SYNOPTIC STUDY REPORT - Clinical Trials - Bristol-Myers Squibb

Ixabepilone 

BMS-247550 

CA163012 

Synoptic Study Report 

SYNOPTIC STUDY REPORT 

Name of Sponsor/Company: 

Bristol-Myers Squibb 

Name of Finished Product: 

Not Available 

Name of Active Ingredient: 

Ixabepilone 

Individual Study Table Referring 

to the Dossier 

(For National Authority Use 

Only) 

TITLE OF STUDY: A Phase 2 Study of BMS-247550 in Patients with Metastatic Colorectal Cancer 

Previously Treated with a Fluoropyrimidine and Irinotecan 

INVESTIGATORS/STUDY CENTERS: Total Number of Investigators: 13 (6 in the United States, 4 

in France, and 3 in Germany) 

The name and location of each site is presented in Appendix A. 

PUBLICATIONS: None. 

STUDY PERIOD: Date first patient enrolled: 26-Feb-2001 

Date last patient completed: 05-Aug-2002 

CLINICAL PHASE: 2 

INTRODUCTION: This study investigated the safety and clinical activity of BMS-247550 (ixabepilone) 

in patients with metastatic colorectal cancer who had been previously treated with one prior regimen of 

fluoropyrimidine and irinotecan chemotherapy for metastatic disease. The modified Gehan’s design in this 

study required 19 response-evaluable patients for the first stage. After 21 patients had been enrolled at the 

original dose of 50 mg/m 2 infused over 1 hour every 21 days, the protocol was amended because of 

possible neurotoxicity at this dose. One partial response (PR) was observed with the 50 mg/m 2 dosing. The 

new dose was 6 mg/m 2 infused over 1 hour for 5 consecutive days every 21 days. Thirty-two patients were 

enrolled at this dose. The study was terminated because there were no responders during Stage 1 of the 

daily x 5 regimen and it was concluded that the drug was not efficacious in this tumor type. This synoptic 

report summarizes the key safety parameters for the 20 evaluable patients who received ixabepilone every 

21 days at 50 mg/m 2 and the 31 evaluable patients who received ixabepilone at 6 mg/m 2 for 5 consecutive 

days every 21 days. The pharmacokinetic data will be presented in a separate population pharmacokinetics 

report. 

OBJECTIVES: 

Primary Objective(s): 

To assess the clinical activity of ixabepilone, as measured by the tumor response rate in patients with 

metastatic colorectal cancer who had previously been treated with a fluoropyrimidine and irinotecan for 

metastatic disease, who were given ixabepilone as a 1 hour infusion daily for 5 consecutive days (Days 

1 - 5) every 21 days. 

Approved v2.0 930008512 2.0

Ixabepilone 

BMS-247550 

CA163012 


Secondary Objectives: 

1) To evaluate the activity and safety of ixabepilone administered as a 1 hour infusion every 3 weeks in 

patients with metastatic colorectal cancer who had previously been treated with a fluoropyrimidine and 

irinotecan for metastatic disease; 

2) To evaluate the safety of ixabepilone administered as a 1-hour daily for 5 consecutive days (Days 

1 - 5) every 21 days in patients with metastatic colorectal cancer who had previously been treated with 

a fluoropyrimidine and irinotecan for metastatic disease; 

3) To assess the response duration, time to progression and survival of patients with metastatic colorectal 

cancer who had previously been treated with a fluoropyrimidine and irinotecan for metastatic disease, 

who were given ixabepilone as a 1 hour infusion for 5 consecutive days (Days 1 - 5) every 21 days; 

4) To provide ixabepilone plasma concentration versus time data for a future population pharmacokinetic 

evaluation of ixabepilone. 

METHODOLOGY: This was a Phase 2, multicenter, multinational, nonrandomized, single-arm, openlabel 

study of ixabepilone in patients with metastatic colorectal cancer. Patients must have received at least 

1 prior therapy with irinotecan and a fluoropyrimidine for metastatic disease. A modified Gehan’s design 1 

was used to test whether the objective response rate was of clinical interest. Ixabepilone was to be 

administered on Day 1 to Day 5 every 21 (consecutive) days at a dose of 6 mg/m²/day (as per amendment, 

the original protocol dosed patients at 50 mg/m 2 once every 3 weeks). Prior to ixabepilone administration, 

patients were premedicated with H 1 and H 2 blockers to prevent potential hypersensitivity reactions 

observed in prior studies due to the cremaphor in the formulation used. Patients were to be assessed at 

regular intervals during treatment. Six blood samples were to be collected during Cycle 1, on Day 5, for the 

measurement of ixabepilone plasma concentrations. The protocol, amendment, and administrative letters 

for study CA163012 are provided in Appendix B. A sample Case Report Form (CRF) is provided in 

Appendix C. 

NUMBER OF PATIENTS: In this study, patients were treated with ixabepilone either at a dose of 

50 mg/m 2 once every 21 days or 6 mg/m 2 /day for 5 days every 21 days. 

Ixabepilone 50 mg/m 2 q 21 days 

Twenty-one patients were enrolled to be treated with ixabepilone 50 mg/m 2 every 21 days (Supplemental 

Table S.1; Appendix 1). One patient (CA163012-6-605) never received treatment because the patient had 

surgery for Grade 4 colitis and the investigator decided not to start this patient on study drug. Three patients 

were deemed ineligible: 2 of these patients were granted exemptions (Supplemental Table S.3): patient 

CA163012-1-104 had a platelet count < 125,000 mm 3 and patient CA163012-2-202 had previous 

chemotherapy completed less than 4 weeks prior to enrollment; patient CA163012-2-203 had baseline 

ECOG of 2 which was out of the acceptable 0 - 1 range and was not granted an exemption (Appendix 3). 

One patient (CA163012-1-102) received irinotecan and fluorouracil that was characterized only as adjuvant 

therapy and not for metastatic disease; the patient was enrolled and treated with ixabepilone in this study. 

