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Clinical Trials |
1 Division of Hematology-Oncology, Department of Internal Medicine, and 2 Center for Biostatistics, The Ohio State University, Columbus, Ohio; 3 Department of Medicine, University of Chicago, Chicago, Illinois; 4 Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts; and 5 Cancer Therapy Evaluation Program, Bethesda, Maryland
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ABSTRACT |
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Experimental Design: A total of 16 patients with measurable metastatic carcinoid (n = 12) or islet cell (n = 4) tumors received i.v. bolus of single agent bortezomib at a dose of 1.5 mg/m2 on days 1, 4, 8, and 11 every 21 days. Tumor response was assessed at 12-week intervals using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. All patients were chemotherapy naïve and had Eastern Cooperative Oncology Group performance status of 0 to 1.
Results: No patient achieved a partial or a complete remission. The patients received total of 264 doses of therapy with a median of 15 doses per patient. Grade 4 toxicities were not observed. The most common grade 3 adverse events included peripheral sensory neuropathy (37%), diarrhea (25%), vomiting (18%), and ileus (18%). Six of 10 patients who experienced grade 2 to 3 peripheral sensory neuropathy also had grade 2 to 3 dizziness (n = 2), orthostatic hypotension (n = 2), syncope (n = 1), ileus (n = 2), or abdominal cramps (n = 1). Changes in tumor marker levels did not correlate with tumor response. The mean percentage of 20S proteasome inhibition achieved in whole blood at 1 and 24 hours after bortezomib administration was 68 and 30%, respectively.
Conclusions: Despite achieving the surrogate biologic end point, single-agent bortezomib did not induce any objective responses in patients with metastatic carcinoid or islet cell tumors. Additional investigation is warranted to clarify the possible association of autonomic neuropathy with bortezomib.
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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B by degradation of its inhibitory protein inhibitor of nuclear factor-B (5)
. Nuclear factor-B is necessary, in part, to maintain cell viability through transcription of inhibitors of apoptosis in response to stress or cytotoxic agents. Nuclear factor-B has also been implicated in controlling gene expression of endothelial cell surface adhesion molecules such as intercellular adhesion molecule 1, vascular cell adhesion molecule, and E-selectin (6)
, which are involved in tumor metastasis and angiogenesis. Furthermore, the proteasome is implicated in in vivo angiogenesis, a phenomenon essential for tumor growth and metastasis (7)
.
Bortezomib [Velcade (Millennium Pharmaceuticals, Inc., Cambridge, MA), previously known as PS-341] is a dipeptidyl boronic acid that is a specific, potent and reversible inhibitor of the 26S proteasome. Preclinical work revealed significant antitumor activity of bortezomib in vitro and in vivo. In the cell line screen of the National Cancer Institute, bortezomib demonstrated a unique pattern of growth inhibitory and cytotoxic activity against a broad range of solid tumors (8)
. Bortezomib also significantly reduced tumor volumes in several murine and human tumor xenograft models including the Lewis lung, HT-29 human colon, PC-3 human prostate, squamous cell carcinoma, and pancreatic cancer (9, 10, 11, 12, 13)
. The initial dose and schedule of bortezomib for phase I clinical trials was chosen based on the acute and multiple dose toxicity studies performed on rodents and primates (14)
. Preclinical studies in animals showed that bortezomib was rapidly removed from the vascular compartment and distributed widely, quickly approaching the limits of detection. Therefore, a sensitive, accurate and reproducible ex vivo 20S proteasome inhibition assay to monitor bortezomib activity in whole blood was developed (15)
. Several phase I and/or II clinical trials done to date showed that the target proteasome inhibition of 
70% can be achieved in cancer patients with a reasonable safety profile. Moreover, complete responses, partial responses, or minor responses were observed in the variety of solid tumors and hematologic malignancies (16, 17, 18, 19, 20)
. Bortezomib was recently approved by the Food and Drug Administration for its use in the patients with refractory or relapsed multiple myeloma.
Carcinoid and islet cell tumors are generally classified at the less-aggressive end of the spectrum of neuroendocrine tumors. They are thought to derive from enterochromaffin cells, which are distributed throughout the gastrointestinal and respiratory system. Although plasma chromogranin A and 24-hour urine for 5-hydroxy indole acetic acid are known prognostic markers for survival in patients with carcinoid tumors, the role of other tumor markers is not well described (21
, 22)
. Although local or locoregional carcinoid or islet cell tumors are surgically manageable, metastatic disease is present in 50% of patients at the time of diagnosis, and the overall 5-year survival for patients with distant metastasis is only 22%. Somatostatin analogues, IFN-
or hepatic artery chemoembolization provide good palliation of the symptoms of carcinoid syndrome associated with such tumors. However, no systemic therapy has been shown to consistently elicit tumor responses and prolong survival. The ineffectiveness of systemic chemotherapy in metastatic neuroendocrine tumors may relate to their unique biological features such as slow growth pattern or hypervascularity.
