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Journal of Clinical Oncology, Vol 22, No 24 (December 15), 2004: pp. 4944-4950 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.05.034 Gemcitabine and ISIS-2503 for Patients With Locally Advanced or Metastatic Pancreatic Adenocarcinoma: A North Central Cancer Treatment Group Phase II TrialFrom the Mayo Clinic and Mayo Foundation, Rochester, MN; Rapid City Regional Oncology Group, Rapid City; Sioux Community Cancer Consortium, Sioux Falls, SD; Meritcare Hospital CCOP, Fargo, ND; Wichita Community Clinical Oncology Program, Wichita, KS; Carle Cancer Center CCOP, Urbana, IL; Geisinger Clinic & Medical Center CCOP, Danville, PA; and Scottsdale CCOP, Scottsdale, AZ Address reprint requests to Steven R. Alberts, MD, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: alberts.steven{at}mayo.edu
PURPOSE: Gemcitabine remains the standard therapy for metastatic pancreatic adenocarcinoma (ACA), but has limited activity. ISIS-2503 is an antisense compound directed against H-ras with preclinical activity against pancreatic ACA in tumor models. The combination of ISIS-2503 and gemcitabine has been evaluated in a prior phase I study. METHODS: Patients with metastatic or locally advanced pancreatic ACA not amenable to surgery or local radiation received gemcitabine 1,000 mg/m2 intravenously over 30 minutes on days 1 and 8 and ISIS-2503 6 mg/kg/d as a continuous intravenous infusion over 14 days of an every-3-weeks cycle. Responses were monitored by radiologic imaging every 6 weeks. RESULTS: Forty-eight eligible patients were enrolled, 43 with metastatic disease. Median follow-up was 12.6 months (range, 2.2 to 16.8 months) for living patients. A median of four cycles of treatment was given (range, 1 to 18 cycles). All patients were assessable for response and toxicity. The 6-month survival percentage was 57.5% (95% CI, 44.9% to 73.5%) and the median survival was 6.6 months. The response rate was 10.4% (one complete response, four partial responses). Clinically significant toxicity was limited except for one fatal pulmonary embolism. CONCLUSION: This study shows a promising response rate to the combination of gemcitabine and ISIS-2503 in patients with pancreatic ACA. The observed 6-month survival rate in these patients met our protocol-defined criteria for success. This regimen is tolerable, but is of unclear benefit. Additional studies evaluating the role of gemcitabine and ISIS-2503 in the treatment of pancreatic ACA should be considered.
Approximately 31,000 patients develop pancreatic cancer each year.1 The majority of these patients have either locally advanced disease not amenable to surgical resection, or metastatic disease.2 Metastatic pancreatic adenocarcinoma (ACA) is frequently refractory to standard forms of chemotherapy. The median survival with fluorouracil (FU) -based therapy is 4 months, with an expected response rate of less than 10%.3,4 Combination regimens have yielded response rates that are equal to or only slightly better than single-agent FU. More recently, gemcitabine was approved as a therapy for pancreatic ACA based on symptom improvement and improvement in overall survival as demonstrated in a phase III study, with a reported median survival of 5.7 months.5 However, even with gemcitabine, the overall response rate and the duration of response remain poor. As such, there is a need for new agents that will have greater activity in patients with pancreatic ACA. A variety of molecular abnormalities have been identified in pancreatic ACA. One of the most frequent abnormalities involves the proto-oncogene ras.6 The proteins encoded by members of the ras family serve as critical components of the cell-signaling pathway by serving as cell surface receptors. As cell surface receptors, they are involved in the control of cellular proliferation, differentiation, and cell death. The ras family includes H-ras, K-rasA, K-rasB, and N-ras.7 These genes are ubiquitously expressed in mammalian cells. Recent work suggests that each of the ras homologues may preferentially mediate distinct cellular pathways.
