Current Clinical Trials of Epothilone B Analog (BMS-247550)

September 1, 2001

BMS-247550 is a methyl, semi-synthetic analog of the natural product epothilone B. Provided to the National Cancer Institute (NCI) by Bristol-Myers Squibb, BMS-247550 was chosen for clinical development because it demonstrated

BMS-247550 is a methyl, semi-synthetic analog of the naturalproduct epothilone B. Provided to the National Cancer Institute (NCI) byBristol-Myers Squibb, BMS-247550 was chosen for clinical development because itdemonstrated antitumor activity in paclitaxel (Taxol)-sensitive, paclitaxel-insensitive,and paclitaxel-resistant human tumor models. The first NCI-sponsored clinicaltrial of BMS-247550 was initiated in February 2000.

Clinical Trials Referral Resource is designed to serve as a ready reference for oncologists to help identify clinical trials that might be suitable for their patients. We hope it will also enhance accrual to clinical trials by informing practicing oncologists of ongoing protocols. Currently in the United States less than 10% of eligible adult patients are entered into clinical trials. The result is a delay in answering important therapeutic and scientific questions and disseminating therapeutic advances to the general oncology community.

It should be emphasized that including a specific trial does not imply that it is more important than another trial. Among the criteria for selection are that the trial is addressing an important question and is not expected to close in the immediate future (less than 1 year), and that initial staging or laboratory tests required for patient eligibility are widely practiced and available. Information on other protocols can be accessed via Physician’s Data Query (PDQ).*

We emphasize that this is an attempt to encourage referral of patients to these trials. We are specifically not soliciting additional members for the cooperative groups, nor are we suggesting how practicing oncologists should be treating patients who are not in a study.

This month’s installment of Clinical Trials Referral Resource is devoted to clinical trials of epothilone B analog (BMS-247550).

For patient entry information, see the individual trials.

* PDQ is a comprehensive database service provided by the National Cancer Institute’s International Cancer Information Center and Office of Cancer Communications for retrieval of cancer treatment information, including peer-reviewed statements on treatment options, supportive care, screening, and prevention; and an international clinical trials registry. For more information on PDQ, Internet access is available at http://cancernet.nci.nih.gov/pdqfull.html, or contact the Cancer Information Service offices (1-800-4-CANCER).

Taxanes represent one of the most effective classes of anticancertherapeutics; however, many human cancers either do not respond to or becomeresistant to taxane-based therapy. Therefore, screening programs have soughtmicrotubule-stabilizing compounds with a broader range of activity and/oractivity against taxane-refractory cancers. Fermentation products in the culturebroth of the cellulose-degrading myxobacteria Sorangium cellulosum were found tohave antifungal and cytotoxic activity. German investigators isolatedepothilones A and B from this culture broth and elucidated theirstructures.[1,2]

Bollag and colleagues found that the epothilones A and B inducepolymerization of tubulin and enhance microtubule stability.[3] The epothilonescompete with the taxanes for binding to tubulin, suggesting a singlepharmacophore for these two classes of agents. The epothilones’ microtubulestabilization causes mitotic arrest and therefore, precipitates cell-cyclearrest at the G2/M transition, with resultant apoptosis.[4] The epothilones,unlike the taxanes, retain their activity against P-glycoprotein-expressing,multiple drug-resistant tumors and cell lines as well as tumors resistant tothe taxanes based on tubulin mutations.[3]

Epothilone B, unlike paclitaxel, does not elicit endotoxin-signaling pathwaysin murine macrophages, yet the effects of microtubule stabilization arepreserved. Therefore, the production of proinflammatory cytokines and nitricoxide seen with paclitaxel has not been observed with epothilone B.[5]These preclinical data raise the possibility that the antitumor effects ofpaclitaxel may be preserved in epothilone B, whereas some adverse reactions—suchas arthralgias and myalgias—associated with a proinflammatory state, may not.

