Cancer Therapy: Clinical
Phase I Dose Finding Studies of Obatoclax (GX15-070), a
Small Molecule Pan-BCL-2 Family Antagonist, in Patients with
Advanced Solid Tumors or Lymphoma
Jimmy J. Hwang1, John Kuruvilla2, David Mendelson3, Michael J. Pishvaian1, J.F. Deeken1, Lillian L. Siu2,
Mark S. Berger4, Jean Viallet4, and John L. Marshall1
Purpose: Two phase I, single-agent studies were conducted to determine the dose and regimen of oba-
toclax, an antagonist of all BCL-2 antiapoptotic proteins, for evaluation in phase II trials. The two studies,
GX001 and GX005, evaluated the safety and tolerability of weekly 1-hour and 3-hour infusions of oba-
Experimental Design: Eligible patients in both studies were adults with solid tumor or lymphoma and
performance status 0-1 for whom standard therapies were not appropriate. In the GX001 study an accel-
erated dose titration design was initially used with subsequent cohorts of three to six patients with 40%
dose increments between levels. In the GX005 study three to six patients entered at each dose level with
40% dose increments between levels.
Results: Thirty-five patients were enrolled in studies GX001 (n = 8) and GX005 (n = 27). Clinically
significant central nervous system (CNS) toxicity was observed using the 1-hour infusion schedule. The
obatoclax maximum tolerated dose (MTD) in GX001 was 1.25 mg/m2due to these infusional CNS
events. The 3-hour infusion schedule studied in GX005 had improved tolerability, and the obatoclax
MTD was 20 mg/m2. One patient in GX005 with relapsed non-Hodgkin's lymphoma achieved partial
response of 2 months' duration, and one patient with relapsed non-Hodgkin's lymphoma had stable
disease for 18 months.
Conclusions: The 1-hour infusion schedule of obatoclax was associated with neuropsychiatric dose-
limiting toxicities at relatively low doses (MTD, 1.25 mg/m2). The 3-hour i.v. infusion of obatoclax ad-
ministered once weekly to patients with solid tumors was better tolerated (MTD, 20 mg/m2), and
evidence of clinical activity was observed. Clin Cancer Res; 16(15); 4038–45. ©2010 AACR.
Defects in apoptotic pathways are an essential element
of tumor pathogenesis (1). One common cancer-causing
defect arises from the overproduction of the antiapoptotic
protein BCL-2 and related family members, including
BCL-XLand MCL-1, which inactivate the apoptotic path-
way in many types of cancer cells. Blocking proapoptotic
signaling leads to the survival of genetically unstable cells,
thus promoting resistance to immune effectors, radiation,
and most cytotoxic agents.
The BCL-2 family consists of both antiapoptotic pro-
teins (such as BCL-2) and proapoptotic proteins (such as
BH3-only BIM and the apoptotic effectors BAX and BAK).
The antiapoptotic proteins of the BCL-2 family are fre-
quently overexpressed in a heterogeneous pattern across
tumor types. Thus, antagonists of all the BCL-2 antiapop-
totic proteins are likely to be active across a wide range of
Obatoclax (GX15-070, Gemin X Pharmaceuticals) is a
small-molecule antagonist of all of the antiapoptotic
BCL-2 family members. The inhibition of antiapoptotic
BCL-2 family proteins by obatoclax sensitizes tumor
cells to the proapoptotic stress signals inherent in can-
cer cells, inducing apoptosis. Obatoclax has been
shown to induce cell death in a wide range of cancer
cell lines in vitro, including non–small cell lung cancer,
mantle cell lymphoma, multiple myeloma, acute mye-
loid leukemia, and melanoma (2–6). In animal toxico-
logy studies, the major acute toxicities seen were
transient and reversible neurobehavioral symptoms con-
sisting of reduced activity, uncoordinated movements,
tremors, and somnolence.
Authors' Affiliations:1Lombardi Cancer Center, Georgetown Medical
Center, Washington, District of Columbia;2Princess Margaret Hospital,
Toronto, Ontario, Canada;3Premiere Oncology of Arizona, Scottsdale,
Arizona; and4Gemin X Pharmaceuticals, Malvern, Pennsylvania
Note: Supplementary data for this article are available at Clinical Cancer
Research Online (http://clincancerres.aacrjournals.org/).