Ixabepilone 6 mg/m 2 /day x 5 days q 21 days 

Thirty-two patients were enrolled to be treated with ixabepilone 6 mg/m 2 /day for 5 consecutive days every 

21 days (Supplemental Table S.2; Appendix 2). One patient (CA163012-1-110) never received treatment 

because the patient declined to enter the study after signing informed consent. Four patients were deemed 

ineligible and 3 patients were granted exemptions (Supplemental Table S.4): patient CA163012-2-206 had 

no bidimensional lesion; patient CA163012-10-1003 had no prior chemotherapy containing both 

fluoropyrimidine and irinotecan for metastatic disease and had prior chemotherapy completed less than 4 

Approved v2.0 930008512 2.0

Ixabepilone 

BMS-247550 

CA163012 


weeks prior to enrollment; patient CA163012-17-1702 was, in fact, eligible for the study, however, the 

patient was incorrectly given an exemption status. Patient CA163012-2-204 received the first dose of 

ixabepilone 3 weeks after her last chemotherapy (rather than 4 weeks as required per protocol); the patient 

was classified as ineligible and not granted an exemption, however, the patient received 2 courses of study 

drug (Appendix 4). One patient (CA163012-14-1401) received irinotecan and fluorouracil that was 

characterized only as adjuvant therapy and not for metastatic disease; the patient was enrolled and treated 

with ixabepilone in this study. 

DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION: Patients had: 1) histologically or 

cytologically confirmed colorectal adenocarcinoma which was metastatic; 2) received either (a) 1 prior 

regimen of irinotecan and a fluoropyrimidine in combination in the metastatic setting, or (b) 2 prior 

regimens, with a fluoropyrimidine-based first line and irinotecan-based second line in the metastatic setting 

[patients may have received cetuximab (IMC-C225) and/or fluoropyrimidine as part of the second-line 

regimen], and progression of disease must have been demonstrated either on or within 4 months of 

treatment with irinotecan-based therapy (additional prior adjuvant or neoadjuvant chemotherapy was 

allowed); 3) completed prior chemotherapy at least 4 weeks prior to study enrollment and there must have 

been adequate recovery from side effects of this therapy; 4) at least 1 bidimensionally measurable lesion; 5) 

adequate hematologic function as defined by: absolute neutrophils ≥ 2,000/mm 3 and platelets 

> 125,000/mm 3 ; 6) adequate hepatic function as defined by: serum bilirubin ≤ 1.5 times the upper limit of 

normal (ULN), ALT ≤ 2.5 times ULN (≤ 5 times ULN if hepatic metastases were present); 7) adequate 

renal function as defined by serum creatinine ≤ 1.5 times ULN; 8) adequate recovery from recent surgery 

and radiation therapy (1 week must have elapsed from the time of a minor surgery, 3 weeks for major 

surgery and radiation therapy); 9) life expectancy of at least 12 weeks; 10) ECOG performance status of 

0 - 1; 11) age ≥ 18 years; 12) available for follow-up; and 13) women of childbearing potential must have 

had a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) 

within 72 hours prior to start of study medication. 

Significant exclusion criteria included: more than 2 prior regimens of cytotoxic chemotherapy for 

metastatic disease; prior oxaliplatin therapy; CTC Grade 2 or greater neuropathy (sensory or motor); prior 

radiation therapy must not have contained a target lesion unless the lesion had been shown to progress after 

completion of radiation treatment (recovery period of at least 3 weeks after completion of radiation therapy 

prior to enrollment); known central nervous system metastases; impaired cardiac function; serious 

intercurrent infections; concurrent active malignancy other than non-melanoma skin cancer or carcinoma in 

situ of the cervix; known prior severe (CTC Grade 3 or 4) hypersensitivity reactions to agents containing 

Cremophor ® EL. 

TEST PRODUCT, DOSE AND MODE OF ADMINISTRATION, BATCH NUMBERS: Ixabepilone 

is a semisynthetic analog of the natural product epothilone B, a non-taxane tubulin polymerization agent 

obtained by fermentation of the myxobacteria Sorangium cellulosum. BMS-247550 has a molecular 

formula of C 27 H 42 N 2 O 5 S and its molecular weight is 506.71 g/mole. BMS-247550 for Injection was 

supplied as a lyophilized, white to off-white, whole or fragmented cake in a vial. A second vial containing 

5.5 mL of a vehicle for constitution (diluent) was also supplied which appeared clear to slightly hazy and 

was colorless to pale yellow in color. The diluent was comprised of an ethanol + polyoxyethylated castor 

oil (Cremophor ® EL) mixture (1:1 by volume). 

Ixabepilone was supplied as a 2-vial system for the 10-mg/vial potency and a 3-vial system for the 20- 

mg/vial potency. Ixabepilone was administered over 1 hour once every 21 days at an initial dose of 

50 mg/m 2 to 21 patients. Per protocol amendment, ixabepilone was administered to the next 32 patients at 

an initial dose of 6 mg/m 2 on Days 1 - 5 of each cycle repeated every 21 days. Study drug was administered 

providing the patient met all the retreatment criteria. 

Approved v2.0 930008512 2.0

Ixabepilone 

BMS-247550 

Batch numbers for ixabepilone are presented in Table 1. 

CA163012 


Table 1: 

Batch Numbers of Study Drug 

Product Description 

Ixabepilone 

10 mg vial 

20 mg vial 

Batch Numbers 

C00159, C00198 

C00355, C01181 

Diluent, 5.5 ml C99377, C00325, C00400, 

C01077, C01162 C99248 

Infusion kit C76300-1 

DURATION OF TREATMENT: Duration of treatment was based on tumor reassessments performed 

every second cycle. Patients with stable disease (SD) or partial response received treatment until 

progression or a maximum of 18 cycles. Patients with SD or PR could receive additional treatment if it was 

in their best interest to do so, and agreed to by both the Investigator and Sponsor. Patients who achieved a 

complete response (CR) could receive treatment for up to a maximum of 4 cycles post-CR. Treatment was 

also discontinued if unacceptable toxicity occurred. 

