1 orlowski targeted-therapies
46
ROBERT ORLOWSKI, MD, PhD Houston, USA • Professor, Department of Myeloma/Lymphoma, at the University of Texas MD Anderson Cancer Center • Dr. Orlowski has published numerous book chapters, articles, and abstracts on cancer therapy, with a focus on the molecular pathogenesis of oncologic disease processes and the mechanisms of action of chemotherapeutics. His clinical research efforts focus on the translation of promising laboratory based findings into novel clinical trials for patients with hematologic malignancies. He has published in, and is a reviewer for, several journals, including Blood, Cancer Research, Journal of Clinical Oncology , and the New England Journal of Medicine. He has received several awards, including The Leukemia & Lymphoma Society Scholar in Clinical Research and the Jefferson-Pilot Fellowship in Academic Medicine.
Transcript of 1 orlowski targeted-therapies
ROBERT ORLOWSKI, MD, PhDHouston, USA
• Professor, Department of Myeloma/Lymphoma, at the University of Texas MD Anderson Cancer Center
• Dr. Orlowski has published numerous book chapters, articles, and abstracts on cancer therapy, with a focus on the molecular pathogenesis of oncologic disease processes and the mechanisms of action of chemotherapeutics. His clinical research efforts focus on the translation of promising laboratory based findings into novel clinical trials for patients with hematologic malignancies. He has published in, and is a reviewer for, several journals, including Blood, Cancer Research, Journal of Clinical Oncology, and the New England Journal of Medicine. He has received several awards, including The Leukemia & Lymphoma Society Scholar in Clinical Research and the Jefferson-Pilot Fellowship in Academic Medicine.
Recent Updates on Targeted Therapies for Multiple Myeloma
Robert Z. Orlowski, Ph.D., M.D.Director, Myeloma Section
Florence Maude Thomas Cancer Research Professor
Departments of Lymphoma/Myeloma & Experimental Therapeutics
Principal Investigator, MD Anderson SPORE in Multiple Myeloma and MD Anderson Moon Shot in High Risk Myeloma
Chair, SWOG Myeloma Committee
Outline
• Novel targeted small molecules
• Novel targeted monoclonal antibodies
2013 ASH Abstract 285
Prolonged Survival and Improved Response Rates with ARRY-520 in Relapsed/Refractory Multiple Myeloma (RRMM) Patients with Low -1 Acid α
Glycoprotein (AAG) Levels : Results From a Phase 2 Study
Sagar Lonial, Jatin J. Shah, Jeffrey Zonder, William I. Bensinger, Adam D. Cohen, Jonathan L. Kaufman, Ajay K. Nooka, Donna M. Weber, Brandi Hilder, Selena A.
Rush, Ann Ptaszynski, Duncan Walker, and Robert Z. Orlowski
Mechanism of Action
Study Design
Response Data by AAG Levels
Survival Curves
Single-Agent Filanesib(median 6 previous therapies)
Filanesib + Dex(median 8 previous therapies)
100
75
50
25
00 6 12 18 24 30 36
OS (Mos)
Su
rviv
al (
%)
100
75
50
25
00 6 12 18 24 30 36
OS (Mos)
Su
rviv
al (
%)
Low*HighAll
2013 ASH Abstract 1982
Phase 1 Study of the Novel Kinesin Spindle Protein Inhibitor ARRY-520 + Carfilzomib (Car) in Patients with Relapsed and/or Refractory Multiple Myeloma
(RRMM)
Jatin J. Shah, Lei Feng, Sheeba K. Thomas, Donna M. Weber, Michael Wang, Brandi Hilder, Raymond Alexanian, and Robert Z. Orlowski
Trial Design
Initial Efficacy Data
• All patients were bortezomib-refractory• 63% achieved an MR or better in this phase I• Growth factor support was not needed after
cycles 1 and 2
2014 ASH Abstract 3453
Oprozomib and Dexamethasone in Patients with Relapsed and/or Refractory Multiple Myeloma: Initial
Results from the Dose Escalation Portion of a Phase 1b/2, Multicenter, Open-Label Study
Parameswaran N. Hari, Kenneth H. Shain, Peter M. Voorhees, Nashat Gabrail, Muneer H. Abidi, Jeffrey Zonder, Ralph V. Boccia, Paul G. Richardson, Linda L.
Neuman, Sandra J. Dixon, and Claudia Paba Prada
2014 ASH Abstract 34
Clinical Profile of Single-Agent Oprozomib in Patients (Pts) with Multiple Myeloma (MM) : Updated Results
from a Multicenter, Open-Label, Dose Escalation Phase 1b/2 Study
Ravi Vij, Michael Savona, David S. Siegel, Jonathan L. Kaufman, Ashraf Badros, Irene M. Ghobrial, Agne Paner, Sundar Jagannath, Andrzej Jakubowiak, Joseph R.
