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Clinical Trials |
Cancer Research Campaign Department of Medical Oncology, Beatson Oncology Centre, Western Infirmary, Glasgow G11 6NT, United Kingdom [J. S. d. B., S. E., T. R. J. E.]; Department of Medical Oncology, St. George’s Hospital Medical School, London SW 17 0RE, United Kingdom [A. G. D., J. D., F. J. L.]; Cancer Research Campaign Department of Clinical Oncology, Nottingham City Hospital, Nottingham NG5 1PB, United Kingdom [J. C., D. F.]; Quintiles SA Strasbourg, Lingolshiem BP306, 67832 Tanneries Cedex, France [R. J. G.]; Quintiles Scotland Limited, Heriot-Watt University Research Park, Edinburgh EH14 4AP, United Kingdom [C. J. B.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, the potentiation of
tumor-infiltrating macrophages, and the inhibition of angiogenesis.
Interleukin (IL)-1, IL-6, and IL-12 induction by ONO-4007 activates
cytotoxic natural killer cells to up-regulate IFN-
and nitric oxide
synthase activity. ONO-4007 was given to 24 patients (13 males and 11
females; median age, 53 years) as a 30-min i.v. infusion on day 1,
followed on day 15 by a first treatment cycle consisting of three
weekly infusions at the same dose, followed by a rest period of 1 week.
Cohorts of six patients received up to a maximum of four treatment
cycles at increasing dose levels (75, 100, and 125 mg). The maximum
tolerated dose was 125 mg, with grade 3 National Cancer Institute
Common Toxicity Criteria toxicity (rigors with cyanosis) occurring in
two of six patients at this dose level. An additional six patients were
treated at 100 mg, the dose below the maximum tolerated dose. Other
toxicities included grade 2 National Cancer Institute Common Toxicity
Criteria myalgia, nausea, and hypotension. The pharmacokinetics of
ONO-4007 appeared to be independent of dose and showed linearity with
respect to time. ONO-4007 has a low systemic clearance (
1.3 ml/min)
and a small volume of distribution (5–8 liters) with a long
t1/2 of 74–95 h. The administration of
ONO-4007 was shown to result in a significant increase in circulating
levels of tumor necrosis factor and IL-6. No objective antitumor
responses were observed. Seven patients maintained stable disease for
at least two cycles, whereas five patients maintained stable disease
for the full four-cycle duration of the study. Additional studies are
required to determine the antitumor activity of ONO-4007. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In preclinical models, ONO-4007 demonstrated antitumor activity with
considerably less toxicity than LPS. In vivo studies in mice
bearing the murine tumors Meth-A (sarcoma), MH-134 (hepatoma), M-5076
(reticulum cell sarcoma), and MM-46 (mammary carcinoma) demonstrated
significant tumor inhibitory effects, in some cases with complete
regression of tumors (9
, 10)
. Additional studies conducted
with nude mice bearing transplanted human pancreas cancer cells, MIA
paca-2 and Panc-1, demonstrated significant inhibition of tumor growth
and prolongation of survival compared to controls (11)
.
These effects were associated with increased intratumoral TNF-
activity. In vitro studies with peripheral blood monocytes
or myelomonocytic cell lines cultured with ONO-4007 demonstrated
induction of TNF- production (12)
. These investigations
have shown that ONO-4007 induces the secretion of TNF-, IFN-,
IL-1, IL-6, and GM-CSF in a dose-proportional manner in splenic
mononuclear cells. There appears to be no cytotoxic effect on tumor
cells in the absence of macrophages, suggesting that the antitumor
effect of the drug is dependent on the stimulation of macrophages to
express these cytokines. These findings are in keeping with previous
studies performed on murine tumor cells transfected with human TNF-
(10)
. In addition, lipid A analogues also inhibit tumor
angiogenesis (13)
, partly through induction of TNF-
(14)
.
