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Journal of Clinical Oncology, Vol 23, No 13 (May 1), 2005: pp. 3069-3073
© 2005 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2005.00.372
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Evaluation of Epothilone B Analog in Advanced Soft Tissue Sarcoma: A Phase II Study of the Phase II Consortium

Scott Okuno, William J. Maples, Michelle R. Mahoney, Tom Fitch, James Stewart, Paula M. Fracasso, Michael Kraut, David S. Ettinger, Fitzroy Dawkins, Charles Erlichman

From the Mayo Clinic College of Medicine, Rochester, MN; Mayo Clinic, Division of Oncology, Jacksonville, FL; Mayo Clinic, Department of Hematology/Oncology, Scottsdale, AZ; University of Wisconsin Comprehensive Cancer Center, Madison, WI; Howard University, Washington, DC; Washington University School of Medicine, St Louis, MO; Karmanos Cancer Institute at Wayne State University, Detroit, MI; and The Johns Hopkins Oncology Center, Baltimore, MD

Address reprint requests to Scott H. Okuno, MD, Mayo Clinic College of Medicine, 200 First St, Southwest, Medical Oncology, Rochester, MN 55905; e-mail: okuno.scott{at}mayo.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
PURPOSE: Epothilones are a new class of nontaxane tubulin polymerization agents that have activity in taxane-resistant tumors. Epothilone B (BMS-247550) is a semisynthetic analog of the natural product epothilone B. This study was performed to determine the activity of BMS-247550 in patients with soft tissue sarcomas (STSs) who had not received prior chemotherapy for metastatic disease.

PATIENTS AND METHODS: Patients with measurable, advanced, or metastatic STS with no prior chemotherapy for metastatic disease were treated with BMS-2457550 50 mg/m2 intravenously during 1 hour every 21 days. All responses were confirmed 4 weeks later.

RESULTS: Thirty-one patients (median age, 54 years; range, 19 to 78 years; 48% female) were entered onto the trial and were assessable for response. All but one patient had an Eastern Cooperative Oncology Group performance score of 0% or 1%, and 39% had received prior adjuvant chemotherapy. Mean follow-up was 22 months, with a confirmed response rate of 6% (95% CI, 0% to 17%). Median time to progression was 4.5 months (95% CI, 1.9 to 8.3 months), and 1 year progression-free survival was 17% (95% CI, 8% to 38%). Median survival was 16.4 months, with a 1-year survival of 61% (95% CI, 46% to 81%). Toxicity was mainly hematologic, with eight of 31 (26%) patients experiencing grade 3 to 4 leukopenia; 15 of 31 patients (48%) experienced grade 3 to 4 neutropenia. The grade 3 to 4 nonhematologic toxicities included neuropathies (26%), myalgia (13%), and fatigue (10%).

CONCLUSION: BMS-247550 has limited activity against STSs when given in this dose and schedule. The clinical toxicity is similar to that of taxanes.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
Soft tissue sarcomas (STSs) are composed of cancers with various biologic activities. It is estimated that there will be 8,680 new cases of STS diagnosed in 2004 with an estimated mortality of 40%.1 Despite adequate primary treatment, STSs can recur locally as well as metastasize to distant sites. Once the STS has metastasized, the only chance of long-term survival is with metastasectomy. Unfortunately, only a few patients are candidates for metastasectomy.

The most active chemotherapy agents against STSs include doxorubicin and ifosfamide, with response rates of 23% and 24% respectively.2 Although targeted therapy with imatinib mesylate for the subset of STSs, GI stromal tumors, is active, chemotherapy for patients with metastatic STSs is largely palliative. New active agents are needed.

