A phase I study of veliparib in combination with metronomic cyclophosphamide in adults with refractory solid tumors and lymphomas.
OBJECTIVE
Oral administration of the alkylating agent cyclophosphamide at low doses, metronomic dosing, is well tolerated, with efficacy in multiple tumor types. PARP inhibition potentiates effects of cyclophosphamide in preclinical models. We conducted a phase I trial of the PARP inhibitor veliparib and metronomic cyclophosphamide in patients with refractory solid tumors and lymphoid malignancies.


METHODS
Objectives were to establish the safety and maximum tolerated dose (MTD) of the combination; characterize veliparib pharmacokinetics (PK); measure poly(ADP-ribose) (PAR), a product of PARP, in tumor biopsies and peripheral blood mononuclear cells (PBMC); and measure the DNA-damage marker γH2AX in PBMCs and circulating tumor cells (CTC). Cyclophosphamide was administered once daily in 21-day cycles in combination with veliparib administered once daily for 7, 14, or 21 days.


RESULTS
Thirty-five patients were enrolled. The study treatment was well tolerated, and the MTD was established as veliparib 60 mg with cyclophosphamide 50 mg given once daily. Seven patients had partial responses; an additional six patients had disease stabilization for at least six cycles. PAR was significantly decreased in PBMCs (by at least 50%) and tumor biopsies (by at least 80%) across dose levels (DL); γH2AX levels were increased in CTCs from seven of nine patients evaluated after drug administration.


CONCLUSIONS
The combination of veliparib with metronomic cyclophosphamide is well tolerated and shows promising activity in a subset of patients with BRCA mutations. A phase II trial of the combination compared with single-agent cyclophosphamide is ongoing in BRCA-positive ovarian cancer, triple-negative breast cancer, and low-grade lymphoma.
National Cancer Institute, Bethesda, MD, USA.
Shivaani
S
Kummar
Jiuping
J
Ji
Robert
R
Morgan
Heinz-Josef
HJ
Lenz
Shannon L
SL
Puhalla
Chandra P
CP
Belani
David R
DR
Gandara
Deborah
D
Allen
Brian
B
Kiesel
Jan H
JH
Beumer
Edward M
EM
Newman
Larry
L
Rubinstein
Alice
A
Chen
Yiping
Y
Zhang
Lihua
L
Wang
Robert J
RJ
Kinders
Ralph E
RE
Parchment
Joseph E
JE
Tomaszewski
James H
JH
Doroshow
D059250:Administration, Metronomic; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D001562:Benzimidazoles / Q000008:administration & dosage*; D003520:Cyclophosphamide / Q000008:administration & dosage*; D004334:Drug Administration Schedule; D005260:Female; D006657:Histones / Q000032:analysis; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy
D001562:Benzimidazoles; C468783:H2AX protein, human; D006657:Histones; C521013:veliparib; D003520:Cyclophosphamide