Mikhael, Prashant Kapoor, Linda L. Neuman, Ju RueyJiuan Lee, and Jesus G. Berdeja
Study Design
Hematologic Adverse Events
Other Adverse Events
Response Data
2014 ASH Abstract 301
Phase 1 Study Update of the Novel Pan-Pim Kinase Inhibitor LGH447 in Patients with Relapsed/
Refractory Multiple Myeloma
Marc S. Raab, Enrique M. Ocio, Sheeba K. Thomas, Andreas Günther, Yeow-Tee Goh, Daniel Lebovic, Andrzej Jakubowiak, Dongweon Song, F. Xiang, Apurva Patel,
K. Gary Vanasse, and Shaji Kumar
Preclinical Rationale
Garcia, P et al. Blood 122:1666, 2013.
Study Design
• Primary endpoint: MTD/RP2D• Secondary endpoints: safety, tolerability, preliminary anti-
myeloma activity, pharmacodynamics, pharmacokinetic profile
Dose Escalation Dose Expansion
MTD/RDE
Relapsed and/or refractory MM
LGH447 daily, oral≈ 12 patients
Relapsed and/or refractory MM
LGH447 daily, oral
70 m
g
150
mg
200
mg
250
mg
350
mg
300
mg
500
mg
700
mg
400
mg
Safety
AEs Suspected Related to Study Drug Gr 3/4, n (%)
TotalN = 59
Thrombocytopenia 18 (30.5)
Neutropenia 11 (18.6)
WBC decreased 9 (15.2)
Anemia 8 (13.6)
Fatigue 7 (11.9)
Lymphopenia 5 (8.5)
Diarrhea 3 (5.1)
Hyperglycemia 3 (5.1)
Hypophosphatemia 3 (5.1)
• The MTD was 500 mg once daily
• 10 DLTs: thrombocytopenia most common (1 pt each @ 200-, 250-, 350-, 400-, & 500-mg); fatigue @ higher doses (500 & 700 mg)
• Grade 3/4 AEs were mostly hematologic
• No deaths on study
Efficacy Data
• ORR: 10.5%; CBR: 21.1%; DCR: 71.9%• Median duration of response was 23.0 weeks
2014 ASH Abstract 31
Ibrutinib, Single Agent or in Combination with Dexamethasone, in Patients with Relapsed or
Relapsed/Refractory Multiple Myeloma (MM) : Preliminary Phase 2 Results
Ravi Vij, Carol Ann Huff, William I. Bensinger, David S. Siegel, Sundar Jagannath, Jesus Berdeja, Nikoletta Lendvai, Daniel Lebovic, Larry D. Anderson Jr., Caitlin L. Costello, Keith E. Stockerl-Goldstein, Jacob P. Laubach, Laurence Elias, Fong Clow,
Maria Fardis, Thorsten Graef, Elizabeth Bilotti, and Paul G. Richardson
Study Design
Efficacy Data
Outline
• Novel targeted small molecules
• Novel targeted monoclonal antibodies
2014 ASH Abstract 302
Final Results for the 1703 Phase 1b/2 Study of Elotuzumab in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed/Refractory
Multiple Myeloma
Paul G. Richardson, Sundar Jagannath, Philippe Moreau, Andrzej Jakubowiak, Marc S. Raab, Thierry Facon, Ravi Vij, Darrell White, Donna E. Reece, Lotfi Benboubker, Jeffrey Zonder, L. Claire Tsao, Kenneth C. Anderson, Eric Bleickardt, Anil K. Singhal, and Sagar
Lonial
Preclinical Rationale
Study Design
Response Data
Adverse Event Profile
Infusion Reactions
2014 ASH Abstract 84
Safety and Efficacy of Daratumumab with Lenalidomide and Dexamethasone in Relapsed or
Relapsed, Refractory Multiple Myeloma
Torben Plesner, Hendrik-Tobias Arkenau, Henk M. Lokhorst, Peter Gimsing, Jakub Krejcik, Charlotte Lemech, Monique C. Minnema, Ulrik Lassen, Jacob P. Laubach,
Tahamtan Ahmadi, Howard Yeh, Mary E. Guckert, Huaibao Feng, Nikolai Constantin Brun, Steen Lisby, Linda Basse, Antonio Palumbo, and Paul G.
Richardson
Rationale for Targeting CD38
Study Design
Response Curves
Response & Duration on Therapy
Response Rates
Safety Data
Infusion-related Reactions
2014 ASH Abstract 83
A Phase Ib Dose Escalation Trial of SAR650984 (Anti-CD-38 mAb) in Combination with Lenalidomide and
Dexamethasone in Relapsed/Refractory Multiple Myeloma
Thomas G. Martin III, Rachid Baz, Don M. Benson Jr., Nikoletta Lendvai, Frank Campana, Eric Charpentier and Ravi Vij
Patient Population
Efficacy Analysis
Response Durability
Safety Profile
Conclusions
• Oral proteasome inhibitors are moving forward that will improve patient convenience
• Small molecules targeting new pathways are showing efficacy, and are in registration studies
• Monoclonal antibodies recognizing myeloma surface antigens may soon achieve regulatory approvals
• Additional studies are needed to understand how these new tools can best be incorporated into our armamentarium against myeloma