While it has been shown that pancreatic ACA has the highest incidence of ras mutations of all cancers studied, the potential role of each member of the ras family is less clear. K-ras, in particular, will be mutated in up to 100% of tumors and almost always involves codon 12.6 H-ras has been less well characterized in pancreatic carcinomas. A recent analysis of two pancreatic cancer cell lines showed an important role for H-ras in promoting growth.8 In these cell lines, the H-ras-extracellular regulated kinase cascade appeared to have a significant role in promoting growth in response to tumor growth factor-alpha (TGF- ISIS-2503 is a phosphorothioate oligonucleotide antisense inhibitor of human H-ras mRNA expression. As reviewed in detail elsewhere,9 antisense oligonucleotides function by blocking the expression of mRNA. Antisense oligonucleotides are designed as a complimentary sequence of base pairs to a specific mRNA that in turn permits the sequence to bind to the mRNA and therefore block its expression. ISIS-2503 is a synthesized antisense oligonucleotide designed to bind to the translation initiation region of human H-ras mRNA. In vitro studies have shown ISIS-2503 to be a potent and selective inhibitor of H-ras.10 ISIS-2503 has shown significant antitumor activity against a variety of human tumors implanted in athymic nude mice, including two pancreatic carcinoma cell lines. A phase I trial of gemcitabine and ISIS-2503 established the safety of this combination. The trial determined the appropriate schedule as gemcitabine, given at a dose of 1,000 mg/m2 on days 1 and 8 every 3 weeks, and ISIS-2503, given at a dose of 6 mg/kg/d as a continuous 14 day intravenous (IV) infusion, beginning on day 1 of the gemcitabine administration.11 Disease stabilization was seen in one patient with pancreatic cancer. Building on the potential activity of gemcitabine and ISIS-2503, we performed a multicenter phase II study through the North Central Cancer Treatment Group (NCCTG) on the combination in patients with either locally advanced pancreatic ACA or metastatic pancreatic ACA. Six-month survival served as the primary end point.
Goals The primary end point of this study was to determine the 6-month survival rate for patients with locally advanced or metastatic pancreatic ACA who received gemcitabine and ISIS-2503. The secondary end points were to assess overall survival, tumor response, and toxicity.
Patient Selection Prior use of gemcitabine and prior radiation to more than 25% of bone marrow were not allowed. The use of other chemotherapy was only permitted if used as a radiosensitizer. Pregnant or lactating women were not eligible. Other contraindications included CNS metastases, prior biologic or immunologic therapy within 4 weeks of study entry, or any history of prior malignancy diagnosed within 5 years were not allowed, with the exception of basal or squamous cell carcinoma of the skin and cervical carcinoma-in-situ. This study was approved by the Mayo institutional review board and by the institutional review boards of the individual memberships of the NCCTG that elected to participate in this study. A signed written informed consent was obtained from all patients before initiating therapy. This study was funded through the NCCTG grant from the National Cancer Institute. There was no direct industrial funding of this study. ISIS-2503 was provided free of charge to the patients.
Treatment
Patient Evaluation During the course of treatment, hematologic parameters were collected weekly. Before the next course of treatment, a history of adverse events experienced was collected and blood chemistries were repeated. Adverse events were collected using the National Cancer Institute's Common Toxicity Criteria, Version 2.0. Unless noted otherwise, all adverse events are reported, regardless of attribution to study treatment. Tumor measurements were obtained at 6 weeks and 12 weeks, and assessments were repeated every 6 to 12 weeks unless more frequent assessments were needed to document a response. Following the discontinuation of study treatment, patients were observed for disease progression every 3 months for 1 year, then every 6 months for up to 4 years past their registration date. At the time of disease progression, patients were monitored for their status for a maximum of 4 years postregistration.
Disease Assessment
Statistical Analysis
After the first 20 assessable patients had been on-study for 6 months, an interim analysis was performed. If at least nine of these 20 patients survived Secondary end points included adverse event rates, overall survival, time to disease progression, duration of response, and the confirmed response rate. Adverse events were evaluated before each cycle of treatment. The maximum grade for each type of adverse event was recorded for each patient and frequency tables were used to determine adverse event patterns. Kaplan-Meier15 methodology was used to estimate the distributions of survival time and time to disease progression. The duration of response was calculated from the date of the patient's first objective response of PR or CR to the date of progression. The confirmed response rate was estimated by the number of patients who had documented objective responses (PR or CR maintained for a minimum of 4 weeks) divided by the total number of patients assessable (eligible, started treatment) for response. All analyses were conducted using SAS Version 8.0 (SAS Institute, Cary, NC).
Patient Characteristics Between February and November 2001, 48 patients were enrolled on this study through the NCCTG, with no patients declared ineligible (Table 1). Forty-three (90%) of the patients had metastatic disease.
Outcome Measures Overall, 45 of the 48 patients have had evidence of progressive disease and 45 have died. Twenty-eight (58%) of the patients survived  6 months (95% CI, 34% to 77%), which easily met our predefined criteria for success in this trial. The overall median survival (Fig 1) was 6.7 months (95% CI, 5.2 to 8.2 months). The median time to progression was 3.8 months (95% CI, 2.8 to 4.8 months).
All 48 patients were assessable for response. The overall confirmed response rate was 10.4% (95% CI, 3.5% to 22.7%), which consisted of four confirmed PRs and one confirmed CR. The median duration of response (for these five patients) was 6.5 months (range, 1.7 to 21.9 months). Two additional patients experienced PRs that were not confirmed on a subsequent scan.
