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Clinical Trials |
Lombardi Cancer Center, Georgetown University Medical Center, Washington DC 20007 [H. X. C., J. L. M., E. N., N. R., W. D., M. J. H.], and Hybridon, Inc., Milford, Massachusetts 01757 [R. R. M., B. D., J. M., M. M.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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of type I protein kinase A, which plays an important role in
growth and maintenance of malignancies. Preclinically, GEM231 inhibited
human cancer xenografts either alone or synergistically with
chemotherapeutic agents and has demonstrated an improved metabolic
stability and safety profile compared to the first-generation
compounds. Objectives of this study were to define the safety profile
and pharmacokinetics of GEM231 administered as 2-h IV infusions twice
weekly in patients with refractory solid tumors.
Fourteen patients (13 evaluable for safety) received escalating doses
of GEM231 at 20–360 mg/m2 (2.5–9 mg/kg). Tumor
histologies included non-small cell lung cancer, renal cell cancer,
sarcoma, and others. The plasma pharmacokinetics of GEM231 were linear
and predictable. Maximum plasma concentration
(Cmax) reached 50–70 µg/ml (8–13
µM) at dose 360 mg/m2 and 27–32 µg/ml at
dose 240 mg/m2. The plasma half-life was about 1.5 h.
The only clinical toxicities were transient grade I-II fever and
fatigue at doses 
240 mg/m2. There was no
treatment-related complement activation or thrombocytopenia at any dose
level, except with the first dose in one patient who had pre-existing
borderline thrombocytopenia. Transient activated partial thrombin time
prolongation occurred at doses 160 mg/m2. Dose-limiting
toxicities included transient activated partial thrombin time
prolongation (one of three patients at 360 mg/m2) and
cumulative reversible transaminase elevation (three of three patients
at 360 mg/m2 and three of six patients at 240
mg/m2 during weeks 3–10). One patient with colon cancer
had stabilization of a previously rising carcinoembryonic
antigen.
Thus, in this first clinical evaluation of a mixed-backbone oligonucleotide in cancer patients, high plasma concentrations of GEM231 were well tolerated without significant acute toxicities, but prolonged treatment was associated with reversible transaminitis. Although 240 mg/m2 by 2-h infusion twice weekly was safe for a 4-week treatment duration, alternative dosing schedules are being tested to minimize the cumulative toxicity, which will be essential to extend the duration of therapy at the highest GEM231 dose tested.
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. It is an
18-mer AON containing a PS-oligo backbone with terminal
2'-O-methyl ribonucleoside modification.
PKA-I as a target of anticancer treatment has been supported by many
studies. Protein kinase A exists as type I and II (PKA-I and type II
protein kinase A), which differ in their regulatory subunits
(9)
. The two isoforms differentially regulate the systems
that control cell proliferation and differentiation (10)
.
Whereas type II protein kinase A is preferentially expressed in normal
tissues and involved in growth arrest and differentiation
(10, 11, 12)
, PKA-I plays an important role in cell
proliferation and neoplastic transformation (10)
, in
G1-to-S cell cycle transition (13)
,
and signal transduction of mitogenic effects of growth factors such as
epidermal growth factor and transforming growth factor
(14, 15, 16)
. PKA-I is overexpressed in the majority of human
cancers and correlated with unfavorable clinicopathological features
and prognosis (17, 18, 19)
.
Selective down-regulation of PKA-I by a cAMP analogue (8-Cl-cAMP; Refs.
14
, 20
, and 21
) or antisense
compounds against PKA-RI (22, 23, 24)
induced growth arrest
and differentiation of several human cancer cell lines in both in
vitro and in vivo models. GEM231 is a mixed backbone
PKA-RI antisense bearing the same sequence as the first-generation
compounds that showed sequence-specific antitumor activities.
