Conditions: Cervical Carcinoma Cervical Adenocarcinoma Cervical Adenosquamous Carcinoma Cervical Carcinoma, Non-SquamousType
Keywords: Ixabepilone BMS-247550 Ixempra Cervical Cancer Epothilone
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 41
Healthy volunteers: no

Brief summary:
Background:

* Ixabepilone is a member of the class of drugs called epothilones. These drugs interfere with the ability of cancer cells to replicate.
* Epothilones are similar to taxanes, another class of drugs, which includes the drug Taxol. Taxol is widely used to treat a variety of cancers.
* Ixabepilone can work in cells that are resistant to Taxol.

Objectives:

* To determine whether ixabepilone is effective for treating cervical cancer.

Eligibility:

* Women 18 years of age or older with cervical cancer.

Design:

* Patients receive ixabepilone intravenously (through a vein) over 60 minutes on the first 5 days of each 21-day treatment cycle. Their dosage may be adjusted according to how their bodies respond to the drug.
* The number of cycles each woman receives depends on her response to the treatment.
* Patients have CT (computed tomography) scans and other tests before starting treatment and then every other treatment cycle to determine the response of the tumor to ixabepilone.
* Patients who can undergo a tumor biopsy (surgical removal of a sample of tumor tissue) are asked to have a biopsy done before starting treatment with ixabepilone and again on the fourth or fifth day of treatment. This procedure is optional.

Detailed description:
Background

* Ixabepilone (Ixempra (Trademark), BMS-247550, NSC 710428) is a semi-synthetic analog of the natural product epothilone B.
* The epothilones are a novel class of non-taxane microtubule-stabilizing agents obtained from the fermentation of the cellulose degrading myxobacteria, Sorangium cellulosum.
* Ixabepilone is active against cancer models that are naturally insensitive to paclitaxel or have developed resistance to paclitaxel, both in-vitro and in-vivo.

Objectives

Primary-

\- Establish the efficacy of the investigational agent ixabepilone in patients with cervical carcinoma when administered as a daily one-hour infusion on days 1 to 5 every three weeks, as measured by overall response (PR (partial response) +CR (complete response)).

Secondary-

* Assess pharmacodynamic endpoints to determine the extent of tubulin polymerization and whether or not there has been activation of cellular death pathways distal to the target.
* Estimate progression-free survival and duration of response.

Eligibility

* Age greater than 18
* Histologic or cytologic confirmation of cervical carcinoma; either squamous cell or non-squamous consisting of cervical adenocarcinoma, cervical adenosquamous carcinoma or cervical carcinoma, non-squamous type.

Design

* Phase II study, open, non-randomized
* Ixabepilone will be administered at a dose of 6mg/m\^2 daily on days 1 through 5, every three weeks.
* Restaging will be done every two cycles using RECIST (Response Evaluation Criteria in Solid Tumors)
* Planned maximum enrollment 76 persons

Arms:
arm 1: Squamous cell carcinoma is a histologic subtype of cervical cancer. Squamous cell carcinoma of the cervix (80%) is much more common than adenocarcinoma of the cervix.

Non squamous carcinoma is a histologic subtype of cervical cancer. It is the second most common form of cervical cancer; consists of adenocarcinoma, adenosquamous and non squamous (not otherwise specified) subtypes.

All participants in both arms received ixabepilone 6 mg/m\^2 x 5 days, each cycle.

Interventions: intervention 1: Ixempra (Ixabepilone (BMS-247550) )
Intervention descriptions: intervention 1: Participants received Ixabepilone 6mg/m\^2 for a total of 30mg/m\^2 inpatient or outpatient intravenously over an hour on the first five days of each 21 day cycle.

Protocol document:
Prot_SAP_000.pdf: 
Ixabepilone in Cervical Carcinoma
CC # 09-C-0037, NCI # 6620
Amendment I, Version Date: 02/04/13
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A Phase II Clinical Trial of Ixabepilone (Ixempra®, BMS–247550, NSC 710428), an 
Epothilone B Analog, in Cervical Cancer
NCI Protocol Number 6620
National Cancer Institute
Center for Cancer Research
Medical Oncology Branch
Drugs used: IXABEPILONE (Bristol-Myers Squibb)/(NSC 710428)
Sponsor:
CTEP (Cancer Treatment Evaluation Program, NCI)
Short Title:
Ixabepilone in Cervical Carcinoma
NCI investigators and points of contact:
Principal Investigator:
Tito Fojo, M.D.1
Building 10 Room 12N226
Bethesda, Maryland 20892
(301) 496-4916
tfojo@helix.nih.gov
Research Nurse:
Maureen Edgerly, R.N.1
Associate Investigators:
Susan Bates, M.D.1
Christina Annunziata, M.D.1
David Kohler, Pharm.D.2
Seth Steinberg, Ph.D.3
Sanjeeve Balasubramaniam, M.D. 1
1 NCI/CCR/Medical Oncology, Bldg 10/12N226
2NIH Clinical Center Pharmacy
3NCI/BDMS
IND Holder:
CTEP (Cancer Treatment Evaluation Program, NCI)
IND Number:
59699
Institutional Review Board:
Michael Hamilton, MD –NCI, CCR, IRB Chairperson 
Building 82, Room 100 (Campus Mail)
9030 Old Georgetown Rd. (Delivery/Hand carry) 
Bethesda, MD 20892-8200
Phone: 301-496-6375
Fax: 301-594-7951
Email (nciirbadmin@mail.nih.gov)


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Précis:
Background
x
Ixabepilone (Ixempra®, BMS-247550, NSC 710428) is a semi-synthetic analog of 
the natural product epothilone B.
x
The epothilones are a novel class of non-taxane microtubule-stabilizing agents 
obtained from the fermentation of the cellulose degrading myxobacteria, 
Sorangium cellulosum.
x
Ixabepilone is active against cancer models that are naturally insensitive to 
paclitaxel or have developed resistance to paclitaxel, both in-vitro and in-vivo.
Objectives
Primary-
x
Establish the efficacy of the investigational agent ixabepilone in patients with 
cervical carcinoma when administered as a daily one hour infusion on day 1 to 5 
every three weeks, as measured by overall response (PR+CR).
Secondary-
x
Assess pharmacodynamic endpoints to determine the extent of tubulin 
polymerization and whether or not there has been activation of cellular death 
pathways “distal” to the target.
x
Estimate progression free survival and duration of response.
Eligibility
x
Age > 18
x
Histologic or cytologic confirmation of cervical carcinoma; either squamous cell or 
non-squamous consisting of cervical adenocarcinoma, cervical adenosquamous 
carcinoma or cervical carcinoma, non-squamous type.
Design
x
Phase II study, open, non-randomized
x
Ixabepilone will be administered at a dose of 6mg/m2 daily on days 1 through 5, 
every three weeks.
x
Restaging will be done every two cycles using RECIST 
x
Planned maximum enrollment 76 persons


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Table of Contents
1 
INTRODUCTION...................................................................................................... 7 
1.1 
STUDY OBJECTIVES........................................................................................ 7 
1.1.1 
Primary: ....................................................................................................... 7 
1.1.2 
Secondary: .................................................................................................. 7 
1.2 
BACKGROUND, TRANSLATIONAL STUDIES AND RATIONALE.................... 7 
1.2.1 
Cervical Carcinoma ..................................................................................... 7 
1.2.2 
Drugs targeting microtubules..................................................................... 10 
1.2.3 
Epothilones................................................................................................ 10 
1.2.4 
Ixabepilone [Ixempra®].............................................................................. 10 
1.2.5 
Translational Studies ................................................................................. 15 
1.2.6 
Rationale for current trial ........................................................................... 18 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT................................................ 21 
2.1 
ELIGIBILITY CRITERIA ................................................................................... 21 
2.1.1 
Inclusion criteria:........................................................................................ 21 
2.1.2 
Exclusion criteria: ...................................................................................... 21 
2.2 
RESEARCH ELIGIBILITY EVALUATION ........................................................ 22 
2.3 
PATIENT REGISTRATION AND TREATMENT RANDOMIZATION................ 22 
3 
STUDY IMPLEMENTATION.................................................................................. 23 
3.1 
STUDY DESIGN .............................................................................................. 23 
3.2 
DRUG ADMINISTRATION............................................................................... 23 
3.2.1 
General guidelines..................................................................................... 23 
3.2.2 
Ixabepilone administration and dosage ..................................................... 23 
3.2.3 
Potential for hypersensitivity reactions related to Cremophor®EL............. 23 
3.2.4 
Immediate management of Allergic/Hypersensitivity Reaction .................. 24 
3.3 
TREATMENT MODIFICATIONS...................................................................... 26 
3.3.1 
General guidelines for treatment modifications at the time of re-treatment 26 
3.3.2 
Treatment modifications for hematologic toxicities and delay in start of cycle
26 
3.3.3 
Treatment modifications for non-hematologic toxicities ............................. 26 
3.4 
CORRELATIVE STUDIES ............................................................................... 27 
3.4.1 
Biopsies for Research Purposes ............................................................... 27 
3.4.2 
Pharmacokinetics ...................................................................................... 28 
3.4.3 
Pharmcodynamics..................................................................................... 28 
3.5 
ON STUDY EVALUATION............................................................................... 29 


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3.5.1 
Cycle one................................................................................................... 29 
3.5.2 
Every restaging cycle................................................................................. 29 
3.5.3 
Every cycle ................................................................................................ 29 
3.5.4 
Weekly treatment monitoring..................................................................... 29 
3.6 
CONCURRENT THERAPIES .......................................................................... 29 
3.7 
SURGICAL GUIDELINES ................................................................................ 30 
3.8 
RADIATION GUIDELINES............................................................................... 30 
3.9 
OFF TREATMENT CRITERIA ......................................................................... 30 
3.9.1 
Post-Treatment Evaluation (Upon Meeting Off Treatment Criteria)........... 30 
3.10 
OFF-STUDY CRITERIA................................................................................ 30 
3.10.1 
Off Study Procedure............................................................................... 31 
3.11 
Follow-Up for Progression Free Survival and Duration of Response............ 31 
4 
SUPPORTIVE CARE............................................................................................. 31 
5 
DATA COLLECTION and EVALUATION............................................................... 32 
5.1 
DATA COLLECTION AND RECORD KEEPING.............................................. 32 
5.2 
RESPONSE CRITERIA (RECIST)................................................................... 32 
5.3 
Toxicity Criteria: Adverse Event Reporting Criteria .......................................... 36 
5.4 
STATISTICAL SECTION ................................................................................. 36 
5.4.1 
Trial Design: .............................................................................................. 36 
5.4.2 
Duration of trial: ......................................................................................... 37 
5.5 
MULTI-INSTITUTIONAL GUIDELINES............................................................ 37 
6 
Human Subjects Protections.................................................................................. 37 
6.1 
RATIONALE FOR SUBJECT SELECTION...................................................... 37 
6.1.1 
Selection based on gender, ethnic background, or race............................ 37 
6.1.2 
Strategies/procedures for recruitment ....................................................... 37 
6.1.3 
Justification for exclusions......................................................................... 38 
6.2 
PARTICIPATION OF CHILDREN .................................................................... 38 
6.3 
EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS .......................... 38 
6.3.1 
Potential benefits to subjects expected from the trial................................. 38 
6.3.2 
Alternative approaches or treatments........................................................ 38 
6.3.3 
Procedure for protecting against or minimizing any potential risks............ 38 
6.3.4 
Provisions for monitoring data collection to ensure safety of subjects....... 39 
6.3.5 
Evaluation of risk/benefit ratio for patients in this trial................................ 39 
6.4 
CONSENT AND ASSENT PROCESSES AND DOCUMENTS........................ 39 


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7 
SAFETY REPORTING REQUIREMENTS/DATA SAFETY MONITORING PLAN . 40 
7.1 
Definitions ........................................................................................................ 40 
7.1.1 
Adverse Events ......................................................................................... 40 
7.1.2 
Suspected adverse reaction ...................................................................... 40 
7.1.3 
Unexpected adverse reaction.................................................................... 41 
7.1.4 
Serious ...................................................................................................... 41 
7.1.5 
Disability .................................................................................................... 41 
7.1.6 
Life-threatening adverse drug experience ................................................. 41 
7.1.7 
Protocol Deviation (NIH Definition)............................................................ 41 
7.1.8 
Protocol Violation (NIH Definition) ............................................................. 42 
7.1.9 
Unanticipated Problem .............................................................................. 42 
7.2 
NCI –IRB Reporting ......................................................................................... 42 
7.2.1 
NCI-IRB Expedited Reporting of Adverse Events, Unanticipated Problems, 
and Deaths............................................................................................................. 42 
7.2.2 
NCI-IRB Requirements for PI Reporting of Adverse Events at Continuing 
Review 42 
7.2.3 
NCI-IRB Reporting of IND Safety Reports................................................. 42 
7.3 
CTEP ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ....... 43 
7.3.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) 
Ixabepilone (BMS 247550, NSC 710428) .............................................................. 43 
7.3.2 
Adverse Event Characteristics................................................................... 46 
7.3.3 
Expedited Adverse Event Reporting.......................................................... 47 
7.3.4 
Expedited Reporting Guidelines ................................................................ 47 
7.3.5 
Routine Adverse Event Reporting ............................................................. 48 
7.3.6 
Secondary Malignancy .............................................................................. 48 
7.4 
DATA AND SAFETY MONITORING PLAN:..................................................... 49 
7.5 
Clinical Trials Agreement ................................................................................. 49 
8 
PHARMACEUTICAL INFORMATION.................................................................... 51 
8.1 
BMS-247550 (710428) ..................................................................................... 51 
8.1.1 
Chemical Name......................................................................................... 51 
8.1.2 
Other Names ............................................................................................. 51 
8.1.3 
Molecular Formula..................................................................................... 51 
8.1.4 
Mode of Action........................................................................................... 51 
8.1.5 
Description................................................................................................. 51 
8.1.6 
How Supplied ............................................................................................ 51 


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8.1.7 
Preparation................................................................................................ 51 
8.1.8 
Storage...................................................................................................... 52 
8.1.9 
Stability...................................................................................................... 52 
8.1.10 
Route of Administration.......................................................................... 52 
8.1.11 
Incompatibilities...................................................................................... 52 
8.1.12 
Potential Drug Interactions ..................................................................... 52 
8.1.13 
Drug ordering and accountability............................................................ 53 
8.1.14 
Precautions/overdose............................................................................. 53 
8.1.15 
Disposition of study medications ............................................................ 53 
8.2 
DIPHENHYDRAMINE HYDROCHLORIDE (HCl) INJECTION......................... 53 
8.2.1 
General issues........................................................................................... 53 
8.2.2 
Other pharmaceutical issues: .................................................................... 54 
8.3 
RANITIDINE HYDROCHLORIDE (HCl) INJECTION ....................................... 54 
8.3.1 
General issues........................................................................................... 54 
8.3.2 
Other pharmaceutical issues: .................................................................... 54 
9 
REFERENCES....................................................................................................... 56 
10 
Appendices.......................................................................................................... 61 
APPENDIX A:  Data/Specimen Collection, Storage and Disposition Procedures...... 61 
APPENDIX B: Study Calendar .................................................................................. 63 
APPENDIX C: List of drugs that may have potential CYP3A4 interactions................ 64 
APPENDIX D:  Care of fingernails during treatment with Ixabepilone ....................... 66 


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1
INTRODUCTION
1.1
STUDY OBJECTIVES
1.1.1 Primary: 
x
Establish the activity of ixabepilone administered daily as a one-hour infusion on
five successive days (daily x 5), every three weeks in patients with cervical 
carcinoma previously treated with chemotherapy, as determined by overall 
response (PR+CR). Activity will be measured using standard RECIST guidelines. 
1.1.2 Secondary:
x
Assess pharmacodynamic endpoints after ixabepilone administration to 
determine the extent of tubulin polymerization and whether or not there has been 
activation of cellular death pathways “distal” to the target.
x
Determine progression free survival and duration of response
1.2
BACKGROUND, TRANSLATIONAL STUDIES AND RATIONALE
1.2.1 Cervical Carcinoma
Cervical cancer is the second most common cancer among women worldwide [1]. The 
proportion and absolute incidence of the adenocarcinoma subtype has increased 
relative to the more common squamous cell subtype of cervical cancer [2, 3]. Although 
a recent study found that the adenocarcinoma subtype had only a minor prognostic 
importance for survival, the prognostic significance of the adenocarcinoma subtype 
remains controversial [4, 5].  Consequently, there has been no attempt to sub classify 
recurrent adenocarcinoma in therapeutic trials. In the United States cervical cancer 
there were an estimated 9710 new cases in 2006 (NCI SEER CACJC 2006) with an 
estimated 3700 estimated deaths.
Table 1: Epidemiology of Cervical Cancer
Stage at Presentation:
Localized
55%
Regional
31%
Distant
8%
Unstaged
6%
Histopathology: 
Squamous cell carcinoma
75 - 80 %
Large cell, keratinizing
Large cell, nonkeratinizing
Small cell (not neuroendocrine)
Verrucous carcinoma
Adenocarcinomas
15 - 20 %
Adenous malignum
Mucinous
Papillary
Endometrial
Clear cell
Adenoid cystic


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Adenosquamous
Rare
Glassy cell carcinoma
Rare
Neuroendocrine small cell carcinoma
Rare
Metastatic Cervical Carcinoma
Systemic chemotherapy in metastatic squamous carcinoma of the cervix
Squamous cell carcinoma (SCC) of the cervix (80%) is much more common than 
adenocarcinoma of cervix (15%). Several single chemotherapy agents and combination 
regimens are active in patients who present with metastatic disease or suffer a 
recurrences of SCC of cervix that are not amenable to potentially curative treatment 
with surgery and/or radiation therapy. The most active single agents are cisplatin (RR  
20-32%) [6], ifosfamide (RR 22 %) [7], paclitaxel (RR 17 %) [8], vinorelbine (RR 15 %) [9] 
and topotecan (RR 19 %) [10].
While combination regimens (cisplatin/ifosfamide, cisplatin/paclitaxel, cisplatin/topotecan,
or carboplatin/paclitaxel) have demonstrated higher response rates than the single agent 
platinum compounds, the only trial to show a survival benefit to multiagent therapy with 
advanced disease was cisplatin (50 mg/m2 every three weeks) with topotecan (0.75 
mg/m2 days 1 to 3 every three weeks). Compared to cisplatin alone, the 
topotecan/cisplatin group had a median survival 9.4 versus 6.5 months (p = 0.017), but 
significantly more toxicity [11].
Systemic chemotherapy in metastatic adenocarcinoma of the cervix:
Systemic chemotherapy is the recommended treatment for metastatic or recurrent 
adenocarcinoma of the cervix not amenable to irradiation or surgery. However, there is 
limited data on the treatment of recurrent cervical adenocarcinoma because of its 
infrequent occurrence and the paucity of active chemotherapeutic agents. The available 
data on the use of chemotherapy in cervical adenocarcinoma comes from clinical trials, 
many of which have been conducted by the Gynecologic Oncology Group (GOG) [12-
24]. Single agent trials in patients who had received prior irradiation and/or 
chemotherapy demonstrated evidence of activity for six chemotherapeutic agents: 
cisplatin, piperazinedione, ifosfamide gallium nitrate, 5-FU plus leucovorin and paclitaxel
(Table 1). Agents that have been tested and deemed ineffective include: CCNU, methyl-
CCNU, mitoxantrone, etoposide (VP-16), teniposide (VM-26), vinblastine, 
aminothiadiazole, echinomycin, ICRF-159 (Razoxane), dianhydrogalactitol, diaziquone 
(AZQ) and tamoxifen.
Several studies have noted the activity of paclitaxel in cervical adenocarcinoma. The 
first published suggestion that paclitaxel may be active in cervical adenocarcinoma 
came from a study in which paclitaxel was used as part of a combination chemotherapy 
regimen principally in the neoadjuvant setting [23]. Whereas a prior study had noted an 
overall pathologic response rate of 47% with weekly cisplatin and epirubicin as 
neoadjuvant therapy [22], Lissoni and colleagues reported that the addition of paclitaxel 
to this neoadjuvant regimen resulted in a pathologic response rate of 65% [23]. 
Subsequent to this, single agent activity was reported in a phase 2 GOG study of 46 
patients treated with 170 mg/m2 paclitaxel (or 130 mg/m2 for patients with prior pelvic 
irradiation) given as a 24 hour infusion every three weeks [16]. The overall response 
rate for the 42 assessable patients was 31% (4 CRs and 9 PRs). In addition, Ota et al 


