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Keywords:

  • antigastrin antibodies;
  • cisplatin;
  • 5-fluorouracil;
  • Karnofsky performance status;
  • overall survival;
  • time to tumor progression;
  • gastric cancer;
  • vaccination

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

BACKGROUND

Gastrin hormone is trophic to in vitro gastric cancer, and the antigastrin antibodies (AGAs) are antiproliferative and antimetastatic. Human gastric cancers overexpress gastrin genes and receptors that react to gastrin's trophic effects. Immunogen G17DT elicits a specific and high-affinity AGA. The authors evaluated G17DT vaccination given with cisplatin plus 5-fluorouracil for the treatment gastric adenocarcinoma.

METHODS

In this multicenter, Phase II study, patients received G17DT vaccination intramuscularly on Weeks 1, 5, 9 and 25 and cisplatin plus 5-fluorouracil every 28 days. Eligible patients had untreated, metastatic, or unresectable gastric or gastroesophageal adenocarcinoma with near-normal organ function. The primary endpoint of the study was the over response rate (ORR), and secondary endpoints included overall survival (OS), safety, and the impact of successful vaccination on patient outcome.

RESULTS

In total, 103 patients were enrolled in 5 countries. Seven patients who were overdosed inadvertently with 5-fluorouracil (a major protocol violation) were removed from the analysis. The confirmed ORR was 30% in 79 patients who were evaluated for response. The median time-to-progression (TTP) was 5.4 months, and the median survival (MS) was 9.0 months (n = 96 patients). Sixty-five of 94 patients who were vaccinated (69%) had 2 consecutive AGA titers of ≥1 units (successfully vaccinated patients or immune-responders). The TTP was longer in immune-responders than in immune-nonresponders (P = .0005). Similarly, the MS was longer in immune-responders than in immune-nonresponders (10.3 months vs. 3.8 months; P ≤.0001). In a multivariate analysis, successful vaccination was an independent OS prognosticator (P = .0001). G17DT did not have an adverse effect on safety.

CONCLUSIONS

The results demonstrated that successful G17DT vaccination was correlated with longer TTP and MS. AGA response was an independent OS prognosticator. A Phase III evaluation of G17DT in gastric cancer is warranted. Cancer 2006. © 2006 American Cancer Society.

Growth factors are critical for the proliferation and survival of cancer cells, and it has been demonstrated that they are important targets for anticancer therapy in breast, lung, and colon carcinomas. The gastrin hormone is a growth factor for a variety of cancers, including adenocarcinoma of the stomach, and it has trophic effects on gastric cancer cell lines and human-derived gastric cancers.1–4 Gastrin-17 is the predominant form of gastrin that circulates under normal conditions.5 Gastric and other gastrointestinal cancers overexpress the gastrin gene and are sensitive to the trophic effects of gastrin in animal models.6, 7 Various cancers, including gastric cancer, produce gastrin hormone (autocrine) and also react to gastrin in a paracrine manner.5, 7–9 Gastrin is proangiogenic10 and is antiapoptotic through the up-regulation of Bcl-2 and sruvivin,11 through the down-regulation of mitochondrial cytochrome C efflux,12 and through activation of the potent antiapoptotic factor protein kinase B/Akt13 and the transcriptional nuclear factor κB (NFκB).14 Gastrin also promotes proliferation of gastric mucosa and faster progression to gastric cancer than that induced by Helicobacter pylori alone.15 Gastrin and gastrin receptor-mediated pathways are shown in Figure 1.

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Figure 1. This chart illustrates the gastrin pathways. PKB/Akt: phosphorylated protein kinase B; CCK-2: cholecystokinin 2; ERK: extracellular signal-regulated kinase; MAPK: microtubule-associated protein kinase; PKC: protein kinase C; MMP: matrix metalloproteinase; FAK: focal adhesion kinase; NFκB: nuclear factor κB; HB-EFG: heparin-binding epidermal growth factor; COX-2: cyclooxygenase 2.

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G17DT is a therapeutic immunogen that is formulated as a water-in-oil emulsion for intramuscular injection. The G17DT conjugate contains a 9-amino-acid epitope derived from the amino-terminal sequence of gastrin-17 (G17), which is conjugated to diphtheria toxoid (DT). G17DT elicits specific and high-affinity antigastrin antibodies (AGAs) that bind G17, thus preventing its trophic activity.1 In animal models, AGAs reduce the growth and metastatic spread of gastrointestinal tumors.16–20 More impressively, gastrin appears to impart resistance to a variety of cytotoxic agents, including cisplatin. Thus, the combination of chemotherapy and antigastrin vaccination provides a highly attractive investigative approach for advanced gastric cancer for which chemotherapy alone has provided only a limited advantage.

It was shown previously that G17DT doses ≥100 μg were immunogenic.1 A comparison of immune response rates among patients with gastrointestinal cancers suggested that G17DT doses ≥250 μg resulted in a significant percentage (57-92%) of AGA producers.1 In addition, after administration of a 500-μg dose of G17DT as a monotherapy, AGA production was detected in all 7 volunteers who received the treatment.1

To examine the practicality, efficacy, and safety of combining vaccination against G17 with cisplatin and 5-fluorouracil (5-FU), an open-label, multicenter, multinational, phase II study in chemotherapy-naive patients with advanced gastric or gastroesophageal cancer was conducted with the primary endpoint of confirmed overall response rate (ORR) and secondary endpoints of the rate of successful vaccination and its correlation with overall survival (OS).