Preclinically, GEM231 down-regulated the PKA-RI expression in tumor
tissues and inhibited growth of a number of human cancer cell
xenografts in nude mice (colon, breast, ovary, prostate, lymphoma,
lung, etc.). Furthermore, synergistic effects were observed when GEM231
was combined with several chemotherapeutic agents (taxanes, platinums,
or topoisomerase II inhibitors; Ref. 14
) and/or a chimeric
monoclonal antibody (C225) against epidermal growth factor receptor
(25)
. In addition, compared to a first-generation
counterpart, GEM231 has demonstrated markedly reduced toxicities in
murine models with respect to thrombocytopenia, aPTT prolongation, and
transaminase elevation (7)
. The in vivo
metabolic stability was also increased, resulting in a longer tissue
half-life in rats (26)
. The present Phase I clinical trial
was conducted to define the safety profile and pharmacokinetics of
GEM231 by 2-h infusion twice weekly.
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MATERIALS AND METHODS |
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Study Drug.
GEM231 (HYB0165) is an 18-base DNA/RNA hybrid PS-oligo synthesized by
Hybridon, Inc. The sequence
(5'-GCGUGCCTCCTCACUGGC-3') is complementary to
the mRNA of NH2-terminal codon 8–13 of
the RI subunit of PKA-I. The underlined four bases on the 5' and 3'
ends have ribose sugars modified with a 2'-O-methyl group;
the 17 internucleotide linkages are chiral O-linked
phosphorothioate. GEM231 has a molecular weight of 6287 atomic mass
units in its 17 Na+ salt form and 5913 atomic
mass units as the free acid. The compound is supplied in lyophilized
form and reconstituted in normal saline to a final concentration of 10
mg/ml within 24 h of use.
Patient Population.
Patients were eligible if they were 18 years of age or older, had
histologically confirmed measurable or evaluable advanced solid cancers
for which no curative or reliably effective therapies existed, and had
an Eastern Cooperative Oncology Group performance status of 0–2 and
estimated life expectancy of at least 12 weeks. Patients were required
to have adequate organ functions: bone marrow function (absolute
neutrophil count 1500/mm3; platelet count
100,000/mm3; hemoglobin 8.5 g/dl), and normal
prothrombin time/aPTT, kidney (creatinine 
1.25 times the upper limit
of normal), and liver (serum bilirubin 1.25 times the upper limit of
normal; ALT and aspartate aminotransferase 3 times the upper limits
of normal). At least 3 weeks must have elapsed from prior chemotherapy
or radiotherapy, and all reversible significant toxicities must have
resolved. Patients were not eligible if pregnant or if fertile and
unwilling to use contraception. Other exclusion criteria included
potential renal tubular dysfunction (indicated by 2+ proteinuria),
known hypersensitivity to any oligonucleotides, or progressive central
nervous system metastasis within the previous 4 months.
Treatment Plan.
GEM231 was administered on an outpatient basis by 2-h i.v. infusion
twice a week for 8 consecutive weeks with evaluation at 4 weeks. The
drug was given at six dose levels: 20 mg/m2, 40
mg/m2, 80 mg/m2, 160
mg/m2, 240 mg/m2, and 360
mg/m2. The starting dose was one-sixth of the MTD
observed in monkeys. One hundred percent dose escalation and
one-patient cohorts were used in the lower dose range because minimal
toxicities were anticipated; above dose level 160
mg/m2 or upon development of toxicity, the dose
escalation was reduced to 50%, and cohort size was increased to three
to six. Patients for successive dose levels were entered after 4 weeks
of treatment had been received by the previous cohort, until DLT.
Grading of toxicities used to define DLT was based on the Southwest Oncology Group Criteria (Expanded National Cancer Institute Common Toxicity Criteria; Ref. 27 ). DLT for this study included: grade 4 hematological toxicity (WBC <1000/mm3; Platelet count <25,000/mm3), grade 3 aPTT prolongation (more than three times the normal), grade 3 liver enzyme abnormality (transaminase 2.6–5.0 times the upper limit of normal), and grade 3 fever/flu-like syndrome. MTD was defined as the highest dose that produces DLT at the end of the 4-week treatment in fewer than two patients of a group of three to six patients at that dose level.
The disease status was assessed every 8 weeks using the standard criteria for response assessment. The treatment was continued until disease progression or unacceptable toxicity.
Safety Assessment.