Preclinical toxicology studies4 revealed significant interspecies variation, with rats being the most sensitive species. In rats, death occurred after a single administration at 50 mg/kg or higher, with toxicological changes at doses above 5 mg/kg when administered repeatedly (every day for 4 weeks to 6 months, or intermittently for 6 months). In dogs, no marked toxicological changes were noted after a single administration of 50 mg/kg or repeated administration (every day for 2–4 weeks) at a dose of 10 mg/kg. In monkeys, no toxicological changes were observed after a single dose of 50 mg/kg. However, anemia, thrombocytopenia, prolonged coagulation time, changes in liver function tests, hemorrhagic findings in various organs, necrosis of hepatocytes, and death were reported with daily repeated administration (daily for 2 weeks or intermittently for 4 weeks) at 25 mg/kg or higher. The symptoms of toxicity seen in monkeys on repeated administration are thought to be due to the maintenance of very high blood levels of the drug for extended periods of time.
Based on this preclinical data, a three-center Phase I study was performed. The main aims of this study were as follows: (a) to determine the safety and toxicity of an initial single dose of ONO-4007; (b) to determine the MTD of ONO-4007 when administered as an intermittent treatment cycle; (c) to evaluate the PK and PD of ONO-4007; and (d) to record any antitumor activity.
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PATIENTS AND METHODS |
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18 years; (c) Karnofsky
performance status 70%; (d) life expectancy of 4
months; (e) body weight between 40 and 90 kg; (f)
adequate hematological (hemoglobin 10 g/dl; leukocytes
4 x 109/liter; granulocytes 2 x 109/liter; platelets 100 x
109/liter), renal (serum creatinine < 1.5x
the upper limit of normal), and hepatic function (serum bilirubin < upper limit of normal; transaminases and alkaline phosphatase < 2.5x the upper limit of normal); (g) no chemotherapy,
radiotherapy, immunotherapy, endocrine therapy, or major surgery within
the 4 weeks prior to commencing ONO-4007; and (h) no
systemic corticosteroids within 2 weeks of starting treatment.
Exclusion criteria included cerebral metastases, pregnancy or
lactation, psychiatric illness, clinically significant medical
conditions, major fluid collections, a history of infection with HIV or
hepatitis B or C, a history of autoimmune disease or organ
transplantation, and concurrent systemic Gram-negative bacterial
infections.
Study Design.
The study was performed according to good clinical practice guidelines.
Baseline laboratory evaluations included a full blood count with
differential, clotting factors, urea and electrolytes, serum
creatinine, calcium, phosphate, total protein, albumin, glucose,
alkaline phosphatase, aspartate aminotransferase, alanine
aminotransferase, bilirubin, thyroid function tests, and uric acid.
Complete medical history, physical examination, radiological assessment
of disease, urinalysis, chest X-ray, electrocardiogram, and tumor
markers (if appropriate) were also performed. In addition, a full blood
count with differential, clotting factors, biochemical parameters, and
vital signs was assessed weekly during the study. Response evaluation
was performed by physical examination and radiology and assessed
according to the WHO criteria after each treatment cycle.
Drug Administration.
ONO-4007 was supplied by ONO Pharmaceutical Company Limited, Japan, as
an injectable formulation in ampoules containing 50 or 100 mg of
ONO-4007 dissolved in 1 or 2 ml of 55% ethanol, respectively. ONO-4007
was aseptically diluted to a final volume of 100 ml in 5% dextrose
before administration and then stored below 5°C and used within
8 h of reconstitution. Because ONO-4007 has similarities to
bacterial cell wall, patients previously exposed to this antigen could
potentially develop an allergic reaction. Consequently, a prick test
was performed 24 h before administration of the first infusion.
The prick test was considered positive if the average diameter of the
wheal associated with erythema was >3 mm after 15 min, or if the
erythema was >3 mm around the test site after 24 h. Patients with
a positive prick test were then withdrawn from the study. ONO-4007 was
administered as a single i.v. infusion over 30 min via a peripheral
venous catheter. The first infusion was followed by a 2-week
observation period. The first cycle of treatment was then commenced
with a repeated dose schedule in which ONO-4007 was administered weekly
as a 30-min infusion for 3 consecutive weeks, followed by a 1-week rest
period. This 4-week cycle was repeated up to a maximum of four cycles
of treatment. The patient and the investigator had the right to stop
treatment with ONO-4007 at any time for any reason, including
unacceptable toxicity, intercurrent illness, treatment failure, or
protocol violation. Patients who experienced drug-related NCI-CTC grade
3 toxicity could be retreated after complete resolution of the adverse
event at the dose level of the preceding cohort.