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Study Design

This was a multicenter, multinational, open-label, Phase II study of G17DT plus 5-FU and cisplatin. The primary endpoint was to assess the confirmed ORR, and secondary objectives were to evaluate the correlation of the immune response and the time to progression (TTP), OS, and safety profile of this immunochemotherapy.

Eligibility Criteria

Patients with metastatic or unresectable, measurable, histologically documented adenocarcinoma of the stomach or gastroesophageal junction were eligible. Patients age 18 years or older who had a Karnofsky performance status (KPS) ≥70% and a life expectancy ≥12 weeks were eligible. Patients were required to have adequate hematologic, hepatic, and renal functions. Patients with severe comorbid conditions or evidence of brain metastases were excluded. All patients were required to sign an approved informed consent.

Pretreatment Evaluations

All patients underwent a complete history and physical examination; documentation of KPS; computed tomography scans of the abdomen, chest, and pelvis; documentation of measurable cancer; urinary pregnancy test (for women of childbearing age); complete blood count (CBC); and serum chemistries, including electrolytes and magnesium levels.

Immunization (vaccination)

All treatments were received in the outpatient setting. G17DT was injected intramuscularly at a dose of 500 μg (volume, 0.2 mL) in Weeks 1, 5, 9, and 25. If patients had significant local reactions, then the dose of G17DT could be reduced to 250 μg or discontinued.

Chemotherapy

All chemotherapy was received in the outpatient setting. Cisplatin was administered every 4 weeks on the first day of each treatment cycle, starting at Week 0, as a 1-hour to 3-hour intravenous infusion at a dose of 100 mg/m2. 5-FU was administered every 4-weeks during the first 5 days of each cycle as a continuous infusion at a dose of 1000 mg/m2 per day. A cycle of chemotherapy was 28 days long. Patients received appropriate antiemetic and hydration support in a standard manner.

Evaluations During Therapy

Patients underwent a weekly CBC and serum chemistry panel before each cycle of therapy. Radiologic imaging was performed every 2 cycles to assess response to therapy.

Response and Toxicity Assessment Criteria

The Response Evaluation Criteria in Solid Tumors (RECIST) for tumor response and the National Cancer Institute Common Toxicity Criteria (version 2.0) for toxicity assessment (www.cancer.gov) were used.

Statistical Methods

Sample size

Assuming a mean 40% ORR, the lower 95%, 1-sided confidence limit was 30% (the lowest acceptable ORR). If the actual ORR was 45%, then an 80% power was exercised to detect a significant improvement from 30%. Thus, a sample size of 70 evaluable patients was proposed to allow only a <5% chance of missing treatment-emergent adverse events (TEAEs). Stopping rules based on patient safety were implemented.

Descriptive analyses were used for the planned safety and efficacy parameters. The data were summarized by using means, geometric means, standard deviations, medians, minimums, maximums, and 95% confidence intervals. All analyses were performed by using SAS® software (version 8.2). Kaplan–Meier analyses were performed to evaluate survival time and the time-to-disease progression. A Cox regression model was used for the multivariate analysis.

Immune response

Immune response was determined by using blood that was collected from patients every 2 weeks for the first 12 weeks and monthly thereafter. Immunoassays were performed by a G17 antigen-based enzyme-linked immunosorbent assay (ELISA). For the primary and exploratory analyses, 2 definitions were used. According to the primary definition, patients were considered immunized (vaccinated) if they had an AGA titer ≥1 ELISA unit for 2 consecutive assays. According to the secondary definition, patients were considered vaccinated if they had ≥1 AGA titer ≥1.2 ELISA units at any time during the study postbaseline and post-G17DT treatment. AGA responders (i.e., patients who were considered vaccinated or immune-responders) and immune-nonresponders also were compared for baseline characteristics, such as gender, age, race, histology type, location of metastases, number of organ systems involved with metastases, and KPS, to determine any correlation between AGA response and patient outcome.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Patient Characteristics

For this multinational, multicenter trial, 50 patients were enrolled at sites in the United States, and 53 patients were enrolled at non-U.S. sites (Russia, Israel, Poland, and Thailand) between August 15, 2000 and February 25, 2003. In total, 162 potential patients were screened, and 103 patients were accrued. Seven patients with major protocol violations were removed from this analysis (see below). The patient characteristics of 96 patients are shown in Table 1. Eighty percent of patients had symptoms at baseline, including 59% who had gastrointestinal symptoms.

Table 1. Patient Characteristics by Country and Cumulative Survival
CharacteristicNo. of Patients (%)
United States (N = 50)Israel (N = 5)Poland (N = 8)Russia (N = 28)Thailand (N = 5)All Sites (N = 96)
  1. SD: standard deviation.