Throughout the study, patients were required to have periodic history
and physical examination. Vital signs were monitored frequently during
each infusion. Laboratory monitoring included: routine blood tests
(hematology, chemistry, and liver function tests), urine analysis, and
measurement of complement split product Bb. PT/aPTT were
measured before and at the end of each 2-h infusion. For infusions 1
and 7, aPTT/PT were also measured at 4 h and 24 h after the
start of infusions.
Pharmacokinetic Assessment.
Multiple blood samples were taken for plasma GEM231 concentration
before and up to 48 h (hour 0, 1, 2, 2.25, 2.5, 3, 4, 6, 8, 24,
and 48) after the beginning of the infusion for dose 1 and dose 7 or 8.
The oligonucleotide was measured by high-performance liquid
chromatography, and Cmax, AUC,
plasma half-life, and volume of distribution were determined.
Descriptive statistics were calculated for each parameter after
infusion 1 and infusion 7 or 8. Difference between the two time points
were evaluated for statistical significance using the two-tailed paired
t test with a type I error of 0.05.
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RESULTS |
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, 7 were males and 6 females, with a
median age of 57 (range, 49–75). Cancer histologies included non-small
cell lung cancer (3 patients), renal cell carcinoma (3 patients),
sarcoma (3 patients), breast cancer (1 patient), mesothelioma (1
patient), colorectal cancer (1 patient), and hepatocellular cancer (1
patient). All patients but one (mesothelioma) had been pretreated and
were refractory to chemotherapies (2–9 regimens); seven patients also
had radiation, immunotherapy, or hormonal therapies. Eastern
Cooperative Oncology Group performance statuses were 0–1. All patients
had normal organ functions by blood tests at the time of eligibility
screening.
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and 3
.
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, treatment at all dose levels was well tolerated,
with the only side effects being occasional mild fever and fatigue (two
of six patients at 240 mg/m2 and two of three
patients at 360 mg/m2). Two of the patients with
fever were found to have concurrent central line infection. Fever was
of low grade and transitory, beginning 0–6 h after infusion and
lasting for <24 h; it was associated mostly with the first infusion
and did not recur with subsequent doses. Electrocardiogram, blood
pressure, and pulse were unaffected. Mild diarrhea was reported by one
patient (240 mg/m2) and appeared to be
treatment-related because the symptom resolved upon the completion of
the course of the therapy.
The most consistent laboratory abnormality (Table 3)
after GEM231 administration was
transient prolongation of aPTT at doses 160
mg/m2. The effect was maximal at the end of the
infusion and returned to the normal range within hours (Fig. 1)
. The extent of peak aPTT prolongation
was directly proportional to dose and peak plasma concentrations
(Cmax) of the drug (Table 4)
. The first aPTT elevation occurred at
a Cmax of 26 µg/ml (at the
160-mg/m2 dose). At the highest dose level tested
(Cmax, 52–71 µg/ml), the majority
of the peak aPTT values were between 43 and 62 s and did not
require dose modification; only one subject had an aPTT of 87 s
(grade III) upon a single measurement and was dose-reduced. Prothrombin
times were only minimally prolonged (16% change from baseline), and
elevations were less clearly dose-dependent. No hemorrhagic events
occurred in association with the transitory aPTT abnormality.
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. Although a small and transient decrease in
platelet counts of 20–60,000/mm3 occurred in
most patients after the first infusion at dose levels 240
mg/m2, in no cases except for the patient
described below did the platelet counts drop below
100,000/mm3. In the one subject whose platelet
counts fluctuated between 60 and 110,000/mm3
before the study, further decrease in platelets resulted in grade II
thrombocytopenia (51,000/mm) after the first dose and recovered to
baseline after 3 days. This change in platelet counts was associated
only with the first dose and did not recur with 16 subsequent
treatments.
Complement activation was measured by the postinfusion change of the
plasma concentrations of factor Bb, a split product of the alternative
pathway. Based on this parameter, no evidence of complement activation
was observed at any dose level. Maximum increment of Bb was 0.8 mg/ml
in one patient at dose level 360 mg/m2 and was
associated with a GEM231 concentration of 71 µg/ml (Table 3)
.