Pulse, blood pressure, and body temperature were recorded immediately before and at the end of each infusion of ONO-4007, and these vital signs were also recorded 2 h after the end of the first single infusion and after the first infusion of cycle 1 of therapy. Diclofenac sodium was used for both the treatment and the prophylaxis of acute flu-like symptoms induced by ONO-4007. Body weight was also recorded at baseline and at the start of each new treatment cycle. Furthermore, the full blood count was measured 2 h after completion of the first single infusion and the first infusion of cycle 1 of therapy.
Dose Escalation and Modification Procedures.
The starting dose in this study was based on preliminary information
available from unpublished studies in the Japanese
population.5
The
starting dose was 75 mg/patient. This dose level was felt to be safe
based on the safety profile of the drug at 50 mg/patient in the
multiple administration study in Japan and accounting for the
difference in body surface area between the Japanese and Occidental
populations (1.5 m2 compared with 1.75–1.8
m2). The subsequent planned dose levels were 100,
125, and 150 mg/patient, with further dose escalation in 25-mg
increments as necessary. There was no dose correction for body surface
area, in keeping with the administration schedules of most
immunotherapy agents and other agents thought to act as cytostatic
agents rather than cytotoxic agents. The PK data from the preliminary
Japanese studies demonstrated almost complete clearance of the drug
within 1 week of administration. Given the relatively long half-life of
the drug, a weekly administration was proposed that was predicted to
avoid the accumulation of the drugs. A rest period (1 week) was
incorporated into each 4-week treatment cycle to allow recovery from
any possible toxicity and to avoid or reduce the rebound
down-regulation of the immunological reaction observed with other
immunotherapies. Cohorts of six patients were entered at each dose
level, with no dose escalation in individual patients. Toxicities were
recorded in all patients on a weekly basis using the standard NCI-CTC.
DLT was defined as any toxicity of NCI-CTC grade 3, with the
exception of pyrexia treatable by nonsteroidal anti-inflammatory drugs
or toxicities considered by the investigator to be unrelated to the
study drug. Dose escalation was performed when all six patients in any
cohort had received at least the first single infusion of ONO-4007. The
MTD was defined as the dose level of ONO-4007 at which two of six
patients in one cohort expressed DLT. An additional cohort of six
patients was then recruited at the dose level immediately below the MTD
to further characterize the toxicity profile.
ONO-4007 was discontinued if a patient experienced any NCI-CTC grade 4
toxicity, unless the investigator considered it in the patient’s best
interest to continue at a lower dose. If a patient experienced
drug-related grade 3 toxicity, drug treatment was withheld until the
toxicity had recovered to 
grade 1, with subsequent treatment being at
the dose level of the preceding cohort or reduced by 50% if the
toxicity occurred at the first dose level. If the same grade 2 toxicity
recurred, the drug was again withheld until recovery to grade 1 and
then recommenced at the dose level of the preceding cohort (or at 50%
of the dose if this toxicity occurred at the first dose level). There
were no dose escalations.
PK and PD Studies.
PK and PD samples were analyzed at Quintiles Scotland Limited
(Edinburgh, United Kingdom). The PK of ONO-4007 were studied after both
the initial single infusion and the multiple dose administration for
the first treatment cycle only. For the initial single infusion, blood
samples (5 ml) were taken predose, at the end of the infusion, and
0.5, 1, 1.5, 2, 6, 12, 24, 72, 120, and 168 h after the end of
infusion. For the first repeat administration cycle, blood samples were
taken predose, at the end of the infusion, and 1 h after the end
of infusion for the first two weekly administrations; for the third
week, the sampling times were as described for the initial single
infusion administration. All blood samples were collected into tubes
containing sodium heparin as anticoagulant and centrifuged at (300 rpm)
for 10 min at 4°C, and at least 2 ml of plasma were retained in a
separate tube and stored at -20°C until analysis. Plasma
concentrations of ONO-4007 were measured using reverse phase-HPLC. The
following PK parameters were estimated using noncompartmental methods
and WinNonlin Version 1.1. from the drug concentration-time data
obtained: Cmax,
Tmax, apparent terminal rate constant
(k), apparent terminal half-life
(t1/2), AUClast,
AUCinf, Vss and
clearance, observed degree of accumulation
(AUClast day 29:AUClast day
1) and theoretical degree of fraction.