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reported a single case of metastatic cervical adenocarcinoma with a complete response 
after twenty cycles of weekly paclitaxel [17].
Table 1: Chemotherapy for Adenocarcinoma of the Cervix
Single Agent Chemotherapy
Author (Year)
Agent
Pts
RR1
Comments
Thigpen (86)12
Cisplatin
122
25%
Only 50 mg/m2 q3wks; lowest 
WBC: 1600/mL
Thigpen (86)12
Piperazinedione
62
17%
9 mg/m2 q 3wks; drug not 
available
Sutton (93)13
Ifosfamide
412
15%
1.5 g/m2/d x 5d (1.2 if prior RT); 
28 pts with adenocarcinoma
Malfetano 
(95)14
Gallium Nitrate
262
11%
750 mg/m2 q3wks; 21 pts with 
adenocarcinoma
Look (97)15
5-FU + High Dose Leucovorin
43
13%
370 mg/m2 qd x 5d q4wks; G3/4 
ANC: 53%
Curtin (01)16
Paclitaxel (24h infusion q3 weeks)
422
31%
170 mg/m2; 130 mg/m2 if prior 
pelvic RT; G3/4 ANC: 74%
Ota (01)17
Paclitaxel (weekly)
1
1/1
Case report.  70 mg/m2 by 1h 
infusion
Combination Chemotherapy Regimens
Author (Year)
Agent
Pts
RR
Comments
Kavanagh 
(87)18
Cisplatin/5-FU/Doxorubicin
24
42%
Cis: 50-60mg/m2; 5-FU: 500-800mg/m2;
Dox: 40-50mg/m2 G3/4ANC: 38%
Bates (91)19
Cisplatin/Mitomycin C
1
1/1
Case report. Cis: 50 mg/m2 q3wks; 
MMC: 10 mg/m2/q6wks
Fanning (95)20
Cisplatin/5-FU/Ifosfamide
92
78%
Cis: 90 mg/m2/5-FU: 1500 mg/m2; Ifos: 3 
g/m2; G4ANC:6%
Umesaki 
(99)21
Cisplatin/Mitomycin/Etoposide
31
16%
Cis: 50 mg/m2; MMC: 10 mg/m2; E: 100 
mg/m2x3; G3/4ANC: 45%
Zanetta (97)22
Cisplatin/Epirubicin
22
50%
Neoadjuvant. Cis: 50 mg/m2 qwk; Epi: 
70 mg/m2 q3wks; +GF; G3/4ANC: 45%
Lissoni (97)23
Cisplatin/Epirubicin/Paclitaxel
19
53% 
17 neoadjuvant. Cis: 50 mg/m2; Epi: 70 
mg/m2 Pac: 135-175 mg/m2; G3/4 ANC: 
60%
Saito (04)24
Cisplatin/Aclacinomycin 
A/Mitomycin C
16
75%
IV or Intra-arterial for localized disease
1Some responses have been recalculated from that reported based on currently accepted criteria and 
histologic breakdown
2Data reported for “Nonsquamous Carcinoma”. Insufficient information given to determine activity in 
adenocarcinoma subtype
Abbreviations: Pts: patients; RR: response rate; RT: radiation therapy; G: toxicity grade; ANC: 
neutropenia; +GF: growth factor (GCSF or GMCSF)


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1.2.2 Drugs targeting microtubules
Vincristine, first used in clinical oncology in the 1950’s, was the first drug to target the 
microtubules (MTs). Since then, the successful introduction of similar agents has 
established the MT as an effective target [24]. While most microtubule-targeting agents 
(MTAs) initially used in clinical oncology resulted in depolymerization of microtubules, 
the success of the taxanes demonstrated that stabilization of microtubules was an 
equally or more efficacious mechanism of action [26,27].
1.2.3 Epothilones
The activity of the taxanes, evidenced by their widespread use, led to the search for 
additional agents with similar mechanisms of action. Several classes of MTAs were 
identified, and these are at various stages of development [28-36]. Among these, are 
the epothilones, a novel class of non-taxane MT-stabilizing agents obtained from the 
fermentation of the cellulose degrading myxobacteria, Sorangium cellulosum, that have 
received special attention [28-31]. As a group the epothilones are more potent than the 
taxanes and are active against tumors refractory to taxanes, especially those 
expressing P-glycoprotein (Pgp). These two properties have driven the development 
of the epothilones and it is because of their ability to overcome tumor resistance 
mechanisms that this class of agents has been of great interest to our groups in 
the Medical Oncology Branch whose focus of research and clinical investigations 
are mechanisms of drug resistance and ways to overcome drug resistance 
clinically. Finally the epothilones are also more soluble than the taxanes and have 
enhanced oral bioavailability. These properties make these agents desirable candidates 
for clinical development. This phase II study is designed to examine activity of the 
epothilone B analog, ixabepilone (Ixempra®) against cervical carcinoma [37].
1.2.4 Ixabepilone [Ixempra®]
General comments: Ixabepilone (Ixempra®) is a member of the novel class of non-
taxane MT-stabilizing compounds known as epothilones obtained from the fermentation 
of the cellulose degrading myxobacteria, Sorangium cellulosum [28-31]. Similar to 
paclitaxel and other taxanes, epothilones block cells in mitosis, resulting in cell death 
[28-30]. Ixabepilone is being developed by Bristol-Myers Squibb for the treatment of 
cancer [37].
Chemistry: The epothilones are a new class of agents that like the taxanes, promote the 
polymerization of tubulin. The epothilones are obtained from the fermentation of the 
myxobacterium, Sorangium cellulosum. The chief components of the fermentation 
process are epothilones A and B.  These natural products are polyketide derived, 
sixteen-membered ring macrolides. Ixabepilone, [1S-[1R*, 3R*(E), 7R*, 10S*, 12R*, 
16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-
thiazolyl)ethenyl]-17-oxa-4-azabicylo[14.1.0]heptadecane-5,9-dione, is a semisynthetic 
derivative of epothilone B that has improved in vivo metabolic stability when compared 
to its natural precursor.The key difference between ixabepilone and epothilone B is the 
replacement of the macrolide ring oxygen atom with a nitrogen atom to give the 
corresponding macrolactam. Ixabepilone has a molecular formula of C27H42N2O5S 
and a molecular weight of 506.7 grams/mole.


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Preclinical pharmacology studies: In preclinical pharmacology studies ixabepilone 
demonstrated significant improvement over paclitaxel in several critical aspects. [A] 
Ixabepilone is active against cancer models that are naturally insensitive to paclitaxel or 
have developed resistance to paclitaxel, both in-vitro and in-vivo, most notably efflux 
transporters (eg, P-glycoprotein and multidrug-resistance protein-1) and in preliminary 
studies, models with relative insensitivity mediated by the expression of the class III 
isoform of beta-tubulin [38, 39]. Ixabepilone exhibits a very impressive and broad 
spectrum of antitumor activity against paclitaxel-sensitive (A-2780, HCT 116 and LS 
174T) tumors as well as paclitaxel-resistant human colon tumors (HCT116/VM46), 
ovarian carcinoma (Pat-7 and A2780Tax) and breast carcinoma (Pat-21) models. [B] 
Ixabepilone is orally efficacious; the antitumor activity produced after oral administration 
is comparable to that produced by parenteral administration of the drug.  [C] Synergistic 
activity of ixabepilone with a number of antineoplastic agents has been demonstrated in 
vitro. These preclinical efficacy data suggest that ixabepilone has the potential to 
demonstrate improved clinical efficacy in paclitaxel-insensitive and sensitive disease 
types.
Clinical Information: Ixabepilone has undergoing phase I/II/III testing in humans. The 
NCI has had extensive experience with ixabepilone dating to the initial phase I trials. 
Several intravenous infusion schedules were evaluated in the phase I setting, including 
a single dose every 3 weeks, a daily dose for 3 days every 3 weeks, a weekly schedule, 
and a daily dose for five consecutive days every 21 days. Both the daily dose for 3 days 
every 3 weeks and a daily dose for five consecutive days every 21 days were 
developed in the Medical Oncology Branch of the NCI. A bolus regimen every three 
weeks established 50 mg/m2 as the MTD, with neurotoxicity and neutropenia as dose 
limiting toxicities – although subsequent trials eventually established lower doses of 30 
to 40 mg/m2 as the recommended doses [40-42]. In these three studies ixabepilone was 
administered every 21 days to sixty-three patients with the schedule at several dose 
levels in the range of 7.4–65 mg/m2. After observing a hypersensitivity reaction in one 
patient on the 30-mg/m2 dose, oral H1/H2 blockers were administered in all three 
studies [39]. Responses were observed in patients with melanoma, non-small cell lung 
cancer (prior docetaxel), ovarian cancer (prior paclitaxel), and breast cancers (taxane 
naïve and taxane refractory). Although both 40 and 50 mg/m2 doses emerged as the 
recommended doses for phase II trials subsequent experience found 50 mg/m2
ixabepilone every three weeks intolerable and identified 40 mg/m2 as the better 
recommendation. DLTs included prolonged grade 4 neutropenia, peripheral neuropathy, 
gastrointestinal discomfort, fatigue, and emesis.
Phase I studies were also designed to establish the MTD for ixabepilone administered 
as a 1-hour infusion on five consecutive days every 3 weeks - the schedule pursued in 
the Medical Oncology Branch of the NCI. In the initial phase I study 27 patients were 
enrolled. Twenty-one of these 27 patients had received prior taxane therapy including 
five who had received prior Taxol® or Taxotere® less than six months prior to receiving 
ixabepilone. Dose levels included 1.5, 3, 6 and 8 mg/m2/d administered on each of five 
successive days. Intra-patient dose escalation without/with GCSF was permitted if 
dose-limiting toxicity (DLT) was not observed in the previous cycle. All three patients 
receiving 8 mg/m2/d without GCSF in cycle 1 experienced grade 4 neutropenia as the 
DLT. Accordingly 6 mg/m2/d was identified as the maximum tolerated dose (MTD) 


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ZLWKRXW*&6)DQGWKHUHFRPPHQGHGSKDVH,,GRVH$GRVHPJP2/d was 
DGPLQLVWHUHGLQF\FOHVWRSWV$OOSDWLHQWVUHFHLYHGDGRVHPJP2/d either 
initially or after intra-patient dose escalation. A total of 102 cycles were administered 
PHGLDQRISHUSDWLHQWZLWKSDWLHQWVUHFHLYLQJF\FOHV1LQHW\-nine of the 102 
F\FOHVZHUHJLYHQDWDGRVHPJP2/d. Non-hematologic grade 3 toxicities included: 
fatigue (7 cycles), stomatitis (2 cycles) and anorexia (1 cycle). All other non-hematologic 
toxicities were grade 2 or less including neurotoxicity in 17 patients. Pharmacokinetic 
studies indicated steady state is reached by day 3, with Cmax and Cmin values 
suggesting no accumulation (day 5 vs. day 1). Additional parameters include: a t1/2a of 
.115 ± .062 hours, a t1/2b of 12.7 ± 4.4 hours, a Vdss of 8.08 ± 3.99 L/kg, and a 
clearance of 419 ± 123 ml/min/m2. A partial response was observed in 5 patients 
including two patients with breast cancer, two patients with cervical cancer and one 
patient with basal cell carcinoma; with > 50% reduction in CA125 in two of 12 patients 
with advanced ovarian cancer (all breast, cervical and ovarian cancer patients had prior 
taxane therapy). Hypersensitivity reactions were not observed using a pre-medication 
regimen consisting of H1 and H2 antagonists without steroids prior to each dose of 
ixabepilone. We concluded that a dose of 6 mg/m2/d x 5d of ixabepilone was well 
tolerated, and clinically active in patients with cancer who have previously received 
taxane therapy [43]. In addition, twenty-six patients were enrolled in a phase I trial in 
which ixabepilone was administered as a 1-hour infusion on three consecutive days 
every 3 weeks [44]. The DLT was, once again, grade 4 neutropenia and again there 
was no grade 3 or 4 peripheral neuropathy. Interestingly, the recommended dose of 
ixabepilone administered on a daily for three consecutive days schedule every 21 days 
was 8 mg/m2 per day (24 mg/m2 per cycle) a total dose that was less the 30 mg/m2 of 
the daily for five consecutive days. Ixabepilone was also evaluated on a weekly 
schedule.
Finally, in trials with weekly administration investigators were able to administer weekly 
doses of 30 mg/m2, with neurotoxicity noted as the DLT. However, because of a lack of 
significant advantages, this schedule has not been aggressively pursued [45-47].
Phase I trials also demonstrated the feasibility of combining ixabepilone with other 
cytotoxic agents much like the taxanes. Combinations included: (a) ixabepilone 40 
mg/m2 plus carboplatin AUC 5 [48] (b) ixabepilone at 40 mg/m2 initially with 2,000 
mg/m2 capecitabine per day for 14 days with a 1-week rest every 21 days and 
subsequently with lower capecitabine doses [49,50] (c) ixabepilone on day 1 of a cycle 
with gemcitabine on days 1 and 8 of a 21-day cycle with ixabepilone at a dose of 20 
mg/m2 and gemcitabine at a dose of 900 mg/m2 the recommended doses [51].
In phase II studies, single-agent ixabepilone showed very encouraging clinical activity in 
metastatic breast cancer, with objective response rates ranging from 12% in patients 
that had been “heavily pretreated” and whose disease was deemed refractory to 
anthracyclines, taxanes, and capecitabine to 42% in patients with metastatic disease 
whose prior therapy had been limited to adjuvant anthracycline-based chemotherapy 
[52-55]. In the first trial, conducted in the Medical Oncology Branch, ixabepilone was 
administered at 6 mg/m2 per day on days 1–5 every 3 weeks to 37 patients with 
advanced breast cancer with measurable disease who had received at least one prior 
regimen that contained paclitaxel or docetaxel [52]. An overall response rate of 21% in 


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these patients who had received at least one prior regimen that contained paclitaxel or 
docetaxel was noteworthy. Grade 3 and 4 toxicities included neutropenia (35%), febrile 
neutropenia (14%), fatigue (14%), diarrhea (11%), nausea/vomiting (5%), 
myalgia/arthralgia (3%), and sensory neuropathy (3%). A second study was also 
conducted to determine the efficacy and safety of ixabepilone in patients with taxane-
refractory or taxane-naïve metastatic breast cancer [53]. Patients who had experienced 
disease progression while receiving or within 4 months of taxane therapy (6 months if
adjuvant taxane only), and who had a taxane as their last regimen, received ixabepilone 
(1- or 3-hour infusion of 50 mg/m2 or 3-hour infusion of 40 mg/m2 every 3 weeks). Of 49 
patients treated with 40 mg/m2 ixabepilone during 3 hours, 35 (73%) had experienced 
disease progression within 1 month of their last taxane dose. The response rate was 
12% (95% CI, 4.7% to 26.5%). All responses (n = 6) were partial. Each of the 
responders had extensive tumor metastases at baseline and had experienced 
progressive disease after multiple prior therapies. Five of these patients entered the 
study having experienced disease progression within 1 month of their last dose on their 
most recent taxane-containing regimen, while only one had responded to the most 
recent taxane therapy. In responders, the median response duration was 10.4 months. 
In 20 patients (41%), stable disease was the best outcome. Median time to progression
was 2.2 months (95% CI, 1.4 to 3.2 months); median survival was 7.9 months. For 
treated patients across all cohorts (intent-to-treat population), the response rate was 
also 12% (eight of 66). Treatment-related adverse events in the study were manageable 
and primarily grade 1/2. The most frequent treatment-related grade 3 adverse events 
were fatigue (27%), sensory neuropathy (12%), myalgia (10%), nausea (6%), and 
vomiting (6%). Treatment-related neuropathy was mostly sensory, mild to moderate in 
severity (grade 1 or 2), cumulative, and reversible, not unlike the experience with the 
taxanes. Treatment-limiting or severe neuropathy generally resolved or lessened in 
intensity within 1–2 months after therapy discontinuation, again not unlike the taxanes. 
In terms of hematological toxicities, only six patients (12%) required growth factor 
support for neutropenia during their treatment. Treatment-related febrile neutropenia 
was reported in three patients (6%) (two patients reported febrile neutropenia; one 
patient reported infection with neutropenia). The results of this study provided further 
support for the pre-clinical observations demonstrating ixabepilone could be active 
against taxane-resistant tumors of cross-resistance especially since in the latter study, 
the taxane had to have been the most recent therapy administered and there had to be 
evidence of disease progression while on therapy or within 4 months of the last dose. 
Thus, the patient population consisted of those with tumors highly resistant to a taxane 
and as such provided a very demanding test of the hypothesis.
On October 16, 2007, the U.S. Food and Drug Administration (FDA) approved 
ixabepilone for injection (Ixempra™, made by Bristol-Myers Squibb) for the following 
two indications:
x
Ixabepilone is indicated in combination with capecitabine for the treatment of patients 
with metastatic or locally advanced breast cancer resistant to treatment with an 
anthracycline and a taxane, or whose cancer is taxane resistant and for whom further 
anthracycline therapy is contraindicated.
x
Ixabepilone is indicated as monotherapy for the treatment of metastatic or locally
advanced breast cancer in patients whose tumors are resistant or refractory to 
anthracyclines, taxanes, and capecitabine.