Investigators at Bristol-Myers Squibb conducted an extensive screeningprogram of more than 300 semisynthetic analogs of epothilones A and B.BMS-247550, a lactam analog of epothilone B, emerged as the leading candidatefor further development, having outperformed paclitaxel in a series ofpreclinical tumor models.[6]

Preclinical Studies

BMS-247550 has demonstrated a broad spectrum of activity against a panel oftumor lines in vitro, including human ovarian, breast, prostate, colon, lung,and epithelial cancer lines and leukemia cell lines. Median inhibitoryconcentration (IC50) values were between 1.4 and 34.5 nM, based on a 72-hourexposure. BMS-247550 retained its activity against paclitaxel-resistant lines,compared to paclitaxel-sensitive lines. Tubulin polymerization assaysdemonstrated a 2.5-fold greater potency for BMS-247550 over paclitaxel.BMS-247550 causes virtually complete cell-cycle arrest in G2/M at 7.5 nM, whichis approximately the mean IC90 in vitro.[6]

Mouse tumor models, including models of mouse fibrosarcoma and humanpancreatic, ovarian, colon, and breast cancers have shown that log cell kill ofBMS-247550 is equal or superior to that of paclitaxel in both paclitaxel-sensitiveand -resistant tumors in virtually all cases, when the drugs are administeredaccording to their respective optimal doses and schedules.

Preclinical data suggest that the efficacy of BMS-247550 may beschedule-dependent. A study of A2780 (ovarian) tumors in mice demonstrated aless frequent dosing schedule, allowing for higher doses to be administered,with a maximum tolerated dose of 16 mg/kg per injection on an every-4-days ×3schedule vs 6.3 mg/kg per injection on an every-2-days ×5 schedule.

Similar results were demonstrated in an HCT116 (colon) model: A maximumtolerated dose of 24 mg/kg per injection on an every-8-days ×2 schedule vs 6.3mg/kg per injection on an every-2-days × 5 schedule. In both of these models,the antitumor effects were markedly superior in the mice treated on theintermittent schedules as well.[6] In two other studies in the Pat-7(pancreas) and HCT116/VM46 (paclitaxel-resistant colon) tumors, the efficacy oftwo IV treatment schedules (every 2 days × 5 and every 4 days × 3) werecompared, and in both cases, the two regimens yielded essentially equivalentantitumor activities.

BMS-247550 is bioavailable orally. Experiments with the HC116 (colon) mousetumor model have demonstrated that the antitumor activity of oral BMS-247550 isidentical to that of the intravenous regimen.

Clinical Studies

Phase I studies of BMS-247550 evaluating three schedules are ongoing and havebeen reported in abstract form.

Adverse reactions attributed to BMS-247550 have included neutropenia,arthralgia/myalgia, fatigue, weakness, constipation, diarrhea, nausea, vomiting,rash, alopecia, and peripheral neuropathy. Dose-limiting toxicities on theevery-21-day schedule are neutropenia, neuropathy, and arthralgia/myalgia, andthe maximum tolerated dose on this schedule is 50 mg/m² per cycle. The maximumtolerated doses of the every-7-day and 5 × daily every-21-day schedules havenot yet been defined, but the patterns of toxicity are similar thus far, withthe possible exception of diminished neuropathy on the daily × 5 days schedule.BMS-247550 is administered in Cremaphor EL solution, and hypersensitivityreactions have been observed in patients who were not premedicated. There havebeen no reports of clinically relevant hypersensitivity in patients receiving H1and H2 blockers as premedication.[7-11]

Preliminary pharmacokinetic and pharmacodynamic studies in humans demonstratea wide volume of distribution for BMS-247550 (399-1157 L/m²) and a terminalhalf-life of approximately 1 to 2 days, with a clearance of 230 to 423 mL/min/m2.[12]Enhanced tubulin polymerization in peripheral blood mononuclear cells has beenseen at several dose levels. Plasma area under the concentration-time curve (AUC)values appear to be proportional to dose.

