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Keywords:

  • melanoma;
  • phase 2;
  • interleukin-18;
  • immunotherapy

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. Conflict of Interest Disclosures
  8. References

BACKGROUND:

Phase 1 studies demonstrated evidence of recombinant human IL-18 (rhIL-18)-mediated immunomodulatory and clinical activity, and defined a biologically active dose range.

METHODS:

A phase 2 study of rhIL-18 was conducted in untreated AJCC stage IV melanoma. Patients were randomized to 1 of 3 dose groups (0.01, 0.1, and 1.0 mg/kg/d) of rhIL-18 administered as 5 daily intravenous infusions repeated every 28 days. A 2-stage design with a stopping rule was used.

RESULTS:

A total of 64 patients (median age, 57.5 years) with metastatic melanoma (M1a/b (30), M1c (34)) were accrued to stage I, and randomized to 3 groups (21 [0.01 mg/kg/d], 21 [0.1 mg/kg/d], 22 [1.0 mg/kg/d]). Five patients experienced 10 grade 3 drug-related adverse events (AEs): polyarthritis (1 subject: 0.01 mg/kg); deep vein thrombosis, pulmonary embolism (1:0.01 mg/kg); cognitive disorder (1:0.1 mg/kg); fatigue, dyspnea, pleural effusion, lymphopenia (1:1.0 mg/kg); fatigue, lymphopenia (1:1.0 mg/kg). One patient experienced a grade 4 AE of increased lipase (0.1 mg/kg) that led to permanent discontinuation from the study. Among 63 subjects evaluable for response, 1 (M1c; 0.01 mg/kg) achieved a partial response after 4 cycles. Four subjects (3 at 0.01 mg/kg and 1 at 1.0 mg/kg) had stable disease maintained for 6 months or longer. Due to the low apparent level of clinical efficacy using RECIST criteria, the study was terminated at the end of stage 1. The median progression free survival for the 3 groups was 7.5 (0.01), 7.4 (0.1), and 7.3 (1.0) weeks.

CONCLUSIONS:

rIL-18 as tested in this trial was well tolerated, but had limited activity as a single agent in patients with metastatic melanoma. Cancer 2009. © 2009 American Cancer Society.

For patients with distant metastatic melanoma (AJCC stage IV), median survival is 6 to 10 months, and fewer than 2% survive for 5 or more years.1 Available active chemotherapy agents for this stage of disease are of limited value. Dacarbazine as a single agent induces objective responses in less than 10% of patients in recent randomized controlled trials, and an impact on survival has never been shown for this or any other single agent.2 Combination chemotherapy regimens have shown improved response rates but also failed to confer a survival benefit.3, 4

Immunotherapy using interleukin-2 (IL-2) and IFN-α has produced the most promising and durable results to date in metastatic melanoma. High-dose IL-2 was approved by the United States Food and Drug Administration (US FDA) on the basis of a retrospective analysis of 270 patients that demonstrated an objective response rate of 16%, including 6% complete responses, and with 60% of complete responders remaining progression-free at 5 years.5 The major toxicity and cost associated with high dose IL-2 has restricted its use to selected patients at major medical centers. High dose IFN-α2b also received US FDA approval in the adjuvant setting after demonstrating relapse-free and overall survival benefits in randomized clinical trials.6-8 Biochemotherapy regimens had no impact on survival in randomized controlled trials when compared with chemotherapy alone.9-11

Given the relative success immunotherapeutic approaches have achieved in this disease, the evaluation of new, potentially less toxic immunologic agents capable of altering the Th1/Th2 bias of the immune system, such as IL-18, was of interest. IL-18 is a small nonglycosylated monomer of 18 kd, belonging to the IL-1 cytokine family, which is capable of mediating several immunostimulatory effects relevant to the induction of cellular antitumor immunity. It enhances the release of proinflammatory (Th1) cytokines and the activation of natural killer (NK) cells. In addition, IL-18 has been shown to promote the differentiation of naive CD4 + T lymphocytes into Th1 cells and the development of memory cytotoxic CD8 + T lymphocytes. IL-18 also acts synergistically with IL-12 to induce IFN-γ production and stimulate Th1 immune response.12, 13 Other regulatory functions of IL-18 that may be important in its antitumor activity include the up-regulation of Fas ligand on NK and T cells.14-16

IL-18 has been studied in a variety of preclinical tumor models demonstrating IL-18 mediated cellular immunity and antitumor effects17-22 In addition to IL-18 stimulatory effects on NK and T lymphocytes, investigations demonstrated activation of B lymphocytes leading to immunoglobulin production and possible antibody-mediated cellular cytotoxicity as well as antiangiogenic activity when administered alone and in combination with IL-12.14-16, 23-25 Taken together, these findings supported further investigation of recombinant human IL-18 (rhIL-18; SB-485232).