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Approval was based on:
x
A randomized, multinational, open-label trial of 752 patients with locally 
advanced or metastatic breast cancer that evaluated the efficacy and safety of 
ixabepilone administered at a dose of 40 mg/m2 IV once every three weeks plus 
capecitabine compared to therapy with capecitabine alone [56].
x
A single arm trial of ixabepilone monotherapy in 126 patients with metastatic or 
locally advanced breast cancer previously treated with an anthracycline, a taxane 
and capecitabine, and who had disease progression or, in the case of the 
anthracycline, received a minimum required cumulative dose [57].
In the randomized, multinational, open-label trial that evaluated the efficacy and safety 
of ixabepilone plus capecitabine compared to therapy with capecitabine alone, patients 
had to have previously received an anthracycline and a taxane, had evidence of 
disease progression or resistance, or, in the case of the anthracycline, received a 
minimum required cumulative dose. Treatment arms were balanced with regards to
prior therapies, disease sites, hormone receptor status and HER2 expression. Patients 
receiving combination therapy had a statistically significant improvement in progression-
free survival (PFS), defined as radiologic progression or death from any cause (hazard 
ratio 0.69, p < 0.0001). The median PFS was 5.7 months in the combination arm and 
4.1 months in the capecitabine alone arm. Patients in the combination arm also had an 
increased objective tumor response rate. Survival data for this trial are to be reported in 
late 2008. In this trial treatment with ixabepilone caused new or worsening peripheral
neuropathy in ~65% of patients treated. Grade 3/4 peripheral neuropathy occurred in 
23% of patients treated with ixabepilone and capecitabine. Grade 3/4 peripheral 
neuropathy was not reported in the capecitabine alone arm. By comparison, in the 
ixabepilone monotherapy trial, 14% of patients experienced grade 3/4 peripheral 
neuropathy. With cessation of therapy neuropathy was reversible to grade 1 or better in 
the majority of patients. Ixabepilone in combination with capecitabine resulted in a 68% 
incidence of grade 3/4 neutropenia compared to 11% with the capecitabine alone 
regimen. That ixabepilone was the principal offending agent was supported by a 54% 
incidence of grade 3/4 neutropenia when ixabepilone was used as monotherapy. 
Twelve patients receiving ixabepilone with capecitabine died from complications arising 
from neutropenia. The incidence of neutropenia-associated deaths was higher in 
patients with moderate or severe hepatic impairment baseline when treated with both 
ixabepilone and capecitabine. These observations led the FDA to recommend that the 
combination of capecitabine plus ixabepilone should not be used in patients with 
moderate or severe hepatic impairment. Other commonly observed toxicities (> 20%) 
included anemia, leukopenia, thrombocytopenia, fatigue/asthenia, myalgia/arthralgia, 
alopecia, nausea, vomiting, stomatitis.
In the single arm trial of ixabepilone monotherapy patients with measurable disease 
who had tumor progression while receiving prior anthracycline, taxane, and 
capecitabine were enrolled. Ixabepilone 40 mg/m2 monotherapy was administered as a 
3-hour intravenous infusion on day 1 of a 21-day cycle. The primary end point was 
objective response rate (ORR), assessed by an independent radiology facility (IRF). A 
total of 126 patients were treated and 113 were assessable for response. Patients were 
heavily pretreated with 88% having received at least two lines of prior chemotherapy in 


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the metastatic setting. IRF-assessed ORR was 11.5% (95% CI, 6.3% to 18.9%) for 
response-assessable patients. Investigator-assessed ORR for all treated patients was 
18.3% (95% CI, 11.9% to 26.1%). Fifty percent of patients achieved stable disease 
6'DFKLHYHG6'PRQWKV0HGLDQGXUDWLRQRIUHVSRQVHDQGSURJUession-
free survival were 5.7 and 3.1 months, respectively. Median overall survival was 8.6 
months. Patients received a median of 4.0 treatment cycles (range, one to 16 cycles), 
DQGRISDWLHQWVUHFHLYHGHLJKWF\FOHV*UDGHWUHDWPHQW-related events
included peripheral sensory neuropathy (14%), fatigue/asthenia (13%), myalgia (8%), 
and stomatitis/mucositis (6%). Resolution of grade 3/4 peripheral sensory neuropathy 
occurred after a median period of 5.4 weeks. The authors concluded that ixabepilone 
demonstrated clear activity and a manageable safety profile in patients with MBC 
resistant to anthracycline, taxane, and capecitabine. Responses were durable and 
notable in patients who had not previously responded to multiple prior therapies.
Ixabepilone has also been evaluated in the neoadjuvant setting [58]. That study was 
designed to determine the pathological response obtained with ixabepilone as 
neoadjuvant therapy for breast cancer and to obtain tumor samples for analysis of gene 
expression and identification of potential predictors of response to ixabepilone. Based 
on the genomic study, patients with hormone receptor–negative disease were more 
likely to respond to ixabepilone [58].
Finally, based on the presence of Cremophor® EL in the formulation of ixabepilone, the 
potential for hypersensitivity reactions exists with intravenous administration of this 
compound. Although the quantity of Cremophor® EL in ixabepilone is equivalent to 
three times that in the same dose of Taxol®, its greater potency has resulted in a 
Cremophor® EL to total volume that is less than that achieved when Taxol®, which 
includes Cremophor® EL in its formulation, has been administered (15). In clinical trials, 
anaphylaxis and severe hypersensitivity reactions (dyspnea, hypotension requiring 
treatment, angioedema, and generalized urticaria) have occurred in 2% of patients 
receiving Taxol®. It is not known whether the hypersensitivity reaction is due to 
paclitaxel, Cremophor® EL, or both. The reported incidence of anaphylaxis with other 
Cremophor® EL-containing compounds is much lower than with Taxol® (16). For 
example, cyclosporine for injection has rarely been associated with anaphylactic 
reactions (approximately 1 in 1,000). Although the low incidence of anaphylactic 
reactions with Cremophor® EL containing compounds other than Taxol®, suggest this 
may not be a significant problem, some cases of hypersensitivity have been reported 
with ixabepilone but the incidence of this has been very low and very rare in the NCI 
experience with a daily administration on 5 consecutive days. Prophylaxis for 
hypersensitivity reactions has been similar to the “standard” Taxol® pre-medication 
regimen but has not included steroids; instead consisting of the following: (1) 
diphenhydramine 50 mg IV, 30 to 60 minutes before the administration of ixabepilone; 
and (2) cimetidine 300 mg or ranitidine 50 mg IV, 30 to 60 minutes before the 
administration of ixabepilone. 
1.2.5 Translational Studies
Every attempt will be made to recruit patients with disease that can be sampled by 
biopsy. In these patients, every attempt will be made to obtain tissue before the start of 
treatment and after the completion of the fourth or fifth dose of ixabepilone. Both 


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biopsies will be processed in one of three ways: (1) for immunohistochemical staining; 
(2) for RNA; and (3) for protein isolation, if a sufficient quantity is available. We would 
note here that we have extensive experience examining the effect of microtubule 
targeting agents on tumors both in renal cell carcinoma and in breast cancer using both 
immunoblot analysis and immunohistochemistry [59]. In renal cell carcinomas, we 
pursued a strategy validated in our laboratories that exploited the fact that alpha-tubulin 
can undergo several posttranslational modifications after assembly into stabilized 
microtubules, including acetylation and detyrosination. We had previously observed 
these modifications in cell culture after exposure to agents that stabilize microtubules. 
Our objective was to develop a straightforward and dependable assay to show tubulin 
target engagement in tumor tissue after treatment of patients with ixabepilone. To that 
end we assessed the levels of post-translationally modified alpha-tubulin in lysates of 
cultured malignant cell lines, as well as in both tumor tissue and peripheral blood 
mononuclear cells derived from patients before and after treatment with ixabepilone. 
Modification-specific antibodies permitted quantitative Western blot analysis. In cultured 
cell lines, the levels of detyrosinated (glu-terminated) and acetylated alpha-tubulin 
increased after microtubule stabilization induced by ixabepilone. ixabepilone treatment 
also induced a 2-fold to 25-fold increase in detyrosinated alpha-tubulin levels in 11 of 13 
serial biopsies and a 2-fold to 100-fold increase in acetylated alpha-tubulin in 11 of 12 
serial biopsies obtained from patients receiving ixabepilone. Overall, little or no 
difference in tubulin modifications were observed between the before and after 
ixabepilone treatment in lysates from their peripheral blood mononuclear cells at the 
time point examined. We concluded based on this experience that assessing the levels 
of detyrosinated and/or acetylated alpha-tubulin provides a simple and reliable assay to 
show target engagement by the microtubule-stabilizing agent, ixabepilone. Furthermore, 
this type of analyses can provide further understanding of therapeutic success or failure 
of microtubule-stabilizing agents in cancer therapy, since one can discern whether 
failure to benefit a patient by shrinking their tumor is a consequence of failure of the 
drug to engage its target or a consequence of a distal block to cell death – the 
possibility we wish to further elucidate in the current study. In breast cancer biopsies 
were collected at baseline and during cycle 2 from five patients (one patient had a 
partial response, two patients had stable disease, and two patients had progressive 
disease) and were confirmed by pathology to contain tumor. Four of these paired patient 
biopsies were analyzed by Western blot. For one patient, the baseline sample was not 
adequate. Increased acetylation of alpha-tubulin was seen by Western blot for all four
patients, as was increased detyrosination (glu terminated alpha-tubulin). Because the 
protein lysates run on Western blot contain both tumor and stromal components of the 
biopsy, we next chose to quantify tumor changes alone by immunohistochemistry. Four 
of the five paired patient biopsies had tissue available for sectioning for 
immunohistochemistry. For one patient who had a partial response to ixabepilone, levels 
of acetylated alpha-tubulin were detected in both tumor and stromal cells in the baseline 
sample and increased in both cellular compartments with treatment. In contrast, in a 
patient who had progressive disease, levels of acetylated alpha-tubulin were detected 
only in stromal cells at baseline and increased in the stroma but were still absent in the 
tumor cells with treatment. Baseline levels of acetylated alpha-tubulin were present 
before treatment and increased after treatment in the patients with response and stable 


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disease, and levels of glu-terminated alpha-tubulin increased in all patients with 
treatment. Thus from the available paired tumor biopsies, we observed increased levels 
of both glu-terminated and acetylated alpha-tubulin after treatment, indicating that 
ixabepilone stabilized microtubules in the target tissue. Measures of stabilized 
microtubules may not only demonstrate a drug effect, but may also help to predict
response when examined in a pretreatment specimen. Interestingly, we found that 
acetylated alpha-tubulin levels were higher at baseline in the tumor cells of patients 
whose tumors responded or in patients with stable disease than in the patient whose 
tumor did not respond. In the patient with progressive disease, baseline levels of 
acetylated alpha-tubulin within the tumor were not detectable by immunohistochemistry. 
Thus, our results suggest that a tumor with inherent microtubule stability might be more 
likely to respond to a stabilizing agent with additional microtubule stabilization and 
decreased proliferation. Although the small numbers of patients biopsied in this group 
limits our ability to make more definitive statements, these interesting observations are 
hypothesis generating and should be considered for additional study. This again is an 
observation we seek to pursue in this trial.
The following translational studies will be performed:
1) Immunohistochemical staining will be performed using antibodies that as 
described above can assess the extent of tubulin stabilization (antibodies that 
detect acetylated alpha-tubulin and detyrosinated (glu-terminated) alpha-tubulin.
Specifically we will be looking to see if in the malignant cells, tubulin 
polymerization occurs following treatment with ixabepilone as evidenced by 
enhanced staining with the acetylated alpha-tubulin and detyrosinated (glu-
terminated) alpha-tubulin antibodies. If there are normal cells in the biopsy (a 
likely possibility) we will be able to compare the observations in malignant cells 
with that in normal cells. This will allow us to determine if ixabepilone has 
reached its target and resulted in tubulin polymerization, by comparing the results 
in the post-treatment sample with those in the pre-treatment sample. This 
information will be valuable in analyzing the reasons for treatment failure by 
discriminating between an absence of an effect on the target (tubulin) versus a 
lack of subsequent events that leads to cell death. Because both the pre-
treatment and post-treatment samples will be in blocks we will be able to easily 
perform additional studies, including additional immunohistochemical stains. One 
such stain will utilize an antibody that detects the 85kDa fragment generated 
when PARP cleavage occurs. We are aware of the use of this antibody in other 
settings, and in one center, it has been used to examine some tumor samples 
obtained after the administration of ixabepilone. In one patient with breast 
adenocarcinoma metastatic to the skin, investigators were able to demonstrate 
immunostaining with the antibody against 85kDa fragment 24 hours after the 
administration of ixabepilone. Immunostaining for p53 will also be performed [42]. 
2) RNA, and will be extracted and this will be banked. Its fate will depend on the 
response rates observed in this trial. If ixabepilone is found to be active in over 
20% of patients, then all samples obtained will be analyzed by cDNA microarray 
to determine if differences exist which can discriminate responding from non-
responding tumors. However, if no significant activity is observed with 
ixabepilone in cervical cancer, it is unlikely that cDNA microarray, which entails a 


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substantial amount of work, will be carried out. Also, if ixabepilone is found to be 
active in over 20% of patients, the expression of beta-tubulin isotypes will be 
determined to discern in a preliminary analysis if there is any correlation between 
b-tubulin isotype expression pattern and response to therapy. In NSCLC a 
correlation between the expression of E-tubulin isotypes and response to therapy 
has been demonstrated with reduced response to therapy found in patients with 
higher level of class III beta-tubulin [61, 62].
3) If the sample is sufficiently large, we will isolate protein and determine the extent 
to which tubulin polymerization has occurred using the antibodies used in the 
immunohistochemical analyses described above. This would be performed in a 
manner similar to that described for the peripheral mononuclear cells.
1.2.6 Rationale for current trial
The conduct of this trial is supported by the knowledge that tubulin is an excellent target 
for chemotherapeutic agents, combined with the clinical success of the taxanes, and the 
putative advantages of the epothilones. The possibility that an agent with activity as 
broad as that observed with the taxanes might be active in cervical carcinoma is an 
exciting possibility. The recent approval of ixabepilone for the treatment of breast cancer 
confirms the activity of this microtubule-stabilizing agent, and its superiority over the 
taxanes. In addition the trial seeks to use the tissue obtained from the patients enrolled 
on study who undergo biopsies to further our understanding of the mechanisms of drug 
sensitivity clinically. As detailed, assessment of microtubule stabilization and the 
activation of cell death pathways will be queried to assist in understanding drug 
sensitivity clinically.
The treatment of metastatic and recurrent cervical carcinoma and cervical 
adenocarcinoma remains a difficult and challenging problem. We have treated two
patients with adenocarcinoma of the cervix (described below) in which an objective 
tumor response was observed following treatment with ixabepilone. These patients 
were part of our phase I study of patients with solid tumors who had progressed after 
standard chemotherapy. Despite the devastating clinical outcome of the first case, in 
both cases presented, we were impressed with the remarkable reduction in tumor 
volume seen after extensive prior chemotherapy. We feel that ixabepilone will replace 
the taxanes in the therapy of breast cancer, and if activity is demonstrated in cervical 
cancer, and this activity, as that observed in breast cancer is superior to that of the 
taxanes, then this agent could be beneficial to women suffering from this disease, that 
when it presents with metastases is incurable.
The infrequent occurrence of cervical adenocarcinoma has made it difficult to evaluate 
the efficacy of chemotherapy in a rigorous manner. Although it is difficult to draw firm 
conclusions, the available data suggests that combination therapy may be better, and 
that as a single agent, paclitaxel may be the most beneficial chemotherapeutic agent. 
Given existing data demonstrating paclitaxel’s efficacy in adenocarcinoma of the cervix, 
it is not surprising that the epothilones would be shown to have activity. However, both 
patients whom we treated and in whom we observed a response to therapy had 
received prior paclitaxel, without a response, and the demonstration of a response to 
ixabepilone, especially after additional chemotherapy had been administered, is 


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encouraging, albeit preliminary. The ultimate role of ixabepilone and multiagent 
chemotherapy in the treatment of adenocarcinoma of the cervix remains to be 
determined.
While these patients had cervical adenocarcinoma, the trial will recruit all patients with a 
diagnosis of cervical cancer, and will stratify patients into squamous carcinoma or non-
squamous carcinoma. The latter will include patients with adenocarcinoma as well as 
patients with adenosquamous histology.
Furthermore while we have extensive experience examining tubulin polymerization in 
patients with kidney cancer, we will seek to extend those observations in these patients, 
while also trying to probe further the effect of ixabepilone. To that end we will also 
examine whether there is evidence of activation of pathways of cell death, initially by 
examining the activation of PARP.
CASE REPORTS
MF was a 54 year old Hispanic female who was diagnosed in 1/99 with stage 4 
adenocarcinoma of the cervix with metastases to the small bowel, omentum, both 
fallopian tubes, ovaries, paracolic fat and surface of the small intestine. She underwent 
a modified radical hysterectomy, bilateral salpingo-oophorectomy, and omentectomy. 
Postoperatively she received six cycles of carboplatin and paclitaxel (2/99 -7/99). In 
12/99 a needle biopsy of a vaginal mass was positive for adenocarcinoma, and she was 
subsequently treated with five doses of weekly gemcitabine (3/00), three cycles of doxil 
(5/00), seven doses of weekly vinorelbine  (7/00), five cycles of topotecan (ending 
12/00), and one cycle of carboplatin (1/01). Because of a rising CA-125 she was 
referred to the NCI for a clinical trial on 3/21/01. Her initial evaluation revealed a left 
lower quadrant abdominal mass most prominent at the level of the umbilicus, 1.0 cm 
right axillary and 1.5 cm left inguinal nodes, and multinodular extension of tumor from 
the vaginal apex and anterior wall of the vagina to within 5 cm of the introitus. The CT 
scan showed scattered nodules in both lungs (largest 1 cm in diameter), a mediastinal 
mass (1.8 cm x 1.0 cm), an ill-defined mass in the pelvis (approximately 3.4 cm x 3.0 
cm), a soft tissue mass anterior to the left psoas muscle (4 cm x 2.9 cm), and bilateral 
axillary adenopathy. Her CA-125 was 5,391. She started treatment with ixabepilone at a 
dose of 6 mg/m2/d X 5d every three weeks on 3/22/01. She tolerated the first cycle well 
but during cycle 2, she was admitted for dizziness and fever and found to have oral 
thrush, mucocutaneous herpes simplex, and neutropenia. Other side effects of 
chemotherapy included grade 2 fatigue, grade 1 nausea, nail changes, alopecia, and 
grade 1 neuropathy. Repeat CT scan after the second cycle of ixabepilone 
demonstrated a marked improvement, with a reduction in the size of the mediastinal 
adenopathy (1.6 cm x 0.4 cm), and the pelvic mass (2.1 cm x 2.0 cm) complete 
disappearance of the soft tissue mass anterior to the psoas, and nearly complete 
disappearance of axillary adenopathy. Pelvic examination revealed dramatic resolution 
of the previously noted tumor. Her CA-125 had fallen to 21. Her next two cycles were 
uneventful, and a CT scan performed prior to the start of the fifth cycle demonstrated 
continued shrinkage or disappearance of tumor at sites of previous disease. Mediastinal 
adenopathy had been replaced by a thin tissue remnant measuring 1.4 cm x 0.3 cm, 
while the mass in the pelvis measured at most 1.4 cm x 0.7 cm. On 7/29/01 midway 
through her fifth cycle she was admitted to the hospital with complaints of constipation, 


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abdominal pain and light-headedness. Because of persistent hypotension unresponsive 
to intravenous hydration she was transferred to the intensive care unit but her condition 
continued to deteriorate and she expired during intubation. Postmortem examination of 
the chest and abdomen revealed no gross evidence of disease. There was cardiac 
tamponade with microscopic evidence of adenocarcinoma in the intrapericardial fibrin 
clot. Pericardial involvement with tumor had not been appreciated prior to the autopsy 
and was felt to be etiologic in the patient’s demise. It was felt that this was not a drug-
related toxicity. The only other microscopic tumor found was in intraparenchymal lymph 
nodes in the lung and a single small cluster of adenocarcinoma in the left upper lobe of 
the lung. No tumor was found in the pelvis.
LY a 43 -year old white female underwent a radical hysterectomy for a grade 2 deeply 
infiltrative mucin secreting adenocarcinoma of the cervix on 4/22/96. Ten left and seven 
right pelvic nodes were negative for metastatic disease. Postoperatively, she received 
5.4 gy of total pelvic irradiation. Follow-up examination in 8/96 revealed residual disease 
and on 11/96 she underwent a total pelvic exenteration with an ileal conduit, transverse 
colostomy, an omental pelvic graft, and a gracilus myocutaneous flap for neovaginal 
reconstruction. The final pathology reported only residual adenocarcinoma-in-situ at the 
vaginal apex. The patient was in remission until 5/99 when a single right lung nodule 
was detected on chest x-ray. A CT scan several months later showed bilateral multiple 
pulmonary nodules. Biopsy of one of the lung nodules revealed recurrent moderately 
differentiated adenocarcinoma. The patient was then treated with three cycles of 
cisplatin and paclitaxel between 1/00 and 3/00. Follow-up CT scans revealed stable 
disease and chemotherapy was discontinued because of two hospitalizations for 
pyelonephritis. Tamoxifen was started on 3/00 and discontinued on 9/00 because of 
progressive disease. She was then treated with thalidomide from 9/00 to 1/01, and this 
was discontinued because of progressive disease. The patient was first evaluated at the 
NCI on 2/2/01 at which time a CT scan revealed multiple pulmonary nodules and a 
pelvic mass. She was treated with two cycles of vinorelbine in combination with the P-
glycoprotein antagonist tariquidar (XR-9576).  She was taken off study in 04/01 because 
of progressive disease. On 8/9/01 she began a phase I trial of ixabepilone at a dose of 8
mg/m2/d X 5d every 21 days. After the first cycle, she reported a decrease in pelvic 
pressure. The dose was escalated to 10 mg/m2/d X 5d, and she subsequently 
developed fatigue, thrush, a urinary tract infection, and neutropenia requiring 
hospitalization. Repeat CT scans obtained after completion of the first two cycles of 
ixabepilone demonstrated a decrease in the size of her tumor. Two pelvic masses 
shrank from 3.6 X 1.7 cm and 3.3 X 3.1 cm to 2.5 X 1.1 cm and 2.5 X 2.1 cm). The size 
of the largest lung nodule was reduced from 2.9 X 1.7 cm to 2.0 X 0.6 cm with marked 
resolution of an area of lung consolidation. In addition, her CA-125 fell from a pre-
treatment value of 50 to 24 by 10/24/01.  The third and fourth cycles were given at a 
dose of 8 mg/m2/d X 5 and were well tolerated. A restaging CT scan after cycle four 
revealed a further reduction in the size of all lesions, with nearly complete 
disappearance of her pelvic masses. This was the first chemotherapeutic agent to which 
the patient’s tumor had demonstrated and objective response. Non-hematologic 
toxicities included grade 2 fatigue, stomatitis, vomiting, and neuro-sensory changes, 
with grade 1 diarrhea. She received two additional cycles of ixabepilone and upon 
restaging was noted to have had a small increase in the size of the largest pulmonary 


