ADI-PEG 20 Plus Best Supportive Care versus Placebo Plus Best Supportive Care in Patients with Advanced Hepatocellular Carcinoma

Abstract

Background:
Arginine depletion is a putative target in hepatocellular carcinoma (HCC). HCC often lacks argininosuccinate synthetase, a citrulline to arginine-repleting enzyme. ADI-PEG 20 is a cloned arginine degrading enzyme - arginine deiminase - conjugated with polyethylene glycol. The goal of this study was to evaluate this agent as a potential novel therapeutic for HCC after first line systemic therapy.

Methods and patients:
Patients with histologically proven advanced HCC and Child-Pugh up to B7 with prior systemic therapy, were randomized 2:1 to ADI-PEG 20 18 mg/m2 vs. placebo intramuscular (IM) injection weekly. The primary endpoint was overall survival (OS), with 93% power to detect a 4 to 5.6 months increase in median OS (1-sided α = 0.025). Secondary endpoints included progression-free survival (PFS), safety, and arginine correlatives.

Results:
635 patients were enrolled: median age 61, 82% male, 60% Asian, 52% hepatitis B, 26% hepatitis C, 76% stage IV, 91% Child-Pugh A, 70% progressed on sorafenib and 16% were intolerant. Median OS was 7.8 months for ADI-PEG 20 vs 7.4 for placebo (p = 0.88, HR = 1.02) and median PFS 2.6 months vs. 2.6 (p = 0.07, HR = 1.17). Grade 3 fatigue and decreased appetite occurred in less than 5% of patients. Two patients on ADI-PEG 20 had ≥ grade 3 anaphylactic reaction. Death rate within 30 days of end of treatment was 15.2% on ADI-PEG 20 vs. 10.4% on placebo, none related to therapy. Post-hoc analyses of arginine assessment at 4, 8, 12 and 16 weeks, demonstrated a trend of improved OS for those with more prolonged arginine depletion.

Conclusion:
ADI-PEG 20 monotherapy did not demonstrate an OS benefit in second line setting for HCC. It was well tolerated. Strategies to enhance prolonged arginine depletion and synergize the effect of ADI-PEG 20 are underway.

Clinical trial number:
www.clinicaltrials (NCT 01287585).

Full text

ORIGINAL ARTICLE
Phase III randomized study of second line ADI-PEG
20 plus best supportive care versus placebo plus
best supportive care in patients with advanced
hepatocellular carcinoma
G. K. Abou-Alfa
1,2
*,S.Qin
3
, B.-Y. Ryoo
4
, S.-N. Lu
5,6
, C.-J. Yen
7
, Y.-H. Feng
8
, H. Y. Lim
9
, F. Izzo
10
,
M. Colombo
11
, D. Sarker
12
, L. Bolondi
13
, G. Vaccaro
14
, W. P. Harris
15
, Z. Chen
16
, R. A. Hubner
17
, T. Meyer
18
,
W. Sun
19
, J. J. Harding
1,2
, E. M. Hollywood
1
,J.Ma
1
,P.J.Wan
1
,M.Ly
1
, J. Bomalaski
20
, A. Johnston
20
,
C.-C. Lin
21
, Y. Chao
22
& L.-T. Chen
6,23,24
1
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York;
2
Department of Medicine, Weill Cornell Medical College, New York, USA;
3
Department of Oncology, The Chinese People’s Liberation Army 81 Hospital, Nanjing, China;
4
Department of Oncology, Asan Medical Center, Seoul, South Korea;
5
Department of Medical Oncology, Kaohsiung Chang Gung Memorial Hospital;
6
Chang Gung University College of Medicine;
7
Department of Oncology, National
Cheng Kung University Hospital;
8
Department of Oncology, Chi Mei Medical Center-Yong Kang, Taiwan;
9
Department of Medical Oncology, Samsung Medical
Center, Seoul, South Korea;
10
Department of Medicine, Fondazione Giovanni Pascale, Napoli;
11
Department of Medicine, Fondazione IRCCS Ca, Milan, Italy;
12
Department of Medicine, King’s College Hospital, London, UK;
13
Department of Medicine, Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy;
14
Department of Medicine, Oregon Health Sciences University, Portland;