Preliminary evidence of antitumor activity has been reported on all schedulesunder investigation and has included the following tumor types: ovarian, colon,breast, melanoma, non-small-cell lung, anal, and head and neckcancers.[7,9-11]

The Cancer Therapy Evaluation Program (CTEP) at the NCI is sponsoring a broadrange of phase I and II clinical trials of BMS-247550, both as a single agentand in combination with other agents on various schedules. Bristol-Myers Squibbis sponsoring trials in patients with breast, colorectal, gastric, melanoma, andnon-small-cell lung cancer. The following list includes approved and/or activeclinical trials examining treatments with the epothilone B analog BMS-247550,which are being sponsored by CTEP. Information about these studies can beobtained from the principal investigator or the contacts listed for each trial,or from A. Dimitrios Colevas, MD, at CTEP (colevasd@ctep.nci.nih.gov),301-435-9128.

Gastrointestinal Cancer Phase II

Title: Phase II Study of BMS-247550 in Patients With HepatobiliaryCancer
Protocol Number: UCCRC-NCI-3656
Participating Institutions: University of Chicago, Lutheran GeneralHospital, Evanston Hospital, University of Illinois, Weiss Memorial Hospital,Decatur Memorial Hospital, Oncology-Hematology Associates, Montefiore MedicalCenter, Fort Wayne Medical Oncology/Hematology Inc, Michigan HematologyOncology, PC, Central Illinois Hematology Oncology Center
Protocol Status: Approved; not yet active
Contact: Hedy L. Kindler, MD, (773) 702-0360, hkindler@bsd.uchicago.eduLatest Information:http://cancernet.nci.nih.gov/

Title: Phase II Study of BMS-247550 in Patients With AdvancedPancreatic Adenocarcinoma
Protocol Number: SWOG-S0107
Participating Institution: Southwest Oncology Group 
Protocol Status: Active
Contact: Robert P. Whitehead, Chair, (409) 772-1164; for a completelisting of study contacts, click hereLatest Information: http://cancernet.nci.nih.gov/

Genitourinary Cancer Phase II

Title: A Phase II Clinical Trial of BMS-247550 (NSC # 710428) in PatientsWith Renal Cell Carcinoma
Protocol Number: 3654
Participating Institution: National Cancer Institute Medicine Branch
Protocol Status: In review
Contact: Antonio T. Fojo, MD, (301) 402-1357,tfojo@helix.nih.gov 

Title: Phase II Study of BMS-247550 in Patients With AdvancedCarcinoma of the Urothelium
Protocol Number: E-E3800
Participating Institution: Eastern Cooperative Oncology Group
Protocol Status: Active
Contact: Robert Dreicer, Chair, (216) 445-4623; for a complete listing ofstudy contacts, click hereLatest Information: http://cancernet.nci.nih.gov/

Title: Phase II Study of BMS-247550 in Patients WithHormone-Refractory Prostate Cancer
Protocol Number: SWOG-S0111, CTSU
Participating Institution: Southwest Oncology Group
Protocol status: Open/active
Contact: Maha Hadi A. Hussain, Chair, (313) 745-2357; for a completelisting of study contacts, click hereLatest Information: http://cancernet.nci.nih.gov/

Phase I/II

Title: Phase I/II Randomized Study of BMS-247550 With or WithoutEstramustine in Patients With Progressive Androgen-Independent Adenocarcinoma ofthe Prostate
Protocol Number: MSKCC-01064A, NCI-3634
Participating Institutions: Memorial Sloan-Kettering Cancer Center
Protocol Status: Open/active
Contact: William K. Kelly, MD, (212) 639-7992, kellyw@mskcc.orgLatest Information: http://cancernet.nci.nih.gov/

Gynecologic CancerPhase II

Title: Phase I/II Study of BMS-247550 in Patients With Advanced SolidTumors or Advanced or Recurrent Ovarian Epithelial or Breast Cancer
Protocol Number: AECM-9911378, NCI-98
Participating Institution: Albert Einstein Comprehensive Cancer Center
Protocol Status:
Active/new
Contact: Franco M. Muggia, MD, (212) 263-6485
Latest Information:http://cancernet.nci.nih.gov/