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metastasis and was removed from the study. No further therapy was planned and the 
patient was referred home. She subsequently developed pneumonia, but despite 
aggressive pulmonary care died of respiratory failure on 2/10/02.
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT
2.1
ELIGIBILITY CRITERIA
2.1.1 Inclusion criteria:
Patients must fulfill all of the following criteria to be eligible for study admission:
1. $JH\HDUV
2. Histologic or cytologic confirmation of cervical carcinoma, squamous or non-
squamous. Within the non-squamous cohort is adenocarcinoma and 
adenosquamous as well as non-squamous (not otherwise specified).
3. Subjects with unresectable recurrent cervical cancer are eligible.
4. Measurable disease that can be assessed using RECIST criteria.
5. Performance Status ECOG 0-2.
6. Life expectancy of 3 months or greater.
7. Suitable candidate for receiving planned therapy as evidenced by screening 
laboratory assessments of hematologic, renal, hepatic, and metabolic functions: 
SODWHOHWFRXQWPP3DEVROXWHJUDQXORF\WHFRXQW$*&PP3,
serum FUHDWLQLQHRUDPHDVXUHGFUHDWLQLQHFOHDUDQFHPOPLQ6*37
DQG6*27[1/DQGWRWDOELOLUXELQ[1/LQSDWLHQWVZLWKFOLQLFDO
evidence of Gilberts' GLVHDVH[1/
8. Note: A diagnosis of Gilbert’s disease will be made in the presence of (1) 
unconjugated hyperbilirubinemia noted on several occasions; (2) normal results 
from CBC count, reticulocyte count, and blood smear; (3) normal liver function 
test results; and (4) an absence of other disease processes that can explain the 
unconjugated hyperbilirubinemia.
9. ZHHNVIURPSULRUUDGLDWLRQLQWUDYHQRXVFKHPRWKHUDS\RULPPXQRWKHUDS\
ZHHNVIURPSULRUQLWURVRXUHDZHHNVIURPDSULRU³SKDVHVWXG\´
10.No serious intercurrent medical illness.
11.The ability to understand and willingness to sign a written informed consent form, 
and to comply with the protocol.
12.Prior therapy with cisplatin or carboplatin is required.  
2.1.2 Exclusion criteria:
Patients with any of the following will be excluded from study entry:
1. Pregnant or nursing women are not eligible; neither are women of childbearing 
potential unless using effective contraception as determined by the patient’s 
physician.
2. Patients with a history of CNS metastases, because symptoms/signs of progressive 
disease may be confused with drug-related toxicities, unless control has been achieved 
with either radiation or surgical resection at least three months prior to enrollment on 
study.
3. Patients who are poor medical risk because of other non malignant systemic disease or 
active, uncontrolled infection.


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4. HIV positive patients will be considered for eligibility; as long as they are not receiving 
antiretroviral drugs with strong CYP3A4 inhibitory activity (see 3.6 and Appencix C).
5. Prior craniospinal radiation, or total body irradiation (TBI).
6. Patients receiving other investigational drugs, or strong CYP3A3 inhibitors (see Section 
3.6 for details) that cannot be discontinued or substituted. 
7. CTCAE Grade 2 or greater motor or sensory neuropathy.
8. Known prior severe hypersensitivity reactions to agents containing Cremophor® EL.
9. Women with localized disease who are potentially curable through surgical resection.
2.2
RESEARCH ELIGIBILITY EVALUATION
1. Pathological confirmation of diagnosis by the Laboratory of Pathology, CCR, NCI.
Within 4 weeks of study entry:
2. Imaging studies: PA and lateral chest X-ray; CT or MRI scans as medically 
indicated.
3. Metastatic bone series, bone scan, or nuclear scans as medically indicated.
4. HIV screen.
5. Urinalysis.
Within 7 days of study entry*:
6. Complete history and physical examination with documentation of measurable 
disease and performance status.
7. Laboratory tests: CBC with differential and platelet count, and CHEM 20 Panel.
8. Urine or serum pregnancy test in women of childbearing potential.
*Any abnormal laboratory tests of clinical significance (CHEM 20 Panel) should be 
repeated within 48 hours of study initiation. The principal investigator should be 
contacted to determine if the test(s) need to be repeated.
2.3
PATIENT REGISTRATION AND TREATMENT RANDOMIZATION
1. On-study: Ms Maureen Edgerly, RN (301-435-5604, pager 102-10728) or her 
designee must be notified before entering any patients on study. Authorized staff 
must register an eligible candidate with NCI Central Registration Office (CRO) 
within 24 hours of signing consent. A registration Eligibility Checklist from the 
web site (http://intranet.cancer.gov/ccr/welcome.htm) must be completed and faxed to 
301-480-0757.  After confirmation of eligibility at Central Registration Office, CRO 
staff will call pharmacy to advise them of the acceptance of the patient on the 
protocol prior to the release of any investigational agents. Verification of 
Registration will be forwarded electronically via e-mail. A recorder is available 
during non-working hours. Please note, it is very important for all registrars to 
acquire encrypted e-mail from NIH Help Desk, since the verification of 
registration includes patient’s information. 
2. Off-study: Authorized staff must notify Central Registration Office (CRO) when a 
patient is taken off-study. An off-study form from the web site
(http://intranet.cancer.gov/ccr/welcome.htm) main page must be completed and faxed to 
301-480-0757.


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3. This trial does not involve randomization.  Patients will be stratified according to 
histology: (1)squamous cell cohort and (2)non-squamous cell cohort consisting of 
adenocarcinoma, adenosquamous and non-squamous (not otherwise specified). 
3
STUDY IMPLEMENTATION
3.1
STUDY DESIGN
This is a phase II trial designed to determine the activity of ixabepilone administered 
daily x 5, every three weeks, in women with cervical carcinoma. The dose will be 6 
mg/m2/day, daily x 5, for a total dose per cycle dose of 30 mg/m2. There will be no dose 
escalations. If indicated the dose may be reduced to 4.5 mg/m2/day level. Every attempt 
to administer cycles at intervals of 3 weeks will be made. Following cycle 6, at the 
discretion of the PI, cycles may be extended to 4 or 5 weeks in duration to 
accommodate neurosensory changes and or fatigue. This will be determined on a case-
by-case basis. 
Research biopsies will be done prior to Day 1 and post Day 4 or 5 dosing to assess 
tubulin polymerization and the extent of PARP activation. On Day 4 or 5, the patient will 
receive ixabepilone in the morning hours and have the biopsy within 4 hours of 
completing the infusion. 
The primary and secondary endpoints for the study are tumor response per RECIST 
and the degree of tubulin polymerization as it relates to cellular death pathways. 
Patients will be evaluated for tumor response after every 2 cycles. Biopsies will be 
obtained during cycle one only, before and after chemotherapy to obtain tubulin 
polymerization data and to examine other molecular markers.
3.2
DRUG ADMINISTRATION
3.2.1 General guidelines
Chemotherapy may be administered as an inpatient or as an outpatient. Inpatient 
administration may be chosen if this is in the patient’s best interest. Administration may 
be through either a peripheral IV site or a central venous access catheter. Both options 
are acceptable. Care should be taken to avoid extravasation, since this drug is likely to 
be a vesicant. If a catheter is used a single lumen central venous access catheter is 
sufficient and should be in place before initiating therapy. Placement may be arranged 
before the start of therapy, or a catheter may be placed immediately before a cycle.
3.2.2 Ixabepilone administration and dosage
Ixabepilone will be given on days 1, 2, 3, 4, and 5 of each three week cycle as a one 
hour intravenous infusion. The dose will be 6 mg/m2/day on five successive days.
For ixabepilone preparation instructions, see Section 8, Pharmaceutical Information.
3.2.3 Potential for hypersensitivity reactions related to Cremophor®EL
Premedication: All patients must be pre-medicated before each administration of 
ixabepilone to prevent a hypersensitivity reaction.
x
Regimen 1 described below is the pre-medication regimen recommended for 
routine use.


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x
If a patient experiences a hypersensitivity reaction with oral H1 and H2 blockers 
(Regimen 1) then the patient, if re-treated, should be pre-medicated according to 
Regimen 2 below. See the section 3.2.4 below for immediate management of 
reactions.
x
If a subject continues to experience a HSR with Regimen 2 then the subject, if 
retreated, the patient should be pre-medicated according to the recommended 
Regimen 3.
x
Regimen 4 is suggested as the approach for re-treatment with ixabepilone after 
a Grade 2 or greater HSR despite premedication with Regimen 1, 2 or 3.
Regimen 1: Premedicate approximately one hour prior to the infusion of ixabepilone 
with:
a) Oral H1 antagonist (may consist of diphenhydramine 50 mg or equivalent H1 
antagonist) and  
b) Oral H2 antagonist (may consist of ranitidine 150 - 300 mg or cimetidine 300 -
800 mg or nizatidine 150 - 300 mg or famotidine 20 - 40 mg or another H2 
antagonist
Note: In the event a given patient does not tolerate the specified antihistamines, 
alternatives may be substituted at the Investigator’s discretion. In addition, if the 
specified antihistamine is not available, alternatives may be substituted including IV 
formulations
Regimen 2: Premedicate approximately 30 - 45 minutes prior to each infusion of 
ixabepilone with:
a) Dexamethasone 20 mg IV (or equivalent)
b) Diphenhydramine 50 mg IV (or equivalent), and 
c) Ranitidine 50 mg IV (or equivalent).
Regimen 3: Premedicate with:
a) Dexamethasone 20 mg po administered, approximately 12 and 6 hours prior to 
the infusion of  ixabepilone,
b) Diphenhydramine 50 mg IV, approximately 30 - 45 minutes prior to each infusion 
of ixabepilone,
c) Cimetidine 300 mg IV or ranitidine 50 mg IV (or equivalent), approximately 
30 - 45 minutes prior to each infusion of ixabepilone.
Regimen 4: A suggested approach for re-treatment with ixabepilone after a Grade 2 or 
greater HSR despite premedication with Regimen 1, 2 or 3 is as follows:
a) Dexamethasone 20 mg IV or p.o. (or equivalent) every 6 hours for 4 doses with 
the last dose administered 30 minutes before rechallenge with ixabepilone; With 
the last dexamethasone dose begin:
x
Diphenhydramine 50 mg IV (or equivalent) 30 minutes before ixabepilone,
x
Cimetidine 300 mg or ranitidine 50 mg IV (or equivalent) 30 minutes before 
ixabepilone.
b) Begin ixabepilone at 25% of the previous rate for 1 hour;
c) Increase rate gradually to complete the total infusion within 6 hours from the time 
the drug was initially diluted.
3.2.4 Immediate management of Allergic/Hypersensitivity Reaction


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Allergic/Hypersensitivity Reaction (transient rash, drug fever < 38°C): Supervise without 
further treatment.  If progression of symptom(s) is(are) noted, follow the guidelines 
described below. 
Allergic/Hypersensitivity Reaction (urticaria, drug fever greater than or equal to 38°C 
and/or asymptomatic bronchospasm):  Interrupt the infusion.  Administer additional 
doses of H1 and/or H2 blockers intravenously as needed.  Typically 25 mg 
diphenhydramine IV is sufficient to relieve symptoms.  If symptoms abate, attempt re-
infusion at a slower rate, as detailed.  Restart the remaining infusion at one quarter the 
hourly rate x 15 minute, then increase the rate to one half the hourly rate x 15 minutes, 
then increase the rate to complete the remaining infusion within one hour of the restart 
time.  If the symptoms recur, discontinue infusion and follow guidelines below.
Subsequent Infusions following Allergic/Hypersensitiviy Reactions:
When a patient experiences an allergic/hypersensitivity reaction and is able to resume 
the infusioin without recurrence of the reaction, the following day’s infusion will be given 
according to the following rate schedule:  First start the infusion at one quarter the 
hourly rate x 15 minutes, then increase the rate to one half the hourly rate x 15 minutes, 
then increase the rate to complete the remaining infusion within one hour of the start 
time.   If the patient does not have another reaction, the subsequent infusions may be 
given at the full hourly rate from the start of the infusion.    No additional H1 or H2 
blockers are indicated for these doses, beyond the standard premedications 
administered 30 to 60 minutes before the administration of ixabepilone.  Consultation 
with study team is indicated to determine if steroids are indicated per Regimen 2. 
Recurrent CTCAE Grade 2 or CTCAE Grade 3 or 4 Allergic/Hypersensitivity Reactions: 
Stop the infusion.  Administer additional doses of H1 and H2 blockers intravenously.  
Administer IV steroids (see discussion below) and consider epinephrine and 
bronchlodilators as clinically indicated.  Further treatment should be delayed 24 hours.  
Prior to re-challenge and with all subsequent cycles, give both an H1 and H2 blocker 
intravenously plus dexamethasone 20 mg x 2 doses (orally or intravenously) 12 and 6 
hours pre ixabepilone. Dexamethasone could be used at the investigator’s discretion in 
subsequent cycles for recurrent (i.e. occurring despite slowing infusion as discussed 
above) grade 2 reactions but is not mandated.
Grade 4 (anaphylaxis): Discontinue therapy.  Do not attempt re-challenge.
Note: The administration of dexamethasone immediately prior to ixabepilone is unlikely 
to be effective.
Note:  If dexamethasone is administered, it will initially be administered prior to all 
doses.  However, since dexamethasone has a long half-life, and since daily 
administration would mean patients would receive 100 mg or more of dexamethasone 
every three weeks, a dose reduction to 5 mg dexamethasone administered 
intravenously prior to each dose of ixabepilone may be attempted at the discretion of 
the Principal Investigator. Please note that the above regimens 1 – 4 are standard for 
ixabepilone that is given as a one day infusion every 3 weeks, not a daily x 5 schedule. 
The decision to administer this regimen will be guided by: (1) the severity of the initial 
reaction that prompted the use of dexamethasone; (2) the patient’s reaction to 


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ixabepilone after the institution of dexamethasone premedication; and (3) the number of 
additional cycles the patient is anticipated to receive.  Regarding the latter, if a patient 
appears to be responding to the treatment and it is anticipated that he/she will receive 
several more cycles, then in such a patient attempts to reduce the steroid dose would 
be beneficial.
Note:  Dexamethasone premedication may be used, if in the opinion of the Principal 
Investigator such precaution should be taken.  For example, in a patient with a prior 
history of sensitivity to paclitaxel or cyclosporin.
3.3
TREATMENT MODIFICATIONS
3.3.1 General guidelines for treatment modifications at the time of re-treatment
Adverse Events:
The descriptions and grading scales found in the revised NCI Common Terminology
Criteria for Adverse Events (CTCAE) version 3.0 will be utilized until December 31, 
2010 for AE reporting.  CTCAE version 4.0 will be utilized beginning January 1, 2011.  
All appropriate treatment areas should have access to a copy of the CTCAE version 
4.0.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov).
Dose adjustments will be made according to the guidelines below, with dose levels defined 
as follows:
Level -1:
4.5 mg/m2/day x 5 days
Level 1:
6 mg/m2/day x 5 days
There is only one dose reduction allowed.  Patients who have continued toxicities on the 
reduced dose level (4.5 mg/m2/day x 5 days) will be removed from study.
3.3.2 Treatment modifications for hematologic toxicities and delay in start of cycle
Doses will be modified if the start of a cycle is delayed more than two weeks (in all 
cycles after the first cycle, the day 1 dose will be administered only when the ANC is 
greater than 1000/mm3 and the platelet count is above than 75,000/mm3). There will be 
no dose modification for a delay of two weeks or less.
Doses will also be modified based upon the nadir from the previous cycle according to 
the following guidelines.
Toxicity:
Dose Adjustment:
$1&PP3 IRUGD\V
Reduce ixabepilone one dose level
3ODWHOHWFRXQWPP3
Reduce ixabepilone one dose level
Delay in starting cycle > 2 weeks
Reduce ixabepilone one dose level
3.3.3 Treatment modifications for non-hematologic toxicities
If non-hematologic grade 3 and 4 toxicities occur, treatment will be interrupted until the 
toxicity:
x
Resolves to grade 2 or less if the toxicity is fatigue, anorexia, or fingernail 
changes, or 


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x
Resolves to grade 1 or less if the non-hematologic toxicity is other than those 
enumerated in the previous bullet.
,IWR[LFLW\GRHVQRWUHVROYHWRJUDGHZLWKLQWZRZHHNVWKDWSDWLHQWZLOOEHUHPRYHG
from study. Once a toxicity resolves to the required grade as enumerated above, 
treatment may be restarted and drug dosing modified according to the guidelines below. 
However, patients who experience grade 4 non-hematologic toxicities will be individually 
evaluated with regard to continuation of treatment. These patients should not be 
restarted on therapy once toxicity resolves unless there is some clear indication of 
patient benefit in the form of objective tumor response. In these cases, the reason(s) for 
restarting therapy will be clearly indicated in the case report form, and the medical 
record, and the risks and potential benefits will be discussed with the patient.  
Dose modifications for non-hematologic toxicities will be based upon the toxicity from 
the previous cycle. All toxicities must resolve to grade 2 or less as indicated above prior 
to the initiation of a subsequent cycle. The following apply:
Maximum toxicity grade:
Ixabepilone dose
1
Unchanged
2
Unchanged
3Note 1
Reduce ixabepilone one dose 
level
4Note 2
Reduce ixabepilone one dose 
level
Note 1: If grade 3 fatigue occurs but resolves to grade 2 or less 
by the start of the next cycle, the dose of ixabepilone will remain 
unchanged.
Note 2: As noted above, patients who experience grade 4 non-
hematologic toxicities will be individually evaluated with regard to 
continuation of treatment. Exceptions to the need for individual 
evaluation include patients with a grade 4 toxicity included in the 
list that follows, in which case adjustments will be made in 
accordance with the guidelines listed above.
Grade IV hypocalcemia with normal ionized calcium
Grade IV hypokalemia that responds to medical intervention
Grade IV hypomagnesemia that responds to medical intervention
Grade IV hypophosphatemia that responds to medical 
intervention
Grade IV sepsis with source identified and treatment successfully 
instituted
Grade IV stomatitis
3.4
CORRELATIVE STUDIES
3.4.1 Biopsies for Research Purposes
As indicated in the introduction, every attempt will be made to recruit patients with 
disease that can be sampled by biopsy. In these patients, every attempt will be made to 
obtain tissue before the start of treatment and after the completion of the fourth or fifth 