Age, y      
 Mean56.955.451.455.554.055.8
 SD12.615.312.110.59.911.8
 Median604648545255.5
 Range34, 8141, 7336, 7229, 7345, 6929, 81
 ≤65 y34 (68)3 (60)7 (88)24 (86)4 (80)72 (75)
 <65 y16 (32)2 (40)1 (13)4 (14)1 (20)24 (25)
Gender      
 Male41 (82)3 (60)6 (75)15 (54)2 (40)67 (70)
 Female9 (18)2 (40)2 (25)13 (46)3 (60)29 (30)
Race      
 White41 (82)5 (100)8 (100)28 (100)082 (85)
 Black3 (6)00003 (3)
 Hispanic3 (6)00003 (3)
 Asian3 (6)0005 (100)8 (8)
Weight, kg      
 Mean77.9463.0064.2562.8050.1470.16
 SD20.109.3313.2111.407.8918.41
 Median76.1562.0062.0060.5050.0067.00
 Range43.2–132.550–7243–8442–9240.4–58.840.4–132.5
Body surface area, m2      
 Mean1.9111.6901.7731.7151.4821.807
 SD0.2650.2040.2890.1920.1490.264
 Median1.9001.7501.7601.7001.5201.780
 Range1.42–2.551.45–1.891.40–2.401.42–2.401.28–1.641.28–2.55

All 96 patients were assessed for OS and safety, 94 patients were vaccinated and assessed for immune response, and 79 patients were assessed for ORR. The median number of chemotherapy cycles was 4 (range, 1-12 cycles). The reasons for discontinuation of therapy are listed in Table 2.

Table 2. Reasons for Discontinuing Study Drugs
 No. of Patients (%)
Reason for DiscontinuationUS Sites (N = 50 patients)Non-US Sites (N = 46 patients)All Sites (N = 96 patients)
  • US: United States.

  • *

    Normal completion was 12 months on study.

Normal completion*4 (8)1 (2)5 (5)
Adverse event10 (20)4 (9)14 (15)
Lost to follow-up1 (2)1 (1)
Death1 (2)5 (11)6 (6)
Noncompliance2 (4)4 (9)6 (6)
Disease progression20 (40)25 (54)45 (47)
Other14 (28)9 (20)23 (24)

Protocol Deviations

Protocol deviations were recorded in 65 patients; however, major deviations were recorded in 7 patients (7%). Thirty-two patients did not strictly meet 1 or more of the eligibility criteria. Fourteen patients received incorrect scheduling or doses of G17DT, and 21 patients had some deviation of chemotherapy schedule or dosing (including 7 major deviations). Other protocols deviations predominantly included missed assessment timings.

Seven major protocol deviations occurred at 1 non-U.S. site; this involved 7 patients who received the total calculated daily 5-FU dose as a daily bolus injection. It was determined that 6 of 7 patients died of 5-FU toxicity. All regulatory agencies were promptly notified, and the protocol at the site in question was terminated. These 7 patients have been removed from the current analyses.

Response to Therapy (Primary Endpoint)

We assessed the best ORR and confirmed ORR. The ORR to chemoimmunotherapy could be assessed in 79 patients who had received ≥1 cycle of chemoimmunotherapy and had a response assessment performed. Among the excluded 24 patients, 1 patient did not receive protocol therapy, and 23 patients did not have a follow-up response assessment. Seventy evaluable patients were needed based on the statistical stipulations. For the 79 evaluable patients, the best ORR was 50%, but the confirmed ORR was 30% (Table 3). For the intent-to-treat (ITT) population of 96 patients, the best ORR was 42%, and the confirmed ORR was 25%.

Table 3. Response, Time to Tumor Progression, and Survival in Assessable Patients
AssessmentNo. of Patients (%)
  • *

    All 79 patients with tumor assessments had anti-G17 antibody titer data.

Total no. of patients96
No. with confirmed response available79
 Complete response1 (1)
 Partial response23 (29)
No. with best overall response available79*
 Complete response1 (1)
 Partial response39 (49)
 Stable disease25 (32)
 Progressive disease14 (18)
Time to tumor progression (days)58
 Kaplan–Meier estimate, days 
  Median165
  Range8–325
Total no. of deaths87
 Kaplan–Meier estimate, days 
  Median274
  Range8–1061

Survival and Time-to-Progression (Secondary Endpoint)

Eighty-seven of 96 patients (91%) had died at the time of this report. The median survival (MS) was 274 days (9.0 months) according to the Kaplan–Meier estimates (Table 3). The median TTP estimated in 58 patients was 165 days (5.4 months) according to the Kaplan–Meier estimates (Table 3). The MS also was correlated with the baseline KPS; it was only 2.2 months for the lowest tier of KPS (70%), but was 9.3 months for patients who had a KPS ≥80% (P ≤.0001) (Fig. 2).

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Figure 2. This Kaplan–Meier plot for survival was based on baseline Karnofsky performance status (KPS) among the intent-to-treat population.

