1 Mayo Clinic and Mayo Foundation, Rochester, MN 55905; 2 Iowa Oncology Research Association CCOP, Des Moines, IA 50309; 3 Illinois Oncology Research Association, Peoria, IL 61615; 4 Toledo Community Hospital Oncology Program CCOP, Toledo, OH 43623; 5 Cedar Rapids Oncology Project CCOP, Cedar Rapids, IA 52403; 6 Scottsdale CCOP, Scottsdale, AZ 852595404; 7 Meritcare Hospital CCOP, Fargo, ND 58122; 8 Mayo Clinic Jacksonville, Jacksonville, FL 32224; 9 BC Cancer Agency, Vancouver, British Columbia, V6M 2C6, Canada
* Correspondence to: Dr S. R. Alberts, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Tel: +1-507-284-8694; Fax: +1-507-284-1803; E-mail: alberts.steven{at}mayo.edu
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Abstract |
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Patients and methods: Patients were randomized to receive 3-week cycles of either arm A: PS-341 1.5 mg/m2 i.v. bolus (over 35 s) on days 1, 4, 8 and 11 or arm B: PS-341 1.0 mg/m2 (same as arm A otherwise) plus gemcitabine 1000 mg/m2 i.v. on days 1 and 8. Patients progressing on arm A were allowed to receive arm B treatment.
Results: Arm A: 42 evaluable patients were enrolled with a confirmed RR of 0% (95% CI 0% to 8%), median survival of 2.5 months (95% CI 2.03.3), and median time to progression (TTP) of 1.2 months (95% CI 1.11.3). Twelve of 43 evaluable patients (28%) experienced at least one grade 4+ AE. Arm B: 39 evaluable patients yielded a 6-month survival rate of 41% (16/39, 95% CI 29.8% to 67.0%), median survival of 4.8 months (95% CI 2.47.4), median TTP of 2.4 months (95% CI 1.53.1), and confirmed RR of 10% (4 partial responses/0 complete responses, 95% CI 3% to 24%). Eleven of 43 evaluable patients (26%) experienced at least one grade 4+ AE. One patient had grade 5 hypotension.
Conclusion: The use of PS-341 alone or in combination with gemcitabine did not result in an overall survival and RR better than that expected for gemcitabine alone. Based on the lack of efficacy and the toxicity seen in our trial, there does not appear to be a role for PS-341 in pancreatic adenocarcinoma with either of the schedules used in this trial.
Key words: chemotherapy, clinical trial, pancreatic cancer, Proteosome inhibitor
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Introduction |
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PS-341 (bortezomib, VELCADE®; Millennium Pharmaceuticals, Inc.) is a small, cell-permeable molecule that specifically and selectively inhibits the proteasome by binding in a reversible manner. Initial preclinical screening of PS-341 against a NCI tumor cell panel showed it to be active against a broad range of tumor types [5]. Subsequent studies have shown PS-341 to have significant activity in a variety of in vitro, in vivo and xenograft tumor models, including pancreatic cancer [2
, 6
]. Subsequent studies have shown an increased expression of NF-
B in human pancreatic cancer cell lines [7
, 8
]. Building on this observation, preclinical studies with PS-341 indicate that it can induce apoptosis as well as enhance sensitivity to chemotherapy [9
12
].
PS-341 produced an 84% reduction in tumor volume in a mouse xenograft containing BxPC3 human pancreatic cancer cells compared with control animals [9]. In a separate study of a mouse xenograft, using MIA-PaCa-2 human pancreatic cancer cells, gemcitabine caused a 59% reduction in tumor volume compared with control animals with a slightly better response to PS-341 [12
]. The combination of gemcitabine and PS-341 increased growth inhibition to 75%. Based on these findings it appeared that PS-341 was an active agent in pancreatic cancer and that it enhanced the activity of gemcitabine. A phase II study was therefore undertaken.
Tolerable schedules and doses have been defined for PS-341 when given as monotherapy, as well as in combinations, although much of this information remains in meeting abstracts [1316
]. In clinical studies, PS-341 has been given as an i.v. push injection over 35 s. Based on phase I data, PS-341 is tolerated well when given twice a week for 2 weeks (days 1, 4, 8 and 11) followed by a 10-day rest period [17
]. The maximum tolerated dose (MTD) was determined to be between 1.3 and 1.5 mg/m2/dose in patients with solid tumors. This schedule fits well with a modified schedule for gemcitabine (days 1 and 8, followed by a 13-day rest period). A phase I study of PS-341 plus gemcitabine has been completed, but results have been published only in abstracts [18
, 19
]. This trial indicated that a PS-341 dose of 1.0 mg/m2 in combination with gemcitabine was the recommended phase II dose. Using information from this phase I trial we performed a randomized phase II trial in patients with metastatic pancreatic adenocarcinoma (ACA), assessing PS-341 alone and in combination with gemcitabine.