Dose Intensity
Toxicity All 48 patients were assessable for adverse events. Hematologic and nonhematologic grade 3 or greater adverse events (includes all adverse events except those clearly not related to study treatment) are outlined in Table 3. The most common hematologic grade 3+ adverse event was neutropenia (Table 3). Fifty-six percent of the patients had grade 3+ neutropenia, while 40% experienced grade 3+ thrombocytopenia. Grade 3 febrile neutropenia occurred in 4% of patients and one patient (2%) experienced a grade 4 infection without neutropenia. There were no treatment-related deaths as a result of hematologic toxicity. Common grade 3+ nonhematologic adverse events included pain (abdominal; 10%), bilirubin (8%), thrombosis (13%), and fatigue (23%). There was a death due to a combination of thrombosis and arrythmia that was felt to be potentially treatment-related. No other treatment-related deaths occurred. One patient with responding disease discontinued treatment after 27 cycles of therapy due to increasing dyspnea of uncertain etiology.
Gemcitabine has served as the standard treatment option for patients with metastatic pancreatic ACA. Given the activity of gemcitabine, a variety of studies have now assessed its activity when combined with other chemotherapy or novel agents. These studies have shown varying degrees of success with no combination showing clear evidence of significantly superior activity. We therefore assessed the combination of gemcitabine with the H-ras antisense oligonucleotide ISIS-2503, building on preclinical studies and early clinical trials showing activity in pancreatic cancer. In this phase II trial, the combination of gemcitabine and ISIS-2503 demonstrated activity in patients with pancreatic ACA. In a patient population in which 90% of the patients had metastatic disease, we observed a median overall survival of 6.7 months and an objective response rate of 10%, including one complete response. This compares to an expected median survival of 5.7 months and a 5% response rate for gemcitabine alone in the phase III trial of Burris et al.5 It should also be noted that only 72% of patients receiving gemcitabine in that trial had stage 4 disease, while 28% of patients had either stage 2 or 3 disease. While the 1-month improvement in median survival and doubling of response rate in our trial are modest improvements, it is in the setting of a group of patients with more advanced disease. For patients demonstrating a response, the median duration of response was 6.5 months, with one patient responding for nearly 2 years. The combination of gemcitabine and ISIS-2503 appeared to be well tolerated. There appeared to be a modest increase in hematologic toxicities, but not in nonhematologic toxicities, compared to those expected from gemcitabine alone.5 By cycle 4, the median dose of ISIS-2503 had remained unchanged from the starting dose, and the median dose of gemcitabine was 81% of the starting dose. As such, it did not appear that toxicity had any meaningful adverse affect on clinical outcome. Only a limited number of ras-directed therapies for pancreatic cancer have been reported, primarily as meeting abstracts. This is the first study reporting the use of an inhibitor specifically directed at ras in combination with chemotherapy. Other agents have been evaluated that may act on ras-mediated pathways, including the investigational agent R115777, a farnesyltransferase inhibitor. When used as a single agent, R115777 achieved a 25% 6-month survival rate with no objective responses.16 A randomized phase III trial of gemcitabine with either R115777 or placebo showed no difference in survival.17 As such, it appears that agents targeted at H-ras specifically may be of greater benefit. No attempt was made to measure the suppression of H-ras in this study. Determining the ability of ISIS-2503 to suppress H-ras expression has proved difficult. In a prior phase I trial of this antisense compound, inconsistent suppression of H-ras mRNA was observed,18 a finding noted in other trials of antisense compounds. However, the dose of ISIS-2503 used in this study exceeded the IC50 value determined in prior in vitro studies.9 It would thus seem unlikely that more meaningful results could be obtained with higher concentrations of the antisense compound. A prior phase I trial of gemcitabine and ISIS-2503 also demonstrated no significant change in plasma levels of either of the two agents when used together.11 Based on the results of our study, therapy directed against H-ras, using the antisense compound ISIS-2503, is of unclear benefit for patients with metastatic pancreatic ACA when combined with gemcitabine. Further work needs to be done to better clarify tumor characteristics that may help better predict response to therapy.
Additional participating institutions include: CentraCare Clinic, St Cloud, MN (Harold E. Windschitl, MD); Saskatchewan Cancer Centre, Saskatoon, and Allan Blair Cancer Centre, Regina, Saskatchewan, Canada (Muhammad Salim, MD); Ann Arbor Regional CCOP, Ann Arbor, MI (Philip J. Stella, MD); Medcenter One Health Systems, Bismarck, ND (Ferdinand Addo, MD); Cedar Rapids Oncology Project CCOP, Cedar Rapids, IA (Martin Wiesenfeld, MD); Altru Health Systems, Grand Forks, ND (Daniel J. Walsh, MD); Siouxland Hematology-Oncology Associates, Sioux City, IA (John C. Michalak, MD); Missiouri Valley Cancer Consortium, Omaha, NE (James A. Mailliard, MD).