Transaminase elevations were the cumulative DLT observed in all of the
three patients treated at 360 mg/m2 and in three
of the six patients entered at the 240 mg/m2 dose
level (Table 3)
. The effects were mainly on ALT and to a lesser
extent on aspartate aminotransferase, as depicted in Fig. 2
. The onset of the abnormality was more
than 4 (4–10.5) weeks into the uninterrupted treatment, except in one
patient at 240 mg/m2 who developed the
abnormalities before 4 weeks. In all cases, the transaminase elevations
were reversible within 2 weeks after discontinuation of the therapy.
There were insufficient data to determine an association between the
presence of liver metastasis and the occurrence of liver enzyme
abnormalities. None of these transaminase alterations were accompanied
by the development of abnormalities in other tests of the liver
function, including prothrombin time, albumin, or bilirubin.
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). The
curves based on dose 1 and dose 7 or 8 overlapped, suggesting that
there was no plasma accumulation of GEM231 with multiple doses. Table 5
summarizes the values derived from
pharmacokinetic parameters of all dose levels.
Cmax was as high as 52–71 µg/ml
(9–13 µM) at 360 mg/m2
and 23–55 µg/ml at 240 mg/m2.
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, doses of GEM231 administered in this study were
equivalent to 0.5–9.1 mg/kg over 2-h infusion. It appeared that the
correlation between dose and Cmax was
better when dose was expressed as body surface area as opposed to
weight (correlation coefficient R2=
0.77 versus 0.57; Fig. 4A).
Similarly,
correlation of dose with AUC was more reliable when dose was expressed
as per m2 (R2 =
0.80 versus 0.54; Fig. 4B).
MTD.
The MTD of GEM231 administered by 2-h infusion twice weekly for 4 weeks
or less was not reached. However, in view of the acute DLT (aPTT
prolongation) in one of three patients at 360
mg/m2 and cumulative DLT (ALT elevation) after 4
weeks of treatment at doses 240 mg/m2, it was
determined that 240 mg/m2 twice weekly can be
safely given for a 4-week treatment duration.
Antitumor Activity.
There were no objective antitumor responses in this dose-escalating
study. The only colon cancer patient enrolled in the study (dose level,
360 mg/m2) exhibited a stabilization of a
previously rising carcinoembryonic antigen at the end of 8 weeks
of treatment.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Synthetic oligonucleotides commonly produce plasma concentration-dependent toxicities, due in part to the polyanionic nature of the molecules. In clinical trials with the first-generation PS-oligos given as 2-h infusions, doses of 1–2 mg/kg (which achieved plasma Cmax of 10–20 µg/ml) were associated with clinical symptoms of fever and chills as well as laboratory abnormalities, including aPTT prolongation, complement activation, and thrombocytopenia (4 , 5 , 28 , 29) . For this reason, most AON studies for efficacy evaluation have used continuous infusion as the mode of administration to avoid dose-limiting peak plasma concentrations. GEM231 as a prototype of MBOs contains a PS-oligo backbone with 2'-O-methyl ribonucleoside modifications. In a comparison study in rats (7) between GEM231 and its first-generation counterpart bearing the same sequence, the first-generation compound at 10 mg/kg and 30 mg/kg caused significant thrombocytopenia, aPTT prolongation, and ALT elevation, whereas the same doses of GEM231 did not produce these adverse effects.
The present clinical study supported the preclinical prediction of
improved concentration-dependent side effects of GEM231. Notably,
thrombocytopenia and complement activation did not appear to be a
problem over this range of GEM231 doses, even at the highest plasma
concentrations achieved (52–71 µg/ml). Despite a transient decrease
in platelet counts in some patients after the initial GEM231 infusion,
the magnitude of change was negligible except in a patient with
pre-existing borderline platelet counts. Unlike the experience with the
first-generation PS-oligos in which aPTT was prolonged at doses 1
mg/kg by 2-h infusion, aPTT in this study was not elevated until the
dose reached 160 mg/m2 (4 mg/kg). Even at the
highest dose level tested (360 mg/m2 or 7–9
mg/kg), aPTT prolongations were mostly grade II, and in all cases, were
of no clinical significance. As is the case with first-generation
PS-oligos, the aPTT changes were brief, paralleling the short plasma
half-life of GEM231.