15
Department of Medicine, University of Washington Medical Center, Seattle, USA;
16
Department of Oncology, 2nd Hospital of Anhui Medical University, Hefei, China;
17
Department of Medicine, The Christie NHS Foundation Trust, Manchester;
18
Department of Medicine, Royal Free Hospital and UCL Cancer Institute, London, UK;
19
Department of Medicine, University of Pittsburgh, Pittsburgh;
20
Department of Research and Development, Polaris Pharmaceuticals, Inc., San Diego, USA;
21
Department of Medical Oncology, Chang Gung Medical Foundation
LK;
22
Department of Medicine, Veterans General Hospital-Taipei, Taipei;
23
Department of Medical Oncology, National Institute of Cancer Research, National Health
Research Institutes, Tainan;
24
Department of Oncology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
*Correspondence to: Dr Ghassan K. Abou-Alfa, Department of Medicine, Memorial Sloan Kettering Cancer Center, 300 East 66th Street, New York, NY 10065, USA.
Tel: þ1-646-888-4184; Fax: þ1-646-888-4255; E-mail: abou-alg@mskcc.org
Background: Arginine depletion is a putative target in hepatocellular carcinoma (HCC). HCC often lacks argininosuccinate
synthetase, a citrulline to arginine-repleting enzyme. ADI-PEG 20 is a cloned arginine degrading enzyme—arginine deiminase—
conjugated with polyethylene glycol. The goal of this study was to evaluate this agent as a potential novel therapeutic for HCC
after first line systemic therapy.
Methods and patients: Patients with histologically proven advanced HCC and Child-Pugh up to B7 with prior systemic
therapy, were randomized 2 : 1 to ADI-PEG 20 18 mg/m
2
versus placebo intramuscular injection weekly. The primary end point
was overall survival (OS), with 93% power to detect a 4–5.6 months increase in median OS (one-sided a¼0.025). Secondary end
points included progression-free survival, safety, and arginine correlatives.
Results: A total of 635 patients were enrolled: median age 61, 82% male, 60% Asian, 52% hepatitis B, 26% hepatitis C, 76% stage
IV, 91% Child-Pugh A, 70% progressed on sorafenib and 16% were intolerant. Median OS was 7.8 months for ADI-PEG 20 versus
7.4 for placebo (P¼0.88, HR ¼1.02) and median progression-free survival 2.6 months versus 2.6 (P¼0.07, HR ¼1.17). Grade 3
fatigue and decreased appetite occurred in <5% of patients. Two patients on ADI-PEG 20 had grade 3 anaphylactic reaction.
Death rate within 30 days of end of treatment was 15.2% on ADI-PEG 20 versus 10.4% on placebo, none related to therapy. Post
hoc analyses of arginine assessment at 4, 8, 12 and 16 weeks, demonstrated a trend of improved OS for those with more
prolonged arginine depletion.
Conclusion: ADI-PEG 20 monotherapy did not demonstrate an OS benefit in second line setting for HCC. It was well tolerated.
Strategies to enhance prolonged arginine depletion and synergize the effect of ADI-PEG 20 are underway.
Clinical Trial number: www.clinicaltrials.gov (NCT 01287585).
Key words:hepatocellular carcinoma, HCC, ADI-PEG20, argininosuccinate synthetase, ASS1
V
CThe Author(s) 2018. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: journals.permissions@oup.com.
Annals of Oncology 29: 1402–1408, 2018
doi:10.1093/annonc/mdy101
Published online 5 April 2018
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Introduction
Arginine, a nonessential amino acid in humans, is synthetized
from citrulline via argininosuccinate synthetase (ASS1) and argini-
nosuccinate lyase [1]. Hepatocellular carcinoma (HCC) cells lack
ASS1, and thus cannot metabolize citrulline into arginine [2,3].