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Impact of Immunization and its Correlation with Outcome (Secondary Endpoint)

Table 4 shows the frequency of immune response in various categories of assessments. Sixty-five of 94 patients (69%) had ≥2 consecutive titers of AGA ≥1 ELISA unit and, thus, were considered adequately vaccinated according to the primary definition. Seventy-six of 90 patients (84%) had ≥1 titer ≥1.2 ELISA units (vaccinated according to the secondary definition).

Table 4. Immune Response Characteristics*
ITT PopulationNo. of Patients (%)
  • ITT: intent to treat; SD: standard deviation.

  • *

    All titers were measured in enzyme-linked immunosorbent assay units.

Total no. of patients94
No. of patients who obtained 2 consecutive anti-G17 titers by Week 1290
 Both titers ≥1 unit 
 Yes56 (62)
 No30 (33)
 Only 1 titer available5 (5)
No. of patients who obtained peak anti-G17 titer by Week 1290
 Mean ± SD45.33 ± 135.34
 Geometric mean ± asymptotic SD13.35 ± 48.20
 Median4.70
 Range0.0–968.9
No. of patients who obtained 2 consecutive anti-G17 titers ≥1 at any time94
 Yes65 (69)
 No26 (28)
 Only 1 titer available3 (3)
No. of patients who obtained any anti-G17 titers ≥194
 Yes76 (81)
 No18 (19)
Peak anti-G17 titer (N = 94 patients) 
 Mean ± SD58.33 ± 147.49
 Median6.32
 Range0.0–968.9
No. of patients with any anti-G17 titer ≥1.2 units postbaseline and post-G17DT treatment available90
 Yes76 (84)
 No14 (16)

Table 5 shows the response according to AGA titers. All immune-responders had a best ORR of 54% compared with immune-nonresponders, who had a best ORR of 30% (P = .1927). However, there was a significant improvement in TTP (median, 5.5 months) for immune-responders compared with immune-nonresponders (median, 2.1 months; P = .0005).

Table 5. Best Overall Tumor Response Analysis by Antigastrin Antibody Response
Anti-G17 Antibody Responder*Best Tumor Response: No. of Patients (%)
No. of patientsORRSD/PD
  • ORR: overall response rate; PD: progressive disease; SD: stable disease; ELISA: enzyme-linked immunosorbent assay.

  • *

    Any anti-G17 antibody titer above the indicated level at any time during the study.

  • All 79 patients with tumor assessments had anti-G17 antibody titer data.

ELISA titer ≥4 units5128 (55)23 (45)
ELISA titer >2 units6534 (52)31 (48)
ELISA titer >1 units6937 (54)32 (46)
Nonresponder103 (30)7 (70)

OS was significantly longer for immune-responders (median, 10.3 months) compared with immune-nonresponders (median, 3.8 months; P ≤.0001) (Fig. 3). ORR, TTP, and survival also were analyzed by using the secondary definition for AGA response, and the differences were maintained (survival, 10.3 months vs. 4.8 months, respectively; P ≤ .0001).

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Figure 3. This Kaplan–Meier plot for survival was based on anti-G17 antibody response. CAT ≥1, anti-G17 antibody responders; CAT <1, nonresponders. CAT: circulating antibody titer.

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There was a significant improvement in TTP for immune-responders (median, 5.5 months) compared with immune-nonresponders (median, 2.1 months; P ≤.0057). The differences were maintained for both definitions of anti-G17 immune response.

Univariate and Multivariate Analyses

In a correlation that focused on immune-responders and immune-nonresponders by using baseline clinical and laboratory values, KPS (P = .02), alkaline phosphatase (P = .02), total protein (P ≤.01), white blood cell count (P ≤.01), and serum albumin (P ≤.01) all reached the level of significance. However, in a multivariate analysis, by using a Cox proportional model, only baseline KPS (grouped by KPS 70% vs. KPS ≥80%) was associated with OS (P <.0001). After adjustment for these parameters, only the predefined AGA response (successful vaccination) was correlated highly as an independent factor for predicting OS (P <.0001).

To examine the correlations between KPS, immune response, and survival, we then calculated the MS for immune-responders and immune-nonresponders according to the baseline KPS. Among patients who had a KPS of 100%, the MS was 10 months for immune-responders and 7.9 months for immune-nonresponders. Among patients who had a KPS of 90%, the MS was 11.2 months for immune-responders and 3.7 months for immune-nonresponders. Among patients who had a KPS of 80%, the MS was 8.9 months for immune-responders and 5.4 months for immune-nonresponders. Among the 10 patients who had a KPS of 70%, the MS was 2.2 months for both groups (P = .61; however, for patients who had a baseline KPS ≥80%, OS was correlated significantly for immune-responders (MS, 10.4 months) compared with immune-nonresponders (MS, 5.4 months; P ≤.001) (Fig. 4).

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Figure 4. Overall survival is illustrated according to Karnofsky performance status (KPS) and response to the therapeutic immunogen G17DT.