Epothilones are a new class of nontaxane tubulin polymerization agents obtained from the myxobacteria, Sorangium cellulosm.3,4 BMS-2475540 is a semisynthetic analog of the natural product, epothilone B, which is more stable than the natural product. BMS-2475540 is active in preclinical human tumor models that are naturally insensitive to paclitaxel.5 In general, STSs are unresponsive to taxanes and thus are a reasonable a group of tumors to evaluate whether epothilones are active in a heretofore taxane-resistant tumor group.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
Patient Selection
Patients with histologic or cytologic evidence of metastatic or unresectable STS were eligible for entry into this trial. Prior chemotherapy, including neoadjuvant and adjuvant chemotherapy at least 4 weeks before study entry, was permitted. Patients had Eastern Cooperative Oncology Group performance scores (PS) of ≤ 2 and life expectancies of ≥ 12 weeks. The inclusion criteria were absolute neutrophil count (ANC) of ≥ 1,500/µL, platelet count (PLT) of 100,000/µL, total bilirubin ≤ 1.5 x the institutional upper limit of normal (ULN), AST ≤ 2.5 x the institutional ULN, creatinine ≤ 1.5 x the institutional ULN (or creatinine clearance ≥ 60 mL/min for patients with creatinine levels > 1.5 x the institutional ULN), age at least 18 years, and negative pregnancy test for women of childbearing potential. All patients were required to have at least one lesion that could be accurately measured with the longest diameter ≥ 2.0 cm.

Exclusion criteria were chemotherapy for metastatic disease; irradiation to only a solitary lesion (unless a > 25% increase had been documented since completion of radiation); pregnancy or lactation; uncontrolled infections; chronic debilitating diseases; concurrent investigational treatments, unconventional therapies, or food supplements; CNS metastases; history of allergic reactions attributed to compounds similar to epothilone B analog (BMS-47550) or polyoxyethylated castor oil (Cremaphor EL; Bristol-Myers Squibb, Candiac, Quebec, Canada); neuropathies ≥ grade 2 (per National Cancer Institute Common Toxicity Criteria Version 2.0); antiretroviral therapy for HIV-positive status; and prior malignancies (unless the patient was disease free for 5 years or had adequately treated basal or squamous cell carcinoma, noninvasive carcinomas, or localized prostate cancer).

Drug Administration
BMS-247550 was administered at a dose of 50 mg/m2 as a 60-minute infusion every 21 days. Premedication with an H1 and H2 blocker was administered orally 1 hour or 30 to 45 minutes before BMS-247550 administration. Re-treatment was considered if ANC ≥ 1,500/µL, PLT ≥ 100,000/µL, and nonhematologic toxicities resolved to baseline or ≤ grade 1. BMS-247550 was increased to 55 mg/m2 for cycle two if nadir leukocyte (WBC) count was ≥ 1,000/µL and ANC ≥ 500/µL, and all other toxicities were less than grade 2. Doses were decreased to 40 mg/m2 if grade 4 neutropenia lasted ≥ 7 days, PLT were less than 25,000/µL, or thrombocytopenia ≥ grade 3 occurred with bleeding and required transfusion; if grade ≥ 3 diarrhea; grade more than 3 neuropathy lasted less than 7 days, or grade 2 neuropathy lasted ≥ 7 days; or more than 1 week delay occurred in re-treatment because of drug toxicity. BMS-247550 was decreased to 30 mg/m2 was made if the same toxicities were found at 40 mg/m2. If at any point there was a delay of greater than 2 weeks, treatment was discontinued, and the patient was entered onto the event-monitoring phase.

Pretreatment Evaluation and Follow-Up Studies
History and physical examination were performed before registration and before each subsequent course of chemotherapy. Studies done at the time of registration included CBC, serum AST, alkaline phosphatase, total bilirubin, and creatinine analyses. Radiographic imaging for tumor measurement and a chest x-ray were also obtained. Hemoglobin, WBC, ANC, and PLT analyses were repeated weekly during treatment. Chemistries were repeated before each subsequent cycle of therapy. Imaging for tumor response was obtained with every other cycle of therapy unless more frequent assessment was needed to document a response.

Disease Assessment
Each patient's disease status was assessed using the Response Evaluation Criteria in Solid Tumors Group6 criteria. Measurable disease was defined as at least one lesion for which the longest diameter could be accurately measured as ≥ 2.0 cm. Clinical lesions were only considered measurable when they were superficial (eg, 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; however, computed tomography was preferable for tracking tumor response. All other lesions (or sites of disease), including small lesions (longest diameter < 2.0 cm) were considered nonmeasurable disease.

Patients were re-evaluated for disease status within 4 to 6 weeks of achieving a complete response (CR) or partial response (PR) to confirm the assessment. Similarly, stable disease was reassessed within 6 to 8 weeks.