CRITERIA FOR EVALUATION: 

Efficacy: 

The primary efficacy endpoint was the objective response rate. Patients were evaluated for best response by 

the investigator according to a modified form of the WHO (World Health Organization) criteria. 2 For 

definitions of CR, PR, SD, and PD, refer to the protocol in Appendix B. Overall response was determined 

based on an algorithm of evaluation of target, non-target, and new lesions. All patients who received study 

drug (intent to treat) were considered evaluable for response (ie, “response-evaluable”) and were included 

in the denominator of the response rate, except for patients with the wrong cancer diagnosis. 

Measurable lesions were those that could be accurately measured, with at least one diameter ≥ 2.0 cm (for 

spiral computed tomography [CT] scan, at least one diameter had to be ≥ 1.0 cm and the lesion had to be 

accurately measureable). Definitions of nonmeasurable lesions/disease, as well as target and non-target 

lesions, are described in the protocol (Appendix B). 

Safety: 

All patients were evaluable for safety if they received study drug. The safety endpoints were the number 

and severity of adverse events and laboratory test abnormalities in hematology and chemistry parameters. 

These safety endpoints were evaluated through adverse events reports and chemistry and hematology 

measurements collected during the study. Adverse events and other symptoms were graded according to the 

National Cancer Institute (NCI) Common Toxicity Criteria (CTC) Version 2.0. WHO or CTC Version 1.0 

were used where the NCI CTC Version 2.0 grading system did not apply, eg, BUN. 

STATISTICAL METHODS: 

This study utilized a modified Gehan’s design to test whether the tumor response rate was of clinical 

interest. This design minimized the expected number of patients who received treatment when the true 

response rate was not of clinical interest. 

Approved v2.0 930008512 2.0

Ixabepilone 

BMS-247550 

CA163012 


This study had at least 95% power to detect an objective response rate (defined as the complete response 

rate plus the partial response rate) of 15%, which would indicate that ixabepilone would be worth 

investigating further in this disease. 

The modified Gehan’s design called for 19 response-evaluable patients to be enrolled in Stage 1. If no 

responder was reported out of the first 19 patients, the study was stopped, rejecting the hypothesis of a 15% 

response rate. Otherwise, if there was at least 1 response, an additional 31 evaluable patients were to be 

accrued in Stage 2. Given an estimated 90% evaluability rate, a total of approximately 55 patients were to 

be enrolled if the accrual continued after Stage 2. 

Descriptive statistics were used in the analyses of demographic and all safety (laboratory and 

adverse events) assessments. The methodology and results of the population pharmacokinetic analyses will 

be reported separately. 

Amendment 1 changed the dosing from 1 dose (50 mg/m 2 ) every 21 days to once daily for 5 days 

(6 mg/m 2 /day) every 21 days. For the purpose of analysis, the patients enrolled after activation of the 

amendment were to be considered independently of the patients treated with the once every 21 day 

schedule. 

PATIENT DISPOSITION/CHARACTERISTICS: 

Twenty-one patients were enrolled in the study prior to Amendment 1. All but 1 patient received study 

treatment (50 mg/m 2 ). All 20 treated patients discontinued prior to completing therapy, with disease 

progression cited as the most common reason for discontinuing the study. After Amendment 1, 32 patients 

were enrolled in the study and all but 1 patient received study treatment (6 mg/m 2 /day for 5 days). All 31 

treated patients discontinued prior to completing therapy, with disease progression cited as the most 

common reason for discontinuing the study. 

Table 2 and Supplemental Tables S.5 and S.6 summarize the patient disposition for all patients who were 

enrolled in the study. 

Table 2: 

Patient Disposition 

Ixabepilone 50 mg/m 2 / 

1 hour 

N (%) 


1 hour x 5 days 

N (%) 

Enrolled Patients 21 32 

Treated Patients 20 (95) 31 (97) 

Still on-study 0 0 

Off-study 20 (95) 31 (97) 

Disease progression 14 (67) 25 (78) 

Study drug toxicity a 5 (24) 0 

Patient request 1 (5) 1 (3) 

Death 0 3 (9) 

Clinical deterioration 0 2 (6) 

Lost to follow-up 0 0 

Never treated 1 (5) 1 (3) 

Source: Supplemental Tables S.5 and S.6 

a Note: Source for discontinuation due to study drug toxicity was the off-treatment page of the CRF and 

not the action taken on the adverse event page. Therefore, the incidence of study drug toxicity presented 

within the patient disposition table does not match the listing of adverse events leading to study 

Approved v2.0 930008512 2.0

Ixabepilone 

BMS-247550 

CA163012 


discontinuation for those patients who received ixabepilone 50 mg/m 2 (Supplemental Table S.59 and 

Appendix 37). 

Baseline characteristics for all patients who were treated in this study are summarized in Table 3. 


Patients treated with ixabepilone 50 mg/m 2 had prior therapy. Sixty-five percent of patients received at least 

1 line of prior chemotherapy and 35% of patients received 2 lines of prior chemotherapy. Seventy-five 

percent of the patients (15) had liver lesions at baseline and half of the patients (10) had metastases in the 

lung. Seventy percent of the patients (14) reported mild to moderate (Grade 1 or 2) baseline signs and 

symptoms (Supplemental Table S.29, Appendix 23). Half of the patients (10) had Grade 1 hemoglobin 

abnormalities; there were no Grade 2, 3 or 4 hemoglobin abnormalities (Supplemental Table S.25, 

Appendix 19). Six patients had Grade 1 or 2 hepatic enzyme abnormalities at baseline (most were alkaline 

phosphatase), and all but 1 of these patients had liver metastases; no patient had Grade 3 or 4 hepatic 

enzyme abnormalities at baseline (Supplemental Table S.27 and Appendix 21). Hematologic and hepatic 

laboratory abnormalities are not uncommon for such an advanced population. 

Additional pretreatment characteristics are presented in Supplemental Tables S.7, S.9, S.11, S.13, S.15, 

S.17, S.19, S.21, S.23, S.25, S.27, and S.29. A by-patient listing of demographic characteristics, tumor type 

and disease sites is provided in Appendices 7, 9 and 11, respectively. A by-patient listing of any prior 

surgery or prior chemo-/immuno-, radio-, and hormonal therapies is provided in Appendix 13. A by-patient 

listing of prior chemotherapy regimens is provided in Appendix 15. A summary of prior hormonal or 

immunotherapy drugs is presented in Supplemental Table S.23. A by-patient listing of prior immuno- and 

hormonal therapies is provided in Appendix 17. A summary of prior adjuvant, neo-adjuvant or metastatic 

chemotherapy is presented in Supplemental Tables S.19 and S.21. A summary of best response by prior 

chemotherapy regimen in the metastatic setting is presented in Supplemental Table S.63. 