Title: Phase II Study of Epothilone B in Relapsed and/or RefractoryStage III or IV Ovarian Cancer, Following Front-Line Treatment With PlatinumPlus Taxane-Based Chemotherapy
Protocol Number: 3632
Participating Institution: Moffitt Cancer Center
Protocol Status: In review
Contact: Kapil N. Bhalla, MD, (813) 903-6861, bhallak@moffit.usf. edu

Title: Phase II Study of BMS-247550 in Patients With Recurrent orPersistent Platinum and Paclitaxel-Refractory Ovarian Epithelial or PrimaryPeritoneal Cancer
Protocol Number: GOG-0126M
Participating Institution: Gynecologic Oncology Group
Protocol Status: Approved; not yet active
Contact:
Robert C. Park, Chair, (215) 854-0770
Latest Information: http://cancernet.nci.nih.gov/

Lymphoma Phase II

Title: A Phase II Study of BMS-247550 Epothilone B in Patients WithAggressive Non-Hodgkin’s Lymphoma
Protocol Number: 4250
Participating Institution: Southern Europe New Drug Organization
Protocol Status:
In review
Contact: Dr. Michele Ghielmini, 011-39-2-559-5349, mghielmini@ ticino.com

Title: A Phase II Study of BMS-247550 in Low-Grade LymphoproliferativeDisorders
Protocol Number: 5342
Participating Institution: Memorial Sloan-Kettering Cancer Center
Protocol Status: In review
Contact:
Owen A. O’Connor, MD, (212) 639-8889, oconnoro@mskcc.org

Melanoma Phase II

Title: A Phase II Study of Epothilone B Analogue, BMS-247550, in Stage IVMalignant Melanoma
Protocol Number: 4470
Participating Institutions: New York University Medical Center,Montefiore Medical Center, Ludwig Institute for Cancer Research, Albert EinsteinCollege of Medicine, Fox Chase Cancer Center
Protocol Status:  In review
Contact: Anna C. Pavlick, MD, (212) 263-6485, anna.pavlick@med.nyu.edu

Sarcoma Phase II

Title: Phase II Study of BMS-247550 in Patients With Advanced SoftTissue Sarcoma
Protocol Number: MAYO-MC007C, NCI-3852
Participating Institutions: Mayo Clinic Cancer Center, Howard UniversityCollege of Medicine, Johns Hopkins Oncology Center, Barbara Ann Karmanos CancerInstitute, Washington University School of Medicine, University of WisconsinComprehensive Cancer Center
Protocol Status: Active
Contact:
Scott H. Okuno, MD, Chair, (507) 284-2511, okuno.scott@mayo.edu;for a complete listing of study contacts, click hereLatest Information: http://cancernet.nci.nih.gov/

Solid Tumors Phase I

Title: Phase I Study of BMS-247550 (NSC # 710428D) Given Every 3 Weeks inPatients With Advanced Malignancies
Protocol Number: 87
Participating Institution: Wayne State University
Protocol Status: In review
Contact: Patricia M. Lorusso, MD, (313) 745-8860, lorussop@karmanos.org

Title: Phase I Study of BMS-247550 in Patients With AdvancedMalignancies
Protocol Number: UTHSC-IDD-99-32, NCI-150, SACI-IDD-99-32
Participating Institutions: University of Texas Health Science Center,Audie L. Murphy Veterans Affairs Hospital, Saint Luke’s Lutheran Hospital,Cancer Therapy and Research Center
Protocol Status: Active
Contact:
Eric K. Rowinsky, MD, Chair, (210) 616-5945, erowinsk@saci.orgLatest Information: http://cancernet.nci.nih.gov/

Title: Phase I Study of BMS-247550 in Patients With RefractoryNeoplasms
Protocol Number: NCI-00-C-0224, NCI-550
Participating Institutions: Center for Cancer Research, Medicine Branch
Protocol Status: Active
Contact: Manish Agrawal, Chair, (301) 435-8724
Latest Information: http://cancernet.nci.nih.gov/