Preclinical in vitro and in vivo work suggests that bortezomib has antitumor activity in a broad spectrum of solid tumors, including the PC-12 neuroendocrine (pheochromocytoma) tumor cell line (23) . Although primarily targeting the proteasome pathway, bortezomib has been shown to affect key proteins involved in cell cycle regulation, angiogenesis, and apoptosis. On the basis of this and the unique antitumor mechanisms of bortezomib, we hypothesize that it may have clinical activity in metastatic carcinoid and islet cell tumors. We thus conducted a phase II clinical trial in patients with metastatic carcinoid and islet cell tumors. On the basis of toxicity and pharmacodynamic data available from initial phase I clinical trials in solid tumor and hematologic malignancies, the dose of 1.5 mg/m2 administered as an i.v. bolus on days 1, 4, 8, and 11 every 21 days was considered optimal for our trial. We report the results of the first prospective phase II study of bortezomib in patients with metastatic neuroendocrine tumors.
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PATIENTS AND METHODS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, systemic chemotherapy, or radiation therapy within the past 4 weeks; no hepatic artery chemoembolization within the past 12 weeks; age 
18 years; Eastern Cooperative Oncology Group performance status 0 to 2; life expectancy 6 months; and adequate organ functions: total bilirubin 
1.5 mg/dL, aspartate aminotransferase/alanine aminotransferase 2.5x upper limit of normal, absolute neutrophil count 1500/µL, platelet count 100,000/µL, and serum creatinine of 1.5 mg/dL. The standard dose (10 to 40 mg every 3 to 4 weeks) of intramuscular long-acting octreotide [Sandostatin LAR (Novartis Pharmaceuticals Co., East Hanover, NJ)] was permitted for the control of carcinoid syndrome symptoms provided that the dose was stable for 3 months before study entry. Exclusion criteria were pregnancy, breastfeeding, and uncontrolled intercurrent illness.
Study Design.
Bortezomib was administered as an i.v. bolus at a dose of 1.5 mg/m2 on days 1, 4, 8, and 11 every 21 days. Antiemetic therapy or growth factor support was not used on a prophylactic basis. Therapy was given for a total of 24 weeks unless patients met one of the following criteria: progressive disease; unacceptable adverse event; off of study drug for >2 weeks; or patient withdrawal from the study. Patients were maintained at the full dose of 1.5 mg/m2 unless patients had grade 3 or 4 adverse event. In case of grade 3 or 4 adverse event, treatment was withheld for 1 week. Upon reevaluation, patients who showed a partial (improvement to grade 1 or 2 adverse event) or a full resolution were started on bortezomib at the reduced dose of 1.0 mg/m2 that was escalated to 1.3 mg/m2 after 1 week and to 1.5 mg/m2 after the second week as tolerated. The patients with persistent grade 3 or 4 adverse event were taken off of the protocol.
History, physical examination, complete blood count, and serum chemistry were obtained within 14 days before initiation of therapy and within 2 to 4 weeks after the last dose of bortezomib (posttreatment). Baseline tumor measurements were performed with computed tomography scan within 4 weeks before initiation of therapy and repeated every 12 weeks during study and at the posttreatment visit. In addition, patients had a history and physical examination performed every 6 weeks and had complete blood count, serum chemistries, and adverse event evaluation performed once a week during their treatment weeks (week 1, 2, 4, 5, and so on). Objective response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and toxicity was assessed according to National Cancer Institute Common Toxicity Criteria, version 2.0 (24) .6
Tumor Marker Studies.
Serum tumor markers (pancreastatin, gastrin, calcitonin, pancreatic polypeptide, vasoactive intestinal peptide, neurotensin, substance-P, gastrin-releasing peptide, glucagon, somatostatin, and serotonin) and 24-hour urine for 5-hydroxy indole acetic acid were obtained within 14 days before initiation of therapy every 12 weeks during therapy and within 2 to 4 weeks posttreatment.
Pharmacodynamic Studies.
We used an ex vivo 20S proteasome inhibition assay to monitor bortezomib activity in whole blood using the previously described method (15)
. This fluorogenic kinetic assay consisted of measuring proteasome activity at chymotryptic and tryptic sites within the 20S core of the proteasome and determining the degree of inhibition conferred by bortezomib. Using the ratio of these chymotryptic:tryptic activities and the catalytic mechanism of the proteasome, percentage of inhibition was calculated compared with predose whole blood obtained from the same patient.