Patients treated with ixabepilone 6 mg/m 2 /day x 5 had prior therapy. Forty-eight percent of patients 

received at least 1 line of prior chemotherapy and 45% of patients received 2 lines of prior chemotherapy; 2 

patients (7%) received 3 prior lines of chemotherapy. Eighty-one percent of the patients (25) had liver 

lesions at baseline and more than a third of the patients (11) had metastases in the lung. Eighty-one percent 

of the patients (25) reported mild to moderate (Grade 1 or 2) baseline signs and symptoms and 4 patients 

(13%) had Grade 3 baseline signs and symptoms (Supplemental Table S.30, Appendix 24). More than half 

of the patients (17, 55%) had Grade 1 hemoglobin abnormalities; 7 patients had Grade 2 and there were no 

Grade 3 or 4 hemoglobin abnormalities (Supplemental Table S.26, Appendix 20). Four patients had Grade 

2 or 3 hepatic enzyme abnormalities at baseline (most were alkaline phosphatase), and all of these patients 

had liver metastases; no patient had Grade 4 hepatic enzyme abnormalities at baseline (Supplemental Table 

S.28 and Appendix 22). Hematologic and hepatic laboratory abnormalities are not uncommon for such an 

advanced population. 

Additional pretreatment characteristics are presented in Supplemental Tables S.8, S.10, S.12, S.14, S.16, 

S.18, S.20, S.22, S.24, S.26, S.28, and S.30. A by-patient listing of demographic characteristics, tumor type 

and disease sites is provided in Appendices 8, 10 and 12, respectively. A summary of prior hormonal or 

immunotherapy drugs is presented in Supplemental Table S.24. A by-patient listing of any prior surgery or 

prior chemo-/immuno-, radio-, and hormonal therapies is provided in Appendix 14. A by-patient listing of 

prior chemotherapy regimens is provided in Appendix 16. A by-patient listing of prior immuno- and 

hormonal therapies is provided in Appendix 18. A summary of prior adjuvant, neo-adjuvant or metastatic 

chemotherapy is presented in Supplemental Tables S.20 and S.22. A summary of best response by prior 

chemotherapy regimen in the metastatic setting is presented in Supplemental Table S.64. 

Approved v2.0 930008512 2.0

Ixabepilone 

BMS-247550 

CA163012 


Table 3: 

Baseline Characteristics 


1 hour 



Treated Patients 20 31 

Age (yr) Median (Min, Max) 61 (41-74) 61 (37-80) 

n (%) 

Gender 

Male 14 (70) 19 (61) 

Female 6 (30) 12 (39) 

Race 

White 20 (100) 26 (84) 

Black 0 4 (13) 

Asian/Pacific Islanders 0 1 (3) 

ECOG Performance Status Score 

0 7 (35) 12 (39) 

1 12 (60) 19 (61) 

2 1 (5) 0 

Tumor type 

Colon 15 (75) 26 (84) 

Rectum 5 (25) 4 (13) 

Colorectal 0 1 (3) 

Disease sites of interest 

Visceral liver 15 (75) 25 (81) 

Visceral lung 10 (50) 11 (36) 

Visceral other 4 (20) 2 (7) 

Node 1 (5) 1 (3) 

Effusion 0 1 (3) 

Intestine 0 1 (3) 

Visceral adrenal 1 (5) 0 

Ascites 2 (10) 1 (3) 

Soft tissue/nodes inside primary 

4 (20) 4 (13) 

area 

Soft tissue/nodes outside 

3 (15) 2 (7) 

primary area 

Bone 0 2 (7) 

Spleen 0 2 (7) 

Other 2 (10) 2 (7) 

Prior Chemotherapy/Immunotherapy 

Number of Prior Regimens 

1 13 (65) 15 (48) 

2 7 (35) 14 (45) 

Approved v2.0 930008512 2.0

Ixabepilone 

BMS-247550 

CA163012 


Table 3: 

Baseline Characteristics 




1 hour 

3 0 2 (7) 

Most Common Prior Chemotherapy/ 

Immunotherapy Regimens 

Any fluorouracil/irinotecan 

regimen 

20 (100) 31 (100) 

Fluorouracil/irinotecan/ 

18 (90) 23 (74) 

leucovorin 

Fluorouracil/leucovorin 4 (20) 7 (23) 

Fluorouracil 0 7 (23) 

Irinotecan 0 5 (16) 

Prior Surgery 19 (95) 31 (100) 

Prior Radiotherapy 1 (5) 7 (23) 

Prior Hormonal Therapy 0 1 (3) 

Source: Supplemental Tables S.7, S.8, S.9, S.10, S.11, S.12, S.13, S.14, S.15, S.16, S.17, and S.18 

EFFICACY RESULTS: 


BMS assessment of responses (Supplemental Table S.45 and Appendix 47) yielded 1 partial response 

(same as the investigator’s assessment, Supplemental Table S.47 and Appendix 31); no complete responses 

were demonstrated. Therefore, the objective response rate was 5% and the 95% exact confidence interval 

was 0.13, 24.9. This patient (CA163012-1-101), a 73-year-old man with rectal cancer with progression 

after 2 prior chemotherapy regimens, achieved a partial response on the first day of his third cycle of 

ixabepilone 50 mg/m 2 . He received another cycle (4 cycles total) and discontinued treatment due to 

continuing Grade 2 sensory neuropathy. 


There were no partial or complete responses (BMS or investigator assessment) in patients who received 

ixabepilone 6 mg/m 2 /day every 5 days (Supplemental Tables 46 and 48, Appendices 32 and 48). 

EXPOSURE: 

The number of patients treated by cycle is presented in Table 4 for both dose schedules. 