Liver is a major site of uptake and metabolism of synthetic oligonucleotides. The reversible ALT elevation defined the cumulative DLT of GEM231 at dose 240 mg/m2 and above, which occurred mostly after >4 weeks of uninterrupted twice-weekly treatment. Similar transaminase abnormalities were also observed with a first-generation PS-oligo (GEM91) when given at 0.67 or 1.0 mg/kg every 8 h or at daily doses of >2.0 mg/kg by continuous IV infusions for up to 14 days (28) . The pathological implication of this isolated transaminase elevation is unclear. In rats and monkeys treated with synthetic oligonucleotides, cytoplasmic vacuoles and histocytic infiltrates have been observed in the livers and kidneys. GEM231, with its improved metabolic stability (8) , has a tissue half-life of 21 days based on 35S-GEM231 data in rats. It is conceivable that the transaminase abnormalities is related to the accumulation of GEM231 in the liver. Alternatively or additionally, the repeated challenges of high plasma concentrations of the drug could saturate the capacity of hepatic clearance. Taken together, the logical next step to minimize the cumulative toxicity would be to introduce planned dose interruptions every 3–4 weeks and/or to slow the infusion rate, e.g., over a 24-h period.
The plasma pharmacokinetics of GEM231 were similar to that reported for first-generation PS-oligos administered as 2-h infusions (28 , 29) . Cmax and AUC increased linearly with dose throughout the study. It also appeared that, at least with GEM231 by 2-h infusions, the correlation of dose with both Cmax and AUC was more reliable when the dose was calculated based on body surface area than on weight. This is consistent with the fact that for the same unit body mass, fatty tissues had much lower distribution of oligonucleotide than muscle tissues (6) . The short plasma T1/2 of GEM231 in clinical studies is consistent with a rapid distribution to tissues, corresponding to the distribution phase seen in animal studies (30) . Thus it is important to recognize that the bioavailability of AON in tumors/tissues cannot be extrapolated from the plasma concentrations.
As with all other AONs, the optimal dose and schedule of GEM231 remains unknown. Consideration should be given to acute and chronic toxicities, delivery of intact oligo compound to the tumor cells, and finally, the status of the target gene modulation. Based on the minimal concentration-dependent side effects observed in this study and animal evidence of prolonged tissue half-life of the intact molecules, delivery of high doses of GEM231 with less frequent infusions may be feasible.
Further clinical studies are under way to test alternative dosing
schedules to minimize the cumulative toxicity and probably to further
escalate the dose. In addition, in an attempt to determine the effect
of GEM231 on PKA-RI expression and validity of PKA-RI as an
anticancer target, novel clinical trials are planned to examine the
intratumor pharmacodynamics of AON and their molecular impact on tumor
cells in perioperative settings. Lastly, combination regimens of GEM231
with cytotoxic agents are being evaluated clinically.
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FOOTNOTES |
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1 Supported by a grant from Hybridon, Inc. 
2 To whom requests for reprints should be
addressed, at Lombardi Cancer Center, Georgetown University Medical
Center, Washington, DC 20007. Phone: (202) 687-2126. E-mail: CHENH1{at}gunet.georgetown.edu
3 The abbreviations used are: AON, antisense
oligonucleotide; aPTT, activated partial thrombin time; AUC, area under
the plasma concentration-time curve; DLT, dose-limiting toxicity; MBO,
mixed-backbone oligonucleotide; MTD, maximum tolerated dose; PKA-I,
type I protein kinase A; PKA-RI, regulatory subunit of PKA-I;
PS-oligo, phosphorothioate oligonucleotide; ALT, alanine
aminotransferase.
Received 9/ 2/99; revised 1/ 6/00; accepted 1/11/00.
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at
different dose levels represents the peak plasma concentration measured
at dose 1 and dose 7 or 8. The correlation coefficients
(R2) based on per-m2 or per-kg
dose calculations were compared. 