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For PD analyses, 10-ml blood samples were collected pre-dose, and
at 1,2, and 6 h after the end of the initial single infusion
administration. For the first repeat administration treatment cycle,
blood samples were collected pre-dose and 1 h after the end of the
infusion for the first 2 weekly administrations and collected pre-dose
and at 1,2, and 6 h after the end of the infusion for the third week.
All blood samples were collected into serum separating tubes, and at
least 5 ml of serum were transferred to separate tubes and stored
at-20°C until analysis. TNF-, IL-6, GM-CSF, and IFN- were
measured using the Immunotech enzyme immunoassay at Quintiles
Laboratories. Neopterin was measured using IBL enzyme
immunoassay.
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RESULTS |
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. Twenty-four patients, 11 females and
13 males, with a median age of 53.5 years (range, 33–77 years) were
treated with ONO-4007 at three escalating dose levels. The most common
tumor types included malignant melanoma (seven patients), renal cell
carcinoma (five patients), and colorectal carcinoma (four patients).
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Toxicity.
All 24 patients who had received at least the single administration of
ONO-4007 were evaluable for toxicity (Table 2)
. The most common toxicities were acute
reactions, usually commencing soon after the start of the infusion and
occurring in over 20% of patients. These included rigors, fever,
nausea, vomiting, flushing, dyspnea, headache, back pain, fatigue, hot
flushes, chest pain, dizziness, and hypotension. In the majority of
cases, adverse events were NCI-CTC grade 2, of short duration,
and usually recovered completely within 24 h.
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as defined by the presence of
cyanosis. In both cases, the patients made a rapid and uneventful
recovery within 30 min, although both required oxygen therapy. For one
patient, no oxygen saturation was determined before the initiation of
oxygen therapy, and this grade 3 rigor was associated with a drop in
blood pressure from 170/90 (preinfusion) to 150/60 during the rigor.
For the other patient, grade 3 rigor commenced 15–20 min after
completion of the infusion and with an oxygen saturation of 88%. This
returned to 100% rapidly after initiating oxygen therapy. This was
associated with a temperature of 39.8°C, but no episode of
hypotension. Subsequently, one patient refused further treatment, and
the other patient went on to complete the four planned cycles of
treatment at the lower dose of 100 mg. ONO-4007 appeared to have little
overall effect on total leukocyte or neutrophil counts. However, there
was a significant drop in lymphocyte counts immediately after
administration of ONO-4007, although the majority of patients had low
lymphocyte counts before starting treatment. Eight patients experienced
a decrease in their hemoglobin during the study, with three patients
experiencing grade 3 or 4 anemia during the study. In these three
cases, this was thought to be due to underlying disease. ONO-4007 had
no significant effects on clotting parameters or platelet counts.
Changes in electrolytes were generally minor and were not considered to
be drug related. Hepatotoxicity was not seen.
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Overall, ONO-4007 was well tolerated, with little in the way of
significant toxicity other than this acute reaction. The majority of
adverse events were mild/moderate in severity (NCIC CTC grade 1 or 2),
and there was no discernible increase in toxicity with continued
treatment. Indeed the frequency of rigors and fever was higher after
the initial dose than that observed with subsequent treatment cycles
(Table 4)
, most probably due to the
frequent use of prophylactic diclofenac with subsequent treatment
cycles (diclofenac was not to be given before the first dose). Although
three patients died during the follow-up phase of the study, all deaths
were considered to be due to progression of the underlying malignancy
and were not associated with the study medication.
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PK.
After the 30-min i.v. infusions of 75, 100, and 125 mg of ONO-4007,
plasma concentrations declined in a biphasic manner, with a mean
apparent terminal half-life of 74–95 h (Fig. 1)
. Peak plasma concentrations of
ONO-4007 increased in a dose-proportional manner from 20 µg/ml at 75
mg to 40 µg/ml at 125 mg. Mean AUC also increased approximately
proportionately with dose (Fig. 2)
. The
PK of ONO-4007 appeared to be time invariant; the accumulation of
ONO-4007 in plasma was predictable and consistent with linear kinetics.