A total of 45 cycles were administered to the 20 treated patients under the original protocol dosing schedule 

of 50 mg/m 2 once every 21 days (Supplemental Table S.31, Appendix 25). Patients received a median of 2 

cycles of chemotherapy (range: 1 to 4 cycles) (Supplemental Table S.33). Two patients each had 1 dose 

reduction (Supplemental Table S.39). For patient CA163012-6-603, this was due to hematological toxicity 

(Grade 4 leukopenia and neutropenia) and for the other patient (CA163012-1-101), the reason was Grade 3 

sensory neuropathy (Supplemental Table S.41 and Appendices 29 and 37). The same 2 patients who had 

dose reductions had a single course delayed for non-hematological reasons; for patient CA163012-1-101, 

Approved v2.0 930008512 2.0

Ixabepilone 

BMS-247550 

CA163012 


this was due to Grade 3 sensory neuropathy and for patient CA163012-6-603, this was due to Grade 3 

asthenia (Supplemental Tables S.35 and S.37, Appendices 27 and 37). 

Fourteen patients (70%) were taken off-treatment for PD or relapse, 5 patients were taken off treatment for 

study drug toxicity, and 1 patient (5%) discontinued treatment by request (Supplemental Table S.43, 

Appendices 5 and 33). 


A total of 88 cycles were administered to the 31 treated patients after implementation of Amendment 1 

which changed the dosing schedule to 6 mg/m 2 /day for 5 days every 21 days (Supplemental Table S.32, 

Appendix 26). Patients received a median of 2 cycles of chemotherapy (range: 1 to 8 cycles) (Supplemental 

Table S.34). Five patients (16%) had a dose reduction for a total of 6 cycles: 2 cycles were reduced due to 

hematological toxicity (1 Grade 4 febrile neutropenia and 1 Grade 3 neutropenia), 3 due to nonhematological 

toxicity (1 Grade 3 fatigue, 1 Grade 2 weight loss, and 1 Grade 2 neuropathic pain), and 1 

due to ‘other’ which was a combination of Grade 2 sensory neuropathy and neuropathic pain and Grade 1 

arthralgia and myalgia (Supplemental Tables S.40 and S.42, Appendices 30 and 38). 

There were 8 delayed cycles in 5 patients: 3 cycle delays were due to delayed hematological recovery 

(Grade 4 neutropenia in first cycle and Grade 3 neutropenia in second cycle in 1 patient, and Grade 2 

neutropenia, leukopenia and hemoglobin in another patient); 1 due to delayed non-hematological recovery 

(Grade 3 fatigue); 3 due to ‘other’ (1 for evaluation for possible surgery, 1 for holiday, and 1 by patient’s 

request); and 1 ‘unknown’ (Supplemental Tables S.36 and S.38, Appendices 28 and 46). 

Twenty-five patients (81%) were taken off-treatment for PD or relapse, 2 patients (7%) were taken off 

treatment for clinical deterioration, 3 patients (10%) died within 30 days of treatment (no patients were 

discontinued due to adverse events), and 1 patient (3%) discontinued treatment by request (Supplemental 

Table S.44, Appendices 6 and 34). 

Table 4: 

Number of Patients Treated Per Cycle 


Cycle 

Ixabepilone 50 mg/m 2 /1 hour 

(N = 20) 

No. (%) of Patients Treated 


(N = 31) 

No. (%) of Patients Treated 

1 20 (100) 31 (100) 

2 18 (90) 29 (94) 

3 4 (20) 11 (36) 

4 3 (15) 10 (32) 

5 0 3 (10) 

6 0 2 (7) 

7 0 1 (3) 

8 0 1 (3) 

Source: Supplemental Tables S.31 and S.32 

Approved v2.0 930008512 2.0

Ixabepilone 

BMS-247550 

CA163012 


SAFETY RESULTS: 

All treated patients were evaluated for safety. Clinical signs and symptoms on study, as well as laboratory 

measurements, were used to determine the safety of the study drug. Both adverse events and laboratory 

values were graded according the NCI CTC Version 2.0 (WHO or CTC Version 1.0 were used where the 

NCI CTC Version 2.0 grading system did not apply, eg, BUN). 

Adverse Events (Non-hematologic Toxicities)Regardless of Relationship: 


Ten patients (50%) reported at least 1 Grade 3 or 4 adverse event regardless of the relationship to study 

drug (Table 5; Supplemental Table S.53). Hypersensitivity reactions were uncommon [4 patients (20%): 3 

Grade 1 - 2 and 1 Grade 4]. One patient (CA163012-3-302) experienced a Grade 4 generalized epileptic 

convulsion 5 minutes after receiving his second dose of ixabepilone; Grade 1 chills and fever were also 

recorded. The seizure resolved without medication and a follow-up head CT was normal. The investigator 

characterized this event as a hypersensitivity reaction, however no flushing, urticaria nor dyspnea occurred 

and the fever and chills did not occur until 45 minutes after the seizure. One patient (CA163012-2-203) had 

her dose interrupted for 15 minutes due to hypersensitivity reactions (Grades 1 - 2); the infusion was 

resumed and the patient received the full dose of ixabepilone (Appendix 37). There were no dose 

reductions due to hypersensitivity reactions (Appendix 29). 

Sensory neuropathy was reported in 9 patients (45%) (Table 5; Supplemental Table S.53). Mild to 

moderate (Grades 1 - 2) sensory neuropathy was reported in 6 patients (30%) and 3 patients (15%) reported 

Grade 3 sensory neuropathy. In 3 cases where sufficient follow-up information was available, the grade of 

neuropathy decreased by the second or third follow-up visit. There were no cases of motor neuropathy. 

Drug-related Grade 4 neutropenia was reported in 3 patients: CA1630102-3-302, CA163012-5-501, and 

CA163012-6-603 (Table 5; Supplemental Table S.55; Appendices 37 and 41). No febrile neutropenia was 

reported. 

A complete listing of adverse events by patient is provided in Appendix 37. 