In a phase 1 dose-escalation study, rhIL-18 was administered for a single cycle as a 2-hour intravenous (IV) infusion for 5 consecutive days to subjects with advanced solid tumors and lymphomas. Doses ranging from 0.003-1.0 mg/kg/d were administered. A total of 28 subjects were treated at dose levels up to 1.0 mg/kg/d for 5 days without reaching a maximally tolerated dose (MTD). Pharmacokinetic data demonstrated daily dosing for 5 days produced 2.5-fold accumulations with a 35-hour accumulation half-life. Preliminary data demonstrated evidence of immunomodulatory activity (increase in serum proinflammatory cytokines and up-regulation of Fas ligand on NK and T cells) and clinical activity (unconfirmed partial responses) observed in 2 patients (metastatic melanoma and renal cell carcinoma) treated at 0.1 mg/kg/d.26

A repeat cycle study with rhIL-18 administered intravenously for 5 days every 28 days tested 3 doses (0.1, 0.5, and 1.0 mg/kg/d) in subjects with advanced solid tumors and follicular lymphoma. Preliminary data with 9 subjects showed that rhIL-18 was well tolerated and did not exceed a MTD at doses up to 1 mg/kg/d. This study helped define a biologically active dose range with 4 of 9 patients completing 6 cycles of treatment with stable disease and 2 patients (1 at 0.5 and 1 at 1.0 mg/kg/d) continuing to receive treatment for 12 and 10 months, respectively.27

Based on these preclinical and phase 1 clinical results, this phase 2 study was designed to evaluate the antitumor activity of 3 dose groups of rhIL-18 administered as a single agent in subjects with previously untreated metastatic melanoma.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. Conflict of Interest Disclosures
  8. References

Patients

Adult subjects with histologically confirmed inoperable and treatment-naive metastatic melanoma were eligible for this study. Additional eligibility criteria included an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1, and adequate organ function parameters. Patients were ineligible if they had a history of, or active brain metastases, or ocular melanoma as the primary tumor. Prior adjuvant therapy for resected metastatic disease was permitted. All patients of the described research provided written informed consent.

Study Design and Treatment

In this phase 2, open-label, randomized study, subjects were randomized to 1 of 3 treatment groups: 0.01, 0.1, and 1.0 mg/kg/d. A complete cycle consisted of 5 consecutive days of rhIL-18 as a 2-hour IV infusion followed by a 23-day rest period. Cycles were repeated every 28 days for up to 6 cycles.

Toxicity and Response Assessments

The National Cancer Institute's Common Toxicity Criteria version 3.0 (NCI-CTCAE v3.0) was used for grading toxicities.

Disease assessment consisted of radiographic imaging (ie, CT or magnetic resonance imaging scans), color photographic imaging, and/or physical examination. Disease response was determined according to the RECIST criteria.28 All subjects had their screening disease assessments reviewed by an independent radiology reviewer (IRR). In addition, any subject who completed more that 2 treatment cycles had their radiographic imaging studies reviewed by the IRR. Only responses confirmed by the IRR were included in the primary endpoint for this study.

Dose Modifications

Study drug-related toxicities requiring 50% dose reduction included grade 3 or higher nonhematologic toxicities; grade 4 hematological toxicities; any isolated or recurrent grade 2 drug-related toxicity, which in the judgment of the investigator required dose reduction; any drug-related toxicity resulting in a delay of >14 days in the start of the next cycle; and any drug-related toxicity resulting in the subject missing ≥2 doses during a given cycle. If upon re-treatment at a reduced dose, there was recurrent or new drug-related toxicity requiring dose modification, the subject was discontinued.

Statistical Methods

The primary objective was efficacy defined by tumor response rate (RR). Secondary efficacy analyses included progression-free survival (PFS), response duration, and time to response.