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dose of ixabepilone. Both biopsies will be processed in one of three ways: (1) for 
immunohistochemical staining; (2) for RNA; and (3) for protein isolation, if a sufficient 
quantity is available. The laboratory correlates on the biopsies will attempt to examine 
tubulin polymerization, and also seek to probe further the effect of ixabepilone. To that 
end attempts will be made to examine whether there is evidence of activation of 
pathways of cell death, initially by examining the activation of PARP, a protein whose 
cleavage generates fragments that can be measured and are recognized as markers of 
cell death or apoptosis.
Biopsies will be obtained from all patients only if they can be performed under local 
anesthesia. General anesthesia will not be used to obtain biopsies that are to be used 
only for research purposes. In order to process the biopsy in the three ways described 
above a tru-cut type core biopsy needle must be used. Ideally three core biopsies would 
be obtained and if possible four. These biopsies may be obtained with the assistance of 
either a surgical consultant or a member of the interventional radiology staff. As an 
alternative, a needle aspiration may be obtained with the assistance of the cytology staff 
or a member of the interventional radiology staff. In the case of a needle aspiration, the 
sample will only be processed for immunohistochemical staining.
Note: It is recognized that a patient may agree to a first biopsy and then decide to not 
have a second biopsy. In such a case, the biopsy will nevertheless be processed as 
planned, although the value of the pre-treatment modification of alpha tubulin in 
predicting response has not been established.
Biopsies performed for research purposes will only be obtained after the procedure has 
been explained to the patient, and informed consent has been secured.
3.4.2 Pharmacokinetics
(not applicable)
3.4.3 Pharmcodynamics
To evaluate the pharmacologic activity of ixabepilone in patients, peripheral blood 
mononuclear cells (PBMCs) will be evaluated to determine the extent to which 
ixabepilone induces a shift from unpolymerized tubulin to tubulin in a polymerized state. 
These samples will only be collected on those patients who undergo research biopsies.  
Schedule for blood sample collection for tubulin polymerization assay using peripheral 
blood mononuclear cells (PBMCs): The ability of ixabepilone to induce tubulin polymer 
formation in  peripheral blood mononuclear cells (PBMCs) will be determined for 
patients during cycle one, following the first intravenous dose of ixabepilone.  A blood 
sample (8 mL)  will be collected prior to the drug infusion, to determine each patient's 
baseline status of unpolymerized tubulin within lysed PBMC pellets versus tubulin that 
exists in the polymerized state.  Following IV administration of ixabepilone, additional 
blood samples (8 mL each) will be collected at 1, 8 and 24 hours, relative to the start of 
the 1-hour infusion on Day One.  
One additional sample will be drawn within one hour of the biopsy following Day 4 or 
Day 5 dosing. The purpose of this blood will be to determine if there exists any 
correlation between the extent of tubulin polymerization in the tumor sample and in the 


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blood sample.  See Appendix A for further information regarding the handling, storage 
and tracking of these samples.
3.5
ON STUDY EVALUATION
3.5.1 Cycle one
Obtained within one week prior to study entry, unless otherwise indicated.
1. History and physical examination.
2. Laboratory studies: CBC with differential, platelet count, and CHEM 20 Panel.
3. Imaging studies: CT or MRI (obtained within four weeks prior to study entry).
3.5.2 Every restaging cycle 
(Following the second, fourth and sixth cycles, and then every third cycle)
1. History and physical examination (for medical record only; not for Research 
record.
2. Laboratory studies: CBC with differential, platelet count, and CHEM 20 Panel.
3. Imaging studies: CT or MRI of known/suspected areas of disease (for medical 
record only; not for research record).
3.5.3 Every cycle
1. History and physical examination (for medical record only; not for Research 
record).
2. Laboratory studies: CBC with differential, platelet count, and CHEM 20 Panel.
3.5.4 Weekly treatment monitoring
1. CBC with differential and platelet count will be obtained twice weekly on
Monday/Thursday, or Tuesday/Friday during the first two cycles; unless the ANC 
falls below 500 cells/mm3 or the platelet count falls below 50,000 cells/mm3, in 
which case every attempt should be made to obtain counts every other day until 
the ANC is above 500 cells/mm3  and the platelet count is above 50,000 
cells/mm3. If the ANC and platelet count do not fall below the above-mentioned 
parameters in the first two cycles, CBCs may be obtained once weekly 
thereafter.
3.6
CONCURRENT THERAPIES
Potential Drug Interactions: Ixabepilone may have a minimal potential to alter the 
metabolic clearance of drugs that are highly metabolized by CYP3A4. When ixabepilone 
was incubated with human liver microsomes along with compounds specific for the 
inhibition of individual cytochrome P450s, significant inhibition was observed only with
the CYP3A4 inhibitors (troleandomycin and ketoconazole) suggesting that ixabepilone 
may be a substrate for CYP3A4 in humans. Data also indicate that the main route of 
metabolism of ixabepilone is through CYP3A4.
The following strong CYP3A4 inhibitors are prohibited on this study:  ketoconazole,
itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, 
amprenavir, indinavir, nelfinavir, delavirdine, and voriconazole).  Other CYP3A4 
inhibitors can be given with caution.  


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A more complete list of CYP3A4 inhibitors is found in Appendix C and should be 
consulted when making decisions regarding concurrent therapies.
In addition, patients should not drink grapefruit juice while on this study.
3.7
SURGICAL GUIDELINES
Elective surgical procedures (dental extractions, mediport placement) for patients 
enrolled on study will be scheduled during the last week of a cycle in order to avoid the 
nadir periods for leukocytes and platelets. All procedures should be done only when 
counts are sufficiently recovered to lessen any risk of infection and or bleeding. Radio-
frequency ablation (RFA) will be allowed for symptomatic relief of pain.  
3.8
RADIATION GUIDELINES
No concurrent radiation therapy will be allowed on study.
3.9
OFF TREATMENT CRITERIA
1. Progression of disease during treatment on study protocol. Decisions will be 
made at the time of restaging (restaging planned after the second, fourth and 
sixth cycles and then every third cycle). However, if clinically indicated, a 
decision may be made following the first cycle, after obtaining the appropriate 
staging studies. 
2. Grade 3/4 toxicity lasting greater than 2 weeks or when therapy is judged 
detrimental to the patient’s health.
3. Grade 4 hypersensitivity reaction to drug administration (anaphylaxis).
4. Patient non-compliance or voluntary withdrawal.
5. Discretion of the Principal Investigator.
6. Unacceptable toxicities that have not resolved at time of “off treatment” or “off 
study” must be followed until stabilization or resolution. 
The reason for treatment removal and the date the patient was removed will be 
documented in the Case Report Form.
3.9.1 Post-Treatment Evaluation (Upon Meeting Off Treatment Criteria)
1. History and physical examination (for medical record only)
2. Laboratory studies: CBC with differential and platelet count, and CHEM 20 Panel.
3. Chest X-ray.
4. Appropriate diagnostic imaging.
5. ECOG performance status assessment
3.10 OFF-STUDY CRITERIA
This study does not involve a preset period of monitoring or follow-up after a patient has 
reached off treatment status. In most cases the Off-treatment and Off-Study dates will 
be the same. If a patient has a treatment related toxicity, and in the opinion of the PI it is 
prudent and medically necessary to monitor the patient further, an individual patient 
may remain on-study, but off-treatment until such time the PI determines it safe to 
remove them from study.


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3.10.1 Off Study Procedure
Authorized staff must notify Central Registration Office (CRO) when a patient is taken 
off-study. An off-study form from the web site   
http://intranet.cancer.gov/ccr/welcome.htm must be completed and faxed to 301-480-
0757.
3.11 Follow-Up for Progression Free Survival and Duration of Response
An objective of this study is to determine progression free survival and duration of 
response in patients who achieve either a Complete Response (CR) or a Partial 
Response (PR). Patients who achieve either a CR or PR and stop receiving study drug 
will be monitored periodically to follow the course of their response.  This follow-up
period will vary per patient, but in general will consist of a CT scan every 6 weeks, 
extending to every 3 to 4 months, per PI discretion. This follow-up may be done here at 
the NIH Clinical Center, or via the patient’s local physician, with scans sent in for 
inclusion in our trial results.  Physical exams, including pelvic exams, will also be done 
at the same time points. 
4
SUPPORTIVE CARE
1. Febrile neutropenia is a life-threatening complication requiring hospitalization and 
urgent broad-spectrum antibiotics. Growth factors may be used in accordance 
with the ASCO guidelines. Growth factors should not be used to raise neutrophil 
counts in order to begin chemotherapy on time. Such cases will be evaluated 
individually to determine the toxicity grade.
2. Symptomatic anemia should be treated with appropriate red blood cell support 
and transfusion is recommended if the hemoglobin falls below 8 g/dl. Alternately 
recombinant erythropoietin may be used if desired by the patient’s local 
physician.
3. Thrombocytopenia should be treated conservatively. In the absence of bleeding 
or a planned invasive procedure, platelet transfusions should only be given for a 
platelet count below 10,000. If invasive procedures are planned or the patient 
develops bleeding, platelet transfusions should be administered in accordance 
ZLWKVWDQGDUGRISUDFWLFHXVXDOO\PDLQWDLQLQJDSODWHOHWFRXQWPP
4. Central venous access devices such as a temporary internal jugular line, PICC 
lines via the brachial vein, semi-permanent HICKMAN®, GROSHONG®, or 
medi-port implanted devices are acceptable for this study. All devices will have 
nursing supervision to include patient self care and cleaning/flushing of the 
devices.
5. Nutritional assessment and psychological support: Refractory neoplasms are 
commonly complicated by malnutrition. Patients with weight loss or evidence of 
wasting syndrome should have a nutritional consult. Patients who are having 
emotional difficulties dealing with their treatment, and disease, or those patients 
who request assistance, will be referred to a Social Worker for evaluation and 
support.
6. Care of the fingernails during ixabepilone trial participation is encouraged. A 
patient information form is included in APPENDIX D.


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5
DATA COLLECTION and EVALUATION
5.1
DATA COLLECTION AND RECORD KEEPING
Data will be prospectively collected and entered into the database at least once every 
two weeks. The NCI C3D database will be used for this report. The responsible 
investigator is Dr. Tito Fojo. All radiographic images will be stored in the Department of 
Radiology, Clinical Center, NIH. All radiographic images will be reviewed by a staff 
radiologist for validity and reliability. The original signed consent goes to Medical 
Records; copy placed in research record
All patients must have signed an informed consent and an on study confirmation of 
confirmation of eligibility form must be filled out before enrollment.
Complete records must be maintained on each patient. These will consist of the hospital 
chart with any supplementary information obtained from outside laboratories, radiology 
reports, or physician’s records. These records will serve as the primary source material 
that forms the basis for the research record. All relevant data will also be entered into 
the NCI C3D database from which formal analyses are done. The primary source 
documentation will assure the following: on study information, including patient eligibility 
data and patient history; and off-study summary sheets, including a final assessment by 
the treating physician.
Data will be submitted to the CTEP/CDUS every three months via the NCI C3D 
database.
5.2
RESPONSE CRITERIA (RECIST)
Eligibility:
Only patients with measurable disease at baseline can have objective tumor response 
evaluated as an endpoint. 
Measurable disease: The presence of at least one measurable lesion. If the measurable 
disease is restricted to a solitary lesion, its neoplastic nature should be confirmed by 
cytology/histology, if possible.
Measurable lesions: Lesions that can be accurately measured in at least one dimension 
with ORQJHVWGLDPHWHUPPXVLQJFRQYHQWLRQDOWHFKQLTXHVRUPPZLWKVSLUDO&7
scan.
Non-measurable lesions: All other lesions, including small lesions (longest diameter < 
20 mm with conventional techniques or < 10 mm with spiral CT scan), bone lesions,
leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast 
disease, lymphangitis cutis/pulmonis, cystic lesions, and also abdominal masses that 
are not confirmed and followed by imaging techniques.
x
All measurements should be taken and recorded in metric notation, using a ruler 
or calipers. All baseline evaluations should be performed as closely as possible 
to the beginning of treatment and never more than 4 weeks before the beginning 
of the treatment.
x
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up.


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x
Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes). For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the 
lesion, is recommended. 
Methods of Measurement:
x
CT and MRI are the best currently available and reproducible methods to 
measure target lesions selected for response assessment. Conventional CT and 
MRI should be performed with cuts of 10 mm or less in slice thickness 
contiguously.  Spiral CT should be performed using a 5 mm contiguous 
reconstruction algorithm. This applies to tumors of the chest, abdomen and 
pelvis. Head and neck tumors and those of extremities usually require specific 
protocols.
x
Lesions on chest X-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable. 
x
For accurate objective response evaluation, ultrasound (US) should not be used 
to measure tumor lesions. However, US is a possible alternative to clinical 
measurements of superficial palpable lymph nodes, subcutaneous lesions and 
thyroid nodules. US might also be useful to confirm the complete disappearance 
of superficial lesions usually assessed by clinical examination.
x
The utilization of endoscopy and laparoscopy for objective tumor evaluation has 
not yet been fully and widely validated. Their uses in this specific context require 
sophisticated equipment and a high level of expertise. Therefore, the utilization of 
such techniques for objective tumor response should be restricted to validation 
purposes. However, such techniques can be useful in confirming complete 
pathological response when biopsies are obtained.
Baseline documentation of "Target" and "Non-Target" lesions:
x
All measurable lesions up to a maximum of five lesions per organ and 10 lesions 
in total, representative of all involved organs should be identified as target lesions
and recorded and measured at baseline.
x
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and their suitability for accurate repeated measurements (either by imaging 
techniques or clinically).
x
A sum of the longest diameter (LD) for all target lesions will be calculated and reported 
as the baseline sum LD.  The baseline sum LD will be used as reference by which to 
characterize the objective tumor.
x
All other lesions (or sites of disease) should be identified as non-target lesions and
should also be recorded at baseline.  Measurements of these lesions are not required, 
but the presence or absence of each should be noted throughout follow-up.
Response Criteria:
Evaluation of target lesions:
Complete Response (CR):
Disappearance of all target lesions.
Partial Response (PR):
At least a 30% decrease in the sum of the LD of target 
lesions, taking as reference the baseline sum LD.
Progressive Disease (PD):
At least a 20% increase in the sum of the LD of target 
lesions, taking as reference the smallest sum LD recorded 


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since the treatment started or the appearance of one or 
more new lesions.
Stable Disease (SD):
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest 
sum LD since the treatment started.
Evaluation of non-target lesions:
Complete Response (CR):
Disappearance of all non-target lesions and normalization 
of tumor marker level.
Incomplete Response/ 
Stable Disease (SD):
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal 
limits.
Progressive Disease (PD):
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions 
[Although a clear progression of "non target" lesions only 
is exceptional, in such circumstances, the opinion of the 
treating physician should prevail and the progression 
status should be confirmed later on by the review panel 
(or study chair)].
Evaluation of best overall response:
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for PD the smallest 
measurements recorded since the treatment started). In general, the patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria.
Target Lesion
Non-Target Lesion
New Lesions Overall Response
CR
CR
No
CR
CR
Incomplete Response/SD
No
PR
PR
Non-PD
No
PR
SD
Non-PD
No
SD
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
x
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should 
be classified as having "symptomatic deterioration". Every effort should be made 
to document the objective progression even after discontinuation of treatment.
x
In some circumstances it may be difficult to distinguish residual disease from 
normal tissue. When the evaluation of complete response depends on this 
determination, it is recommended that the residual lesion be investigated (fine 
needle aspirate/biopsy) to confirm the complete response status.


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Confirmation:
x
The main goal of confirmation of objective response is to avoid overestimating 
responses. In cases where confirmation of response is not feasible, it should be 
made clear when reporting the outcome that the response(s) is(are) not 
confirmed.
x
To be assigned a status of PR or CR, changes in tumor measurements must be 
confirmed by repeat assessments that should be performed no less than 4 weeks 
after the criteria for response are first met. Longer intervals as determined by the 
study protocol may also be appropriate.
x
In the case of SD, follow-up measurements must have met the SD criteria at 
least once after study entry at a minimum interval, not less than 6 weeks.
Duration of overall response:
x
The duration of overall response is measured from the time measurement criteria 
are met for CR or PR (whichever status is recorded first) until the first date that 
recurrence or PD is objectively documented, taking as reference for PD the 
smallest measurements recorded since the treatment started.
Duration of stable disease:
x
SD is measured from the start of the treatment until the criteria for disease 
progression are met, taking as reference the smallest measurements recorded 
since the treatment started.
Response review:
x
Responses will be reviewed by an expert(s) independent of the study at the 
study’s completion. Simultaneous review of the patients’ files and radiological 
images will be conducted.
Reporting of results:
x
All patients initially considered evaluable will be assessed for response to 
treatment, even if there are major protocol treatment deviations or if they are 
ineligible. Each patient will be assigned one of the following categories: 1) 
complete response, 2) partial response, 3) stable disease, 4) progressive 
disease, 5) early death from malignant disease, 6) early death from toxicity, 7) 
early death because of other cause, or 8) unknown (not assessable, insufficient 
data).
x
All of the patients who met the eligibility criteria and are evaluable, will be 
included in the main analysis of responses. Patients in response categories 4-8
will be considered as failing to respond to treatment (disease progression). Thus, 
an incorrect treatment schedule or drug administration will not result in exclusion 
from the analysis of a response.
x
All conclusions will be based on all eligible patients.
x
Sub-analyses may be performed on the basis of a subset of patients, excluding 
those for whom major protocol deviations have been identified (e.g., early death 
due to other reasons, early discontinuation of treatment, major protocol 
violations, etc.).  However, these sub-analyses may not serve as the basis for 


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drawing conclusions concerning treatment efficacy, and the reasons for 
excluding patients from the analysis will be clearly reported.
5.3
Toxicity Criteria: Adverse Event Reporting Criteria
The following adverse event management guidelines are intended to ensure the safety 
of each patient while on the study. 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 3.0 will be utilized until December 31, 
2010 for AE reporting.  CTCAE version 4.0 will be utilized beginning January 1, 2011.  
All appropriate treatment areas should have access to a copy of the CTCAE version 
4.0.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov).
5.4
STATISTICAL SECTION
STUDY OBJECTIVES:
Primary: To establish the activity of ixabepilone administered daily as a one-hour 
infusion on five successive days (daily x 5), every three weeks in patients with cervical 
carcinoma previously treated with chemotherapy, as determined by overall response 
(PR+CR).  Activity will be measured using standard RECIST guidelines. 
Secondary: Assess pharmacodynamic endpoints after ixabepilone administration to 
determine the extent of tubulin polymerization and whether or not there has been 
activation of cellular death pathways “distal” to the target, and to estimate the 
progression free survival and duration of response.
5.4.1 Trial Design:
This trial of Ixabepilone in patients with cervical carcinoma will be conducted using a 
two-stage optimal design (Simon, R, Controlled Clinical Trials, 10:1-10, 1989). With 
alpha = 0.10 (the probability of incorrectly accepting a poor agent), and beta = 0.10 (the 
probability of incorrectly rejecting a good agent), we will try to rule out an undesirably 
low overall response (PR+CR) probability of 5% (p0 = 0.05) in favor of a level indicative 
of modest activity, 20% (p1 = 0.20).
Several histologic subtypes of cervical carcinoma are recognized including: (1) 
squamous cell (2) adenocarcinoma (3) adenosquamous carcinoma and (4) other. 
Among these, squamous is the most common histologic diagnosis, with 
adenocarcinoma second in frequency. While chemotherapy has not been shown to be 
very effective in cervical carcinoma, differences among the histologic subtypes in 
response to therapy may exist. In order to properly evaluate the activity of ixabepilone in 
cervical cancer, we will stratify patients into two cohorts according to histologic 
subtypes: (1) squamous cell (2) non-squamous including adenocarcinoma, 
adenosquamous carcinoma and non-squamous-not otherwise specified.
Initially, 12 evaluable patients will be enrolled in each of the two cohorts. If 0/12
demonstrate an objective response (PR +CR), then accrual to that cohort will stop and 
the agent will be considered inactive in this population. If one or more patients have a 
response, accrual will continue until a total of 37 evaluable patients have been enrolled 
in that cohort. If 1 - 3 of 37 patients demonstrates a response in a cohort, this will be 