Approved v2.0 930008512 2.0

Ixabepilone 

BMS-247550 

Table 5: 

Summary of Common Non-hematologic Toxicity, Regardless of 

Relationship to Ixabepilone: 


CA163012 


Number of Patients (%) 

N = 20 

Grade 1 - 4 Grade 3 Grade 4 

Any Clinical Adverse Event 20 (100) 7 (35) 3 (15) 

Common a Non-hematologic Toxicity 

Gastrointestinal 

Nausea 10 (50) 1 (5) 0 

Diarrhea 7 (35) 1 (5) 0 

Constipation 5 (25) 1 (5) 0 

Vomiting 5 (25) 1 (5) 0 

Anorexia 5 (25) 0 0 

Stomatitis/Pharyngitis 3 (15) 3 (15) 0 

Dehydration 1 (5) 1 (5) 0 

Dermatology/Skin 

Alopecia 17 (85) 0 0 

Rash/Desquamation 6 (30) 1 (5) 0 

Pain 

Myalgia 12 (60) 2 (10) 0 

Arthralgia 11 (55) 2 (10) 0 

Pain - other 8 (40) 1 (5) 0 

Abdominal pain or cramping 6 (30) 1 (5) 0 

Bone pain 3 (15) 1 (5) 0 

Neuropathic pain 3 (15) 1 (5) 0 

Constitutional symptoms 

Fatigue 13 (65) 3 (15) 0 

Constitutional symptoms - other 1 (5) 1 (5) 0 

Neurology 

Neuropathy - sensory 9 (45) 3 (15) 0 

Pulmonary 

Dyspnea 5 (25) 1 (5) 0 

Blood/Bone marrow 

Neutrophils/Granulocytes 4 (20) 1 (5) 3 (15) 

Leukocytes 3 (15) 1 (5) 1 (5) 

Allergy/Immunology 

Allergic reaction/Hypersensitivity 4 (20) 0 1 (5) 

Hepatic 

Bilirubin 1 (5) 1 (5) 0 

Source: Supplemental Table S.53 

Approved v2.0 930008512 2.0

Ixabepilone 

BMS-247550 

a 

CA163012 


A sum of Grade 1 - 4 adverse events occurring in at least 5 patients or any single Grade 3 - 4 adverse 

event occurring in at least 1 patient. 


Seventeen patients (55%) reported at least 1 Grade 3 or 4 adverse event regardless of the relationship to 

study drug (Table 6; Supplemental Table S.54). Hypersensitivity reactions were uncommon [4 patients 

(13%): 2 Grade 1 and 2 Grade 2]; no Grade 3 or 4 hypersensitivity reactions were reported. There were no 

dose reductions due to hypersensitivity reactions (Appendix 30). 

Five patients (16%) had unrelated Grade 4 adverse events: intestinal occlusion (ileus), pneumonia 

(infection without neutropenia, dyspnea, and hypoxia), decreased appetite, dehydration, and gastric outlet 

obstruction. 

Two patients had related Grade 4 adverse events. In 1 patient (CA163012-12-1208), infection with Grade 4 

neutropenia was probably related to study drug. In another patient (CA163012-16-1603), febrile 

neutropenia and leukopenia were considered related to study drug and the dose was reduced. 

No severe neuropathy was reported. Many patients (61%) did not have any sensory neuropathy. In the 

remaining patients (12/31, 39%), all neuropathy was mild to moderate in nature and no patient was 

discontinued because of neuropathy. There were no cases of motor neuropathy. 

A complete listing of adverse events by patient is provided in Appendix 38. 

Approved v2.0 930008512 2.0

Ixabepilone 

BMS-247550 

Table 6: 



Ixabepilone 6 mg/m 2 /1 hour x 5 days 

CA163012 



N = 31 


Any Clinical Adverse Event 31 (100) 10 (32) 7 (23) 

Common a Non-hematologic Toxicity 


Diarrhea 15 (48) 1 (3) 0 

Anorexia 14 (45) 1 (3) 1 (3) 

Nausea 14 (45) 1 (3) 0 


Vomiting 7 (23) 1 (3) 0 

Dehydration 5 (16) 1 (3) 1 (3) 

Ascites 3 (10) 0 1 (3) 


Gastrointestinal - other 2 (6) 0 1 (3) 

Colitis 1 (3) 0 1 (3) 

Ileus 1 (3) 0 1 (3) 

Pain 

Arthralgia 8 (26) 2 (6) 0 

Pain - other 8 (26) 3 (10) 0 

Abdominal pain or cramping 6 (19) 2 (6) 0 

Myalgia 6 (19) 0 0 


Fatigue 21 (68) 4 (13) 0 

Fever 6 (19) 0 0 


Alopecia 13 (42) 0 0 

Neurology 

Neuropathy - sensory 12 (39) 0 0 

Insomnia 8 (26) 0 0 

CNS cerebrovascular ischemia 1 (3) 1 (3) 0 

Pulmonary 

Cough 7 (23) 0 0 

Dyspnea 7 (23) 1 (3) 1 (3) 

Hypoxia 1 (3) 0 1 (3) 


Hemoglobin 7 (23) 2 (6) 0 

Leukocytes 3 (10) 2 (6) 1 (3) 

Approved v2.0 930008512 2.0

Ixabepilone 

BMS-247550 

Table 6: 




CA163012 



N = 31 


Neutrophils/Granulocytes 2 (6) 2 (6) 0 

Infection/Febrile neutropenia 

Infection without neutropenia 4 (13) 2 (6) 1 (3) 

Catheter-related infection 1 (3) 1 (3) 0 

Febrile neutropenia 1 (3) 0 1 (3) 

Infection with Grade 3 - 4 neutropenia 1 (3) 0 1 (3) 


a Grade 1 - 4 adverse event occurring in at least 5 patients or Grade 3 - 4 adverse event occurring in at 

least 1 patient. 

Drug-Related Adverse Events 


The most commonly occurring drug-related (certainly/probably/possibly related) adverse events for the 

ixabepilone 50 mg/m 2 /1 hour group are summarized in Table 7. Nine patients (45%) had at least 1 Grade 3 

or 4 adverse event at least possibly attributed to study drug (Table 7, Supplemental Table S.55). The most 

common treatment-related Grade 3 events were fatigue, sensory neuropathy, and stomatitis/pharyngitis. 