This study used a 2-stage design with a stopping rule to allow early termination of any 1 of 3 arms for lack of efficacy. In stage 1, 60 subjects were planned to be randomized to 1 of 3 dosing groups. If there were <2 responders among 20 evaluable subjects in a particular arm, then this would lead to early termination of that particular dosing group. If there were 2 or more responders in stage I within a given arm, then the study was to proceed to stage II with 20 additional subjects recruited to that particular arm. The probability of early termination for a given arm if the true response rate was 5% is 0.74. If the true response rate was 20%, then the probability of stopping is low at 0.07. The overall probability of falsely declaring the treatment effective for a given stratum at the end of stage II, if it has a response rate of 5%, is less than 0.05, the type 1 error. The study was not powered to provide direct comparison between arms, nor was the study powered for the PFS endpoint.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. Conflict of Interest Disclosures
  8. References

Patient Characteristics

The investigators of this multicenter study failed to restrict enrollment to 60 subjects at the end of stage 1, and therefore 4 additional subjects had been enrolled by the time the study was put on hold for interim analysis. A total of 64 patients with AJCC stage IV melanoma were enrolled between November 2004 and June 2005, and all patients were evaluable for efficacy according to protocol requirements, except 1 subject whose only target lesion at baseline was in a prior radiation field. Patients were randomized to 1 of 3 dosing groups (21 subjects [0.01 mg/kg/d], 21 [0.1 mg/kg/d], 22 [1.0 mg/kg/d]). Among these patients, 27 were female and 37 male, with a median age of 57.5 years (range, 26-88 years) years. Thirty patients had AJCC stage Mla/b and 34 had Mlc.1 A total of 52 patients had primary cutaneous melanoma and 12 had melanoma of unknown primary. Prior adjuvant therapy included cytokine therapy (N = 15), vaccine (N = 4), chemotherapy (N = 4), and radiation (N = 9). Forty-four patients had an ECOG PS 0 (normal), 19 had PS 1 (ambulatory), and for 1 patient the PS is unknown. Baseline patient and disease characteristics are shown in Table 1.

Table 1. Baseline Patient and Disease Characteristics
 Dose Group (mg/kg/d)
Characteristics0.010.11.0Total
  1. ECOG indicates Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase.

No. of subjects enrolled21212264
Age, y, median [range]57 [32-75]55 [34-77]60 [26-88]57.5 [26-88]
 No. (%)No. (%)No. (%)No. (%)
Sex    
 Women11 (52)9 (43)7 (32)27 (42)
 Men10 (48)12 (57)15 (68)37 (58)
Primary melanoma at initial diagnosis    
 Cutaneous15 (71)21 (100)16 (73)52 (81)
 Noncutaneous1 (5)3 (14)4 (6)
 Unknown5 (24)3 (14)8 (13)
M Stage    
 M1a/b10 (48)10 (48)10 (45)30 (47)
 M1c11 (52)11 (52)12 (55)34 (53)
Prior adjuvant therapy    
 None12 (62)12 (67)13 (64)37 (58)
 Cytokine therapy4 (19)5 (24)6 (27)15 (23)
 Vaccine therapy1 (5)1 (5)2 (9)4 (6)
 Chemotherapy3 (19)1 (5)4 (6)
 Radiation therapy4 (19)4 (19)1 (5)9 (14)
ECOG performance status    
 014 (67)14 (67)16 (73)44 (68.8)
 17 (33)6 (29)6 (27)19 (29.7)
 Unknown1 (5)1 (1.5)
LDH status    
 Normal14 (67)11 (52)16 (73)41 (64)
 Elevated6 (29)8 (38)4 (18)18 (28)
 Unknown1 (5)2 (10)2 (9)5 (8)
No. of metastatic sites    
 13 (14)3 (14)7 (32)13 (20)
 26 (29)9 (43)3 (14)18 (28)
 33 (14)4 (19)8 (36)15 (23)
 ≥48 (38)5 (24)4 (18)17 27)
Unknown/missing data1 (5) 

Treatment Details

Thirty-five patients completed 1-2 cycles of therapy, 11 received 3-4 cycles, 7 received 5-6 cycles, and 11 received more than 6 cycles. The most common reason for treatment discontinuation was disease progression (57 patients, 89%). Treatment details are summarized in Table 2.