ADI-PEG 20 is an arginine deiminase enzyme, cloned from
Mycoplasma hominis, produced in Escherichia coli (E. coli)and
conjugated with polyethylene glycol. It turns external supplies of
arginine into citrulline [4]. Degrading arginine external sources via
ADI-PEG 20, combined with the lack of ASS1, renders arginine
depletion a putative target for HCC.
Three phase II clinical trials have evaluated ADI-PEG 20 in
advanced HCC, and have collectively suggested an improvement
in survival [2,5,6], across different etiologies of HCC [2].
Patients and methods
This was a www.clinicaltrials.gov registered (NCT 01287585) multi-
institutional, randomized, placebo-controlled phase III clinical trial, that was
reviewed and approved by the Institutional Review Board (IRB). Written
informed consent was obtained from each patient.
Patients’ eligibility
Patients18 years of age, with unresectable locally advanced, or metastatic
histologically confirmed HCC, with at least one measurable lesion by
RECIST 1.1 [7], and who had received at least one prior systemic therapy
with documented progression of disease or adverse events that resulted in
discontinuance of that therapy were eligible. Patients were required to have
an Eastern Cooperative Oncology Group (ECOG) performance status of 0
or 1, and a Child-Pugh score up to B7. Adequate hematologic function,
renal and hepatic function (total bilirubin 3 mg/dl, albumin2.8 g/dl,
AST/ALT 5 times the upper limit of normal) were required. Serum uric
acid 8 mg/dl possible due to hyperuricemia with ADI-PEG 20 [2, 5, 6]
was required. Antihyperuricemic treatment was allowed, and dietary
restrictions for arginine-rich foods were recommended.
Ineligibility included history of untreated variceal bleed within
3 months, serious inter-current illnesses, known brain metastases, clini-
cally significant other medical history, known HIV infection, pregnant
women, and/or other malignancies that might have affected outcome.
Treatment plan
Eligible patients were randomized (2 : 1) to receive either weekly ADI-
PEG 20 18 mg/m
2
or placebo intramuscularly (i.m.) in a double-blinded
fashion, with best supportive care. One cycle consisted of four weekly
treatments. Patients were evaluated every other week, and assessed for
adverse events weekly. Computed tomography (CT) or magnetic reso-
nance imaging (MRI) scans were carried out every three cycles. Patients
continued treatments except for unacceptable adverse events, death, or
progression of disease.
Study objectives
The primary outcome was overall survival (OS). Secondary objectives
included safety and tolerability using the NCI Common Terminology
Criteria for Adverse Events (CTCAE) version 4.02, response rate, pro-
gression-free survival (PFS), and time to progression (TtP). The latter
two defined as the time from randomization till radiologic disease pro-
gression or death, and the time from randomization to the date of pro-
gression, respectively. Disease control rate was defined as the percentage
of patients with confirmed CR, PR, or stable disease (SD).
Immunogenicity assay
Peripheral blood anti-ADI-PEG 20 antibody titers were assessed using a vali-
dated single-tier semi-quantitative enzyme-linked immunosorbent assay-
based assay [8]. Microtiter plates were coated with ADI-PEG 20. Diluted
human plasma samples were added, incubated for 60 min, and then
treated with a goat antihuman immunoglobulin A þimmunoglobulin
Gþimmunoglobulin M /horseradish peroxidase conjugate. Tetramethy
lbenzidine was added to the plate, react and then the absorbance at 450 nm
was recorded and used as reference. The titer of a sample was based on the
highest dilution that yielded a positive signal.
Pharmacodynamic assay
Peripheral blood arginine levels were measured in samples at baseline
and at the start of each cycle using liquid chromatography [high-
performance liquid chromatography (HPLC)] with tandem mass spec-
trometric detection. Arginine and an isotopically labelled internal control
were extracted from human plasma samples by protein precipitation.
The supernatant was loaded on to a Venusil ASB C18 column. The
mobile phase was 0.1% formic acid in water : acetonitrile (95 : 5, v : v).