Patients who died (or who were lost to follow-up) without progression were considered to have experienced disease progression at the date of death (or last contact) unless documentation proved otherwise, in which case they would be considered as having no progression at the date of last tumor evaluation. Duration of response is calculated from the date of the patient's first best objective status of CR or PR to the date of progression. Time to progression was calculated from study entry to disease progression. Time to death (ie, survival) was calculated from the date of study entry to the date of death, as a result of any cause, or date of last contact. Patients were to be observed until death or a maximum of 5 years after registration.

Statistical Considerations
The primary end point of this trial was to evaluate the confirmed tumor response rate. Confirmed tumor response is defined as an objective tumor response of either CR or PR, which has been sustained for at least two consecutive evaluations taken at least 4 weeks apart. All eligible patients that have initiated treatment are considered assessable for estimating the confirmed tumor response rate. A Fleming7 phase II design was used to evaluate confirmed tumor response in a total of 26 patients. BMS-247550 was considered inactive if no responses were observed in the initial 14 patients (ie, at the interim analyses) or if at most three responses were observed in all 26 patients. A total of four responses in all 26 patients or at least three responses in the initial 14 patients were required to declare promising activity. Using this design, we had 80% power, at a .05 significance level, to detect a confirmed response rate of at least 20% (ie, clinical activity). The CI reported for an estimate of confirmed tumor response rate was calculated via the method of Duffy and Santner.8

Secondary end points included toxicity, duration of response, time to disease progression, and survival. Nonhematologic toxicity was summarized in a tabular manner as a maximum grade for a given type of event. Hematologic nadirs were reported as a minimum value per patient and course of treatment. Hematologic toxicities are summarized in Table 1. Kaplan-Meier methodology9 was used to describe the distribution of duration of response, time to disease progression, and survival. Cox proportional hazards10 modeling was used to identify factors (ie, age, sex, PS) significantly associated with duration of response, time to disease progression, and survival. P values of at least .05 were considered statistically significant in these analyses. All analyses were performed using SAS software (SAS Institute, Cary, NC).


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  		Table 1. Maximum Severity of Toxicity (≥ grade 3), per Patient and Type

 
Patient Characteristics
A total of 31 patients were enrolled between June and December 2001. Table 2 summarizes the characteristics for these patients. All patients were eligible, white, and 48% (15 of 31) were female. At study entry, patients ranged in age from 19 to 78 years (median, 54 years) and 52% (16 of 31) had a PS of 0 (v 1 or 2). Thirty-nine percent of patients (12 of 31) had received prior adjuvant radiation therapy. Sixteen (52%) had lung metastases, 10 (32%) had nodal metastases, and six (19%) had liver metastasis and intra-abdominal metastasis. The histologic type (Table 1) included eight leiomyosarcomas, eight sarcomas not otherwise specified, three malignant fibrous histiocytomas, two fibrosarcomas, two synovial sarcomas, one desmoid, one myxosarcoma, one stromal sarcoma, one hemangiopericytoma, and one chondrosarcoma.


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  		Table 2. Baseline Patient Characteristics (N = 31)

 

   RESULTS
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 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
BMS-247550 Administration and Toxicity
Overall, patients received a total of 96 cycles of treatment (mean, three; range, one to eight). Patients were able to receive a median of 100% (49% to 101%), 100% (59% to 111%), and 100% (99% to 110%) of the targeted dose of BMS-247550 on cycles 1, 2, and 3, respectively. Nine patients had at most two dose reductions. The reasons for dose reductions were neuropathies (four patients), neutropenia (two patients), GI intolerance (two patients), desquamation of hands (one patient), and myalgia (one patient). Treatment delays were seen in 14 of 96 total administered cycles, and occurred most frequently for cycles 2 through 4. The most common reasons for treatment delays were neutropenia (six patients), and myalgia and/or arthralgia (two patients). Reasons for discontinuation of treatment were progressive disease (18 patients), toxicities (10 patients), alternate therapy (one patient), and death considered probably related to BMS-247550 (one patient).

All patients were premedicated with either oral or intravenous (IV) H1 and H2 blockers. Eleven patients received a total of 35 cycles of oral premedication. One patient received one oral and three IV premedication cycles. The remaining 19 patients (61%) received 59 cycles of IV premedication. To control hypersensitivity reactions, five patients (16%) had one cycle interruption, and 10 patients (32%) received dexamethasone for a total of 24 of 34 cycles. One patient (3%) received granulocyte colony-stimulating factor on three of eight cycles for neutropenia.

