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An Open-Labeled, Randomized, Multicenter Phase IIa Study of Gambogic Acid Injection for
Advanced Malignant Tumors
Yihebali Chi1*, Xiao-Kai Zhan2, Hao Yu3, Guang-Ru Xie3, Zhen-Zhong Wang4, Wei Xiao4, Yong-Gang
Wang5, Fu-Xing Xiong6, Jun-Feng Hu7, Lin Yang1, Cheng-Xu Cui1, Jin-Wan Wang1*
1
Department of Medical Oncology, Cancer Institute & Hospital, Chinese Academy of Medical Sciences,
Beijing, China
2
Department of Hematology and Oncology, Chaoyang Hospital, Beijing, China
3
Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University,
Nanjing, China
4
Department of Internal Oncology, Tianjin Tumor Hospital, Tianjin, China
5
Kanion Pharmaceutical Co., Ltd. Lianyungang, China
6
Department of Internal Oncology, Qilu Hospital, Shandong University, Qingdao, China
7
Department of Internal Oncology, The 1st Affiliated Hospital of Anhui Medical University, Hefei, China
8
Department of Internal Oncology, Anhui Tumor Hospital, Hefei, China
* Corresponding authors: Jin-Wan Wang and Yihebali Chi
Tel: +86-10-87788800; Fax: +86-10-88859155; E-mail: [email protected]. [email protected]
Abstract
Background: Gambogic acid is a pure active compound isolated from the traditional Chinese medicinal
plant gamboge (Garcinia morella Desv.). Based on the preliminary results of a phase I study, this phase
IIa study compared the efficacy and safety of different dosage schedules of gambogic acid in patients
with advanced malignant tumors.
Patients and Methods: Patients with advance or metastases cancer who had not received any effective
routine conventional treatment, or who had failed existing conventional treatment were randomly
assigned to receive either 45 mg/m2 gambogic acid intravenously from days 1–5 of a 2-week cycle (group
A), or 45 mg/m2 every other day for a total of five times during a 2-week cycle (group B). The primary
endpoint was objective response rate (ORR).
Results: Twenty-one patients assigned to group A and 26 to group B were included in the final analysis.
The ORRs were 14.29% in group A and 0.00% in group B. It was not possible to analyze the significance
of the difference because one of the values was zero. The disease control rates (DCRs) were 76.2% in
group A and 61.5% in group B (P=0.0456). The observed adverse reactions were mostly grade I and II,
and occurred in most patients after administration of the trial drug. There was no significant difference in
the incidence of adverse reactions between the two arms.
Conclusions: The preliminary results of this phase IIa exploratory study suggest that gambogic acid has a
favorable safety profile when administered at 45 mg/m2. The DCR was greater in patients receiving
gambogic acid on days 1–5 of a 2-week cycle, but the incidence of adverse reactions was similar
irrespective of the administration schedule.
Keywords: gambogic acid; efficacy; toxicity; advanced malignant tumor
Background
Gambogic acid injection (THS) is an antitumor drug prepared from the traditional Chinese herb gamboge
by sequential extraction, purification and refinement1. Gamboge is a gelatinous resin obtained from the
slashed trunk of Garcinia hanbaryi Hook. f. The main producing countries for gamboge are located in
tropical areas in the Northern Hemisphere, including the provinces of Guangdong and Hainan in China,
and in Cambodia, Thailand and Vietnam. The main ingredients of gamboge have been identified as
gambogic acid, neogambogic acid, and allogambogic acid1-4.
Certain anticancer effects of gamboge were observed during an inter-regional collaboration on
2
medicinal herbs conducted by the Chinese government. Several recent pharmacological studies have
confirmed gambogic acid as an active ingredient of gamboge, with activities including apoptosis
induction, inhibition of angiogenesis, human topoisomerase IIα activity and anti-apoptotic Bcl-2 family
proteins, and reversal of tolerance to chemotherapy 5-21. Its antitumor activity has also been confirmed in
several preclinical animal studies. The results of a phase I clinical study found that liver function
abnormalities were the dose-limiting toxicity of this natural herbal compound, including glutamate
oxaloacetate transaminase and glutamate pyruvate transaminase abnormalities22, 23.
THS is a new unlisted drug developed from a traditional Chinese medicine by the Pharmacy School
of Traditional Chinese Medicine of China. A well-designed phase I clinical trial to evaluate the tolerance
and pharmacokinetic profile of THS was conducted between June 2004 and November 2005. The current
phase IIa study aimed to determine the safety and efficacy of THS in patients with advanced malignant
cancers.