Detection was carried out with positive ion electrospray using a Sciex API
5000. The ratio of the peak areas arising from the arginine and isotopi-
cally labelled internal standard was used to quantify the arginine level.
Pharmacokinetic assay
Peripheral blood ADI-PEG 20 levels were measured in samples at baseline
and at the start of each cycle using a fluorometric enzyme activity-based
assay designed to detect the conversion of arginine to citrulline and
ammonia; and the reaction of ammonia with o-phthaldialdehyde (OPA)
to produce a fluorescent isoindole-derivative [9]. Plasma samples were
added to assay buffer, followed by arginine, react, followed by develop-
ment reagent (OPA and reducing agent). The plate was read using a fluo-
rometric plate reader with excitation set at 405 nm and emission set at
460 nm, with known amounts of ADI-PEG 20 used to generate a calibra-
tion curve.
Statistical analyses
Statistical analyses were based on intent-to-treat populations. The safety
population comprised all patients who received at least one dose of study
medication.
Median OS was estimated to be 4 months after progressing on sorafe-
nib [10,11]. An improvement of 40% resulting in a median OS to
5.6 months was deemed to be clinically significant. Estimated 633 accrued
patients were needed with 487 deaths to demonstrate an overall one-
sided type I error rate (a) of 0.025, and an overall type II error rate (b)of
0.07. Treatments were compared using a log-rank test stratified by the
region Asia versus non-Asia and by prior sorafenib exposure. OS, PFS,
and TtP were summarized using the Kaplan–Meier method, with 95%
confidence intervals analyzed by treatment group.
Safety, tolerability, adverse events, and all pharmacokinetic and phar-
macodynamic analyses were summarized descriptively. The relationship
between anti-ADI-PEG 20 antibodies and changes in arginine was
assessed using Pearson’s q.
The relationship between arginine depletion (based on blood samples
taken at weeks 4, 8, 12, and 16) and OS was studied post hoc on the ADI-
PEG 20 group.
ASS1 expression induced by sorafenib in HCC cell
lines
ASS1 protein expression in both untreated and drug treated human HCC
cell lines was assessed by western blot as described [12].
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Results
Patients’ disposition
A total of 854 patients were assessed for eligibility and 635 unique
patients were randomly assigned to receive ADI-PEG 20
(n¼424) or placebo (n¼211) (Figure 1).
Demographics
Demographics were as detailed in Table 1. A total of 332 (52.3%)
patients had hepatitis B as etiology and 338 (53.2%) were accrued in
Asia. The group of prior sorafenib failure encompassed 549 (86.5%).
Treatment
The median number of doses administered of ADI-PEG 20 was
11 (range 0–145) versus 11 (0–98) for placebo, with a duration of
exposure of 10 (range 0–146) and 11 (range 0–109) weeks,
respectively.
Safety and tolerability
The incidence of adverse events was similar between the two
treatment groups (Table 2). There was no statistical difference in
the between the two groups. Fatigue was the most frequent
adverse event. Grade 3 skin puritis or rash was limited to
854 patient screened
218 screen failure
153
14
51
636 patients randomized
424 assigned to ADI-PEG 20 group 211 assigned to placebo group
421 included in safety population 209 included in safety population
416 discontinued treatment
322 disease progression
42 adverse event
28 withdrew consent
13 death
11 other
3 did not receive treatment
1 HCC unconfirmed
2 did not meet inclusion
criteria at dosing
2 did not receive
treatment
2 withdrew consent
5 on treatment as
data cut-off
5 on treatment as
data cut-off
204 discontinued treatment
156 disease progression
17 adverse event
16 withdrew consent
8death
7 other
635 in intent-to-treat population
1 excluded, re-randomized by error
not meet inclusion or exclusion
criteria
declined to participate
other reasons
Figure 1. Consort diagram.
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1 (0.2%) and 2 (1%) patients who received ADI-PEG 20 and
placebo, respectively.
