Phase II study of the c-MET inhibitor tivantinib (ARQ 197) in patients with relapsed or relapsed/refractory multiple myeloma.
The hepatocyte growth factor/c-MET pathway has been implicated in the pathobiology of multiple myeloma, and c-MET inhibitors induce myeloma cell apoptosis, suggesting that they could be useful clinically. We conducted a phase II study with the c-MET inhibitor tivantinib in patients with relapsed, or relapsed and refractory myeloma whose disease had progressed after one to four prior therapies. Tivantinib, 360 mg orally per dose, was administered twice daily continuously over a 4-week treatment cycle without a cap on the number of allowed cycles, barring undue toxicities or disease progression. Primary objectives were to determine the overall response rate and the toxicities of tivantinib in this patient population. Sixteen patients were enrolled in a two-stage design. Notable grade 3 and 4 hematological adverse events were limited to neutropenia in five and four patients, respectively. Nonhematological adverse events of grade 3 or higher included hypertension (in four patients); syncope, infection, and pain (two each); and fatigue, cough, and pulmonary embolism (one each). Four of 11 evaluable patients (36%) had stable disease as their best response, while the remainder showed disease progression. Overall, tivantinib as a single agent did not show promise for unselected relapsed/refractory myeloma patients. However, the ability to achieve stable disease does suggest that combination regimens incorporating targeted inhibitors in patients with c-MET pathway activation could be of interest.
Division of Hematology & Oncology, The University of Nebraska Medical Center, Omaha, NE, USA.|Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Muhamed
http://orcid.org/0000-0002-0630-8458
M
Baljevic
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Shadia
S
Zaman
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Veerabhadran
V
Baladandayuthapani
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Yan Heather
YH
Lin
Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Claudia Morales
CM
de Partovi
Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Zuzana
Z
Berkova
Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Behrang
B
Amini
Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Sheeba K
SK
Thomas
Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Jatin J
JJ
Shah
Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Donna M
DM
Weber
Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Min
M
Fu
Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Charles S
CS
Cleeland
Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Xin Shelley
XS
Wang
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Christine M
CM
Stellrecht
Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Richard E
RE
Davis
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Varsha
V
Gandhi
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. rorlowski@mdanderson.org.|Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. rorlowski@mdanderson.org.
Robert Z
RZ
Orlowski
D000368:Aged; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D006973:Hypertension / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism; D009364:Neoplasm Recurrence, Local; D009503:Neutropenia / Q000139:chemically induced; D010146:Pain / Q000139:chemically induced; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011760:Pyrrolidinones / Q000009:adverse effects / Q000627:therapeutic use*; D011804:Quinolines / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
C551661:ARQ 197; D011760:Pyrrolidinones; D011804:Quinolines; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met
ARQ 197; Multiple myeloma; Relapsed; Tivantinib; c-MET