Materials and Methods
Study methods and resources
This study was designed as an open-label, randomized, non-placebo-controlled, multicenter phase II
clinical trial led by Dr. Jin-Wan Wang, the principal investigator and Head of the Department of
Oncology, Cancer Hospital of Chinese Academy of Medical Sciences (CAMS). This department was the
leading institution and the designer of the protocol for this phase II clinical trial. The trial was approved
by the SFDA (approval no. 2004L00333), and the study protocol was reviewed by the ethical committee
and approved by the institutional review board (IRB) (IRB: 06-02/162) of CAMS.
Enrolled population
Enrolled patients were 18–65 years old with pathologically and/or cytologically confirmed advanced or
metastases lung, gastrointestinal, breast or liver cancer who had not received any effective routine
conventional treatment, or who had failed existing conventional treatment. All patients had at least one
measurable lesion, Eastern Cooperative Oncology Arm (ECOG) 0–2 and a predicted survival time ≥3
months without main organ functional impairment. Laboratory criteria were white blood cell count
>4.0×109/L, neutrophils within 50–70%, platelet count >100×109/L, and hemoglobin >95 g/L. Liver
function parameters included serum bilirubin >1.25-fold, alanine aminotransferase (ALT) and aspartate
aminotransferase (AST) >1.25-fold, and prothrombin time/partial thromboplastin time (PT/PTT) >1.5fold. All patients had signed an informed consent form before being enrolled in the study. A 30-day
washout period was generally allowed in patients who had received chemotherapy prior to this study;
however, a 6-week washout period was allowed after nitrosourea or mitomycin C treatment, and a 4-week
interval after major surgery. Patients had no histories of allergies to the same category of drugs (Table 1).
Treatment
Patients satisfying the enrollment inclusion criteria were randomized to either group A or group B.
Patients in group A received THS 45 mg/m2 via intravenous drip during days 1–5 (D1–D5) repeated
biweekly, while group B received THS 45 mg/m2 via intravenous drip on D1, D3, D5, D7 and D9
repeated biweekly. THS was dissolved in 500 ml of 0.9% physiological saline or 5% glucose solution
before administration. The standard recommended procedure in well-equipped hospitals involved
administering the intravenous drip over 120 min via a central venous catheter to minimize local irritation.
Toxic reactions were evaluated according to NCI-CTCAE 3.0 as a standard criterion of anticancer
drug toxicity evaluation. The investigators were allowed to adjust the dosage according to the patient’s
tolerance, up to a maximum dose of 60 mg/m2.
Efficacy evaluation
Objective efficacy evaluation followed the RECIST standard. Complete medical records were kept for all
patients during their hospital stay, including clinical symptoms and signs, physical examinations,
laboratory examinations (blood, urine and fecal routines, hepatic and renal functions) and cardiac
function examinations.
4
During this trial, patients were monitored closely for clinical signs, including heart rate, respiratory
rhythm, blood pressure, body temperature, weight, appetite, mental status, allergic reactions, local
injection-site reactions and other changes. Blood tests were performed once a week, and urine, fecal, and
hepatic and renal function tests were performed routinely every 3 weeks.
Efficacy and safety were evaluated by RECIST standard after every two cycles of treatment. Patients
with complete remission (CR), partial remission (PR) or stable disease (SD) in efficacy evaluations were
allowed to continue with treatment until tumor progression. Meanwhile, regular follow-up was required
for those who terminated treatment. All undesirable medical events that occurred from the time when
patients signed the informed consent form and started treatment with the trial drug until 1 month after the
end of treatment were considered as adverse events (AEs), regardless of causality (Table 1).
Statistical analysis
We collected the data and performed efficacy and safety analyses. Data were selectively stratified into
arms for different analyses, including a full-analysis set, a per-protocol set, a safety-analysis set, and a
drop-out-analysis set.
All analyses were performed using the SAS 9.1.3 statistical analysis software program. All statistical
tests were two-sided. The level of significance was set at P<0.05 with a 95% confidence interval (CI).
Odds ratio (OR) and relative risk (RR) were calculated using a 2×2 contingency table for additional
analyses.