Two cases of anaphylaxis occurred after the third and eighth
injections, of ADI-PEG 20, respectively. In the first case, there
was no anti-ADI-PEG 20 antibody detected. In the second case, it
was 10
3
.
There were 64 (15.2%) deaths in the ADI-PEG 20 group that
occurred within 30 days of the last dose of study drug, versus 22
(10.5%) in placebo group. Deaths due to causes other than dis-
ease progression were 22/64 (34.4%) in the ADI-PEG 20 group
and 12/22 (54.5%) in the placebo group. These included 10 gas-
trointestinal bleeds (6 in the ADI-PEG 20 group and 4 in the pla-
cebo group); 8 liver failures (6 and 2, respectively); and 1
intracranial hemorrhage, 1 brain stem infarction, and 1 tumor
embolus, all in the ADI-PEG 20 group. One cardiac arrest on
ADI-PEG 20 and 4 respiratory failures (2 in each group) were
reported. Sepsis/infection occurred in three (2 in the ADI-PEG
20 group and 1 in the placebo group). Four patients sustained
general health deterioration (1 in the ADI-PEG 20 group and 3 in
the placebo group). One patient in the ADI-PEG 20 group died
of unexplained abdominal pain.
Outcome
The median OS (Figure 2A) was 7.8 months for the ADI-PEG 20
group versus 7.4 months for the placebo group [hazard
ratio ¼1.022 (95% CI, 0.847–1.233), P¼0.884]. Forest plot and
sensitivity anlayses are shown in supplementary Figure S1, avail-
able at Annals of Oncology online. There was no significant differ-
ence in OS for the treatment and placebo groups when the
geographical regions, or when prior sorafenib failure or nonsora-
fenib subgroups were analyzed. For the nonsorafenib group, the
v
2
value for the comparison was 2.84, P¼0.092.
The median PFS as depicted in Figure 2B was 2.6 months for
both groups [hazard ratio ¼1.175 (95% CI, 0.964–1.432),
P¼0.075].
Table 1. Demographics of ADI-PEG 20 and placebo groups
Parameter ADI-PEG 20
(n5424)
Placebo
(n5211)
Median age (years) 61 62
Male gender 83% (352) 80% (168)
Asia accrual 53% (226) 53% (112)
Etiology
HBV 53% (226) 50% (106)
HCV 26% (112) 26% (55)
Alcohol 12% (51) 15% (32)
NASH 6% (24) 6% (12)
Other 13% (57) 14% (29)
ECOG 0/1 98% (414) 98% (207)
Child pugh
A 91% (387) 89% (188)
B7 9% (37) 10% (22)
BCLC
B 18% (77) 19% (40)
C 82% (347) 81% (170)
Baseline AFP 400 lg/l 210 (49.5%) 107 (50.7%)
Prior therapy
Sorafenib failure 70% (299) 69% (146)
Sorafenib intolerance 16% (68) 17% (36)
Other 13% (57) 14% (29)
1 prior chemotherapy 73% (311) 79% (167)
2 prior chemotherapies 27% (113) 21% (44)
Table 2. Treatment-emergent adverse events by treatment group and CTCAE grade
ADI-PEG 20 (N5421) Placebo (N5209)
CTCAE grade (%) CTCAE grade (%)
Grade 1–5 AEs in patients with
7.5%grade 1–2 events
1–2 3 4 5 Total 1–2 3 4 5 Total
Fatigue 21.4 1.9 0 0 23.3 23.5 3.3 0 0 26.8
Decreased appetite 21.0 1.9 0 0 22.8 18.2 1.4 0 0 19.6
Nausea 18.6 0.5 0 0 19.0 17.2 0.5 0 0 17.7
Abdominal pain 14.2 4.3 0 0.2 18.8 14.8 2.4 0 0 17.2
Edema peripheral 16.2 2.4 0 0 18.5 17.3 1.4 0 0 18.7
Pyrexia 18.3 0 0 0 18.3 18.7 0.5 0 0 19.1
Cough 14.9 0.2 0 0 15.2 17.3 0.5 0 0 17.7
Abdominal distension 13.3 1.2 0 0 14.5 16.3 0.5 0 0 16.7
Diarrhea 12.8 1.0 0 0 13.8 15.6 1.0 0.5 0 17.2
Pruritus 13.1 0.2 0 0 13.3 12.5 0.5 0 0 12.9
Ascites 10.0 2.6 0 0 12.6 9.5 3.3 0 0 12.9