Table 2. Treatment Details
 Dose Group, mg/kg/d
Details0.01 n=210.1 n=211.0 n=22Total N=64
  • *

    The protocol violation, involving this subject who was withdrawn from the study, was due to noncompliance with the protocol, including missing multiple study visits.

  • Investigator decision to remove this subject because of adverse events of flank pain and urinary tract infection. This subject is also included as discontinuing from the study due to adverse events.

  • One subject was considered “completed” because he left the study after completing 6 treatment cycles with stable disease.

No. of cycles completed    
 1-29151135
 3-423611
 5-62327
 >680311
Reason for discontinuation, no. (%)    
 Disease progression20 (95)19 (90)18 (82)57 (89)
 Adverse event1 (5)2 (9)3 (5)
 Protocol violation*1 (5)1 (2)
 Investigator decision1 (5)1 (2)
 Lost to follow-up1 (5)1 (2)
 Completed, subject decision1 (5)1 (5)

Two (3%) subjects (at 1.0 mg/kg) required dose reductions because of weight loss and rash, respectively. Nine (14%) subjects had a total of 11 dose delays, including 4 subjects at 0.01 mg/kg, 2 at 0.1 mg/kg, and 2 at 1.0 mg/kg. Of the 11 dose delays, 8 were due to administrative or scheduling issues. Three subjects experienced dose delays due to toxicity (grade 2 bacteremia and cellulitis, grade 3 pleural effusion, grade 3 cellulitis), none assessed as related to study drug.

Efficacy

Sixty-three subjects were considered evaluable for efficacy. For 1 subject, the only measurable lesion was determined by the IRR to be in a prior radiation field, a violation of exclusion criteria. As a result, the IRR considered this subject not evaluable for efficacy.

One subject with M1c disease achieved a partial response at the end of cycle 4 that was confirmed by the IRR, which was maintained until the end of cycle 8. In addition, 2 subjects (at 0.01 and 0.1 mg/kg) achieved an unconfirmed partial response at the end of cycle 4 but at the next disease assessment (end of cycle 6) 1 subject developed progressive disease based upon review by the IRR. For the second subject, the IRR considered the overall response at the end of cycle 4 to be an unconfirmed PR. The investigator, however, considered the response at the end of cycle 4 to be PD based on the appearance of a new subcutaneous lesion, although there was a significant reduction (34%) in the size of the target lesion.

Four subjects maintained stable disease for 6 months or longer as assessed by the IRR. Three of these subjects were at the 0.01 mg/kg dose and 1 at the 1.0 mg/kg dose. At the conclusion of stage 1, at least 2 confirmed responses were not identified by the IRR in any arm; therefore, the study did not progress to stage II and was terminated at the end of stage 1 per protocol design.

Based on time from randomization to end of study treatment enrollment, the median intervals for on-study duration (in days) were 114 (0.01 mg/kg/d), 57 (0.1 mg/kg/d), and 64.5 (1 mg/kg/d). No significant differences between dose groups were observed. The median PFS for the 3 groups was 7.5 (95% CI, 7.1-15.3) (0.01 mg/kg/d), 7.4 (95% CI, 7.1-7.7) (0.1 mg/kg/d), and 7.3 (95% CI, 7.1-7.4) (1.0 mg/kg/d) weeks. Time to response for the 1 IRR-confirmed partial responder was 107 days. The 4-month PFS rates were 20% (95% CI, 8.3%-48.1%) for the 0.01 mg/kg/d dose group, 5.3% (95% CI, 0.8%-35.5%) for the 0.1 mg/kg/d dose group, and 0% for the 1 mg/kg/d dose group.

Safety

Drug-related adverse events (AEs) were reported for 62 (97%) subjects in this study. The most frequently reported nonhematologic drug-related AEs in at least 7 subjects are summarized in Table 3. The most frequently reported nonhematologic grade 3 or higher AEs are summarized in Table 4. Overall, the majority of these AEs were more common in the highest dose level (1.0 mg/kg/d). No significant differences in incidence were noted between the 2 lower dose levels. The most common hematologic abnormalities are summarized in Table 5 and included lymphopenia, anemia, and neutropenia. The majority of hematologic lab abnormalities were grade 1-2. The most common chemistry laboratory abnormalities were generally grade 1-2 in severity and these are summarized in Table 6.