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Safety (Secondary Endpoint)

Six of 7 patients at 1 study site died as a result of an overdose of 5-FU (see Protocol Deviations, above). Ninety-six patients were evaluated for safety, and 92 patients (96%) reported ≥1 TEAE. Most of those TEAEs were related to chemotherapy. The most frequently reported TEAE was nausea (75%). Injection site-associated events accounted for the majority of G17DT treatment-related TEAEs, with 41% of patients experiencing injection site reactions. Only 6 patients discontinued G17DT administration because of a TEAE. Fifteen patients had ≥1 TEAE that resulted in withdrawal from the study. SAEs (Grade 3 or 4) were reported for 45% of patients. Only 1 serious adverse event (SAE), an injection site abscess, was related to G17DT (Table 6).

Table 6. Summary of National Cancer Institute Common Toxicity Criteria Version 2.0 Grade 3 and Grade 4 Treatment-Emergent Adverse Events by Patient (≥3% of Patients)*
CategoryAll Sites: No. of patients (%)
Grade 3 (N = 96 Patients)Grade 4 (N = 96 Patients)
  • NOS indicates not otherwise specified; TEAE, treatment-emergent adverse event.

  • *

    All 3 patients received an overdose of 5-fluorouracil and died because of profound 5-fluorouracil toxicity.

  • All 79 patients with tumor assessments had anti-G17 antibody titer data.

Blood and lymphatic system disorders  
 Neutropenia14 (15)9 (9)
 Leukopenia, NOS8 (8)1 (1)
 Anemia, NOS7 (7)5 (5)
 Febrile neutropenia4 (4)3 (3)
 Thrombocytopenia3 (3)2 (2)
Gastrointestinal disorders  
 Nausea18 (19)1 (1)
 Emesis, NOS18 (19)1 (1)
 Stomatitis17 (18)1 (1)
 Diarrhea, NOS5 (5)
 Oral pain4 (4)
 Abdominal pain, NOS3 (3)
Vascular disorders  
 Hypertension, NOS4 (4)
 General disorders  
 Mucosal inflammation, NOS12 (13)
 Fatigue10 (10)2 (2)
 Weakness5 (5)1 (1)
Metabolism and nutrition disorders  
 Anorexia11 (12)2 (2)
 Dehydration10 (10)1 (1)
 Infections and infestations  
 Pneumonia, NOS4 (4)
Nervous system disorders  
 Peripheral neuropathy9 (9)
 Syncope5 (5)

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Despite a substantial increase in the number of active chemotherapeutic agents, there is no satisfactory treatment for advanced gastric or gastroesophageal cancer. The combination of cisplatin plus 5-FU remains 1 of the reference regimens21–28 (Table 7). The ORRs to cisplatin plus 5-FU vary substantially, but the confirmed response rates in randomized trials are approximately 23%.21, 22 Nevertheless, the ORR does not correlate with OS.21–28 The current study was designed to build on standard chemotherapy by adding an inhibitor of growth factor gastrin. G17DT blocks gastrin-mediated effects through the genesis of specific and high-affinity AGAs.

Table 7. Studies Using the Combination of 5-Fluorouracil and Cisplatin for Advanced Gastric Cancer
StudyCF RegimenORR (%)Median Survival (Mos)TTP (Mos)
  • CF: combined 5-fluorouracil and cisplatin; ORR: overall response rate; TTP: time to disease progression; C: cisplatin; F: 5-fluorouracil; IV: intravenous; CIV: continuous intravenous; NA: not available.

  • *

    Confirmed ORR.

Current studyG17DT plus CF: C, 100 mg/m2 as 1-3 hr IV infusion on Day 1 every 4 weeks; F, 1000 mg/m2 per day as CIV infusion on Days 1-5 every 4 weeks30*9.05.4
Ajani et al., 200322C, 100 mg/m2 as 1-3 hr IV infusion on Day 1 every 4 weeks; F, 1000 mg/m2 per day as CIV infusion on Days 1-5 every 4 weeks23*8.53.7
Vanhoefer et al/, 200023C, 100 mg/m2 as 1-hr IV infusion on Day 2 every 4 weeks; F, 1000 mg/m2 per day as CIV infusion on Days 1-5 every 4 weeks20*7.24.1
Rougier et al., 199424C, 100 mg/m2 as 1-3 hr IV infusion on Day 2 every 4 weeks; F, 1000 mg/m2 per day as CIV infusion on Days 1-5 every 4 weeks439NA
Kim et al., 199325C, 60 mg/m2 per day on Day 1 every 3 weeks; F, 1000 mg/m2 12 hrs IV on Days 1-5 every 3 weeks518.55
Kyoto Research Group, 199226C, 50 mg/body weight IV over 3 hrs on Day 1 every 2 weeks; F, 250 mg/body weight as IV injection on Days 2-5 every 2 weeks243.9NA
Lacave et al., 199127C, 100 mg/m2 CIV on Day 1 every 4 weeks; F, 1000 mg/m2 per day CIV on Days 2-6 every 4 weeks4110.6NA
Ohtsu et al., 200328C,: 20 mg/m2 0.5-hr IV infusion on Days 1-5 every 4 weeks; F, 800 mg/m2 per day CIV on Days 1-5 every 4 weeks; after 6 cycles, F administered alone347.33.9
Williamson et al., 199529C, 20 mg/m2 0.5-hr IV infusion every 8 weeks then every alternate week; F, 200 mg/m2 24 hrs CIV107.0NA

