Phase I clinical and pharmacology study of clofarabine in patients with solid and hematologic cancers.
OBJECTIVE
To define the maximum-tolerated doses (MTDs) and dose-limiting toxicities (DLTs) of clofarabine, given as a 1-hour infusion daily for 5 days, in patients with solid tumors and with acute leukemia.


METHODS
The initial part of the study defined the MTD and DLT in solid tumors. The second part of the study defined the MTD and DLT in acute leukemia.


RESULTS
The starting dose of clofarabine (15 mg/m(2)) was myelosuppressive, requiring several dose de-escalations to 2 mg/m(2), the dose suggested for phase II studies in solid tumors. Dose escalation in acute leukemia started at 7.5 mg/m(2), with several escalations to 55 mg/m(2). The DLT was reversible hepatotoxicity at 55 mg/m(2). The recommended dose for acute leukemia phase II studies was 40 mg/m(2). Among 32 treated patients with acute leukemia, two achieved a complete response and three had a marrow complete response without platelet recovery (hematologic improvement), for an overall response rate of 16%. At 40 mg/m(2), the median plasma clofarabine level was 1.5 micro mol/L (range, 0.42 to 3.2 micro mol/L; n = 7). Cellular and plasma pharmacokinetic studies suggested dose proportionality but showed a wide variation in intracellular concentrations of clofarabine triphosphate.


CONCLUSIONS
This phase I study defined the following two MTDs for clofarabine given as a 1-hour infusion daily for 5 days: 2 mg/m(2) for solid tumors, the DLT being myelosuppression; and 40 mg/m(2) for acute leukemia, the DLT being hepatotoxicity. Encouraging activity was observed in acute leukemia.
Kantarjian
Hagop M
HM
Departments of Leukemia, Experimental Therapeutics, and Breast and Head and Neck, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. hkantarj@mdanderson.org
Gandhi
Varsha
V
Kozuch
Peter
P
Faderl
Stefan
S
Giles
Francis
F
Cortes
Jorge
J
O'Brien
Susan
S
Ibrahim
Nuhad
N
Khuri
Fadlo
F
Du
Min
M
Rios
Mary Beth
MB
Jeha
Sima
S
McLaughlin
Peter
P
Plunkett
William
W
Keating
Michael
M
D000227:Adenine Nucleotides; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects* / Q000737:chemistry; D001087:Arabinonucleosides / Q000008:administration & dosage* / Q000009:adverse effects* / Q000737:chemistry; D001853:Bone Marrow / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy; D000077866:Clofarabine; D004334:Drug Administration Schedule; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy; D019337:Hematologic Neoplasms / Q000188:drug therapy*; D006801:Humans; D007262:Infusions, Intravenous; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy; D008099:Liver / Q000187:drug effects; D008175:Lung Neoplasms / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy; D016896:Treatment Outcome
D000227:Adenine Nucleotides; D000970:Antineoplastic Agents; D001087:Arabinonucleosides; D000077866:Clofarabine