Vomiting 11.9 0.7 0 0 12.6 12.4 0 0 0 12.4
Constipation 11.9 0.2 0 0 12.1 13.9 1.0 0 0 14.8
Adbominal pain upper 11.7 0.2 0 0 11.9 10.5 1.0 0 0 11.5
Dyspnea 9.5 1.7 0.5 0.2 11.9 8.6 2.9 0 0 11.5
Back pain 10.3 0.5 0 0 10.7 9.1 2.4 0 0 12.0
Insomnia 10.3 0.2 0 0 10.5 8.2 0.5 0 0 8.6
Rash 10.2 0 0 0 10.2 7.6 0.5 0 0 8.1
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Two and six partial responses were reported for the ADI-PEG
20 and placebo groups, respectively.
There was no difference in AFP (supplementary Table S1,
available at Annals of Oncology online) and AFP decrease did not
correlate with arginine levels (supplementary Table S2, available
at Annals of Oncology online).
Immunogenicity
The median baseline value for anti-ADI-PEG 20 antibodies was 0
in both groups. The median post baseline change was an increase
to a titer of 2 around 8 weeks with a plateau at a titer of 3 at
12 weeks in the ADI-PEG 20 group. The titer remained 0 in the
placebo group. Changes from baseline in anti-ADI-PEG 20 anti-
bodies and blood arginine levels were correlated at all time points
tested (weeks 2, 4, 8, 12, 16; P<0.0001). Levels of anti-ADI-PEG
20 antibodies did not correlate with adverse events. No attempt
was made to discern neutralizing antibodies from non-neutraliz-
ing antibodies.
Pharmacokinetics
In the ADI-PEG 20 group, the mean blood ADI-PEG 20 levels
were highest at weeks 2 and 4, and then decreased to a plateau
level at week 12, to 45% of the highest levels. This was commen-
surate with the development of anti-ADI-PEG 20 antibodies.
Pharmacodynamics
Circulating arginine level markedly decreased after the first dose
of ADI-PEG 20. The median arginine level remained depleted
(reached and remained below 10 lM post ADI-PEG 20 dosing)
for 8 weeks (data not shown).
To determine whether there was a relationship between argi-
nine depletion and OS, a post hoc analysis was carried out at each
1.0
A
B
0.8
0.6
0.4
Survival probability
0.2
0
1.0
0.8
0.6
0.4
Survival probability
0.2
0
010 20 30
Duration of overall survival (months)
Product-limit survival estimates
with number of subjects at risk
Product-limit survival estimates
with number of subjects at risk
40
+ Censored
50
010
ADI-PEG 20 424 216 72 33 18 12 6
3331
111110
0
24
12 52749120211
424 358 263 191 134 90 69 46
27
32 24 18
10
14 8 5 3
111
1
1110
02
23514
20
3856136 96 72181211
Placebo
ADI-PEG 20
Placebo
20 30
Duration of progression-free survival (months)
Treatment ADI-PEG 20 Placebo
Treatment ADI-PEG 20 Placebo
+ Censored
Figure 2. (A) Kaplan–Meier curves depicting OS for the ADI-PEG 20 and placebo cohorts (B). Kaplan–Meier curves depicting PFS for the ADI-
PEG 20 and placebo cohorts.
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of the specified timepoints (4, 8, 12, and 16 weeks). ADI-PEG 20
treated patients were divided into an arginine depletion, those
who no longer met the arginine depletion as defined at the speci-
fied timepoint. Patients who had died, progressed, withdrawn
consent, or were otherwise unable to have a blood draw at the
specified timepoint were excluded (supplementary Table S3,
available at Annals of Oncology online). At all four timepoints
tested, the patients with arginine depletion trended to have
improved OS.