Presented in part at 2006 Meeting of the American Society of Clinical
Corresponding Author: John Marshall, Lombardi Cancer Center, 3800
Reservoir Road, NW Washington, DC 20007-2113. Phone: 202-444-
7064; Fax: 202-444-1229; E-mail: firstname.lastname@example.org.
©2010 American Association for Cancer Research.
Clin Cancer Res; 16(15) August 1, 2010
blood-brain barrier. The BCL-2 antiapoptotic protein BCL-
XLis highly expressed in CNS neurons, suggesting that
CNS symptoms may be due to target effects. Another
BCL-2 family antagonist, ABT-737, has been shown to
alter the recovery of synaptic responses in vitro after repet-
itive synaptic activity (9), but ABT-737 is too large to cross
the blood-brain barrier. Thus, it is possible that the CNS
effects of obatoclax may be target effects. Laboratory eval-
uation of the direct effects of obatoclax on synaptic re-
sponses of CNS neurons is in progress.
The pharmacokinetic profile of obatoclax when admin-
istered as a 3-hour i.v. infusion was characterized by a rap-
id distribution phase and a slow terminal elimination
phase. The majority of obatoclax was eliminated from
the plasma by 4 to 5 hours after the end of infusion.
The increase in Cmaxand AUC with dose was approximate-
ly linear. There was no systemic accumulation of obatoclax
following 2 weeks of dosing. At the 28 mg/m2dose level,
pharmacokinetic data did not suggest a correlation be-
tween exposure and CNS adverse events. Nevertheless
CNS symptoms are clearly related to overall levels of expo-
sure, as grade 3 infusional CNS adverse events occur only
in higher-dosage groups.
At doses up to 28 mg/m2administered over 3 hours
once weekly, best response on treatment based on the in-
vestigator's assessment was a partial response reported in
one patient with stage IV lymphoma who had received
multiple prior therapies. Activity was also observed in
one patient with stage IV lymphoma who had received
multiple prior therapies and who experienced prolonged
stable disease during 72 weeks of therapy.
In another study of obatoclax in patients with chronic
lymphocytic leukemia (CLL; ref. 10), the peak plasma con-
centration of oligonucleosomal DNA increased with dose.
In this study, largely in patients with colon cancer and
non-Hodgkin's lymphoma, correlations between dose or
response and levels of oligonucleosomal DNA were not
apparent. This suggests that differences in the plasma le-
vels of oligonucleosomal DNA released after obatoclax
treatment may depend on tumor type, or, alternatively,
that obatoclax may have been more effective in inducing
apoptosis in patients with CLL than in patients with colon
cancer and non-Hodgkin's lymphoma.
One previously published phase I study (10) evaluated
obatoclaxadministered as both1-hour and3-hour i.v. infu-
sions in patients with advanced CLL. In that study 1-hour
for 3-hour infusions was 28 mg/m2, slightly higher than
mas in this study. Another previously published phase I
obatoclax study (11) evaluated obatoclax administered by
24-hour infusion. CNS adverse events were less prominent
than with shorter infusions, as indicated by escalation to
28 mg/m2, the highest dose planned, without DLT.
In conclusion, the 1-hour infusion schedule of obato-
clax was associated with neuropsychiatric DLTs at relative-
ly low doses with an MTD of 1.25 mg/m2. The MTD of
obatoclax administered using a 3-hour i.v. infusion once
weekly to patients with solid tumors was 20 mg/m2. Evi-
dence of clinical activity was observed in two patients with
stage IV lymphoma who experienced partial response and
prolonged stabilization of their disease, respectively. Fur-
ther studies with this promising agent should be done in
both lymphomas and solid tumors at a weekly dose of
20 mg/m2administered i.v. over 3 hours.
Disclosure of Potential Conflicts of Interest
J.L. Marshall: honoraria from speakers bureau and ownership interest/
patents, Roche, Genentech, and Amgen.
The costs of publication of this article were defrayed in part by the
payment of page charges. This article must therefore be hereby marked
advertisement in accordance with 18 U.S.C. Section 1734 solely to
indicate this fact.
Received 03/30/2010; revised 05/25/2010; accepted 06/01/2010;
published OnlineFirst 06/10/2010.
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Clin Cancer Res; 16(15) August 1, 2010www.aacrjournals.org