Blood samples were collected at 0 hour (just before administration of bortezomib), 1 hour, and 24 hours after bortezomib on days 1 and 4 of the first course of therapy. For each time point, 8-mL of blood were collected in one heparinized green top tube, immediately placed on ice, and then frozen at –70°C. Batched samples were shipped on dry ice to Millennium Pharmaceuticals, Inc., for performing an assay. On the basis of the preclinical efficacy and toxicity studies, a target level of 70% proteasome inhibition was considered optimal.
Statistical Considerations.
For this phase II study, the minimax two-stage design of Simon was chosen, resulting in a trial with a decision to proceed to the second stage based on efficacy seen in the first 16 patients. Bortezomib was to be considered ineffective or uninteresting if the true response probability was <10% (p0). The regimen was to be worthy of further study if the true response probability or target response rate was 30% (p1). These figures resulted in a two-stage design of 16 and 25 patients, with an of 0.10 and ß of 0.10. If one or no responses were seen in the first 16 patients, the study was to be terminated early, and this regimen was deemed ineffective for this patient population. If two or more patients respond in the first 16, an additional 9 patients were to be treated for a total of 25.
The primary end point was to assess the objective response (partial remission or complete remission) of bortezomib in metastatic carcinoid and islet cell tumors. Stable disease was not considered an objective response to therapy given the relatively slow-growing nature of these cancers and due to a single-arm study design. Patients who had stable disease were taken off from the protocol at 24 weeks of therapy. Secondary end points were to assess the toxicity of bortezomib in patients with metastatic neuroendocrine tumors, to assess tumor marker response, and to evaluate pharmacodynamics of bortezomib by ex vivo 20S proteasome inhibition assay.
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RESULTS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. A majority of patients (n = 12; 75%) had carcinoid tumors, whereas the rest (n = 4, 25%) had islet cell tumors. Of the four patients with islet cell tumors, one patient had symptoms of diarrhea related to carcinoid syndrome, whereas the rest of the patients had no symptoms associated with abnormally high hormone production (pancreatic polypeptide, gastrin, glucagon, or calcitonin) related to their islet cell tumors.
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Tumor Marker Response.
Serum pancreastatin was consistently elevated at the prestudy evaluation in 13 patients, whereas other tumor markers (pancreatic polypeptide, gastrin, glucagon, calcitonin, or neurotensin) were elevated in only a few patients at baseline (Table 1)
. Tumor markers were evaluable in 10 patients, and marker levels did not correlate with objective tumor response in most patients. Table 2
summarizes serum pancreastatin results in 10 evaluable patients. Of eight patients who showed stable disease, three patients had an 11 to 24% reduction in serum pancreastatin, whereas five patients had an increase (median increase, 44%; range, 7 to 55%) in serum pancreastatin compared with the prestudy levels. Serum pancreastatin was increased by 13 to 18% as compared with baseline in patients who showed progressive disease.
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. The target level of 20S proteasome inhibition was achieved in our study patients, and there was no correlation with type or degree of adverse events or clinical outcome.
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. The worst grade experienced by individual patient was used to report the adverse events. Although the most common adverse event seen was nausea (74%), the most common grade 3 toxicities were peripheral sensory neuropathy (37%), followed by diarrhea (25%). It is noteworthy that four patients (25%) developed viral-associated infections during the study period. Three of these patients had recurrent grade 2 cold sores, whereas one patient had grade 3 conjunctivitis in absence of neutropenia. Three patients (18%) had ileus occur at the cumulative dose (mg/m2) of 6, 7.5, or 10.5. All of these patients had prior laparotomy, two patients had active mesenteric carcinoid tumor, and one patient was on a stable dose of tincture of opium. Ileus resolved within 2 to 3 days of hospitalization with conservative treatment, and patients subsequently received one, three, or eight doses of bortezomib without recurrent ileus. Of the two patients who experienced grade 3 abdominal cramps, one had ileus as noted above.
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. Five of these patients had worsening of neuropathy during the off-study period at a median of 3.5 weeks (range, 3 to 9 weeks) after the last dose of bortezomib. Moreover, one patient had neuropathy symptoms starting at 3 weeks after the last of bortezomib. Grade 3 neuropathy symptoms in this patient improved to grade 2 and to grade 1 at week 12 and at week 18 after the last of bortezomib, respectively, despite subsequent treatment with etoposide and cisplatin. Although peripheral neuropathy is a common side effect of cisplatin, it is usually cumulative and progressive during the course of cisplatin chemotherapy. Thus, spontaneous improvement of neuropathy from grade 3 to grade 1 in our patient during the six cycles of cisplatin-based chemotherapy indicates its likely attribution to bortezomib. Seven of 10 patients had improvement up to grade 1 (n = 5) or grade 0 (n = 2) peripheral neuropathy at a median of 18 weeks (range, 2 to 76 weeks) after the last dose of bortezomib.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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B pathway, cyclin-dependent kinase inhibitors (e.g., p21, p27), or tumor suppressor (e.g., p53) proteins, it is possible that redundant pathways exist for tumor progression and survival of metastatic neuroendocrine tumors.