Results
A total of 50 cancer patients were enrolled between February and June 2006. Twenty-four were assigned
to group A and 26 to group B (Tables 1 and 2). Three patients (6.00%) in group A dropped out (one
refused to continue therapy and two were lost to follow-up), and no patients were excluded from the
study. Of the 47 patients (94%) who completed the trial, 21 (87.5%) were in group A and 26 (100%) in
group B. Patient characteristics are summarized in Table 3.
Treatment
Forty-seven (94%) of the enrolled patients completed gambogic acid therapy. Except for the three patients
who dropped out, no patients in either group discontinued treatment as a result of disease progression,
treatment-related AEs, or death.
Efficacy
Three of 21 patients in group A achieved PR (two with non-small cell lung cancer and one with colon
cancer), 13 had SD, and five experienced PD. The objective response rate (ORR) [(PR+CR)/total
number×100%)] was 14.29% and the disease control rate (DCR) [(CR+PR+SD)/total number×100%] was
76.2%. The 26 patients in group B included 16 with SD and 10 with PD. The ORR was 0.00% and the
DCR was 61.5% (Table 4). It was not possible to analyze the difference between ORRs because one of
the values was zero; however, the DCR was significantly higher in group A compared with group B (type
I error; α=0.05, P=0.046). We further calculated RR and OR for DCR using the 2×2 contingency table
method. The RR (1.450) for the between-group comparison was significant with a CI of 1.021–2.055, and
the OR (2.004) was also significant with a CI of 1.087–3.695.
Notably, one patient with renal cancer in group B experienced pulmonary and hepatic metastases, and
continued treatment according to the group A schedule after completion of this study. This patient
achieved PR after four cycles of treatment, and received a total of 38 cycles (19 months) before tumor
progression (Figure 1).
Safety
The observed toxicities were mostly grade I and II AEs or reactions, rather than grade III and IV. The
incidence rates for AEs and reactions are summarized in Table 5. The RR was 0.926 (CI: 0.7015–1.223)
and the OR was 0.857 (CI: 0.492–1.493) for grade I AEs or adverse reactions, neither of which were
significant. Similarly, neither values were significant in terms of grade II adverse events or adverse
6
reactions (RR: 0.935; CI: 0.702–1.246 and OR: 0.875; CI: 0.497–1.541). The intervals for both grades
spanned “1”. The main AEs are summarized in Table 6. No relevant bone marrow toxicity was observed
during treatment.
Discussion
THS with a purity of 90–95% is an antitumor drug prepared from gambogic acid, the active ingredient
extracted from the traditional Chinese medicinal plant gamboge. Although gamboge has been used to
treat malignant tumors for several hundred years, its application has been limited by its toxicity.
Gambogic acid, however, as an active component of gamboge, and has strong antitumor activity but
weaker toxicity and fewer side-effects2–15. Furthermore, both domestic and international studies on the
mechanisms of THS action have recently demonstrated cytotoxicity and multi-target inhibition of tumor
cells.
THS has been shown to have cytotoxic activity against tumor cells and to kill tumor cells through
several targets. One study demonstrated antitumor effects of THS both in vivo and in vitro 5-23. Tumor
inhibition was observed in a BALB/c-nude mouse model at a range of doses of THS (8, 16, 32 mg/kg),
while human hepatocellular carcinoma (SMMC-7721) 8, human gastric cancer (BGC-823) 23, human
melanoma cells lung colonization (B16-F10) 19 and human leukemia (HL-60) 18 cells all demonstrated
sensitivity to THS .
An earlier phase I clinical trial to determine the maximum tolerance doses (MTD) and doserestrictive toxicity (DLT) of intravenous THS revealed a good safety profile and tolerance in cancer
patients20. DLTs including liver damage and pain occurred at 70 mg/m2, while the AEs were
nausea/vomiting and blood vessel irritation. The MTD was estimated to be 55 mg/m2-20.
The current phase IIa clinical trial was based on the above results and aimed to explore the safety and
effectiveness of different administration schedules of THS. Patients in groups A and B only experienced
grade I–II AEs (mainly injection-site reactions, vascular disorders, skin reactions, phlebitis, abdominal
pain, nausea and fatigue), with similar incidences in both groups. There were no grade III–IV AEs or
treatment-related deaths in either group.