To our knowledge, this is the first trial in which G17DT was coadministered with intensive chemotherapy and steroidal premedication that potentially may attenuate immune response to vaccination. However, >60% of patients with advanced gastric cancer were vaccinated successfully. An immune response equal to an AGA titer of 1 ELISA unit is sufficient to bind 25.6 pmoles/L of G17 gastrin, which is above the mean peak postprandial G17 levels observed in nonimmunized patients in clinical studies with G17DT.1 The median AGA titer after vaccination was 4.70 ELISA units. Immune-responders had a higher ORR (54% vs. 30%) (Table 4), a significantly longer TTP (P = .0005), and longer OS (P ≤.0001) compared with immune-nonresponders. Although the KPS had an influence on OS (Fig. 2), in patients with a KPS ≥80%, who constituted the majority of patients in this study, immune-responders lived longer than immune-nonresponders (P ≤.0001). This was borne out further by the multivariate analysis, in which immune response to G17DT emerged as an independent prognostic variable (P ≤.0001) after adjustment for KPS. Are these results because of nonspecific immune stimulation or specifically because of AGA? In mouse models that used colon cancer cell lines, nonspecific immunization compared with AGA was ineffective in reducing cancer growth (unpublished data). Nonspecific, systemic immunization trials in the 1970s were ineffective. Because gastric cancer has gastrin receptors, and the gastrin hormone is a survival factor, we believe that the observations described above were because of the generation of AGAs by G17DT. The true value of G17DT can be determined only in a randomized trial.

In the current study, our objectives were to assess the ORR and to assess the impact of vaccination on various patient outcomes. For the ORR assessment, we needed 70 evaluable patients to observe a confirmed ORR range between 30% and 45%. In total, 103 patients eventually were enrolled in 5 countries and yielded 79 patients who were evaluable for ORR, 94 patients who were evaluable for G17DT antibody response, and 96 patients who were evaluable for safety and survival assessments. Although the multinational nature of the current trial may improve the generalizability of the results, it also may reduce protocol compliance that does not match that of a single institution or a seasoned cooperative group.

The primary endpoint of our study was ORR: The confirmed ORR in 79 evaluable patients was 30%, and the confirmed ORR for the ITT population (n = 96 patients) was 25%, similar to the rates reported in other studies.21, 22 From our study, it cannot be determined whether G17DT contributed to ORR, although 69% of 94 patients were immune-responders. However, more intriguing results emerged after analysis of the secondary endpoints, particularly the impact of successful vaccination by G17DT on TTP and OS.

Safety evaluation demonstrated that G17DT in combination with cisplatin and 5-FU was tolerated well and elicited an immune response in >60% of patients who received chemotherapy and steroids. Three injection site abscesses were reported, 1 of which was considered serious.

In immune-responders, the titer of AGA did not correlate with survival. What seemed to matter was that successful immunization was accomplished. Therefore, a strategy in the future may be to use a more aggressive immunization schedule than what was used in the current trial to provide the opportunity to immunize more patients.

In conclusion, gastrin is a trophic and survival factor for gastric cancer cells. Administration of G17DT, which targets the ligand (gastrin) of the gastrin receptor, resulted in successful vaccination in the majority of patients with gastric cancer despite concomitant chemotherapy. Although OS and ORR were consistent with published chemotherapy reports, there appears to be an intriguing and significant correlation between immune response to G17DT and clinical efficacy. The response to G17DT was an independent prognostic factor for OS and was independent of other clinical factors, such as KPS or laboratory abnormalities. The potential benefit from G17DT may be occurring in patients who are vaccinated successfully. Methods to increase the fraction of patients who are vaccinated successfully need to be explored (e.g., avoiding immunosuppressive therapy or more aggressive immunization schedules). However, currently, >60% of patients with gastric cancer are immune-responders; therefore, a Phase III investigation of G17DT is warranted to delineate its true contribution to patient survival.