Table 3. Most Frequently Reported Nonhematologic Drug-related Adverse Events (at Least 7 Subjects)
 Dose Level, mg/kg
 0.01 n=210.1 n=211.0 n=22Total n=64
Drug-related Adverse EventsNo. of Subjects (%)
Any drug-related adverse event19 (90)21 (100)22 (100)62 (97)
Most frequent adverse event    
 Chills12 (57)15 (71)19 (86)46 (72)
 Pyrexia9 (43)10 (48)15 (68)34 (53)
 Fatigue10 (48)10 (48)11 (50)31 (48)
 Nausea9 (43)6 (29)11 (50)26 (41)
 Headache6 (29)10 (48)8 (36)24 (38)
 Vomiting2 (10)3 (14)7 (32)12 (19)
 Anorexia4 (19)3 (14)5 (23)12 (19)
 Rash, includes rash erythematous or pruritic2 (10)2 (10)6 (27)10 (16)
 Hyperhidrosis2 (10) 6 (27)8 (13)
 Myalgia1 (5)4 (19)2 (9)7 (11)
 Dysgeusia1 (5)1 (5)5 (23)7 (11)
Table 4. Most Frequently Reported Nonhematologic Grade 3 or Higher Adverse Events Regardless of Causality
 Dose Group, mg/kg/d
 0.01 n=210.1 n=211.0 n=22Total N=64
 No. of Subjects (%)
Adverse EventGrade 3Grade 4Grade 3Grade 4Grade 5Grade 3Grade 4Grade 5Grade 3-5
Fatigue2 (10)2 (9)4 (6)
Abdominal pain1 (5)1 (5)1 (5)3 (5)
Back pain1 (5)1 (5)2 (3)
Dyspnea1 (5)2 (10)1 (5)2 (9)5 (8)
Ascites1 (5)1 (5)2 (3)
Pleural effusion1 (5)2 (9)3 (5)
Polyarthritis1 (5)1 (2)
Deep vein thrombosis1 (5)1 (2)
Pulmonary embolism1 (5)1 (2)
Cognitive disorder1 (5)1 (2)
Lipase increased1 (5)1 (2)
Table 5. Most Common Hematologic Laboratory Abnormalities by Maximum CTC Grade
  Dose Group (mg/kg)
  0.01 n=210.1 n=211.0 n=22Total/Grade N=64Total N=64
ToxicityMaximum CTC GradeNo. of Subjects (%)
  1. CTC indicates Common Toxicity Criteria (version 3, National Cancer Institute).

Lymphopenia11 (5)1 (5)2 (3)39 (61)
 210 (48)5 (24)13 (59)28 (44)
 34 (19)3 (19)2 (9)9 (14)
Anemia15 (24)1 (5)6 (27)12 (19)17 (27)
22 (10)1 (5)3 (5)
31 (5)1 (2)
41 (5)1 (2)
Neutropenia13 (14)5 (23)8 (13)17 (27)
25 (24)3 (14)8 (13)
31 (5)1 (2)
Table 6. Most Common Chemistry Laboratory Abnormalities by Maximum CTC Grade
  Dose Group, mg/kg
  0.01 n=210.1 n=211.0 n=22Total/Grade N=64Total N=64
ToxicityMaximum CTC GradeNo. of Subjects (%)
  1. CTC indicates Common Toxicity Criteria (version 3, National Cancer Institute); AST, aspartate transaminase.

Hyperglycemia15 (24)3 (14)6 (27)14 (22)24 (38)
21 (5)1 (5)4 (18)6 (9)
32 (10)1 (5)1 (5)4 (6)
[UPWARDS ARROW] Alkaline phosphatase11 (5)4 (18)5 (8)10 (16)
21 (5)1 (5)1 (5)3 (5)
32 (10)2 (3)
Hyperkalemia13 (14)4 (20)2 (9)9 (14)10 (16)
31 (5)1 (2)
Hypernatremia14 (19)1 (5)2 (9)7 (11)8 (13)
31 (5)1 (2)
[UPWARDS ARROW] AST11 (5)5 (23)6 (9)8 (13)
21 (5)1 (2)
31 (5)1 (2)
Hypoglycemia11 (5)2 (9)3 (5)6 (9)
21 (5)1 (5)2 (3)
41 (5)1 (2)