Grade 4 neutropenia was observed in 3 patients (CA163012-3-302, CA163012-5-501, and CA163012-6- 

603) (Appendix 37). A complete summary of all drug-related adverse events for this dose group is 

presented in Supplemental Table S.55. 

Approved v2.0 930008512 2.0

Ixabepilone 

BMS-247550 

CA163012 


Table 7: 

Summary of Common Drug-Related Adverse Events 



N = 20 


Any Drug-Related Adverse Event 20 (100) 6 (30) 3 (15) 

Common a Drug-Related Adverse Events 


Nausea 9 (45) 1 (5) 0 

Diarrhea 6 (30) 1 (5) 0 

Vomiting 4 (20) 1 (5) 0 

Stomatitis/pharyngitis 3 (15) 3 (15) 

Pain 

Myalgia 12 (60) 2 (10) 0 

Arthralgia 11 (55) 2 (10) 0 

Pain - other 5 (25) 1 (5) 0 

Bone pain 3 (15) 1 (5) 0 

Neuropathic pain 3 (15) 1 (5) 0 


Fatigue 11 (55) 3 (15) 0 

Constitutional symptoms - other 1 (5) 1 (5) 0 


Alopecia 16 (80) 0 0 

Rash/Desquamation 5 (25) 0 0 

Neurology 

Neuropathy - sensory 9 (45) 3 (15) 0 

Blood/Bone Marrow 

Neutrophils/Granulocytes 4 (20) 1 (5) 3 (15) 

Leukocytes 3 (15) 1 (5) 1 (5) 

Allergy/Immunology 

Allergic reaction/Hypersensitivity 4 (20) 0 1 (5) 

Pulmonary 

Dyspnea 2 (10) 1 (5) 0 





The most commonly occurring drug-related (certainly/probably/possibly related) adverse events for the 

ixabepilone 6 mg/m 2 /day for 5 days dose schedule are summarized in Table 8. Nine patients (29%) had at 

least 1 Grade 3 or 4 adverse event at least possibly attributed to study drug (Table 8, Supplemental Table 

Approved v2.0 930008512 2.0

Ixabepilone 

BMS-247550 

CA163012 


S.56). The most common treatment-related Grade 3 event was fatigue occurring in 3 patients (10%). The 

Grade 4 toxicities in 2 patients were infection with Grade 3 - 4 neutropenia (patient CA163012-12-1208) 

and febrile neutropenia and leukopenia (patient CA163012-16-1603) (Appendices 38 and 46). A complete 

summary of all drug-related adverse events for this dose group is presented in Supplemental Table S.56. 

Table 8: 

Summary of Common Drug-Related Adverse Events 



N = 31 


Any Drug-Related Adverse Event 29 (94) 7 (23) 2 (6) 

Common a Drug-Related Adverse Events 


Nausea 11 (35) 1 (3) 0 

Diarrhea 10 (32) 1 (3) 0 

Anorexia 6 (19) 0 0 



Pain 

Arthralgia 7 (23) 1 (3) 0 

Myalgia 6 (19) 0 0 


Fatigue 15 (48) 3 (10) 0 


Alopecia 8 (26) 0 0 

Neurology 

Neuropathy - sensory 9 (29) 0 0 


Hemoglobin 6 (19) 1 (3) 0 

Neutrophils/Granulocytes 2 (6) 2 (6) 0 

Leukocytes 2 (6) 1 (3) 1 (3) 

Neurology 

CNS cerebrovascular ischemia 1 (3) 1 (3) 0 

Pulmonary 

Dyspnea 3 (10) 1 (3) 0 

Infection/Febrile neutropenia 

Febrile neutropenia 1 (3) 0 1 (3) 

Infection with Grade 3 - 4 neutropenia 1 (3) 0 1 (3) 




Approved v2.0 930008512 2.0

Ixabepilone 

BMS-247550 

CA163012 


Laboratory Toxicities: 


Neutropenia was observed frequently in the group of patients who received ixabepilone 50 mg/m 2 once 

every 21 days (Table 9 and Supplemental Table S.49): 1 patient (5%) had Grade 3 and 4 patients (21%) had 

Grade 4 neutropenia. Only 1 patient had his dose reduced due to Grade 4 neutropenia (Appendices 29 and 

45). Grade 3 - 4 leukopenia was observed in 5 patients (26%). Patients experienced hematologic recovery 

prior to their next cycle. 

In general, the laboratory abnormalities were expected in this population with advanced colorectal cancer 

and extensive liver metastases. A summary of chemistry abnormalities (worst grade per patient) is provided 

in Supplemental Table S.51. A complete by-patient listing of chemistry and hematology values is provided 

in Appendices 43 and 45, respectively. 


Neutropenia was observed in approximately a third of the patients who received ixabepilone 6 mg/m 2 /day x 

5 days (Table 9 and Supplemental Table S.50); 1 patient (3%) had Grade 3 neutropenia and 5 patients 

(16%) had Grade 4. Only 2 patients had their dose reduced for hematological toxicity (1 for Grade 4 

neutropenia and leukopenia and the other for Grade 3 neutropenia and leukopenia (Appendices 30 and 46). 

Patients experienced hematologic recovery prior to their next cycle. 

In general, the laboratory abnormalities were expected in this population with advanced colorectal cancer 

and extensive liver metastases. A summary of chemistry abnormalities (worst grade per patient) is provided 

in Supplemental Table S.52. A complete by-patient listing of chemistry and hematology values is provided 

in Appendices 44 and 46, respectively. 

Table 9: 

Summary of Common Hematologic Toxicity 



50 mg/m 2 q 21 days (N=19) 

Leukopenia 16 (84) 3 (16) 2 (11) 

Neutropenia 14 (74) 1 (5) 4 (21) 

Hemoglobin 16 (84) 0 0 

Platelet count 6 (32) 1 (5) 0 

6 mg /m 2 /day x 5 days q 21 days (N=31) 

Leukopenia 11 (35) 5 (16) 2 (7) 

Neutropenia 10 (32) 1 (3) 5 (16) 

Hemoglobin 31 (100) 6 (19) 0 

Platelet count 7 (23) 1 (3) 0 

Source: Supplemental tables S.49 and S.50 

Deaths: 


No deaths within 30 days of their last dose of study medication occurred in patients treated with 

ixabepilone 50 mg/m 2 once every 21 days (Supplemental Table S.61 and Appendix 35). 