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Patients and methods |
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Patient selection
Patients with histologically confirmed metastatic pancreatic ACA were required to be at least 18 years of age, have an Eastern Cooperative Group (ECOG) performance status of 02, and have disease not amenable to treatment with combined radiation and chemotherapy. Hematologic and chemistry parameters were to be in the following ranges: absolute neutrophil count 1 500/mm2, platelets
100 000/mm2, hemoglobin
9.0 g/dl, total bilirubin
1.5 times the institutional upper normal limit (UNL), AST
5 times the UNL, and creatinine
1.5 times the UNL.
Prior use of PS-341 and prior radiation to 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.
This study was approved by the Mayo Institutional Review Board (IRB) and by the IRBs of the individual memberships of the NCCTG that elected to participate in this study. A signed written informed consent was obtained from all patients prior to initiating therapy. This study was funded through the NCCTG grant from the National Cancer Institute. There was no direct industrial funding of this study. PS-341 was provided free of charge to the patients.
Treatment
For arm A, one 3-week course of treatment consisted of PS-341 1.5 mg/m2 on days 1, 4, 8 and 11, intravenous (i.v.) bolus (over 35 s) into the y-site of a running i.v. of normal saline at 100 ml/h. The dose of PS-341 was subsequently reduced to 1.3 mg/m2 most of the way through the study. Ongoing monitoring of toxicity at the higher dose indicated that it was not well tolerated. For arm B, one 3-week course of treatment consisted of PS-341 1.0 mg/m2 on days 1, 4, 8, and 11, followed by gemcitabine 1000 mg/m2 on days 1 and 8, given as a 30-min i.v. infusion in 250 ml NS, 1 h after PS-341.
Patient evaluation
Within 2 weeks of enrollment, patients underwent a complete history, examination and serum pregnancy test (if applicable). Tumor assessments via chest X-ray, computer tomography (CT) or magnetic resonance imaging (MRI) were required within 28 days prior to enrollment. Blood chemistries and a complete blood count with differential (CBC) were also obtained.
During the course of treatment a CBC was assessed weekly. Prior to each course of treatment, a CBC and blood chemistries were repeated. Adverse events were collected using the National Cancer Institute's Common Toxicity Criteria Version 2.0 (NCI CTC V2.0). Tumor measurements were obtained at baseline, at 6 weeks and then every 6 weeks thereafter, unless more frequent assessments were needed to document a response. Following the discontinuation of study treatment, patients were followed every 3 months until progression, then every 6 months until death or a maximum of 5 years post-randomization.
Disease assessment
Disease was assessed per the RECIST criteria [20]. Measurable disease was defined as at least one lesion whose longest diameter could be accurately measured as
2.0 cm with conventional techniques or as
1.0 cm with spiral CT. Clinical lesions were only considered measurable when they were superficial (e.g. skin nodules, palpable lymph nodes). Lesions on chest X-ray were considered acceptable as measurable lesions when they were clearly defined and surrounded by aerated lung. All other lesions (or sites of disease), including small lesions were considered non-measurable disease. A complete response (CR) was defined as the disappearance of all target lesions. A partial response (PR) was defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD. Progression (PD) was defined as at least a 20% increase in the sum of LD of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Stable disease (SD) was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as references the smallest sum LD.
Statistical analysis
All eligible patients that started treatment were evaluable for the outcome measures used in this study.
Arm A primary end point and analysis
The primary end point for patients who received PS-341 alone (arm A) was the confirmed response rate, calculated as the number of patients who had a confirmed response (i.e. two consecutive responses, either CR or PR, at least 4 weeks apart) divided by the total number of evaluable patients. A two-stage phase II Fleming study design [21] was used to test whether there was sufficient evidence to determine that the confirmed response rate was at least 20% (i.e. clinically promising) versus at most 5% (i.e. clinically inactive). This study had 90% power to detect a confirmed response rate of 20%, with a 0.05 level of significance. Confidence intervals were calculated using the method of Duffy and Santner [22
]. Arm A patients that progressed were allowed to receive treatment as per arm B, but all analyses (excluding survival) were assessed while patients were receiving arm A treatment. Given the potential crossover to arm B, response rate was used as the primary end point for arm A.