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considered insufficient activity, and the agent will not be considered worthy of further 
development in that cohort. If 4 or more of 37 patients in the entire cohort have a 
response, then the agent will be considered active in that group (and at least potentially 
able to produce a response level consistent with 20%). Under the null hypothesis (p0 = 
0.05), the probability of early termination of accrual to any one group is 0.54. With two 
cohorts of patients, the maximum number of evaluable patients in the two cohorts would 
be 74. However, in the event that an inevaluable patient is enrolled in each cohort, a
total enrollment ceiling of 76 patients will be requested. Our goal is to enroll 
adenocarcinoma patients, but we do not want to refuse squamous cell carcinoma 
patients who have no other therapeutic options.
As secondary endpoints, progression free survival and duration of response will also be 
evaluated, using Kaplan-Meier curves. Progression free survival will be measured from 
the on-study date until the date of progression or last follow-up if the patient has not 
progressed. Response duration will be determined beginning at the date a PR or CR is 
first noted and will last until the patient is noted to have progressive disease relative to 
the response identified.
Women, 18 years of age or older, from all racial and ethnic backgrounds, will be eligible 
for the study.  
5.4.2 Duration of trial:
It is expected that 1 to 4 patients may be accrued onto this study per month. In order to 
accrue up to 76 patients (the maximum requested) it is anticipated that about 18 to 24 
months will be needed. Furthermore, the trial will be terminated for futility if less 
than 12 patients are enrolled in the first 9 months of the trial.
5.5
MULTI-INSTITUTIONAL GUIDELINES
Not applicable
6
Human Subjects Protections
6.1
RATIONALE FOR SUBJECT SELECTION
6.1.1 Selection based on gender, ethnic background, or race 
Subjects from all racial/ethnic groups are eligible for this study if they meet the eligibility 
criteria. To date, there is no information that suggests that differences in drug 
metabolism or disease response would be expected in any one patient group. Efforts 
will be made to extend accrual to a representative population, but in this preliminary 
study, a balance must be struck between patient safety considerations and limitations 
on the number of patients exposed to potentially toxic treatments on the one hand and 
the need to explore ethnic aspects of clinical aspects of clinical research on the other. If 
differences in the outcome which correlate with ethnic identity are noted, accrual may 
be expanded or a follow-up study may be written to investigate these differences.
6.1.2 Strategies/procedures for recruitment
Referrals from within the NCI and National Naval Medical Center (NNMC), and from the 
community will be welcomed. In addition, a letter describing the protocol will be mailed 


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to potential referring physicians. This protocol also will be available through the PDQ 
database.
6.1.3 Justification for exclusions
1. Patients infected with the HIV virus will be excluded from this trial because the 
effect of the combination of Ixabepilone on HIV replication and/or the immune 
system is unknown and potentially harmful.
2. Patients that are pregnant or lactating will be excluded from this trial because the 
anti-proliferative activity of the experimental agent may be harmful to the 
developing fetus or the nursing infant. In addition, patients of child-bearing age 
will be instructed to use contraception while receiving Ixabepilone.
6.2
PARTICIPATION OF CHILDREN
Only patients 18 years of age or older will be enrolled on this study, since the safety of 
this agent has not been previously defined in a pediatric population.
6.3
EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS
6.3.1 Potential benefits to subjects expected from the trial
As a result of participating in this trial, patients will receive evaluation and treatment of 
their tumor at the National Cancer Institute’s Clinical Center. All the medications, tests, 
hospitalizations and physician services rendered at the NCI will be free of charge to 
them. This protocol may or may not be helpful to a specific patient, but the results may 
help the investigators learn about the administration of Ixabepilone and may aid in the 
treatment of other patients. This research treatment is not curative but may offer 
temporary control of the disease. Benefit cannot be promised nor can the chance of 
benefit be accurately predicted.
6.3.2 Alternative approaches or treatments
Patients will be consented verbally and in writing regarding the risks and benefits of this 
trial, the treatment requirements, and alternative approaches to entering on this trial.
6.3.3 Procedure for protecting against or minimizing any potential risks
All care will be taken to minimize side effects, but they can be unpredictable in nature 
and severity. This study may involve risks to patients that are currently unforeseeable. 
Patients enrolled in this trial will receive their treatment either in the inpatient ward or the 
outpatient day hospital on a day 1 - day 5 schedule and will be assessed each time. 
Monthly evaluations to monitor the treatment of patients will be performed and recorded 
in the patient chart. In addition to the Clinical Center health care providers, all patients 
will be asked to have a local physician to improve long term care and to monitor for 
complications. If patients suffer any physical injury as a result of the participation in this 
study, immediate medical treatment is available at the NCI’s Clinical Center in 
Bethesda, Maryland. Although no compensation is available, any injury will be 
evaluated and treated in keeping with the benefits or care to which patients are entitled 
under applicable regulations.


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In addition all patient on-study are discussed at the weekly team meeting, usually on 
Wednesdays, prior to clinic. Any known issues or concerns from the patient or staff 
regarding the patient are discussed at that time.
6.3.4 Provisions for monitoring data collection to ensure safety of subjects
As information is gathered from this trial, clinical results will be shared with patients 
although insuring total patient confidentiality. Laboratory and clinical data will be 
frequently gathered and any new significant findings(s) found during the course of the 
research, which may affect a patient’s, willingness to participate further will be 
explained. Moreover, in all publications and presentations resulting from this trial, 
patients’ anonymity will be protected to the maximum extent possible; although, 
authorized personnel from the National Cancer Institute (NCI) and Food and Drug 
Administration (FDA) may have access to research files in order to verify that patient 
rights have been safeguarded. Representatives from Bristol-Myers Squibb Co. will also 
have access to research files, at all times guarding a patient’s anonymity. In addition 
patient names will be given to the Central Registration Office to register and verify 
patient eligibility.
6.3.5 Evaluation of risk/benefit ratio for patients in this trial
Patients enrolled on this study will be those who have no further standard treatment 
options, and generally have a poor prognosis. Thus, patients may experience significant 
treatment related morbidity, and/or have progressive complications of their disease. 
Although ixabepilone is FDA-approved for the treatment of metastatic breast cancer, for 
the purpose of this study it is considered experimental.  Experience with the use of this 
agent in humans has been gathered from completed and ongoing phase I, II & III 
studies, and that information has been and will continue to be used to ensure maximum 
patient safety. Because of the lack of experience with the use of this agent in cervical 
cancer, we cannot predict what activity, if any, this agent will have in patients with this 
type of cancer. However, it is hoped that some patients participating in this trial may 
have a positive benefit/risk ratio, and that this trial may provide some palliation to 
patients with few remaining therapeutic options.
The potential benefit that may result from this study balances the potential risks to the 
patients. Extensive evidence has been gathered which indicates that the microtubules 
are good targets for chemotherapeutic agents. Furthermore experience with the taxanes 
has shown that agents that stabilize microtubules have a broad spectrum of activity. 
Extensive preclinical data indicates that like the taxanes, the epothilones stabilize 
microtubules. Furthermore this data indicates that ixabepilone has activity in a broad 
range of animal models, including many which have been previously shown to be 
resistant to paclitaxel. While all preclinical data has limitations, the evidence is 
encouraging.
6.4
CONSENT AND ASSENT PROCESSES AND DOCUMENTS
The investigational nature and objectives of this trial, the procedures and treatments 
involved and their attendant risks, discomforts, and potential benefits will be carefully 
explained to the patient or the patient’s advocate. This process will include a general 
description of the disease process, as well as a description of the patient’s expected 


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clinical course. Alternative therapies will be fully described, and outlined in the consent 
document. The patient will be asked to read the consent at his/her convenience and will 
be encouraged to ask questions. Enrollment on this study will only occur if the patient 
meets all eligibility criteria, is judged by the Principal Investigator to potentially benefit 
from the therapy, is able and willing to provide full consent, and has signed the consent 
document. Moreover, any experimental invasive procedure will require a separate 
consent form (standard procedure consent form).
Investigators are responsible for informing patients of the nature of the study, the risks and 
benefits of, and alternatives to participation necessary for the subjects to make a considered 
decision whether or not to participate. Investigators are responsible for assessing that subjects 
understand the information provided and that individuals give voluntary consent, free of coercion 
or undue influence. Written consent must be obtained by the Principal Investigator (PI) or by a 
PI-designated member of the research team who is knowledgeable about the protocol
7
SAFETY REPORTING REQUIREMENTS/DATA SAFETY MONITORING PLAN
7.1
Definitions
7.1.1 Adverse Events
An adverse event is defined as any reaction, side effect, or untoward event that occurs 
during the course of the clinical trial associated with the use of a drug in humans, 
whether or not the event is considered related to the treatment or clinically significant. 
For this study, AEs will include events reported by the patient, as well as clinically 
significant abnormal findings on physical examination or laboratory evaluation. A new 
illness, symptom, sign or clinically significant laboratory abnormality or worsening of a 
pre-existing condition or abnormality is considered an AE.  All AEs must be recorded on 
the AE case report form.
All AEs, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until satisfactory resolution. AEs should be 
reported up to 30 days following the last dose of study drug.  AEs that are considered 
treatment related, expected, continuing, but not resolvable by 30 days after treatment 
completion (e.g., alopecia) will not be followed after the 30-day period. 
An abnormal laboratory value will be considered an AE if the laboratory abnormality is 
characterized by any of the following:
x
Results in discontinuation from the study
x
Is associated with clinical signs or symptoms 
x
Requires treatment or any other therapeutic intervention
x
Is associated with death or another serious adverse event, including 
hospitalization. 
x
Is judged by the Investigator to be of significant clinical impact
x
If any abnormal laboratory result is considered clinically significant, the
investigator will provide details about the action taken with respect to the test 
drug and about the patient’s outcome.
7.1.2 Suspected adverse reaction


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Suspected adverse reaction means any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety 
reporting, ‘reasonable possibility’ means there is evidence to suggest a causal 
relationship between the drug and the adverse event. A suspected adverse reaction 
implies a lesser degree of certainty about causality than adverse reaction, which means 
any adverse event caused by a drug.
7.1.3 Unexpected adverse reaction
An adverse event or suspected adverse reaction is considered “unexpected” if it is not 
listed in the investigator brochure or is not listed at the specificity or severity that has 
been observed; or, if an investigator brochure is not required or available, is not 
consistent with the risk information described in the general investigational plan or
elsewhere in the current application. "Unexpected”, also refers to adverse events or 
suspected adverse reactions that are mentioned in the investigator brochure as 
occurring with a class of drugs or as anticipated from the pharmacological properties of 
the drug, but are not specifically mentioned as occurring with the particular drug under 
investigation.
7.1.4 Serious 
An adverse event or suspected adverse reaction is considered serious if in the view of 
the investigator or the sponsor, it results in any of the following:
x
Death,
x
A life-threatening adverse drug experience
x
Inpatient hospitalization or prolongation of existing hospitalization
x
Persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions
x
A congenital anomaly/birth defect.
x
Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious adverse drug experience 
when, based upon appropriate medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in this definition.
7.1.5 Disability
A substantial disruption of a person’s ability to conduct normal life functions.
7.1.6 Life-threatening adverse drug experience
Any adverse event or suspected adverse reaction that places the patient or subject, in 
the view of the investigator or sponsor, at immediate risk of death from the reaction as it 
occurred, i.e., it does not include a reaction that had it occurred in a more severe form, 
might have caused death.
7.1.7 Protocol Deviation (NIH Definition)
Any change, divergence, or departure from the IRB approved study procedures in a 
research protocol that does not have a major impact on the subject’s rights, safety or 
well-being, or the completeness, accuracy and reliability of the study data.


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7.1.8 Protocol Violation (NIH Definition)
Any change, divergence, or departure from the IRB-approved study procedures in a 
research protocol that does have a major impact on the subject’s rights, safety, or well-
being and/or the completeness, accuracy and reliability of the study data.
7.1.9 Unanticipated Problem
Any incident, experience, or outcome that:
x
Is unexpected in terms of nature, severity, or frequency in relation to the research 
risks that are described in the IRB-approved research protocol and informed 
consent document; Investigator’s Brochure or other study documents, and the 
characteristics of the subject population being studied; AND
x
Is related or possibly related to participation in the research; AND
x
Places subjects or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or 
recognized.
7.2
NCI –IRB Reporting
7.2.1 NCI-IRB Expedited Reporting of Adverse Events, Unanticipated Problems, and 
Deaths
The Protocol PI will report to the NCI-IRB:
x
All unexpected serious adverse events that are possibly, probably, or definitely 
related to the research 
x
All deaths, except deaths due to progressive disease 
x
All Protocol Violations or Deviations
x
All Unanticipated Problems
Reports must be received by the NCI-IRB within 7 working days of PI awareness via 
iRIS.
7.2.2 NCI-IRB Requirements for PI Reporting of Adverse Events at Continuing Review
The protocol PI will report to the NCI-IRB: 
1. All Grade 2 unexpected events that are possibly, probably or definitely related to 
the research; 
2. All Grade 3 and 4 events that are possibly, probably or definitely related to the 
research; 
3. All Grade 5 events regardless of attribution; 
4. All Serious Events regardless of attribution. 
NOTE: Grade 1 events are not required to be reported.
7.2.3 NCI-IRB Reporting of IND Safety Reports
Only IND Safety Reports that require a sponsor recommended change to the protocol or 
the consent form or in the opinion of the PI increases risks to study participants will 
need to be reported to the NCI IRB.


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7.3
CTEP ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 
7.2) will determine whether the event requires expedited (via AdEERS) reporting in 
addition to routine reporting.
7.3.1 Comprehensive Adverse Events and Potential Risks List (CAEPR) Ixabepilone 
(BMS 247550, NSC 710428)
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single 
list of reported and/or potential adverse events (AE) associated with an agent using a 
uniform presentation of events by body system. In addition to the comprehensive list, a 
subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a 
separate column and is identified with bold and italicized text. This subset of AEs 
(SPEER) is a list of events that are protocol specific exceptions to expedited reporting to 
NCI via AdEERS (except as noted below).  Refer to the 'CTEP, NCI Guidelines: 
Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.p
df for further clarification. Frequency is provided based on 1572 patients. Below is the 
CAEPR for ixabepilone (BMS 247550).
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in 
parentheses next to the AE in the SPEER.  If this CAEPR is part of a combination 
protocol using multiple investigational agents and has an AE listed on different 
SPEERs, use the lower of the grades to determine if expedited reporting is required.
Version 2.5, December 5, 20111
Adverse Events with Possible 
Relationship to Ixabepilone (BMS 247550)
(CTCAE 4.0 Term)
[n= 1572]
Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
(formerly known as ASAEL)
Likely (>20%)
Less Likely (<=20%)
Rare but Serious 
(<3%)
BLOOD AND LYMPHATIC SYSTEM DISORDERS
Anemia
Anemia (Gr 3)
Febrile neutropenia
Febrile neutropenia (Gr 3)
CARDIAC DISORDERS
Atrial fibrillation
Atrial fibrillation (Gr 2)
Atrial flutter
Atrial flutter (Gr 2)
Paroxymal atrial tachycardia
Paroxymal atrial tachycardia (Gr 
2)
Sinus bradycardia
Sinus bradycardia (Gr 2)
Sinus tachycardia
Sinus tachycardia (Gr 2)
Supraventricular tachycardia
Supraventricular tachycardia (Gr 
2)
EYE DISORDERS
Watering eyes
Watering eyes (Gr 2)
GASTROINTESTINAL DISORDERS


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Abdominal pain
Anal mucositis
Anal mucositis (Gr 2)
Constipation
Constipation (Gr 3)
Diarrhea
Diarrhea (Gr 3)
Ileus
Mucositis oral
Mucositis oral (Gr 3)
Nausea
Nausea (Gr 3)
Rectal mucositis
Rectal mucositis (Gr 2)
Small intestinal mucositis
Small intestinal mucositis (Gr 2)
Vomiting
Vomiting (Gr 3)
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
Fatigue
Fatigue (Gr 3)
Fever
Fever (Gr 2)
Pain
IMMUNE SYSTEM DISORDERS
Allergic reaction
Allergic reaction (Gr 2)
INFECTIONS AND INFESTATIONS
Infection2
Infection2 (Gr 3)
INJURY, POISONING AND PROCEDURAL COMPLICATIONS
Radiation recall reaction 
(dermatologic)
Radiation recall reaction
(dermatologic) (Gr 3)
INVESTIGATIONS
Alanine aminotransferase 
increased
Alanine aminotransferase
increased (Gr 2)
Alkaline phosphatase 
increased
Alkaline phosphatase increased
(Gr 2)
Aspartate aminotransferase 
increased
Aspartate aminotransferase 
increased (Gr 2)
Blood bilirubin increased
Creatinine increased
INR increased
INR increased (Gr 3)
Neutrophil count decreased
Neutrophil count decreased (Gr 
4)
Platelet count decreased
Platelet count decreased (Gr 4)
White blood cell decreased
White blood cell decreased (Gr 4)
METABOLISM AND NUTRITION DISORDERS
Anorexia
Anorexia (Gr 3)
Dehydration
Dehydration (Gr 3)
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS
Arthralgia
Arthralgia (Gr 2)
Generalized muscle weakness
Generalized muscle weakness
(Gr 2)
Myalgia
Myalgia (Gr 2)
Pain in extremity
Pain in extremity (Gr 2)
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS)
Tumor pain
Tumor pain (Gr 2)
NERVOUS SYSTEM DISORDERS
Dizziness
Dizziness (Gr 2)
Dysgeusia
Dysgeusia (Gr 2)
Dysphasia
Dysphasia (Gr 2)
Headache
Neuralgia
Neuralgia (Gr 2)


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Peripheral motor neuropathy
Peripheral motor neuropathy (Gr 
3)
Peripheral sensory 
neuropathy
Peripheral sensory neuropathy
(Gr 3)
Syncope
Syncope (Gr 2)
PSYCHIATRIC DISORDERS
Insomnia
Insomnia (Gr 2)
RENAL AND URINARY DISORDERS
Urinary retention
Urinary retention (Gr 2)
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS
Cough
Cough (Gr 2)
Dyspnea
Dyspnea (Gr 3)
Hiccups
Hiccups (Gr 2)
Hypoxia
Hypoxia (Gr 3)
Laryngeal mucositis
Laryngeal mucositis (Gr 2)
Pharyngeal mucositis
Pharyngeal mucositis (Gr 2)
Pleural effusion
Pneumonitis
Pneumonitis (Gr 3)
Tracheal mucositis
Tracheal mucositis (Gr 2)
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
Alopecia
Alopecia (Gr 2)
Erythema multiforme
Nail loss
Nail loss (Gr 2)
Palmar-plantar 
erythrodysesthesia 
syndrome
Pruritus
Pruritus (Gr 2)
Rash maculo-papular
Rash maculo-papular (Gr 2)
VASCULAR DISORDERS
Capillary leak syndrome
Capillary leak syndrome (Gr 2)
Flushing
Flushing (Gr 2)
Hypotension
Hypotension (Gr 2)
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be 
distributed to all Principal Investigators at the time of revision.  The current version can 
be obtained by contacting PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the 
investigator, the protocol and the agent should be included in the e-mail.
2Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS 
SOC.
3Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, 
Esophageal perforation, Gastric perforation, Ileal perforation, Jejunal perforation, Rectal 
perforation, and Small intestinal perforation under the GASTROINTESTINAL 
DISORDERS SOC.
Also reported on ixabepilone (BMS 247550) trials but with the relationship to
ixabepilone (BMS 247550) still undetermined:
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Disseminated intravascular 
coagulation