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Received more than $2,000 a year from a company for either of the last 2 years: Steven R. Alberts, Sanofi-Synthelabo Inc.
This study was conducted as a trial of the North Central Cancer Treatment Group and Mayo Clinic and was supported in part by Public Health Service grants CA-25224, CA-37404, CA-15083, CA-63826, CA-35101, CA-35195, CA-35448, CA-35415, CA-60276, CA-63848, CA-52352, CA-37417, CA-35103, and CA-63849 from the National Cancer Institute Department of Health and Human Services. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Jemal A, Murray T, Samuels A, et al: Cancer statistics, 2003. CA Cancer J Clin 53:5-26, 2003 2. Trede M, Saeger HD, Schwall G, et al: Resection of pancreatic cancer—surgical achievements. Langenbecks Arch Surg 383:121-1288, 1998[Medline] 3. Cullinan SA, Moertel CG, Fleming TR, et al: A comparison of three chemotherapeutic regimens in the treatment of advanced pancreatic and gastric carcinoma. Fluorouracil vs fluorouracil and doxorubicin vs fluorouracil, doxorubicin, and mitomycin. JAMA 253:2061-2067, 1985[Abstract] 4. DeCaprio JA, Mayer RJ, Gonin R, et al: Fluorouracil and high-dose leucovorin in previously untreated patients with advanced adenocarcinoma of the pancreas: Results of a phase II trial. J Clin Oncol 9:2128-2133, 1991[Abstract]
5. Burris HA 3rd, Moore MJ, Andersen J, et al: Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomized trial. J Clin Oncol 15:2403-2413, 1997 6. Sirivatanauksorn V, Sirivatanauksorn Y, Lemoine NR: Molecular pattern of ductal pancreatic cancer. Langenbecks Arch Surg 383:105-115, 1998[Medline]
7. Rebollo A, Martinez AC: Ras proteins: Recent advances and new functions. Blood 94:2971-2980, 1999 8. Seufferlein T, Van Lint J, Liptay S, et al: Transforming growth factor alpha activates Ha-Ras in human pancreatic cancer cells with Ki-ras mutations. Gastroenterology 116:1441-1452, 1999[CrossRef][Medline] 9. Geary RS, Leeds JM, Henry SP, et al: Antisense oligonucleotide inhibitors for the treatment of cancer: 1. Pharmacokinetic properties of phosphorothioate oligodeoxynucleotides. Anticancer Drug Des 12:383-393, 1997[Medline]
10. Monia BP, Johnston JF, Ecker DJ, et al: Selective inhibition of mutant Ha-ras mRNA expression by antisense oligonucleotides. J Biol Chem 267:19954-19962, 1992
11. Adjei AA, Dy GK, Erlichman C, et al: A phase I trial of ISIS 2503, an antisense inhibitor of H-ras, in combination with gemcitabine in patients with advanced cancer. Clin Cancer Res 9:115-123, 2003
12. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205-216, 2000 13. Fleming TR: One sample multiple testing procedure for phase II clinical trials. Biometrics 38:143-151, 1982[CrossRef][Medline] 14. Duffy D, Santner T: Confidence intervals for a binomial parameter based on multistage tests. Biometrics 43:81-93, 1987[CrossRef] 15. Kaplan E, Meier P: Nonparametric estimation for incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef]
16. Cohen SJ, Ho L, Ranganathan S, et al: Phase II and pharmacodynamic study of the farnesyltransferase inhibitor R115777 as initial therapy in patients with metastatic pancreatic adenocarcinoma. J Clin Oncol 21:1301-1306, 2003 17. Van Cutsem E, Oettle K, Vervenne W, et al: Phase III trial comparing gemcitabine + R115777 (Zarnestra) versus gemcitabine + placebo in advanced pancreatic cancer (PC). Proc Am Soc Clin Oncol 21:130a, 2002 (abstr 517) 18. Cunningham CC, Holmlund JT, Geary RS, et al: A Phase I trial of H-ras antisense oligonucleotide ISIS 2503 administered as a continuous intravenous infusion in patients with advanced carcinoma. Cancer 92:1265-1271, 2001[CrossRef][Medline] Submitted May 12, 2004; accepted September 22, 2004. This article has been cited by other articles:
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
). Growth could be prevented by inhibiting TGF-
1.5x institutional upper normal limit (UNL), AST 