A total of 5 patients experienced 10 grade 3 AEs that were believed to be drug-related, including polyarthritis (1 subject, 0.01 mg/kg); deep vein thrombosis and pulmonary embolism (1, 0.01 mg/kg); cognitive disorder (1, 0.1 mg/kg); fatigue, dyspnea, pleural effusion, and lymphopenia (1, 1.0 mg/kg); fatigue and lymphopenia (1, 1.0 mg/kg). One subject experienced a grade 4 AE of increased lipase (0.1 mg/kg) that was believed to be drug-related and led to permanent discontinuation from the study.

In addition to lymphopenia, other grade 3 or higher hematologic AEs included grade 3 neutropenia (1 subject, 0.01 mg/kg), grade 3 anemia (1 subject, 1 mg/kg), and grade 4 anemia (1 subject, 1 mg/kg). Grade 3 or higher laboratory abnormalities included grade 3 hyperglycemia (N = 4), hyperkalemia (N = 1), hypernatremia (N = 1), elevation in AST (N = 1) and alkaline phosphatase (N = 2), and grade 4 hypoglycemia (N = 1). Two subjects who died during the study had serious adverse events reported including dyspnea (1 subject, 0.1 mg/kg) and abdominal pain (1 subject, 1.0 mg/kg). Both events were considered to be related to underlying disease progression and were not considered drug-related. A total of 7 subjects died during this study. All deaths were due to either the disease under study or disease progression and occurred ≥24 days following the last dose of study drug.

Eight subjects were permanently discontinued from the study due to AEs. One serious AE (increased lipase) was related to study drug. Many of these AEs appear to be related to underlying progressive disease.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. Conflict of Interest Disclosures
  8. References

IL-18 is a proinflammatory cytokine that plays a central role in inflammation and the polarization of the immune response. It has been shown to mediate cellular immunity and antineoplastic effects in a variety of preclinical tumor models,17-22 leading to its development and testing as a potential new therapeutic agent for cancer. Phase 1 trial testing of rhIL-18 demonstrated evidence of immunomodulatory and clinical activity over a wide range of doses leading to the definition of a biologically active dose range and the subsequent testing in phase 2 against melanoma, as reported in this study.

This clinical trial evaluated the efficacy of 3 dosages (groups of 0.01, 0.1, and 1.0 mg/kg/d) of rhIL-18 administered as 5 daily IV infusions repeated every 28 days. The 3 dose regimens were chosen based on the biological activities observed over this dose range as defined in earlier phase 1 studies.29 A 2-stage study design with a stopping rule was used to allow early termination of an arm for lack of efficacy. The primary objective was drug efficacy by tumor response rate and early termination was likely to occur only if the true response rate was too low to be of any clinical benefit. Sixty-four patients were accrued to stage 1 of the study (21 [0.01 mg/kg/d], 21 [0.1 mg/kg/d], 22 [1.0 mg/kg/d]). Among 63 subjects evaluable for response at the end of stage 1, 1 patient (at 0.01 mg/kg) with M1c disease achieved a partial response at the end of cycle 4 that was maintained until the end of cycle 8. Due to lack of efficacy by response criteria, no arm progressed to stage II, and the study was terminated at the end of stage I. There is, however, the possibility that rhIL-18 might be effective in stabilizing and/or improving survival. Evidence for this could be lost as a result of early closure of the study, but this decision was taken according to the study's original plan. Researchers have recently started to explore the utility of OS or PFS as a benchmark for efficacy in phase 2 studies, instead of the traditional objective tumor response rate.30 Based on a recent meta-analysis of previously collected data from 42 melanoma phase 2 trials conducted by SWOG, ECOG, CALGB, NCCTG, and NCIC-CTG between 1975 and 2005, Korn et al have suggested the use of 1-year OS or 6-month PFS as benchmarks for future phase 2 studies.31 The meta-analysis based on 1278 patients provided an estimate of the 1-year OS rate (25.5%) defined by 4 statistically significant independent prognostic factors that include performance status, presence of visceral metastasis, sex, and the exclusion of patients with brain metastasis. This work provides a table of information that is relevant to the design of current trials using a 1-year OS rate as the endpoint and gives us predicted values based on a logistic regression analysis according to PS, sex, presence of visceral metastasis, and whether a trial allowed patients with brain metastasis. To account for the immaturity of follow-up for some patients, it is recommended to exclude patients that were alive with less than 1 year of follow-up. In our study, the overwhelming majority of patients are censored, and the censoring occurred before 12 months. No patients were followed beyond disease progression, so this analysis was not of value, and of the other endpoint analyzed in this review, 6-month PFS rate, was not available in this study. In our study, the 4-months PFS rates were 20% (95% CI, 8.3%-48.1%) for the 0.01 mg/kg/day-dose group, 5.3% (95% CI, 0.8%-35.5%) for the 0.1 mg/kg/day-dose group, and 0% for the 1 mg/kg/day-dose group.

