YK, Wang D, Phelps MA, Hofmeister CC, Poi MJ. XRCC1-mediated DNA repair is associated with progression-free survival of multiple myeloma patients after autologous stem cell transplant. Mol Carcinog. 2019 Dec;58(12):2327-2339. Epub 2019 Sep 22. doi: 10.1002/mc.23121. PMID: 31544312.
3. Poi MJ, Li J, Johnson JA, Cho YK, Sborov DW, Phelps MA, Hofmeister CC. A Single Nucleotide Polymorphism in SLC7A5 Was Associated With Clinical Response in Multiple Myeloma Patients. Anticancer Res. 2019 Jan;39(10):67-72. doi: 10.21873/anticanres.13080. PMID: 30591441. 
4. Cho YK, Irby DJ, Li J, Sborov DW, Mould DR, Badawi M, Dauki A, Lamprecht M, Rosko AE, Fernandez S, Hade EM, Hofmeister CC, Poi M, Phelps MA. Pharmacokinetic-Pharmacodynamic Model of Neutropenia in Patients with Myeloma Receiving High-Dose Melphalan for Autologous Stem Cell Transplant. CPT Pharmacometrics Syst Pharmacol. 2018 Nov;7(11):748-758. Epub 2018 Oct 20. doi: 10.1002/psp4.12345. PMID: 30343510. PMCID: PMC6263666. 
5. Sborov DW*, Cho YK*, Cottini F*, Hade EM, Lamprecht M, Tackett K, Sharma N, Williams N, Li J, Devine S, Poi M, Phelps MA**, Hofmeister CC**. G-CSF improves safety when you start the day after autologous transplant in multiple myeloma. Leuk Lymphoma. 2017 Dec;58(12):2947-2951. Epub 2017 May 16. doi: 10.1080/10428194.2017.1318436. PMID: 28509594. PMCID: PMC6607907. 
6. Cho YK, Sborov DW, Lamprecht M, Li J, Wang J, Hade EM, Gao Y, Tackett K, Williams N, Benson DM, Efebera YA, Rosko AE, Devine SM, Poi M, Hofmeister CC, Phelps MA. Associations of High-Dose Melphalan Pharmacokinetics and Outcomes in the Setting of a Randomized Cryotherapy Trial. Clin Pharmacol Ther. 2017 Sep;102(3):511-519. Epub 2017 May 26. doi: 10.1002/cpt.644. PMID: 28160288.  PMCID: PMC5821248.
7. Poi MJ, Li J, Sborov DW, VanGundy Z, Cho YK, Lamprecht M, Pichiorri F, Phelps MA, Hofmeister CC. Polymorphism in ANRIL is associated with relapse in patients with multiple myeloma after autologous stem cell transplant. Mol Carcinog. 2017 Jul;56(7):1722-1732. Epub 2017 Feb 16. doi: 10.1002/mc.22626. PMID: 28150872. 

Relevant Abstracts and Presentations:

1. Donald Irby, Francesca Cottini, Erinn Hade, Craig C. Hofmeister, Mitch Phelps. Modeling Thrombocytopenia as a Predictor of Outcomes Following Single, High Dose Melphalan and Stem Cell Transplant in Multiple Myeloma. American Society for Clinical Pharmacology and Therapeutics Annual Meeting, Houston, TX, March 2020. (cancelled due to COVID-19)

For pharmacologists, the answer to this question seems obvious – higher drug clearance leads to lower drug exposure and therefore less effect on the drug target. However, the problem is much more complex with ICIs, which have dramatically changed the clinical landscape over the past decade for many solid tumors where limited effective therapies were available. Despite the advances with ICIs, still only a subset of patients respond, and those who do may develop refractory disease within a short time period. This project aims to discover the underlying mechanisms linking elevated ICI clearance and poor outcomes, which seems to be more prevalent in patients with cancer-associated muscle wasting disease, or cachexia. Within this translational research project we are using murine cancer cachexia models to explore specific pathways involved in antibody drug clearance and acquiring data and samples within IRB approved clinical trials where patients are receiving ICI or other antibody drugs as either standard-of-care or within experimental combination drug regimens. With improved understanding of the underlying mechanisms involved, we hope to be able to identify patients less likely to respond to ICI therapy and develop combination therapies with ICIs and other agents that can improve outcomes in these patients.