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. ONO-4007 displayed time-invariant
kinetics.
ONO-4007 has a low systemic clearance (approximately 1.3 ml/min) with a
small volume of distribution (6–8 liters), which results in the
relatively long apparent terminal half-life (Table 5)
. The volume of distribution of
ONO-4007 has a value equivalent to that of the distribution volume of
albumin, suggesting that ONO-4007 is largely confined to the plasma.
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, IFN-, IL-6, GM-CSF, and neopterin in
blood collected on days 1, 15 22, and 29. All of the patients were
evaluable at least at one time point (either on day 1 or day 15) for
evaluation of pharmacodynamic effects. Furthermore all of the patients
showed a significant increase in TNF- after administration of
ONO-4007, with the majority of patients having at least a 10-fold
increase in levels posttreatment (Fig. 3)
. TNF- levels decreased rapidly
after the completion of the infusion, although they were generally
still above the predose levels 6 h later. Similarly, IL-6
circulating levels increased markedly in all patients after treatment
and then decreased rapidly but remained above the predose level 6 h after infusion (Fig. 4
). There were no
significant changes in the circulating levels of GM-CSF, IFN-, or
neopterin after the administration of ONO-4007.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The findings described by this study are comparable to the results obtained by the concurrent ongoing Japanese study that reported a similar toxicity profile, DLT, and MTD. In the Japanese study, ONO-4007 was well tolerated at single doses up to 75 mg, with the MTD defined as 100 mg/patient with grade 3 pyrexia, chills, cough, dyspnea, tachycardia, Raynaud’s syndrome, and abnormal coagulation being reported. When adjusted for differences in body surface area, the MTD is similar to that observed in this study. The toxicities observed with ONO-4007 are similar to those observed with other studies with purified LPS (15 , 16) , namely, constitutional symptoms such as fever, rigors, fatigue, and headache, and these are also among the toxicities of systemic administration of recombinant TNF (reviewed in Ref. 17 ). Furthermore, when ibuprofen was used to abrogate these toxicities and enable dose escalation in one of these studies with LPS (15) , additional toxicities were reported including dyspnea (without a decrease in oxygen concentration), hypotension, and hepatic toxicity, the latter of which was dose limiting. A similar pattern of toxicities has also been reported with other agents that possess macrophage activator properties including GM-CSF (18) , macrophage colony-stimulating factor (19) , and muramyltripeptide-phosphatidyl ethanolamine (20 , 21) .
The PK of ONO-4007 appears to be independent of dose within the dose range of 75–125 mg and shows linearity with respect to time. ONO-4007 is a drug with low systemic clearance (1.3 ml/min) and a small volume of distribution (6–8 liters). Because this volume of distribution is equivalent to that of albumin, ONO-4007 appears to be largely confined to the plasma. This results in a long apparent terminal half-life (74–95 h). Consequently, consideration should be given to a revised schedule of administration in future studies, e.g., twice weekly, although it has previously been reported that shorter intervals between repeated injections of LPS lead to the development of LPS tolerance (15) .
Pharmacodynamic studies have shown that the administration of ONO-4007
results in a significant increase in the release of TNF- and IL-6.
These levels increase and subsequently decrease rapidly, lasting for
approximately 6 h. These studies also suggested that there is a
trend for higher ONO-4007 doses to result in higher circulating levels
of TNF-. There was no significant change in circulating levels of
GM-CSF, IFN-, or neopterin after ONO-4007 administration. However,
all patients had advanced malignancy, and most had received at least
one prior systemic treatment modality, all of which could have
contributed to the suppression of the patients’ immune system such
that no increase in circulating levels of these cytokines was produced
on stimulation by ONO-4007.
The rise in IL-6 levels, which remain above the baseline, may in fact be a detrimental effect of ONO-4007 because increased IL-6 levels are associated with a variety of malignancies (22) , especially multiple myeloma. It may be possible to enhance the antitumor activity of ONO-4007 by decreasing IL-6 (e.g., with anti-IL-6 antibody) in future studies.