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CARDIAC DISORDERS - Left ventricular systolic dysfunction; Myocardial infarction; 
Palpitations; Pericardial effusion
EYE DISORDERS - Blurred vision; Conjunctivitis
GASTROINTESTINAL DISORDERS - Colitis; Dry mouth; Dyspepsia; Dysphagia; 
Esophagitis; Gastrointestinal disorders - Other (impaired gastric emptying); 
Gastrointestinal perforation3; Rectal hemorrhage; Upper gastrointestinal hemorrhage
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema 
face; Edema limbs; Edema trunk; Injection site reaction; Non-cardiac chest pain
HEPATOBILIARY DISORDERS - Hepatic failure
INFECTIONS AND INFESTATIONS - Infections and infestations – Other (Opportunistic 
infection associated with >=Grade 2 Lymphopenia)
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Cardiac troponin T 
increased; Lymphocyte count decreased; Weight gain; Weight loss
METABOLISM AND NUTRITION DISORDERS - Acidosis; Hypercalcemia; 
Hyperglycemia; Hyperkalemia; Hypernatremia; Hypertriglyceridemia; Hypoalbuminemia; 
Hypocalcemia; Hypoglycemia; Hypokalemia; Hypomagnesemia; Hyponatremia; 
Hypophosphatemia
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Bone 
pain
NERVOUS SYSTEM DISORDERS - Ataxia; Encephalopathy; Intracranial hemorrhage; 
Ischemia cerebrovascular; Seizure; Vasovagal reaction
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression
RENAL AND URINARY DISORDERS - Acute kidney injury; Hematuria; Renal 
hemorrhage; Urinary incontinence
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Hematosalpinx; Ovarian 
hemorrhage; Prostatic hemorrhage; Spermatic cord hemorrhage; Testicular 
hemorrhage; Uterine hemorrhage; Vaginal hemorrhage
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Allergic rhinitis; 
Bronchopulmonary hemorrhage; Epistaxis; Respiratory failure
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Dry skin; Skin and 
subcutaneous tissue disorders - Other (pigmentation changes); Urticaria
VASCULAR DISORDERS - Hot flashes; Hypertension; Phlebitis; Thromboembolic 
event
Note: Ixabepilone (BMS 247550) in combination with other agents could cause an 
exacerbation of any adverse event currently known to be caused by the other agent, or 
the combination may result in events never previously associated with either agent.
.
7.3.2 Adverse Event Characteristics
x
CTCAE term (AE description) and grade:  The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 3.0 will be utilized until December 31, 2010 for AE reporting.  
CTCAE version 4.0 will be utilized beginning January 1, 2011.  All appropriate 
treatment areas should have access to a copy of the CTCAE version 4.0.  A copy 


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of the CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov).
x
“Expectedness”:  AEs can be ‘Unexpected’ or ‘Expected’ (see Section 7.1
above) for expedited reporting purposes only.  ‘Expected’ AEs (the ASAEL) are 
bold and italicized in the CAEPR (Section 7.1.1).
x
Attribution of the AE:
-
Definite – The AE is clearly related to the study treatment.
-
Probable – The AE is likely related to the study treatment.
-
Possible – The AE may be related to the study treatment.
-
Unlikely – The AE is doubtfully related to the study treatment.
-
Unrelated – The AE is clearly NOT related to the study treatment.
7.3.3 Expedited Adverse Event Reporting
Expedited AE reporting for this study must use AdEERS (Adverse Event Expedited 
Reporting System), accessed via the CTEP home page (http://ctep.cancer.gov).  The 
reporting procedures to be followed are presented in the “CTEP, NCI Guidelines: 
Adverse Event Reporting Requirements” which can be downloaded from the CTEP 
home page (http://ctep.cancer.gov).  These requirements are briefly outlined in the table 
below (Section 7.3.4).
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, a 
24-hour notification phoned in must be entered electronically into AdEERS by the 
original submitter at the site.
7.3.4 Expedited Reporting Guidelines
AdEERS Reporting Requirements for Adverse Events that occur within 30 Days1 of 
the Last Dose of the Investigational Agent on Phase 2 and 3 Trials
Grade 1
Grade 2
Grade 2
Grade 3
Grade 3
Grades
4 & 52
Grades
4 & 52
Unexpected 
and 
Expected
Unexpected Expected
Unexpected
Expected
Unexpected 
Expected
Hospitalization
With 
Without
With 
Without 
Unrelated
Unlikely
Not
Required
Not
Required
Not
Required
10
Calendar
Days
Not
Required
10
Calendar
Days
Not
Required
10
Calendar
Days
10
Calendar
Days
Possible
Probable
Definite
Not
Required
10 Calendar
Days
Not
Required
10
Calendar
Days
10
Calendar
Days
10
Calendar
Days
Not
Required
24-Hour;
5 Calendar
Days
10
Calendar
Days
1Adverse events with attribution of possible, probable, or definite that occur greater than
30 days after the last dose of treatment with an agent under a CTEP IND require reporting
as follows:
AdEERS 24-hour notification followed by complete report within 5 calendar days for:
x
Grade 4 and Grade 5 unexpected events 
AdEERS 10 calendar day report:
x
Grade 3 unexpected events with hospitalization or prolongation of hospitalization
x
Grade 5 expected events
2Although an AdEERS 24-hour notification is not required for death clearly related to progressive 
disease, a full report is required as outlined in the table.


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December 15, 2004
Note:  All deaths on study require both routine and expedited reporting regardless 
of causality.  Attribution to treatment or other cause must be provided.
x
Expedited AE reporting timelines defined:
¾ “24 hours; 5 calendar days” – The investigator must initially report the AE via 
AdEERS within 24 hours of learning of the event followed by a complete 
AdEERS report within 5 calendar days of the initial 24-hour report.
¾ “10 calendar days” - A complete AdEERS report on the AE must be submitted 
within 10 calendar days of the investigator learning of the event. 
x
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates 
hospitalization (or prolongation of existing hospitalization) must be reported
regardless of attribution and designation as expected or unexpected with the 
exception of any events identified as protocol-specific expedited adverse event 
reporting exclusions. 
x
Any event that results in persistent or significant disabilities/incapacities, 
congenital anomalies, or birth defects must be reported via AdEERS if the event 
occurs following treatment with an agent under a CTEP IND.
x
Use the NCI protocol number and the protocol-specific patient ID assigned during 
trial registration on all reports.
7.3.5 Routine Adverse Event Reporting
All Adverse Events must be reported in routine study data submissions.  AEs reported 
through AdEERS must also be reported in routine study data submissions.  
Routine data will be reported to CTEP via the web-based Clinical Data Update System 
on a quarterly basis.
7.3.6 Secondary Malignancy
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, radiation 
or chemotherapy). A secondary malignancy is not considered a metastasis of 
the initial neoplasm. 
CTEP requires all secondary malignancies that occur following treatment with 
an agent under an NCI IND/IDE be reported via AdEERS. Three options are 
available to describe the event: 
x
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic 
leukemia [AML]) 
x
Myelodysplastic syndrome (MDS) 
x
Treatment-related secondary malignancy 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also 
be reported via the routine reporting mechanisms outlined in each protocol. 


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7.4
DATA AND SAFETY MONITORING PLAN:
Monitoring of this protocol will consist of continuous, close monitoring by the Principal 
Investigator, with prompt reporting of serious adverse events to the IRB and the Cancer 
Treatment and Evaluation Program (CTEP). The Principal Investigator will monitor the 
trial with the assistance of the Associate Investigators including the Research Nurse(s). 
In the event that any severe or unexpected side effects are noted, these will be reported 
to the IRB and CTEP in accordance with the guidelines in Section 7.1 and 7.2. This 
approach will ensure that adverse event reporting requirements are met. In addition, 
data will be examined weekly at a Protocol Review Meeting, usually conducted on the 
day of clinic. These meetings will assess the progress of the protocol and discuss any 
side effects observed, including both expected and unexpected side effects. At this time 
the accuracy of the accrued data is verified.  
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0.  
Cumulative CDUS data will be submitted quarterly to CTEP by electronic means.  
Reports are due January 31, April 30, July 31, and October 31. Instructions for 
submitting data using the CDUS can be found on the CTEP web site 
(http://ctep.cancer.gov).  Note: All adverse events that have occurred on the study, 
including those reported through AdEERS, must be reported via CDUS.
7.5
Clinical Trials Agreement
The agent used in this protocol, ixabepilone, (hereinafter referred to as the Agent)is 
provided to the NCI under a Clinical Trials Agreement (CTA) between Bristol Myers 
Squibb (hereinafter referred to as the Collaborator) and the NCI Division of Cancer 
Treatment and  Diagnosis. Therefore, the following obligations/guidelines apply to the
use of the Agent in this study:
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor 
can Agent(s) be transferred or licensed to any party not participating in the 
clinical study.  Collaborator(s) data for Agent(s) are confidential and proprietary 
to Collaborator(s) and shall be maintained as such by the investigators. The 
protocol documents for studies utilizing investigational Agents contain 
confidential information and should not be shared or distributed without the 
permission of the NCI. If a copy of this protocol is requested by a patient or 
patient’s family member participating on the study, the individual should sign a 
confidentiality agreement. A suitable model agreement can be downloaded from: 
http://ctep.cancer.gov.
2. For a clinical protocol where there is an investigational agent used in combination 
with (an)other investigational agent(s), each the subject of different CTAs, the 
access to and use of data by each Collaborator shall be as follows (data 
pertaining to such combination use shall hereinafter be referred to as "Multi-Party 
Data):
a. NCI must provide all Collaborators with written notice regarding the existence 
and nature of any agreements governing their collaboration with NIH, the 
design of the proposed combination protocol, and the existence of any 
obligations which would tend to restrict NCI's participation in the proposed 
combination protocol.


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b. Each Collaborator shall agree to permit use of the Multi-Party Data from the 
clinical trial by any other Collaborator to the extent necessary to allow said 
other Collaborator to develop, obtain regulatory approval or commercialize its 
own investigational Agent.
c. Any Collaborator having the right to use the Multi-Party Data from these trials 
must agree in writing prior to the commencement of the trials that it will use 
the Multi-Party Data solely for development, regulatory approval, and 
commercialization of its own investigational Agent.
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available exclusively to Collaborator(s), the NCI, and the 
FDA, as appropriate and unless additional disclosure is required by law or court 
order.. Additionally, all Clinical Data and Results and Raw Data will be collected, 
used and disclosed consistent with all applicable federal statutes and regulations 
for the protection of human subjects, including, if applicable, the Standards for 
Privacy of Individually Identifiable Health Information set forth in 45 C.F.R. Part 
164.
4. When a Collaborator wishes to initiate a data request, the request should first be 
sent to the NCI, who will then notify the appropriate investigators (Group Chair 
for cooperative group studies, or PI for other studies) of Collaborator's wish to 
contact them.
5. Any data provided to Collaborator(s) must be in accordance with the guidelines 
and policies of the responsible Data Monitoring Committee (DMC), if there is a
DMC for this clinical trial.
6. Any manuscripts reporting the results of this clinical trial must be provided to 
CTEP by the Group office for Cooperative Group studies or by the principal 
investigator for non-Cooperative Group studies for immediate delivery to 
Collaborator(s) for advisory review and comment prior to submission for 
publication.  Collaborator(s) will have 30 days from the date of receipt for review.  
Collaborator shall have the right to request that publication be delayed for up to 
an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are 
protected.  Copies of abstracts must be provided to CTEP for forwarding to 
Collaborator(s) for courtesy review as soon as possible and preferably at least 
three (3) days prior to submission, but in any case, prior to presentation at the 
meeting or publication in the proceedings. Press releases and other media 
presentations must also be forwarded to CTEP prior to release. Copies of any 
manuscript, abstract and/or press release/ media presentation should be sent to:
Regulatory Affairs Branch, CTEP, DCTD, NCI
Executive Plaza North, Suite 7111
Bethesda, Maryland  20892
FAX 301-402-1584
Email: anshers@mail.nih.gov
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No 
publication, manuscript or other form of public disclosure shall contain any of 
Collaborator’s confidential/ proprietary information.


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8
PHARMACEUTICAL INFORMATION
8.1
BMS-247550 (710428)
8.1.1 Chemical Name
(1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[(1E)-1-
methyl-2-(2-methyl-4-thiazolyl)ethenyl]-17-oxa-4-azabicyclo[14.1.0]heptadecane-5,9-
dione.
8.1.2 Other Names
Epothilone B analog, Ixabepilone, Ixempra®
8.1.3 Molecular Formula 
C27H42N2O5S M.W.: 506.7 grams/mole
8.1.4 Mode of Action 
BMS-247550 is a semi-synthetic analog of the natural product epothilone B. The 
epothilones are a novel class of non-taxane microtubule-stablizing agents obtained from 
the fermentation of cellulose degrading myxobacteria, Sorangium cellulosum. 
8.1.5 Description
Epothilone B analog
8.1.6 How Supplied 
BMS-247550 appears as a lyophilized, white to off-white color, whole or fragmented 
cake in a vial. The drug product is available in 15 mg and 45 mg vials.  
BMS-
247550 vial 
size
Diluent 
provided
Volume of diluent needed 
for reconstitution of drug vial
Final 
concentration
Actual 
Amount of 
Drug in Vial**
15 mg
8 mL vial
8 mL
2 mg/mL
16 mg
45 mg
23.5 mL 
vial
23.5 mL
2 mg/mL
47 mg
**To account for vial/needle/syringe loss, the actual amount of drug in the vial differs 
from the amount of drug on the product label. 
The Vehicle for Constitution of BMS-247550 for injection (diluent) appears clear to slightly hazy 
and is colorless to pale in color. The diluent is an ethanol plus polyoxyethylated castor oil 
(Cremophor® EL) mixture (1:1 by volume). 
Reconstitute the drug vial with the provided diluent only. Diluents are not interchangeable and 
should only be utilized to reconstitute a particular strength. 
8.1.7 Preparation   
Prior to constitution of the lyophile, bring the lyophile and diluent vial to room 
temperature for approximately 30 minutes. (If the diluent is stored in the refrigerator, a 


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white precipitate may appear when it is first removed. The precipitate will disappear 
once the vehicle reaches room temperature.)
Slowly inject 8 mL or 23.5 mL of the diluent into the 15 mg vial or 45 mg vial, 
respectively.  Gently swirl the vial until the lyophile is dissolved completely.  This results 
in a 2mg/mL solution. 
Further dilute with Lactated Ringer’s Injection (LRI) to a final BMS-247550 concentration 
of 0.2 mg/mL to 0.6 mg/mL in a non-PVC container before administration to the patient. 
(Please note: BMS-247550 concentrations below 0.2 mg/mL are no longer 
recommended.)    
8.1.8 Storage
Store BMS-247550 for Injection in the refrigerator (2° to 8°C) prior to use and protect 
from light.  
Store the Vehicle for Constitution in the refrigerator or at room temperature (2°C 
to 25°C).
8.1.9 Stability
Shelf life surveillance is ongoing. After initial constitution with the accompanying diluent, 
the product may be stored for a maximum of one (1) hour at room temperature and 
room light.  After final dilution in Lactated Ringers for Injection (LRI) to 
concentrations between 0.2 and 0.6 mg/mL, the drug product is stable at room 
temperature and light for a maximum of 6 hours.
8.1.10 Route of Administration
Administer the BMS-247550 infusion intravenously through an appropriate in-line filter 
with a microporous membrane of 0.22 to 5 microns.  Flush the IV line or extension set 
with LRI at the end of the infusion, if flushing is required.
8.1.11 Incompatibilities
Avoid contact of the diluted product with polyvinyl chloride (PVC) equipment or devices 
that are plasticized with di- (2-ethylhexyl)pthalate (DEHP) to prevent DEHP leaching 
into the infusion medium.  Store diluted BMS-247550 solutions in bottles (glass, 
polypropylene) or plastic bags (polyethylene, polypropylene, polyolefin, ethylene-vinyl-
acetate) and administer through polyetheylene-lined administration sets or PVC sets 
plasticized with TOTM (trioctyl trimellitate).IV sets and components typically used for the 
administration of paclitaxel are compatible with BMS-247550 infusions. 
8.1.12 Potential Drug Interactions
The following strong inhibitors of CYP3A4 are prohibited: ketoconazole, itraconazole, 
ritonavir, amprenavir indinavir, clarithromycin, atazanavir, nefazodone, saquinavir,
telithromycin, nelfinavir, delavirdine, and voriconazole.
If there are no other treatment options other than the above named drugs, consultation 
with the PI is mandatory and each patient’s situation will be reviewed on a case by case 
basis with final decision made by the PI.


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Use caution when considering the use of other CYP3A4 inhibitors with BMS-247550. 
Co-administration of BMS-247550 with CYP3A4 inducers may decrease its plasma 
concentrations and therapeutic effects. 
In vitro, BMS-247550’s weak inhibition of human CYP3A4 suggests that it may have a 
minimal potential to alter the metabolic clearance of drugs metabolized by CYP3A4. 
A more complete list of CYP3A4 inhibitors is found in Appendix C and should be 
consulted when making decisions regarding concurrent therapies.
8.1.13 Drug ordering and accountability 
NCI supplied agents may be requested by the Principal Investigator (or their authorized 
designee) at each participating institution. Pharmaceutical Management Branch (PMB) 
policy requires that drug be shipped directly to the institution where the patient is to be 
treated. PMB does not permit the transfer of agents between institutions, unless prior 
approval from PMB is obtained.  The CTEP assigned protocol number must be used for 
ordering all CTEP supplied investigational agents. The responsible investigator at each 
participating institution must be registered with CTEP, DCTD, through an annual 
submission of FDA form 1572 and a CV. If there are several participating investigators 
at one institution, CTEP supplied investigational agents should be ordered under the 
name of one lead investigator at that institution. Drug may be requested by completing a 
Clinical Drug Request (NIH-986) and mailing it to the Pharmaceutical Management 
Branch, DCTD, NCI, EPN Room 7149, Bethesda, MD 20892 or faxing it to (301) 480-
4612.  For questions call (301) 496-5725.
8.1.14 Precautions/overdose
BMS-247550 is an investigational agent and is contraindicated for all conditions other 
than those mentioned in the protocol and the Investigator Brochure. In the case of 
extravasation of drug into the subcutaneous tissues, the infusion should be stopped 
immediately and appropriate local measures instituted, as per the Nursing Department 
Policy: Hazardous Drugs (HD): Extravasation Guideline: 
http://intranet.cc.nih.gov/nursing/practicedocs/procedures.html.
It should be noted that a specific antidote for administration is not available and the 
recommendations for paclitaxel will be followed.
Also, please refer to the Nursing Department Standard of Practice: Care of the patient 
receiving cytoxic or biologic agents: 
http://intranet.cc.nih.gov/nursing/practicedocs/sop_pdf/SOP Cytotoxic_orBiologic_Agents.pdf
8.1.15 Disposition of study medications
Any remaining solution should be discarded according to institutional procedures for 
cytotoxics.  At the end of the study all unused stock will be returned to CTEP who will 
arrange for its disposition.
8.2
DIPHENHYDRAMINE HYDROCHLORIDE (HCl) INJECTION
8.2.1 General issues 