Publications related to this project:

1. Castillo AMM, Vu TT, Liva SG, Chen M, Xie Z, Thomas J, Remaily B, Guo Y, Subrayan UL, Costa T, Helms TH, Irby DJ, Kim K, Owen DH, Kulp SK, Mace TA, Phelps MA, Coss CC. Single-dose pembrolizumab in murine cancer-cachexia models replicates elevated catabolic pembrolizumab clearance in humans. JCSM Rapid Communications. https://onlinelibrary.wiley.com/doi/full/10.1002/rco2.32.
2. Jain R, Coss C, Whooley P, Phelps M, Owen DH. The Role of Malnutrition and Muscle Wasting in Advanced Lung Cancer. Curr Oncol Rep. 2020 May 15;22(6):54. doi: 10.1007/s11912-020-00916-9. PMID: 32409907.
3. Liva SG, Tseng YC, Dauki AM, Sovic MG, Vu T, Henderson SE, Kuo YC, Benedict JA, Zhang X, Remaily BC, Kulp SK, Campbell M, Bekaii-Saab T, Phelps MA, Chen CS,  Coss CC. Overcoming resistance to anabolic SARM therapy in experimental cancer cachexia with an HDAC inhibitor. EMBO Mol Med. 2020 Feb 7;12(2):e9910. doi: 10.15252/emmm.201809910. Epub 2020 Jan 13. PMID: 31930715. PMCID: PMC7005646.
4. Badawi M, Coss CC, Phelps MA. Letter to the Editor: Exposure-response or clearance-response relationship in immune checkpoint therapy?-A comment on ‘correlation between nivolumab exposure and treatment outcomes in non-small-cell lung cancer’ by Basak et al. Eur J Cancer. 2019 Jun;114:25-26. Epub 2019 Apr 19. doi: 10.1016/j.ejca.2019.02.017. PMID: 31009820. 
5. Coss CC, Clinton SK, Phelps MA. Cachectic Cancer Patients: Immune to Checkpoint Inhibitor Therapy? Clin Cancer Res. 2018 Dec 1;24(23):5787-5789. Epub 2018 Jul 17. doi: 10.1158/1078-0432.CCR-18-1847. PMID: 30018117. PMCID: PMC6279566.

Relevant Abstracts and Presentations:

1. Vu TT, Castillo AMM, Chen M, Xie Z, Thomas J, Guo Y, Remaily B, Subrayan UL, Costa T, Helms TH, Liva SG, Kulp SK,. Mace TA, Coss CC, Phelps MA. Murine Models of Cancer Cachexia Display Elevated Catabolic Clearance of Pembrolizumab. American Society for Clinical Pharmacology and Therapeutics Annual Meeting, online/virtual, 2021
2. Phelps MA. “Antibody Drug Clearance as a Biomarker for Outcomes with Immune Checkpoint Inhibitor Therapy”. University of Illinois Chicago College of Pharmacy, Department of Pharmacy Practice Research Seminar Series. October 14, 2020. https://www.youtube.com/watch?v=oYPNa23G4OU&feature=youtu.be 
3. SG Liva, A Mortazavi, K Dittmar, AR Walker, CC Hofmeister, MA Phelps, CC Coss. AR-42 pharmacokinetics: estimated versus measured patient body composition. American Association of Pharmaceutical Scientists Annual Meeting, Washington, DC, November 2018. 
4. Hugo Valencia, Herbert Newton, Erinn M. Hade, Douglas W. Sborov, Robert Cavaliere, Ming Poi, Mitch A. Phelps, Christopher C. Coss, Jiang Wang, Soun Khountham, J. Paul Monk, Thomas E. Olencki, Charles L. Shapiro, Richard Piekarz, Craig C. Hofmeister, Michael R. Grever, D. Bradley Welling, Amir Mortazavi. A phase 1 study of AR-42 in patients with advanced solid tumors, including nervous system tumors. American Society of Clinical Oncology Annual Meeting, Chicago, IL, 2016.