Acknowledgements

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

The authors thank the following investigators for their participation in this study: Dr. T. Arkadyeva, Krasnodar City Oncology Center (Krasnodar, Russia); Dr. W. Berry, Raleigh Hematology Oncology Clinic (Cary, NC); Dr. M. Biakhov, General Clinical Hospital of the Ministry of Transport (Moscow, Russia); Dr. C. Cathcart, New Mexico Cancer Center Associates (Sante Fe, NM); Dr. J. Costanzi, Lone Star Oncology (Austin, TX); Dr. A. Figer, Oncology Institute (Tel Aviv, Israel); Dr. A. Garin, Blokhin Cancer Research Center (Moscow, Russia); Dr. E. Fishkin, Trinitas Hospital (Elizabeth, NJ); Dr. C. Garrett, H. Lee Moffitt Cancer Center, (Tampa, FL); Dr. M. Guarino, Medical Oncology/Hematology Consultants (Wilmington, DE); Dr. T. Guthrie, University of Florida, Division of Oncology/Hematology (Jacksonville, FL); Dr. W. Hanna, Volunteer Research Group (Knoxville, TN); Dr. J. Holland, Stratton Veterans Administration Medical Center (Albany, NY); Dr. V. Ivanchenko, Novgorod Regional Oncology Center (Velikiy Novgorod, Russia); Dr. R. Just, Scripps Memorial Hospitals, Thomas T. Stevens Cancer Center (San Diego, CA); Dr. E. Kaplan, North Shore Cancer Research Association (Skokie, IL); Dr. J. Kuebler, Columbus Community Clinical Oncology Program (Columbus, OH); Dr. P. Lertsanguansinchai, Chulalongkorn Hospital (Bangkok, Thailand); Dr. M. Lichinitser, Blokhin Cancer Research Center (Moscow, Russia); Dr. V. Lorvidhaya, Maharaj Nakhon-Chingmai Hospital (Chiangmai, Thailand); Dr. A. Makhson, Moscow Oncology Hospital 62 (Moscow, Russia); Dr. G. Manikhas, St. Petersburg Oncology Center (St. Petersburg, Russia); Dr. S. McCachren, Thompson Cancer Survival Center (Knoxville, TN); Dr. S. McKenney, Mamie McFadden Ward Cancer Center (Beaumont, TX); Dr. K. McIntyre, Texas Oncology, P.A. (Dallas, TX); Dr. V. Moiseyenko, Petrov Research Institute of Oncology (St. Petersburg, Russia); Dr. C. Newman, University of Rochester Cancer Center (Rochester, NY); Dr. M. Olsen, Cancer Care Associates (Tulsa, OK); Dr. A. Pluzanska, Klinika Chemioterapii Nowotworow Akademii (Lodz, Poland); Dr. P. Richards, Oncology and Hematology Associates of Southwest Virginia (Bedford, VA); Dr. G. Robbins, Florida Community Cancer Center (Brandenton, FL); Dr. R. Ruxer, Texas Oncology P.A. (Fort Worth, TX); Dr. V. Tchissov, Hertzen esearch Institute of Oncology (Moscow, Russia); Dr. P. Tomczak, Szpital Kliniczny No. 1 (Poznan, Poland); Dr. E. Topuzov, St. Petersburg Mechnikov State Medical Academy (St. Petersburg, Russia); Dr. O. Vtoraya, Arkhangelsk Regional Oncology Center (Arkhangelsk, Russia); Dr. G. Wallner, II Klinika Chirurgii AM (Lublin, Poland); Dr. J. Wasser, DeQuattro Community Cancer Center (Manchester, CT); Dr. D. Watkins, Allison Cancer Center (Midland, TX); Dr. I. Wiznitzer and Dr. I. Oliff, Hematology Oncology Associates of Illinois (Highland Park, IL).