Therefore, as tested in this trial, rhIL-18 has limited activity in patients with metastatic melanoma, and none of the 3 doses tested here could be recommended for phase 3 testing. However, combinations with other immunomodulatory agents may be worthy of evaluation. The exact dosing of rhIL-18 in combinations will likely require phase 1 dose escalation studies in each combination, to be determined. The combined use of IL-18 and Toll-like receptor 9 ligand CpG has been shown to potentiate the antitumor function of natural killer dendritic cells (NKDC). IL-18 alone induced NKDC to secrete IFN-gamma, and the combination of IL-18 and Toll-like receptor 9 ligand CpG resulted in a synergistic increase in IFN-gamma production, both in vitro and in vivo. NKDC selectively proliferated in vitro and in vivo in response to the combination of IL-18 and CpG. Systemic treatment with IL-18 and CpG reduced the number of B16F10 melanoma lung metastases.32

The combined administration of alpha-Galactosylceramide (alpha-GalCer) and IL-18 was shown to suppress pulmonary metastasis of experimental melanoma in a mouse model. Alpha-GalCer shows antitumor effects by activating NK cells indirectly through stimulation of the secretion of cytokines by NKT cells, whereas IL-18 shows antitumor effects by activating NK cells directly. Combined administration of alpha-GalCer and IL-18 enhanced the cytotoxicity of NK cells and increased the number of NK cells in the lung.33

The proinflammatory role of IL-18 in inducing CD4(+) Type-1 T helper (Th1) immune responses essential in promoting durable antitumor immunity through cancer vaccine strategies has been investigated and is promising. Human dendritic cells (DCs) engineered to secrete high levels of the IFN-gamma-inducing cytokines, interleukin (IL)-12p70, and IL-18 by means of recombinant adenoviral infection have been reported to generate an in vitro stimulus capable of promoting previously deficient patient Th1-type responses. Dendritic cells co-infected with Ad.IL-12 and Ad.IL-18 (DC.IL-12 of 18) were more effective at stimulating MAGE-A6 (epitope derived from melanoma antigens) -specific Th1-type CD4(+) T-cell responses than DCs infected with either of the cytokine vectors alone, control Ad.Psi5 virus, or uninfected DCs. The superiority of DC.IL-12 of 18-based stimulation in melanoma patients was independent of disease stage or current disease status. This agent may prove clinically useful as a vaccine strategy to promote the recovery of tumor antigen-specific, Th1-type CD4(+) T-cell responses in patients with cancer.34

CONCLUSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. Conflict of Interest Disclosures
  8. References

Phase 1 evaluation of rhIL-18 as a single agent has demonstrated clinical antitumor activity in patients with metastatic melanoma, which has now been formally tested in this randomized phase 2 study at 3 dose levels and shown to be of limited clinical value. The central immunomodulatory and antitumor roles of IL-18 have repeatedly been demonstrated, but the challenge with this agent lies in defining how to best use its functions in more rational combinations, clinically. Combinations with other immunomodulatory agents, such as TLR-9 agonist CpG, or incorporation into vaccine strategies remain of interest and will warrant further investigation.

Conflict of Interest Disclosures

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. Conflict of Interest Disclosures
  8. References

Supported by GlaxoSmithKline. Kevin H. Laubscher and Mohammed M. Dar are employees of and own stock in GlaxoSmithKline.

References

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. Conflict of Interest Disclosures
  8. References
  • 1
    Balch CM,Buzaid AC,Soong SJ, et al. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol. 2001; 19: 3635-3648.
  • 2
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