This study explored different THS dosage schedules, and both ORR and DCR were higher in the
group that received THS for 5 consecutive days during each 2-week cycle, compared with the group that
received THS on alternate days. Although the ORR could not be examined statistically because of a zero
value, the DCR was significantly higher in group A (α=0.05, P=0.046). The RR and OR were both
significant for DCR, and the CIs were skewed to the right, suggesting that patients treated with schedule
A were 1.45 times more likely in patients who were treated by regiment A than those treated with regimen
B, and 2.004 times more likely to have a positive outcome. Thus although almost half the patients in both
arms developed grade I or grade II AEs or reactions, this novel treatment was still justified in patients
with advanced cancer. The antitumor effect of THS was further evidenced by the fact that one patient with
renal cancer and extensive pulmonary and hepatic metastases achieved PR after treatment with THS
according to regimen A, with a TTP of 19 months. THS thus represents an additional option for future
cancer therapies.
The preliminary results of this phase IIa clinical study demonstrated the efficacy and safety of THS.
The clinical efficacy of THS was better when administered on consecutive rather than alternate days, but
the safety profiles of the two schedules were similar. These results suggest that a phase IIb clinical trial
should be performed to further assess the safety and efficacy of intravenous THS 45 mg/m2 administered
on days 1–5 of a 2-week cycle. The efficacy and tolerance of this drug, with no apparent cumulative
toxicity, suggests that its dose or frequency of administration could be investigated in a phase IIb clinical
study. In addition, combination chemotherapies using THS may also represent a potential therapeutic
option.
8
Conclusions
In conclusion, gambogic acid demonstrates antitumor activity against non-small cell lung, colon and renal
cancers with a good safety profile. These study results suggest that a phase IIb trial of THS should be
performed to further observe the efficacy and safety of this drug in a larger sample.
Competing interests
This study was supported by Kanion Pharmaceutical Co., Ltd. (YC and JWW).
Authors’ contributions
YC, JWW and YH were critically involved in the study design and statistical analysis. YC, JWW, XKZ,
GRX, WYG, FXX, JFH, LY and CXC recruited patients for this trial. YC, JWW, GRX and WYG were
involved in the analysis of clinical response, which was revised by YC and JWW. All authors have read
and approved the final manuscript.
Disclosure
The authors report no conflicts of interest in this work insofar as none of them, nor any member of their
families, has stocks or direct financial interests in any companies as mandated. The authors received no
lecture or conference fees from any companies as addressed in the article. No professional fees were paid
to the authors in respect of clinical investigator status or for institutional involvement with the trial.
Acknowledgments and funding
This study was supported by Kanion Pharmaceutical Co., Ltd. Fund (issue number: 2004L00333). We
would like to thank all our colleagues in the Department of Oncology, Cancer Hospital, CAMS;
Department of Oncology, Tianjin Tumor Hospital; Department of Oncology, Qilu Hospital, Shandong
University; Department of Oncology, The 1st Affiliated Hospital of Anhui Medical University;
Department of Oncology, Anhui Tumor Hospital; Department of Epidemiology and Biostatistics, School
of Public Health, Nanjing Medical University and Kanion Pharmaceutical Co., Ltd, and Professor Jun-Qi
Zheng (Tongji University, School of Medicine, Shanghai, China) for her expert advice and excellent
guidance on English writing.
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Table 1 Distribution of cases at each medical center
No.