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
  • 1
    Aphton Corporation. Aphton Investigator Brochure: Human G17DT Immunogen. San Francisco: Aphton Corporation, 2003. Available at URL: http://www.aphton.com[accessed June 1, 2005].
  • 2
    Kobori O, Vuillor MT, Martin F. Growth response of rat stomach cancer cells to gatro-entero-pancreatic hormones. Int J Cancer. 1982; 30: 6567.
  • 3
    Ochai A, Yasui W, Tahara E. Growth-promoting effects of gastrin on human gastric carcinoma cell line TMK-1. Jpn J Cancer Res. 1985; 76: 10641067.
  • 4
    Watson S, Durrant L, Morris D. Gastrin: growth enhancing effects on human gastric and colonic tumour cells. Br J Cancer. 1989; 59: 554558.
  • 5
    Rehfeld JF, Van Solinge WW. The tumor biology of gastrin and cholecystokinin. Adv Cancer Res. 1991; 63: 295347.
  • 6
    McWilliams DF, Watson SA, Crosbee DM, et al. Coexpression of gastrin and gastrin receptor (CCK-B and delta CCK-B) in gastrointestinal tumour cell lines. Gut. 1998; 42: 795798.
  • 7
    Aly A, Shulkes A, Baldwin GS. Gastrins, cholecystokinins and gastrointestinal cancer. Biochim Biophys Acta. 2004; 1704: 110.
  • 8
    Iwata N, Murayama T, Matsumori Y, et al. Autocrine loop through cholecystokinin-B/gastrin receptors involved in growth of human leukemia cells. Blood. 1996; 88: 268326899.
  • 9
    Schaer JC, Reubi JC. High gastrin and cholecystokinin (CCK) gene expression in human neuronal, renal, and myogenic stem cell tumors: comparison with CCK-A and CCK-B receptor contents. J Clin Endocr Metab. 1999; 84: 223239.
  • 10
    Lefranc F, Mijatovic T, Mathieu V, et al. Characterization of gastrin-induced proangiogenic effects in vivo in orthotopic U373 experimental human glioblastomas and in vitro in human umbilical vein endothelial cells. Clin Cancer Res. 2004; 10: 82508265.
  • 11
    Konturek PC, Nikiforuk A, Kania J, Raithel M, Hahn EG, Muhldorfer S. Activation of NFkappaB represents the central event in the neoplastic progression associated with Barrett's esophagus: a possible link to the inflammation and overexpression of COX-2, PPARgamma and growth factors. Dig Dis Sci. 2004; 49: 10751083.
  • 12
    Wu H, Rao GN, Dai B, Singh P. Autocrine gastrins in colon cancer cells up-regulate cytochrome C oxidase Vb and down-regulate efflux of cytochrome C and activation of caspase-3. J Biol Chem. 2000; 275: 3249132498.
  • 13
    Todisco A, Ramamoorthy S, Witham T, et al. Molecular mechanisms for the antiapoptotic action of gastrin. Am J Physiol Gastrointest Liver Physiol. 2001; 280: 298307.
  • 14
    Ogasa M, Miyazaki Y, Hiraoka S, et al. Gastrin activates nuclear factor kappaB (NFkappaB) through a protein kinase C dependent pathway involving NFkappaB inducing kinase, inhibitor kappaB (IkappaB) kinase, and tumour necrosis factor receptor associated factor 6 (TRAF6) in MKN-28 cells transfected with gastrin receptor. Gut. 2003; 52: 813819.
  • 15
    Wang TC, Dangler CA, Chen D, et al. Synergistic interaction between hypergastrinemia and Helicobacter infection in a mouse model of gastric cancer. Gastroenterology. 2000; 118: 3647.
  • 16
    Watson SA, Michaeli D, Justin T. Pre-clinical evaluation of the gastrimmune immunogen alone and in combination with 5-FU/leucovorin in a rat colorectal cancer model. Int J Cancer. 1998; 75: 873877.
  • 17
    Watson S, Michaeli D, Grimes S. Anti-gastrin antibodies raised by gastrimmune inhibit growth of the human colorectal tumor AP5. Int J Cancer. 1995; 61: 233240.
  • 18
    Watson S, Michaeli D, Morris T. Gastrimmune reduces lung metastases in a human colorectal model [abstract]. Gut. 1995; 37: A37.
  • 19
    Watson SA, Michaeli D, Grimes S, et al. Gastrimmune raises antibodies that neutralize amidated and glycine-extended gastrin-17 and inhibit the growth of colon cancer. Cancer Res. 1996; 56: 880885.
  • 20
    Watson SA, Morris T, Robinson GK, et al. Therapeutic effects of anti-gastrin antibodies raised by gastrimmune on a human gastric cancer ascites line MGLVA1 [abstract]. Proc AACR. 1994; 436: 253.
  • 21
    Ajani JA, Van Cutsem J, Moiseyenko V, et al. Docetaxel (D), cisplatin, 5-fluorouracil compare to cisplatin (C) and 5-fluorouracil (F) for chemotherapy-naive patients with metastatic or locally recurrent, unresectable gastric carcinoma (MGC): interim results of a randomized Phase III trial (V325) [abstract]. Proc Am Soc Clin Oncol. 2003; 22: 249.
  • 22
    Vanhoefer U, Rougier P, Wilke H, et al. Final results of a randomized Phase III trial of sequential high-dose methotrexate, fluorouracil, and doxorubicin versus etoposide, leucovorin, and fluorouracil versus infusional fluorouracil and cisplatin in advanced gastric cancer: a trial of the European Organization for Research and Treatment of Cancer. J Clin Oncol. 2000; 18: 26482657.
  • 23
    Rougier P, Ducrex M, Mahjoubi M, et al. Efficacy of combined 5-flourouracil and cisplatinum in advanced gastric carcinomas: a Phase II trial with prognostic factor analysis. Eur J Cancer. 1994; 30A: 12631269.
  • 24
    Kim NK, Park YS, Heo DS, et al. A Phase III randomized study of 5-fluorouracil and cisplatin versus 5-fluorouracil, doxorubicin, and mitomycin C versus 5-fluorouracil alone in the treatment of advanced gastric cancer. Cancer. 1993; 71: 38133818.
  • 25
    Kyoto Research Group for Chemotherapy of Gastric Cancer (KRGCGC). A randomized, comparative study of combination chemotherapies in advanced gastric cancer: 5-fluorouracil and cisplatin (FP) versus 5-fluorouracil, cisplatin, and 4′-epirubicin (FPEPIR). Anticancer Res. 1992; 12(6B): 19831988.
  • 26
    Lacave AJ, Baron FJ, Anton LM, et al. Combination chemotherapy with cisplatin and 5-fluorouracil 5-day infusion in the therapy of advanced gastric cancer: a Phase II trial. Ann Oncol. 1991; 2: 751754.
  • 27
    Ohtsu A, Shimada Y, Shirao K, et al. Randomized Phase III trial of fluorouracil alone versus fluorouracil plus cisplatin versus uracil and tegafur plus mitomycin in patients with unresectable, advanced gastric cancer: the Japan Clinical Oncology Group study (JCOG9205). J Clin Oncol. 2003; 21: 5459.
  • 28
    Williamson SK, Tangen CM, Maddox AM, et al. Phase II evaluation of low-dose continuous 5-fluorouracil and weekly cisplatin in advanced adenocarcinoma of the stomach. A Southwest Oncology Group study. Am J Clin Oncol. 1995; 18: 484487.