All 31 patients were assessable for toxicity. More than 80% of the patients experienced grade 3 or 4 adverse events related to BMS-247550 (Table 1). The most common toxicities were hematologic (mainly neutropenia). Sixteen patients (52%) experienced ≥ grade 3 nonhematologic toxicity. The most frequent nonhematologic grade 3 to 4 toxicities were neuropathies (26%), myalgia (13%), and fatigue (10%). One patient died as a result of febrile neutropenia after three complete cycles of treatment; this death was considered probably related to BMS-247550.

Patient Outcome
All patients are considered assessable for response. Two PRs were observed (leiomyosarcoma and synovial sarcoma), lasting 9.5 and 4 months, subsequently progressing to the lung and to the lung, bones, and lymph nodes, respectively. The estimated overall confirmed response rate is 6% (two of 31) with a 95% CI of 0 to 0.17. Ninety-four percent of patients (29 of 31) have experienced disease progression, with sites including lung (12 patients), abdomen (eight patients), liver (five patients), and lymph nodes (four patients). Nineteen patients have died, with a median follow-up of 22 months in surviving patients (range, 11 to 25.5 months). The distributions of time to progression and survival are listed in Table 3 and shown in Figure 1.


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  		Table 3. Response and Survival Data (N = 31)

 


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  		Fig 1. Progression-free and overall survival for BMS-247550.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
Authors' Disclosures of...
 REFERENCES
 
Metastatic sarcomas are a difficult group of cancers to treat. They are frequently refractory to treatment. Despite modest activity with the standard chemotherapy agents, doxorubicin and ifosfamide, combination therapy has not demonstrated an improvement in overall survival compared with single-agent treatment.11 Although there is success with targeted therapy with imatinib mesylate for the one subset of STSs, GI stromal tumors, its role in the management of the other more than 30 subtypes of STS is unknown, and new agents are needed for STS.12,13

Taxanes have been inactive against STSs except for vascular sarcomas.14-16 The epothilones are nontaxane tubulin inhibitors that are active in low nanomolar concentrations. They have a unique property of being active in cell lines resistant to taxanes. The agent used in our study, BMS-247550, is a semisynthetic manufactured epothilone B analog. This is the first study of BMS-247550 against STSs, which are generally resistant to taxanes.

This study demonstrated limited activity of BMS-247550 against a variety of STSs. The confirmed response rate of 6% was seen in our study, and responses occurred in patients with grade 3 leiomyosarcoma and synovial sarcoma. The median survival was 16.4 months and 1-year survival was 61%, which is similar to other studies with nondoxorubin/ifosfamide regimens with gemcitabine.17-19 Direct comparison to doxorubicin/ifosfamide regiments is not valid because of patient selection and second-line therapy in other studies. BMS-247550 has modest but manageable toxicities. Hematologic toxicity was mainly neutropenia, with nonhematologic toxicities of myalgia and neuropathy similar to those of taxanes.

Although this study failed to demonstrate activity of BMS-247550 against STSs, the potential role of BMS-247550 in STSs may be worth evaluating. The use of docetaxel combined with gemcitabine infused during 90 minutes has demonstrated activity in up to 40% of leiomyosarcomas and other STSs.20,21 An ongoing confirmatory study comparing gemcitabine versus gemcitabine/docetaxel regimen will help to clarify the role of taxanes in STSs. If gemcitabine plus docetaxel demonstrates activity when docetaxel alone is inactive, then additional testing of BMS-247550 in combination with gemcitabine may be warranted.

The mixture of histologic types of STS is a challenge in evaluating any novel agents. The ideal treatment studies for STSs would be histology-specific trials. This would reduce the chance that a potentially active agent is not pursued because of insufficient numbers. Because of the rarity of STSs, histology-specific studies have been difficult to complete in single-center studies. This phase II consortium study was able to accrue at a rate that could lead to future targeted studies specific to a given histology.


   Authors' Disclosures of Potential Conflicts of Interest
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
REFERENCES
 
The authors indicated no potential conflicts of interest.