Arm B primary end point and analysis
The primary end point for patients who received PS-341 + gemcitabine (arm B) was 6-month survival, calculated as the number of evaluable patients alive at least 6 months post-registration, divided by the total number of evaluable patients. A two-stage phase II Fleming study design [21] was used to test whether there was sufficient evidence to determine that the 6-month survival rate was at least 60% (i.e. clinically promising) versus at most 40% (i.e. clinically inactive). This study had 82% power to detect a 6-month survival rate of 60%, with a 0.06 level of significance. Confidence intervals were calculated using the method of Duffy and Santner [22
].
Secondary end points
Secondary end points included adverse event rates, overall survival, time to disease progression, confirmed response rate for arm B, and quality of life (QoL). Adverse events were evaluated prior to 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. KaplanMeier [23] methodology was used to estimate the distributions of overall survival and time to disease progression. The FACT-C, Symptom Distress Scale (SDS) [24
], and UNISCALE QoL tools were used to assess QoL in this study. A global SDS score was calculated for each patient by taking the average of their non-missing individual SDS items (questions). Global and subscale (i.e. physical, social, emotional and functional) FACT-C scores were also calculated for each patient. All QoL scores were translated into percentages (0100), where the higher the QoL score the better. Simple summary statistics (e.g. mean, median, standard deviation) were used to explore changes in QoL over time. Normality testing via the ShapiroWilk [25
] procedure were used to determine whether parametric or non-parametric procedures would form the basis for analysis (t-tests, Wilcoxon tests). P values <0.05 were considered statistically significant. All analyses were conducted using SAS version 8.0. Adjustments to statistical tests were not made for multiple comparisons.
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Results |
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Arm A.
Between January and November of 2003, 44 patients were enrolled into arm A through the NCCTG, excluding two cancellations (Table 1). Twenty-eight (64%) of the patients were men, two (5%) had prior radiation therapy, 35 (80%) had liver metastases at baseline, and the median age was 66 years (range 3384). Most of the patients had an ECOG performance score of 0 or 1 (89%).
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Outcome measures
Arm A.
Forty-two of the 44 patients were evaluable. Two patients were deemed ineligible (one patient had locally advanced disease only and one patient received prior chemotherapy for metastatic disease). All 42 patients have progressed and died. The overall confirmed response rate was 0% [95% confidence interval (CI) 0% to 8%], which clearly did not meet our predefined criteria for success. The median survival (Figure 1) was 2.5 months (95% CI 2.03.3 months) and the median time to progression (Figure 1) was 1.2 months (95% CI 1.11.3 months). Twelve (29%) of the patients who progressed crossed over to arm B.
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Dose intensity
Arm A.
A median of two cycles of therapy were given (range 16). The original starting dose for PS-341 was 1.5 mg/m2, but it was reduced to 1.3 mg/ m2 for six of the 42 patients due to a higher than expected adverse event rate. The PS-341 median dropped from 100% to 50% from cycles 1 to 3, but only four patients (9%) were treated beyond cycle 3. Of the 29 patients who received cycle 2, 45% received the full dose (relative to the original targeted dose before treatment started).
Arm B.
A median of two cycles of therapy were given (range 118). The PS-341 and gemcitabine medians were both close to 100% for all four cycles, but the individual values varied greatly over the four cycles. Twenty-five (58%) of the 43 patients in cycle 1 received the full dose for both agents. Of the 37 patients that received cycle 2, 19 (51%) patients received the full dose for both agents.
Adverse events
Arm A.
Forty-three patients were evaluable for adverse events (Table 2). Thirty-one (72%) patients experienced at least one grade 3+ adverse event, excluding adverse events that were clearly unrelated to the study medication. Seven (16%) patients experienced at least one grade 4+ adverse event. A grade 5 cerebral ischemia thought unlikely to be related to the study medication also occurred. The most common hematological grade 3+ adverse event was thrombocytopenia, experienced by eight (19%) patients. There were no deaths related to hematologic toxicity. Due to the higher than expected adverse event rate for this treatment arm, the dose of PS-341 was reduced from 1.5 mg/m2 to 1.3 mg/m2. Only six arm A patients received the reduced starting dose for PS-341.