Title: A Phase I Study of Epothilone B Analogue (BMS-247550) inCombination With Carboplatin in Recurrent and/or Refractory Solid Tumors
Protocol Number: 5306
Participating Institution: Moffitt Cancer Center and Research Institute
Protocol Status: In review
Contact: Daniel M. Sullivan, MD (813) 979-3878, sullivad@moffitt.usf.edu

Title: Phase I Trial and Pharmacokinetic Study of BMS-247550 (NSC #710428), an Epothilone B Analogue, in Pediatric Patients With Refractory SolidTumors
Protocol Number: 5425
Participating Institution: National Cancer Institute Pediatric OncologyBranch
Protocol Status: In review
Contact: Brigitte C. Widemann, MD, (301) 496-7387, bw42y@nih.gov

References:

1. Gerth K, Bedorf N, Hölfe G, et al: Epothilones A and B: Aantifungal andcytotoxic compounds from Sorangium cellulosum (Myxobacteria) production,physicochemicaland biological properties. J Antibiot 49:560-563, 1996.

2. Hölfe G, Bedorf N, Steinmetz H, et al: Epothilone A and B—Novel16-membered macrolides with cytotoxic activity: Isolation, crystal structure,and conformation in solution. Agnew Chem Int Ed Engl 35:1567-1569, 1996.

3. Bollag DM, McQueney PA, Zhu J, et al: Epothilones, a new class ofmicrotubule-stabilizing agents with a Taxol-like mechanism of action. Cancer Res55:2325-2333, 1995.

4. Kowalski RJ, Giannakakou P, Hamel E: Activities of themicrotubule-stabilizing agents epothilones A and B with purified tubulin and incells resistant to paclitaxel (Taxol). J Biol Chem 272(4):2534-2541, 1997.

5. Mühlradt PF, Sasse F: Epothilone B stabilizes microtubuli of macrophageslike Taxol without showing Taxol-like endotoxin activity. Cancer Res.57:3344-3346, 1997.

6. Lee FY, Borzilleri R, Fairchild CR, et al: BMS-247550: A novel epothiloneanalog with a mode of action similar to paclitaxel but possessing superiorantitumor efficacy. Clin Cancer Res 7:1429-37, 2001.

7. Awada A, Bleiberg H, de Valeriola D, et al: Phase I clinical andpharmacology study of the epothilone analog BMS-247550 given weekly in patientswith advanced solid tumors (abstract). Proc Am Soc Clin Oncol 20:A427, 2001.

8. Damle BD, Letrent S, Duncan G, et al: Pharmacokinetics (PK) andpharmacodynamics (PD) of BMS-247550, an epothilone analog, in patients withadvanced solid tumors (abstract). Proc Am Soc Clin Oncol 20:A268, 2001.

9. LoRusso PM, Wozniak AJ, Flaherty LE, et al: Phase I clinical trial ofBMS-247550 (epothilone B analog; NSC #710428) in adult patients with advancedsolid tumors (abstract). Proc Am Soc Clin Oncol 20:A2125, 2001.

10. Mani S, McDaid H, Shen H-J, et al: Phase I evaluation of an epothilone Banalog (BMS-247550): Clinical findings and molecular correlates (abstract). ProcAm Soc Clin Oncol 20:A269, 2001.

11. Spriggs D, Soignet S, Bienvenu B, et al: Phase I first-in-man study ofthe epothilone B analog BMS-247550 in patients with advanced cancer (abstract).Proc Am Soc Clin Oncol 20:A428, 2001.

12. Spriggs D, Soignet S, Bienvenu B, et al: Phase I and pharmacology studyof the epothilone B analog BMS-247550 in patients with advanced cancer (abstract#574). Proceedings of the 11th NCI-EORTC-AACR Symposium on New Drugs in CancerTherapy, November 7-10, 2000, Amsterdam, Netherlands.