Three patients died within 30 days of the last dose of study medication at the dose schedule of 6 mg/m 2 /day 

for 5 days every 21 days (Table 10, Supplemental Table S.62 and Appendix 36). In 2 cases, death was 

Approved v2.0 930008512 2.0

Ixabepilone 

BMS-247550 

CA163012 


attributed to disease progression. The other death was due to pneumonia in the absence of Grade 3 or 4 

neutropenia. The narratives for these patients are presented in Supplemental Table S.62.1. 

Table 10: 

Deaths On-Study or Within 30 days of Last Dose - All Treated Patients 


Patient ID 

Gender/Age/ 

Race 

Tumor Type 

Number 

of Days 

Since Last 

Treatment 

Reason Off 

Treatment 

Cause of Death a 

CA163012-10-1004 

Male/59/ 

White 

Rectal 13 Death Pneumonia 

CA163012-14-1402 

Male/55/ 

Progressive 

Colon 12 Death 

White 

Disease 

CA163012-16-1601 

Male/72 

Progressive 

Colon 16 Death 

White 

Disease 

Source: Supplemental Tables S.8, S.10, S.62, Appendices 34 and 36 

a 

As determined by the investigator 

Serious Adverse Events: 


Ten patients (50%) who received ixabepilone 50 mg/m 2 once every 21 days experienced at least 1 serious 

adverse event (SAE) during the study (Supplemental Table S.57; Appendix 39). The most common SAEs 

were stomatitis/pharyngitis (3 patients Grade 3), vomiting (2 Grade 2, 1 Grade 3), and neutropenia (1 Grade 

3, 2 Grade 4). Complete narratives for the 8 patients who experienced treatment-related SAEs are presented 

in Supplemental Table S.57.1 and tabular narratives for all patients who experienced unrelated serious 

adverse events are provided in Supplemental Table S.57.2. 


Twelve patients (39%) who received ixabepilone 6 mg/m 2 /day x 5 days every 21 days experienced at least 

1 SAE during the study (Supplemental Table S.58; Appendix 40). The most common SAEs were 

dehydration (1 patient Grade 2, 2 patients Grade 3 - 4) and dyspnea (1 patient Grade 2, 2 patients Grade 

3 - 4). One patient experienced febrile neutropenia and another patient experienced infection with Grade 4 

neutropenia. Complete narratives for the 4 patients who experienced treatment-related SAEs are presented 

in Supplemental Table S.58.1 and tabular narratives for all patients who experienced unrelated serious 

adverse events are provided in Supplemental Table S.58.2. 

Discontinuation of Study Therapy due to Adverse Events: 


Six patients (30%) discontinued ixabepilone 50 mg/m 2 therapy due to adverse events: 2 due to allergic 

reaction/hypersensitivity [1 Grade 2, 1 Grade 4 (seizure in patient CA163012-3-302)]; 3 due to sensory 

neuropathy (1 Grade 2, 2 Grade 3); and 1 due to Grade 2 subileus (Supplemental Table S.59; Appendices 

37 and 41). * 

* One of the patients who discontinued due to Grade 3 sensory neuropathy (CA163012-1-101) appears in Supplemental 

Table S.59 as an "Error - no corresponding AE". One of the patients who discontinued because of Grade 2 

hypersensitivity (CA163012-10-1001) had "patient request" reported as the reason off-treatment in Table 2. 

Approved v2.0 930008512 2.0

Ixabepilone 

BMS-247550 

CA163012 


Narratives for all patients who discontinued study therapy due to adverse events are provided in 

Supplemental Table S.59.1. 


No patient who received ixabepilone 6 mg/m 2 /day for 5 days every 21 days discontinued treatment with 

study drug due to adverse events (Supplemental Table S.60; Appendix 42). 

CONCLUSIONS: 

In conclusion, study CA163012 demonstrated that ixabepilone administered at a dose of 50 mg/m 2 q 21 

days and daily for 5 days at a dose of 6 mg/m 2 has an acceptable toxicity. Notable toxicities included 

neutropenia with febrile neutropenia occurring in only 1 patient and infection with Grade 4 neutropenia 

occurring in another patient. Sensory neuropathy was less severe with a 6 mg/m 2 /day x 5 regimen than with 

the dose of 50 mg/m 2 once every 21 days. Grade 3 - 4 hypersensitivity reactions were rare. One objective 

response was reported in 20 patients in the 50 mg/m 2 cohort and none were reported in 31 patients with the 

6 mg/m 2 /day x 5 regimen. 

DATE OF REPORT: 30-Sep-04 

Approved v2.0 930008512 2.0

Ixabepilone 

BMS-247550 

LIST OF ABBREVIATIONS 

CA163012 


AE 

ALT 

BUN 

cm 

CR 

CRF 

CT 

CTC 

ECOG 

HCG 

kg 

m 

mg 

mL 

mm 

NCI 

PR 

q 

SAE 

SD 

ULN 

WHO 

adverse event 

alanine aminotransferase 

blood urea nitrogen 

centimeter 

complete response 

case report form 

computed tomography 

Common Toxicity Criteria 

Eastern Cooperative Oncology Group 

human chorionic gonadotropin 

kilogram 

meter 

milligram 

milliliter 

millimeter 

National Cancer Institute 

partial response 

every 

serious adverse event 

stable disease 

upper limit normal 

World Health Organization 

Approved v2.0 930008512 2.0

Ixabepilone 

BMS-247550 

CA163012 


LIST OF REFERENCES 

1 Gehan EA. The determination of the number of patients required in a preliminary and follow-up trial of a 

new chemotherapeutic agent. Journal of Chronic Diseases 1961; 13:346-353. 

2 WHO Handbook of Reporting Results of Cancer Treatment, Geneva, 1979. 

Approved v2.0 930008512 2.0

SYNOPTIC STUDY REPORT - Clinical Trials - Bristol-Myers Squibb

Create successful ePaper yourself

Delete template?

Save as template?