No objective tumor responses were observed in this study. However, disease stabilization was observed in five patients for the duration of the study (18 weeks), including two patients with malignant melanoma and one patient with renal cell carcinoma. In addition, two patients achieved disease stabilization in tumor types not usually responsive to immunotherapy (one colorectal carcinoma and one non-small cell lung carcinoma). The prolonged disease stabilization may suggest that this agent altered the natural history of these tumors (23) . However, optimal benefit from immunotherapy is more likely to be acquired in patients with minimal residual disease.
This study has therefore defined the MTD of ONO-4007 and the
recommended dose for Phase II studies to evaluate the activity of
ONO-4007 in tumors amenable to immunotherapy. However, the optimal dose
for immunomodulating agents may not necessarily equate to the
recommended dose determined by toxicity in clinical Phase I studies.
Preclinical in vivo studies with TNF- suggest that there
is a therapeutic window in which the beneficial antitumor effect can be
obtained without the detrimental (cachectic) effects seen with
prolonged exposure to higher levels of TNF- (24)
. In
these murine preclinical studies, persistent serum levels of TNF-
above 250 pg/ml were shown to cause severe cachexia, whereas lower
levels appeared to be able to inhibit tumor growth in the absence of
severe weight loss. In this Phase I study, TNF- serum levels above
250 pg/ml were observed for up to at least 6 h after completion of
the infusion at all three dose levels tested. Despite the limitations
of mouse models for predicting the optimal biological dose, they do
represent the best preclinical guide for the use of biological agents.
This Phase I study has determined the MTD on the basis of clinical
toxicity. However, the aim of future studies should be to determine the
biologically effective dose of ONO-4007 based on serum TNF- levels
and ideally by measurement of intratumoral TNF- levels as a
pharmacodynamic end point in patients with biopsy-accessible disease.
This would be particularly relevant in correlating biological activity
with objective antitumor activity as the primary clinical end point
within Phase II clinical trials.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by ONO Pharmaceuticals, Japan. 
2 To whom requests for reprints should be
addressed, at Cancer Research Campaign Department of Medical Oncology,
Beatson Oncology Centre, Western Infirmary, Dumbarton Road, Glasgow G11
6NT, United Kingdom. Phone: 0141-211-2000; Fax: 0141-211-6356; E-mail
address: gpmv08@udcf.gla.ac.uk.
3 The abbreviations used are: LPS,
lipopolysaccharide; TNF, tumor necrosis factor; IL, interleukin;
GM-CSF, granulocyte-macrophage colony-stimulating factor; MTD, maximum
tolerated dose; NCI-CTC, National Cancer Institute Common Toxicity
Criteria; DLT, dose-limiting toxicity; PK, pharmacokinetics; PD,
pharmacodynamics; AUC, area under the concentration-time curve.
4 ONO Pharmaceuticals, unpublished data.
5 ONO Pharmaceuticals, personal communication.
Received 6/23/99; revised 10/20/99; accepted 10/21/99.
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in tumor tissues by the administration of a new synthetic lipid A analog, ONO-4007, in hepatoma-bearing rats. Anticancer Drugs, 8: 886-893, 1997.[CrossRef][Medline]
-interferon: toxicity, monocytosis, and clinical effects. Cancer Res., 54: 4084-4090, 1994.This article has been cited by other articles:
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 I. Pollet, C. J. Opina, C. Zimmerman, K. G. Leong, F. Wong, and A. Karsan Bacterial lipopolysaccharide directly induces angiogenesis through TRAF6-mediated activation of NF-{kappa}B and c-Jun N-terminal kinase Blood, September 1, 2003; 102(5): 1740 - 1742. [Abstract] [Full Text] [PDF]
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 Y. N. Wong, D. Rossignol, J. R. Rose, R. Kao, A. Carter, and M. Lynn Safety, Pharmacokinetics, and Pharmacodynamics of E5564, a Lipid A Antagonist, during an Ascending Single-Dose Clinical Study J. Clin. Pharmacol., July 1, 2003; 43(7): 735 - 742. [Abstract] [Full Text] [PDF]
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