Discussion
ADI-PEG 20 at a dose of 18 mg/m
2
did not show an improvement
in OS versus placebo in patients with advanced HCC who had
failed prior systemic therapy. Patients with arginine depletion
trended to have improved OS, similar to prior study [2]. In the
post hoc analysis as there may be a selection bias as some patients
came off study early due to progression and thus could no longer
contribute to the pharmacodynamic analysis. This analysis might
also be affected by the next line of therapy. Although antidrug
antibodies were determined, neutralizing antibodies were not.
A general lack of correlation between neutralizing antibodies and
arginine levels, and the possibility of still present efficacy despite
the presence of neutralizing antibodies for ADI-PEG 20 has been
noted [2,13], similar to other agents [14]. Strategies to prolong
ADI-PEG 20 induced arginine suppression include: (i) an
increased dose of ADI-PEG 20 (36 mg/m
2
)[15], (ii) combination
with cytotoxic agents which may blunt the immune response to
ADI-PEG 20, and (iii) developing a new ADI that would not be
so quickly neutralized by antibodies. This latter approach is cur-
rently under investigation, and would mirror the success
observed with asparaginase from Erwinia chrysanthemi in
patients with acute lymphocytic leukemia (ALL) who have devel-
oped antibodies to E. coli asparaginase [16], as well as by develop-
ing a new formulation [17].
Local injection site reactions, rash, pruritus and anaphylaxis
were expected [18,19], and at occurred at a rate of 0.4%. This
compares favorably with other pegylated non-human enzymes
used in the treatment of patients [20,21]. Local injection site
reactions in the placebo control group were consistent with the
i.m. injection of the placebo solution.
The cases of brain stem infarction and intracerebral hemor-
rhage occurred in the ADI-PEG 20 treated group, thus with an
occurrence rate of 0.4%. In cirrhotic patients intracerebral hem-
orrhage are similarly observed [22,23].
Respiratory failure, consistent with hepatopulmonary syn-
drome, is a well-known complication of cirrhosis, same for infec-
tion [24,25].
While this study was ongoing an experiment was conducted
across multiple HCC cell lines which demonstrated an increase in
ASS1 expression in some cell lines treated with sorafenib (supple-
mentary Figure S2, available at Annals of Oncology online).
Considering that 86% of patients received prior sorafenib, up-
regulation of ASS1 expression may have contributed to the lack
of efficacy in the patient population in this study.
At the time of the design of the study, the 4 months median OS
anticipated for the placebo group seemed reasonable. In retro-
spect, it would be hard to justify nowadays with improved
performance status and a favorable Child-Pugh population
selected for clinical trials. The reported herein 7.4 months median
OS for the placebo group is commensurate with current
data [26].
Capitalizing on the attributes that may help potentiate the effi-
cacy of ADI-PEG 20 would be critical. Another arginine depriva-
tion approach in HCC has been investigated with pegylated
recombinant human arginase [27].
In summary, ADI-PEG 20 at the dose of 18 mg/m
2
proved to
be ineffective in prolonging OS in patients with advanced HCC
who failed prior therapy. However, those with arginine depletion
from ADI-PEG 20 were observed to have a superior OS to those
who did not achieve prolonged depletion. New studies of ADI-
PEG 20 are currently focused on maximizing arginine depletion
through elucidating and testing potential synergistic effects and
on modulating its antigenic structure as well as formulation.
Acknowledgement
The statistical comments of Marinela Capanu, PhD, Memorial
Sloan Kettering Cancer are appreciated.
Funding
The study was funded by Polaris Pharmaceuticals, Inc. No
grants applied.
Disclosure
JB and AJ work for Polaris Pharmaceuticals, Inc. All remaining
authors have declared no conflicts of interest.
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Original article Annals of Oncology
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