   NOTES
 
Authors' disclosures of potential conflicts of interest are found at the end of this article.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
1. Jemal A, Tiwari RC, Murray T, et al: Cancer statistics 2004. CA Cancer J Clin 54:8–29, 2004[Abstract/Free Full Text]

2. Brennan MR, Alextiar KM, Maki RG: Sarcomas of the Soft Tissue and Bones, in DeVita V, Hellman S, Rosenber SA (eds): Cancer Principles and Practice of Oncology. Philadelphia, PA, Lippincott-Raven, 2001, pp 1841-1883

3. Gerth K, Bedorf N, Hofle G, et al: Epothilones A and B: Antifungal and cytotoxic compounds from Sorangium celulosom (Myxobacteria): Production, physico-chemical and biological properties. J Antibiot (Tokyo) 49:560–563, 1996[Medline]

4. Bollag DM, McQueney PA, Zhu J, et al: Epothilones, a new class of microtubule-stabilizing agent with a Taxol-like mechanism of action. Cancer Res 55:2325–2333, 1995[Abstract/Free Full Text]

5. Goodin S, Kane MP, Rubin EH: Epothilones: Mechanism of action and biologic activity. J Clin Oncol 22:2015–2025, 2004[Abstract/Free Full Text]

6. 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[Abstract/Free Full Text]

7. Fleming TR: One sample multiple testing procedures for phase II clinical trials. Biometrics 43:143–151, 1982

8. Duffy DE, Santner TJ: Confidence intervals for a binomial parameter based on multistage tests. Biometrics 43:81–93, 1987[CrossRef]

9. Kaplan E, Meier P: Nonparametric estimation from incomplete observation. J Am Stat Assoc 53:457–481, 1958[CrossRef]

10. Cox DR: Regression models and life tables (with discussion). J R Stat Soc B 74:187–220, 1972

11. Edmonson JH, Ryan LM, Blum RH, et al: Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin, or mitomycin, doxorubicin, and cisplatin against advanced soft tissue sarcoma. J Clin Oncol 11:1269–1275, 1993[Abstract/Free Full Text]

12. Demetri GD, vonMehren M, Blanke CD, et al: Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 347:472–480, 2002[Abstract/Free Full Text]

13. Heinrich MC, Blanke CD, Druker BJ, et al: Inhibition of KIT tyrosine kinase activity: A novel molecular approach to the treatment of KIT-positive malignancies. J Clin Oncol 20:1692–1703, 2002[Abstract/Free Full Text]

14. Casper ES, Waltzman RJ, Schwartz GK, et al: Phase II trial of paclitaxel in patients with soft-tissue sarcomas. Cancer Invest 16:442–446, 1998[Medline]

15. Edmonson JH, Ebbert LP, Nasciment AG, et al: Phase II study of docetaxel in advanced soft tissue sarcomas. Am J Clin Oncol 19:574–576, 1996[CrossRef][Medline]

16. Gill PS, Tulpule A, Espina BM, et al: Paclitaxel is safe and effective in the treatment of advanced AIDS-related Kaposi's sarcoma. J Clin Oncol 17:1876–1883, 1999[Abstract/Free Full Text]

17. Okuno SH, Edomson JH, Mahoney M, et al: Phase II trial of gemcitabine in advanced sarcomas. Cancer 94:3225–3229, 2002[CrossRef][Medline]

18. Okuno SH, Ryan LM, Edmonson JH, et al: Phase II trial of gemcitabine in patients with advanced sarcomas (E1797). Cancer 97:1669–1673, 2003

19. Patel SR, Gandhi V, Jenkins J, et al: Phase II clinical investigation of gemcitabine in advanced soft tissue sarcomas and window evaluation of dose rate on gemcitabine triphosphate accumulation. J Clin Oncol 19:3483–3489, 2001[Abstract/Free Full Text]

20. Hensley ML, Maki R, Venkatraman E, et al: Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma: Results of a phase II trial. J Clin Oncol 20:2824–2831, 2002[Abstract/Free Full Text]

21. Leu K, Ostuszka LJ, Biermann JS, et al: Laboratory and clinical evidence of synergistic cytotoxicity of sequential treatment with gemcitabine followed by docetaxel in the treatment of osteosarcoma. Proc Am Soc Clin Oncol 22:816, 2003 (abstr 3278)

Submitted August 16, 2004; accepted February 1, 2005.


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