Bortezomib was generally well tolerated at the dose and schedule used in our study. Similar to previously reported studies, the most common adverse events in this study included gastrointestinal, neurologic, constitutional, and hematologic. However, we observed a higher (37 versus 12%) incidence of grade 3 peripheral sensory neuropathy in our chemo-naïve patients compared with the phase II trial of bortezomib in multiple myeloma (16)
. It is unclear if grade 3 pain in limb reported in 7% of their study patients was neuropathic pain. Given that 86% of patients in the reported myeloma study had prior thalidomide (and likely Vinca alkaloids), it is possible that an attribution of neuropathy to bortezomib might have been difficult. Although the median duration of therapy administered in both studies was roughly similar (12 versus 15 weeks), the dose of bortezomib was higher (1.5 versus 1.3 mg/m2/dose) in our study. Thus, it is possible that the higher dose may account for the higher incidence of neuropathy seen in our study. A recently reported phase II study used a dose and schedule similar to our study and reported only 9% grade 3 peripheral neuropathy but 47% incidence for all grades of neuropathy (25)
. Although we did not evaluate predisposing factors for neuropathy in a prospective manner, no obvious risk factors (such as diabetes mellitus, concomitant or prior neurotoxic medications, or B12 deficiency) were found in our patients. Peripheral sensory neuropathy was generally dose related, cumulative, and reversible up to less than or equal to grade 1 (Table 4)
. The median time in improvement or resolution of neuropathy was 18 weeks (range, 2 to 76 weeks) after the last dose of bortezomib. However, patients were not required to follow-up at the specific intervals during the off-study period. The clinical pattern seen in our patients with peripheral neuropathy was most consistent with small-fiber painful sensory neuropathy where A-
(small myelinated) and nociceptive C (unmyelinated) nerve fibers are affected. With the striking association of peripheral neuropathy with bortezomib, it is possible that the ileus, abdominal cramps, syncope, dizziness, and orthostatic hypotension seen in seven of our patients (43%) could be a result of bortezomib-related autonomic neuropathy. Six of seven patients who developed such symptoms also developed grade 2 to 3 peripheral neuropathy during the course of their therapy. Although existing predisposing factors (e.g., prior laparotomy, narcotic use, or active bowel carcinoid tumor) could explain the occurrence of ileus in three of our patients (18%), possible association of ileus with bortezomib cannot be excluded. Interestingly, there were eight patients on the study who had prior laparotomy for tumor debulking who did not develop ileus. The high incidence of nausea and vomiting seen our study suggests that patients might benefit from prophylactic antiemetic therapy. Although the given patient population could have diarrhea because of carcinoid syndrome, the baseline symptoms were taken into consideration in grading diarrhea, and no simultaneous worsening of other carcinoid syndrome symptoms was seen. Hematologic toxicity was of short duration alleviating the need for transfusion or growth factor support. We also question whether bortezomib administration might be associated with viral reactivation given that 25% of our patients had either cold sores or conjunctivitis in the absence of neutropenia. Of note, we did not observe any of the electrolyte abnormalities seen in phase I studies.
In conclusion, single-agent bortezomib does not have activity in patients with metastatic neuroendocrine tumors. Bortezomib is safe at the schedule and dose used in our study, with the most significant clinical adverse event being a peripheral sensory neuropathy. The detailed evaluation of bortezomib-associated neurotoxicity, including autonomic neuropathy and value of prophylactic strategies, merits future investigation. These studies will be particularly helpful because this agent may be used with other neurotoxic agents in the future. Furthermore, with growing preclinical data demonstrating synergism between bortezomib and cytotoxic chemotherapy (26, 27, 28, 29, 30) , future studies should evaluate bortezomib in combination with chemotherapy in solid tumors but caution should be taken in combining chemotherapy that may have overlapping gastrointestinal or neurologic toxicity.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Requests for reprints: Manisha H. Shah, The Ohio State University, A438 Starling-Loving Hall, 320 West Tenth Avenue, Columbus, OH 43210. Phone: (614) 293-8629; Fax: (614) 293-3112; E-mail: shah-2{at}medctr.osu.edu
6 Internet address: http://ctep.info.nih.gov/reporting/ctc.html. 
Received 3/ 2/04; revised 4/27/04; accepted 5/ 5/04.
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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indicates maximum doses planned,
indicates individual patient and data label indicates the reason for off study (type of response). PD, progressive disease; SD, stable disease; HTN, hypertension, AF, atrial fibrillation.