Center
Included cases
Lost cases
Excluded cases
Arm A
Arm B
Arm A
Arm B
Arm A
Arm B
4
1
1
0
0
0
5
5
1
0
0
0
6
12
0
0
0
0
6
7
1
0
0
0
Cancer Hospital, the
Chinese Academy of
01
Medical Sciences:
Internal Medicine
Department
02 Tianjin Cancer Hospital
03
Shandong University
Qilu Hospital
The First Affiliated
04
Hospital of Anhui
Medical University
12
Cancer Hospital of
05
Anhui Province
Total
3
1
0
0
0
0
24
26
3
0
0
0
Table 2 General characteristics of two groups of patients
Arm A
Arm B
Total
%
Included cases
24
26
50
100%
Evaluable cases
21(87.5%)
26(100%)
47
94%
11/13
10/16
(45.83/54.17%)
(38.46/61.54%)
Age (years)
56.21
55.04
Median age
56
55.5
36-72
29-73
PS0
3
6
9
PS1
11
10
14
6
25
16
18
50
Male/Femal
Range of Ages
PS2
Height (cm)
Median height
165
165.5
Range of Height
153-180
150-180
Median Weight
65
63
Range of Weight
40-87
43-80
Median Temperature
36.5
36.5
Range of Temperature
36-37.2
36-37.5
Median heart rate
80
80
Range of heart rate
64-96
66-100
Median Breath
20
20
Range of Breath
16-28
18-28
Median systolic pressure
120
120
Range of systolic pressure
90-150
109-140
80
73.5
Weight (kg)
Temperature (℃)
heart rate (time/min)
Breath (time/min)
Systolic pressure
(mmHg)
Diastolic pressure
(mmHg)
Median diastolic pressure
32
Range of diastolic pressure
60-90
60-100
24
26
gastric cancer
12(50.00%)
2(8.33%)
12(46.15%)
3(11.54%)
cancer of colon
5(20.83%)
4(15.38%)
breast cancer
4(16.67%)
415.38%)
Liver cancer
1(4.17%)
2(7.69%)
0(0%)
1(3.85%)
Surgery history
14(58.33%)
14(53.85%)
Chemotherapy history
20(83.33%)
22(84.62%)
Radiotherapy history
4(16.67%)
10(38.46%)
Type of clinical diagnosis
(cases)
lung cancer
renal carcinoma
Table 3: Distribution of cancer disease at each Arm
Kidney
Treatment
lung
gastric
cancer of
breast
Liver
Program
cancer
cancer
colon
cancer
cancer
Cases
12
2
5
4
1
0
％
50.00
8.33
20.83
16.67
4.17
0.00
Cases
12
3
4
4
2
1
％
46.15
11.54
15.38
15.38
7.69
3.85
Arm A
Arm B
clear-cell
Total
carcinoma
24
26
Table 4: Efficacy distribution at each Arm
Treatment
Cases
CR
PR
SD
PD
CR+PR (％)
Arm A
21
0
3
13
5
14.29
Arm B
26
0
0
16
10
0.00
Total
47
0
3
29
15
6.38
Program
Fig. 1. CT-Scan in a 46-year-old patient with Kidney clear-cell carcinoma. Multiple metastatic lesions are
visible bilateral pulmonary and liver. After THS Arm B treatment a remarkable shrink and reduce of the
bilateral pulmonary lesions, and liver metastases lesions shrink too.
14
Table 5 Adverse events and reactions after THS administration
Rate of
Program
Yes
No
Total
adverse
responses (%)
Cases of adverse
Arm A
12
12
24
16
50.00
events
Arm B
12
14
26
46.15
Cases of adverse
ArmA
10
14
24
41.67
reactions
Arm B
10
16
26
38.46
Table 6 Symptoms of adverse reactions following THS administration
Rate of
Symptoms
Program
Yes
No
Total
adverse
responses (%)
Arm A
2
22
24
8.33
Arm B
2
24
26
7.69
Injection site
Arm A
3
21
24
12.50
reactions
Arm B
2
24
26
7.69
Arm A
1
23
24
4.17
Arm B
0
26
26
0.00
Arm A
0
24
24
0.00
Arm B
1
25
26
3.85
Arm A
3
21
24
12.50
Arm B
4
22
26
15.38
Arm A
0
24
24
0.00
Arm B
2
24
26
7.69
Arm A
2
22
24
8.33
Arm B
1
25
26
3.85
Arm A
1
23
24
4.17
Arm B
0
26
26
0.00
Arm A
1
23
24
4.17
Arm B
0
26
26
0.00
Arm A
2
22
24
8.33
Arm B
0
26
26
0.00
Increase in Alkaline
Arm A
1
23
24
4.17
phosphatase (ALP)
Arm B
0
26
26
0.00
Abdominal pain
Vascular irritation
Skin reactions
Phlebitis
Diarrhea
Nausea
Irritability
Increase in Gammaglutamyl
transpeptidase
(GGT)
Vomiting
Arm A
1
23
24
4.17
Arm B
0
26
26
0.00
Arm A
1
23
24
4.17
Arm B
0
26
26
0.00
Arm A
1
23
24
4.17
Arm B
0
26
26
0.00
Arm A
0
24
24
0.00
Arm B
1
25
26
3.85
Arm A
0
24
24
0.00
Arm B
1
25
26
3.85
Gastrointestinal
Arm A
1
23
24
4.17
tract reactions
Arm B
0
26
26
0.00
Chills
Tumor local pain
Fatigue
Lack of energy
Local swelling
GGT: γ-glutamyl transpeptidase; ALP: alkaline phosphatase
18