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Discussion |
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Despite promising preclinical models demonstrating meaningful benefit from PS-341 alone or in combination with gemcitabine, no evidence of benefit was seen in patients with metastatic pancreatic cancer. Median survival with PS-341 alone or in combination with gemcitabine was 2.5 months and 4.8 months, respectively. While the median overall survival was less than that seen with gemcitabine alone, it should be recognized that all patients in this clinical trial had metastatic disease. In the trial by Burris et al. [26], providing a median survival of 5.65 months for gemcitabine alone, only 72% of patients receiving gemcitabine in that trial had stage 4 disease, while 28% of patients had either stage 2 or 3 disease. Despite this difference there is no evidence that PS-341 has any activity in pancreatic cancer beyond some improvement in individual measures of QoL.
There are a variety of potential explanations for why PS-341 failed to provide benefit to patients with metastatic pancreatic cancer. While reports of significant activity in preclinical studies indicated the potential for meaningful clinical benefit from proteasome inhibition [3, 4
, 7
, 9
, 10
, 12
], one report showed marked heterogeneity in cellular response [11
]. Variation in response, including intrinsic resistance, was seen in both cell cultures and in xenografts. Despite these various models predicting at least a mixed response in patients with pancreatic cancer, no responses were observed to either PS-341 alone or combined with gemcitabine. This finding stresses the need to develop a more reliable method of translating preclinical findings into results predictive of clinical outcome.
With a variety of preclinical models demonstrating that proteasome inhibition leads to chemosensitization, sequence of therapy may be of importance in predicting response. In one study, initial exposure to PS-341 followed by chemotherapy appeared to promote cytotoxicity through induction of apoptosis [9]. However, in several other studies use of a cytoxic agent followed by PS-341 provided the greatest inhibition of cell growth [10
, 27
]. In another study apoptosis was blocked when PS-341 was given with docetaxel or prior to docetaxel [10
]. Cell cycle interference was overcome only when PS-341 was given after docetaxel. Given that significant activity was seen with PS-341 and docetaxel administered together the authors of this study suggested that the activity of the combination may be related to death of endothelial cells and a reduction in microvessel density leading to apoptosis, rather than a direct affect of PS-341 causing apoptosis. Our clinical trial used sequential therapy with PS-341 given first and then gemcitabine 1 h later. The results of the preclinical study with PS-341 and docetaxel would suggest that this approach should still be active, although not optimal.
In phase I and II studies, responses have been observed for PS-341 primarily in multiple myeloma, although some activity has been reported in some solid tumors [13, 14
, 16
, 18
, 28
32
]. Tolerability of single agent PS-341 has not been an apparent significant problem. In our clinical trial, the dose of PS-341 was lowered from 1.5 mg/m2 to 1.3 mg/m2 following the observation that a higher than expected rate of grade 3 or greater events was occurring, similar to that experienced in a clinical trial involving patients with renal cell carcinoma [30
]. The occurrence of toxicity, however, did not appear to be a factor in predicting outcome to therapy.
In summary, PS-341 used alone or in combination with gemcitabine provided no benefit to patients with metastatic pancreatic cancer. While it is possible that the sequence of administration may influence response, the preclinical studies would suggest that this is not a major factor. It is clear that further preclinical work is needed to determine the antineoplastic activity of PS-341 in pancreatic cancer and how this may be translated into future clinical trials.
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Acknowledgements |
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Additional participating institutions include: Duluth CCOP, Duluth, MN (Daniel Nikcevich); Wichita CCOP, Wichita, KS (Shaker Dakhil); Allegheny General Hospital, Pittsburgh, PA (Jane Raymond); Carle Cancer Center CCOP, Urbana, IL (Kendrith Rowland); Hematology & Oncology of Dayton, Inc., Dayton, OH (Howard Gross); Geisinger Clinic and Medical Center CCOP, Danville, PA (Albert Bernath); Ann Arbor Regional CCOP, Ann Arbor, MI (Philip J. Stella); Missouri Valley Cancer Consortium, Omaha, NE (James A. Mailliard); Cancer Research Center of Hawaii, Honolulu, HI (William Loui); CentraCare Clinic, St. Cloud, MN (Harold E. Windschitl); Siouxland Hematology-Oncology Associates, Sioux City, IA (John C. Michalak); Spartanburg Regional Medical Center, Spartanburg, SC (James D. Bearden).
Received for publication April 18, 2005. Revision received June 15, 2005. Accepted for publication June 17, 2005.
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