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Diphenhydramine hydrochloride (Benadryl) is an antihistamine drug having the chemical 
name 2-(Diphenylmethoxy)-N, N-dimethylethylamine hydrochloride.  It occurs as a 
white, crystalline powder, is freely soluble in water and alcohol and has a molecular 
weight of 291.82.  The molecular formula is C 17 H 21 NO·HCl.
8.2.2 Other pharmaceutical issues:
8.2.2.1 Supply: Commercially available.
8.2.2.2 Product description: Diphenhydramine HCl injection is available in an injectable 
solution at a 50 mg/ml concentration in single dose ampoules, syringes and 
vials as well as multi-dose vials from multiple manufacturers.
8.2.2.3 Solution Preparation: Diphenhydramine HCl may be given by direct intravenous 
injection without additional dilution. Alternatively the prescribed dose may be 
diluted in a small volume (e.g. 25 - 50 ml) of 5% dextrose in water (D5W) or 
0.9% sodium chloride (NS) and infused over 10 - 15 minutes.
8.2.2.4 Storage: Store commercially available injectable product at controlled room 
temperature.
8.2.2.5 Route of Administration: Diphenhydramine HCl injection may be administered 
by direct IV injection (IV push) at a rate generally not exceeding 25 mg/min. 
Alternatively, diphenhydramine HCl injection may be diluted and given over 10 -
15 minutes (see solution preparation).
8.2.2.6 Toxicities: Sedation, sleepiness, dizziness, disturbed coordination, epigastric 
distress, thickening of bronchial secretions. Diphenhydramine can produce 
additive effects with alcohol or other CNS depressants. Diphenhydramine can 
cause anticholinergic side effects (e.g. dry mouth, fixed or dilated pupils, 
flushing, urinary retention). Diphenhydramine should be used with caution in 
patients with a history of bronchial asthma, increased intraocular pressure, 
hyperthyroidism, cardiovascular disease or hypertension.
PLEASE REFER TO THE PACKAGE INSERT FOR FURTHER INFORMATION.
8.3
RANITIDINE HYDROCHLORIDE (HCl) INJECTION
8.3.1 General issues
Ranitidine hydrochloride (HCl) (the active ingredient in Zantac Injection and Zantac 
Injection Premixed) is a histamine H 2 -receptor antagonist. Chemically it is N[2-[5-
[(dimethylamino)methyl]-2-furanyl]methyl]thio]ethyl]-N'-methyl-2-nitro-1,1-
ethenediamine, hydrochloride.  The empirical formula is C 13 H 22 N 4 O 3 S·HCl, 
representing a molecular weight of 350.87.
8.3.2 Other pharmaceutical issues:
8.3.2.1 Supply: Commercially available.
8.3.2.2 Product Description: Ranitidine HCl injection is available in an injectable 
solution at a 25mg/ml concentration in 2, 10 and 40 ml vials and in a 2 ml 
syringe.  It is also available in a single dose pre-mixed 50 mg parenteral bag in


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50 ml of 0.45% sodium chloride (1/2NS). Ranitidine HCl is manufactured by 
Glaxo Wellcome Inc. under the trade name Zantac.
8.3.2.3 Solution preparation: For direct intravenous injection, dilute prescribed dose 
with a compatible diluent [e.g. 5% dextrose in water (D5W), 0.9% sodium 
chloride (NS) or lactated ringers (LR)] to a total volume of 20 ml prior to 
injection.  For intermittent intravenous infusion, dilute prescribed dose in 25 –
100ml of a compatible diluent (e.g. D5W, NS or LR).  Once diluted in a 
compatible diluent, ranitidine is stable for 48 hours at room temperature and 4 
days refrigerated.
8.3.2.4 Storage: Ranitidine HCl injection should be stored between 4oC and 25oC and 
protected from light and excessive heat.  The premixed infusion solution should 
be stored between 2oC and 25oC.
8.3.2.5 Route of administration: Ranitidine HCl may be administered by direct 
intravenous injection or infusion.  For direct intravenous injection, dilute 
prescribed dose to a volume of 20 ml with a compatible diluent and inject over a 
period of not less than 5 minutes. For intermittent intravenous infusion, infuse 
prescribed dose over 15 - 20 minutes.
8.3.2.6 Toxicities: Headache, reversible confusional states (e.g. mental confusion, 
agitation, psychosis, depression, anxiety, hallucinations, disorientation), 
increased transaminase levels, increased serum creatinine, rash, allergic 
reactions, and hematologic toxicity (e.g. leucopenia, thrombocytopenia, 
pancytopenia).
PLEASE REFER TO THE PACKAGE INSERT FOR FURTHER INFORMATION.


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9
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10 Appendices
APPENDIX A:  Data/Specimen Collection, Storage and Disposition Procedures
Intended use of samples - translational studies on tumor samples:
Tubulin immunostaining: Immunohistochemistry (IHC) will be performed on formalin 
fixed, paraffin embedded sections using microwave antigen retrieval. An automated 
immunohistochemical staining procedure will be used according to manufacturer's 
recommendations (TechMate 1000™, Ventana, Tucson, AZ). Primary antibodies will be 
DO-7 for p53 (Dako, Santa Barbara, CA), and DM1A, a monoclonal anti-a-tubulin 
(Sigma, St Louis, MO).
PARP activation: Fresh patient core biopsies will be Dounce homogenized at 22ºC in 
hypotonic lysis buffer [1 mM MgCl2, 2 mM EGTA, 0.5% Nonidet P-40, 20 mM Tris-HCl, 
pH 6.8, containing protease inhibitors] and vortexed vigorously. The samples will be 
pulse sonicated to clarity prior to centrifugation for 1 min at 1000 rpm to remove unlysed 
debris. Total protein concentrations in the lysates will be determined using the Biorad 
assay and equal amounts of protein will be separated on 4-15% gradient SDS-PAGE 
gels for each pair of pre- and post-treatment samples. To assess apoptosis, PARP 
cleavage will be assayed by probing the Western blot with a rabbit polyclonal anti-PARP 
antibody that detects both the full length and the 85 kDa cleavage product (SC-7150 [H-
250] Santa Cruz, CA). Anti Fractin antibody may also be used. Immunoblots probed 
with either of these antibodies will also be simultaneously or sequentially probed with an 
antibody to either actin or GAPDH, as loading controls for each pair.
cDNA Micro-array: Biopsy material that will be used for micro-array analyses will be 
flash-frozen as soon as practically possible after obtaining the sample (< 20 minutes).  
The biopsy will be flash-frozen using either liquid nitrogen or a dry ice ethanol bath and 
then stored at –70 °C to –80 °C.  Total RNA will be prepared from frozen biopsy tissue 
using RNeasy® Kits (Qiagen, Valencia, CA) following the manufactures instructions.  
Micro-arrays will be used to measure the steady state expression level of nearly all 
known human genes in the fresh-frozen biopsies.  Approximately 3 - 10 mg of total RNA 
will be used to generate fluorescent-labeled cDNA for hybridization to the Human 
Genome U95 gene set (Affymetrix, Inc. Santa Clara CA).  The complete Human U95 
gene set contains 60,000 expression elements that represent approximately 12,000 full 
length genes and 50,000 ESTs.
Collection, handling, and storing of blood specimens for tubulin polymerization assay using 
PBMCs:  (1) Collection: Blood samples are to be collected from an indwelling catheter or by 
direct venipuncture.  Each blood sample should be collected into a pre-labeled 8 mL Becton-
Dickinson CPT Vacutainer® tube.  (2) Handling: Following blood collection, the tubes should be 
inverted several times to ensure mixing with the anticoagulant.  Tubes should remain at room 
temperature and be centrifuged for 30 minutes at approximately 1700 x g at 20°C within 15
minutes of collection.  The PBMCs should be transferred to a separate polypropylene tube and 
washed twice with 10 mL of ice-cold phosphate buffered saline (PBS).  Following each washing, 
cells should be separated by centrifugation at 1700 x g for 10 minutes.  Following the second 
washing, remove as much liquid as possible.  The tube may be inverted on a paper towel for a 
few minutes to remove residual liquid, provided the cell pellet does not become dislodged from 
the tube bottom.  (3) Storing: The PBMC cellular pellet should be stored at -70 to -80°C until 


Ixabepilone in Cervical Carcinoma
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assayed.  Samples should be labelled.  Each label will have the study number, sample matrix, 
and nominal sample time.  Once affixed on tubes, the labels should be wrapped completely by 
applying protective transparent tape for protection during handling, and storage.  The actual 
time, as well as the date, for each sample should be recorded.
Tracking and Storage of Samples
Disposition of samples:
When initially collected, all specimens should be labeled with the patient's name, 
hospital number, date and time of collection. Once the samples reach the laboratory 
they will be appropriately labeled and coded without names.  The information on the 
subjects’ names and ID numbers will be kept in a log book in a locked cabinet.
At this time (11/2008) the samples are recorded in a laboratory notebook in room 12N220. The 
information includes the patient’s name, ID number, date of biopsy and whether the sample is 
pre- or post-ixabepilone administration. We intend to upgrade the tracking process to an 
electronic spreadsheet that contains the patient ID, trial name/protocol number, time drawn, 
cycle time point, dose, material type, as well as box and freezer location. Samples remaining 
after the study completes will be stored in the same freezer in Dr. Fojo’s lab and eventually 
transferred to Dr. Figg’s core facility for possible future study as outlined below. The study 
consent contains a section asking patients for permission to keep the tissue for use in research 
to learn about, prevent, or treat cancer or other health problems.
Material remaining after completion of correlative studies (with the exception of biopsy 
samples) will be transferred to the laboratory of Dr. William Figg to be entered into the Clinical 
Pharmacology Program’s “Patient Sample Database Management System” (PSDMS) -
Labrador. This is a secure program that can only be accessed by authorized users in Dr. Figg’s 
lab. PSDMS creates a unique barcode ID for every sample and sample box that cannot be 
traced back to patients without PSDMS access. These samples will be managed in accordance 
with the laboratory’s policies and procedures.  
The data recorded for each sample includes the patient ID, trial name/protocol number, time 
drawn, cycle time point, dose, material type, as well as box and freezer location. There are 
patient demographics that can be obtained to correlate with the samples through the PSDMS 
system. For each samples, there are notes describing the processing method (delay in sample 
processing, storage conditions on the ward, etc.).  Bar-coded samples are stored in bar-coded 
boxes in a locked freezer at either -20 or -85qC according to stability requirements. These 
freezers are located onsite in Dr. Figg’s lab and offsite at NCI Frederick Central Repository 
Services (Fisher Bioservices) in Frederick, MD.
Samples will be stored until requested by the researcher assigned to the protocol (however, 
those requests must come from a member of Dr. Figg’s laboratory with PSDMS 
access/clearance). All requests are monitored and tracked in the PSDMS system. All 
researchers are required to sign a form stating that the samples are only to be used for research 
purposes associated with this trial (as per the IRB approved protocol – that protocol is stored in 
the PSDMS system) and that any unused samples must be returned to Dr. Figg’s laboratory.
Guidelines for reporting loss or destruction to IRB:
The PI will report any loss or destruction of samples to the IRB. Any new use of the 
samples, specimens, or data outside of this protocol will require prospective IRB review 
and approval.


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APPENDIX B: Study Calendar
EVALUATIONS REQUIRED PRE, DURING, AND POST THERAPY:
A
B
C
D
E
F
Complete medical history
X
Interim medical history
X
X
Physical examination
X
X
X
Weight and height
X
X
Vital signs 
X
X
X
ECOG performance status
X
X
X
X
Urine pregnancy test
X
HIV Screen/Hepatitis B and C Screen
X
Staging laboratory evaluation
X
X
X
Routine laboratory evaluation
X
X
X
CBC with differential and platelet count
X
X
X
X
Staging imaging studies
X
X
X
Biopsy & Research bloods (if indicated)*
X
X
____________________________________________________________________________
A: Within 4 weeks prior to initiating therapy
B: Within 1 week prior to initiating therapy
C: Weekly or twice weekly during period of anticipated neutropenia
D: Every cycle
E: Every 2 cycles (Imaging studies and chest radiograph every third cycle after cycle 6)
F: Study termination.
*Biopsies will be obtained after consent but before Day 1 dosing, and again on either 
Day 4 or Day 5.  Biopsies are optional.
Research Labs for tubulin polymerization will be obtained prior to the Cycle 1 Day 1 drug 
infusion, and 1, 8  and 24 hours after Day 1 infusion start, and on either Day 4 or 5, 
within 1 hour of the biopsy.  The research labs will only be done in those patients who 
have biopsies performed.


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APPENDIX C: List of drugs that may have potential CYP3A4 interactions
(source: ctep.cancer.gov) [Updated on May 1, 2007]
When drugs classified as ‘substrates’ are co-administered with BMS-247550 there is the 
potential for higher concentrations of the ‘substrate’. When BMS-247550 is co-
administered with compounds classified as ‘inhibitors’, increased plasma concentrations 
of BMS-247550 is the potential outcome. The co-administration of ‘inducers’ would 
potentially lower plasma BMS-247550 concentrations. Only major substrates and 
effective inducers are listed.  
List of drugs that may have potential CYP3A4 interactions
CYP3A4 Substrates
Albuterol
Alfentanil
Alprazolam
Amiodarone
Amlodipine
Amprenavir
Aprepitant
Aripiprazole
Atazanavir
Atorvastatin
Benzphetamine
Bisoprolol
Bortezomib
Bosentan
Bromazepam
Bromocriptine
Budesonide
Buprenorphine
Buspirone
Busulfan
Carbamazepine
Cerivastatin
Chlordiazepoxide
Chloroquine
Chlorpheniramine
Cilostazol
Cisapride
Citalopram
Clarithromycin
Clobazam
Clonazepam
Clorazepate
Cocaine
Colchicine
Conivaptan
Cyclophosphamide
Cyclosporine
Dantrolene
Dapsone
Dasatinib (1)
Delavirdine
Diazepam
Dihydroergotamine 
Diltiazem 
Disopyramide 
Docetaxel
Doxepin
Doxorubicin
Doxycycline
Efavirenz
Eletriptan
Enalapril
Eplerenone
Ergoloid mesylates
Ergonovine
Ergotamine
Erythromycin
Escitalopram
Estradiol
Estrogens, conj., synthetic
Estrogens, conj., equine
Estrogens, conj., esterified
Estrone
Estropipate
Ethinyl estradiol
Ethosuximide
Etoposide
Exemestane
Felbamate
Felodipine
Fentanyl
Flurazepam
Flutamide
Fluticasone
Fosamprenavir
Gefitinib
Haloperidol
Ifosfamide
Imatinib
Indinavir
Irinotecan
Isosorbide
Isosorbide dinitrate
Isosorbide mononitrate
Isradipine 
Itraconazole
Ketamine 
Ketoconazole
Lansoprazole
Letrozole
Levonorgestrel
Lidocaine
Losartan
Lovastatin
Medroxyprogesterone 
Mefloquine
Mestranol
Methadone
Methylergonovine
Methysergide
Miconazole
Midazolam
Miglustat
Mirtazapine
Modafinil
Montelukast
Moricizine
Nateglinide
Nefazodone
Nelfinavir
Nevirapine
Nicardipine
Nifedipine
Nimodipine
Nisoldipine
Norethindrone
Norgestrel
Ondansetron
Paclitaxel
Pergolide
Phencyclidine
Pimozide
Pipotiazine
Primaquine
Progesterone
Quetiapine
Quinidine
Rabeprazole 
Ranolazine
Repaglinide
Rifabutin
Ritonavir
Salmeterol
Saquinavir
Sibutramine
Sildenafil
Simvastatin
Sirolimus
Spiramycin
Sufentanil
Sunitinib
Tacrolimus
Tamoxifen
Tamsulosin
Telithromycin
Teniposide
Tetracycline
Theophylline
Tiagabine
Ticlopidine
Tipranavir
Tolterodine
Toremifene
Trazodone
Triazolam
Trimethoprim
Trimipramine
Troleandomycin
Vardenafil
Venlafaxine
Verapamil
Vinblastine
Vincristine
Vinorelbine
Zolpidem
Zonisamide
Zopiclone


Ixabepilone in Cervical Carcinoma
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CYP3A4 Inhibitors
Acetominophen
Acetazolamide
Amiodarone
Amlodipine
Amprenavir
Anastrozole
Aprepitant
Atazanavir
Atorvastatin
Azelastine
Azithromycin
Betamethasone
Bortezomib
Bromocriptine
Caffeine
Cerivastatin
Chloramphenicol
Chlorzoxazone
Cimetidine
Ciprofloxacin
Cisapride
Clarithromycin
Clemastine
Clofazimine
Clotrimazole
Clozapine
Cocaine
Conivaptan
Cyclophosphamide
Cyclosporine
Danazol
Dasatinib (1)
Delavirdine
Desipramine
Dexmedetomidine
Diazepam
Diclofenac
Dihydroergotamine 
Diltiazem
Disulfiram
Docetaxel
Doxorubicin
Doxycycline
Drospirenone
Efavirenz
Enoxacin
Entacapone
Ergotamine
Erythromycin
Ethinyl estradiol
Etoposide
Felodipine
Fentanyl
Fluconazole
Fluoxetine
Fluvastatin
Fluvoxamine
Fosamprenavir
Glyburide
Grapefruit juice (2)
Haloperidol
Hydralazine
Ifosfamide
Imatinib
Indinavir
Irbesartan
Isoniazid
Isradipine
Itraconazole
Ketoconazole
Lansoprazole
Lidocaine
Lomustine
Losartan 
Lovastatin
Mefloquine
Mestranol
Methadone
Methimazole
Methoxsalen
Methylprednisolone
Metronidazole
Miconazole
Midazolam
Mifepristone
Mirtazapine
Mitoxantrone
Modafinil
Nefazodone
Nelfinavir
Nevirapine
Nicardipine
Nifedipine
Nisoldipine
Nizatidine
Norfloxacin
Olanzapine
Omeprazole
Orphenadrine
Oxybutynin
Paroxetine
Pentamidine
Pergolide
Phencyclidine
Pilocarpine
Pimozide
Pravastatin
Prednisolone
Primaquine
Progesterone
Propofol 
Propoxyphene
Quinidine
Quinine
Quinupristin
Rabeprazole
Ranolazine
Risperidone
Ritonavir
Saquinavir
Selegiline
Sertraline
Sildenafil
Sirolimus
Sulconazole
Tacrolimus
Tamoxifen
Telithromycin
Teniposide
Testosterone
Tetracycline
Ticlopidine
Tranylcypromine
Trazodone
Troleandomycin
Valproic acid
Venlafaxine
Verapamil
Vinblastine
Vincristine
Vinorelbine
Voriconazole
Zafirlukast
Ziprasidone
CYP3A4 Inducers
Aminoglutethimide
Carbamazepine
Fosphenytoin
Nafcillin
Nevirapine
Oxcarbazepine
Pentobarbital
Phenobarbital 
Phenytoin
Primidone
Rifabutin
Rifampin 
Rifapentine
St. John’s wort (3)
When drugs classified as ‘substrates’ are co-administered with (Study Agent), there is the potential for higher concentrations of the ‘substrate’. 
When (Study Agent) is co-administered with compounds classified as ‘inhibitors’, increased plasma concentrations of (Study Agent) is the 
potential outcome. The co-administration of ‘inducers’ would potentially lower plasma (Study Agent) concentrations.
Note: Adapted from Cytochrome P450 Enzymes: Substrates, Inhibitors, and Inducers. In: Lacy CF, Armstrong LL, Goldman MP, 
Lance LL eds. Drug Information Handbook 15TH ed. Hudson, OH; LexiComp Inc. 2007: 1899-1912.  
Only major substrates and effective inducers are listed.  
Additional information for drug interactions with cytochrome P450 isoenzymes can be found at http://medicine.iupui.edu/flockhart/.
(1)   Investigator’s Brochure: Dasatinib (BMS 354825). Bristol-Myers Squibb. October 2006.
(2)  Malhotra et al. (2001). Clin Pharmacol Ther. 69:14-23.
(3)  Mathijssen et al. (2002). J Natl Cancer Inst. 94:1247-1249.
      Frye et al. (2004). Clin Pharmacol Ther. 76:323-329.


Ixabepilone in Cervical Carcinoma
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APPENDIX D:  Care of fingernails during treatment with Ixabepilone
During the course of chemotherapy some patients have experienced pain in their 
fingertips, especially in their fingernails. This is especially true when they are trying to 
open a can or apply any pressure to their nails. Some patients have developed 
infections in their nail beds. Others have had their nails “lift off” over a period of time, as 
a new nail grows in.Sometimes the nails have streaks of color in them. This doesn’t 
happen all at once, rather it happens gradually over the course of several months. We 
have developed some guidelines to help you care for your fingernails during 
chemotherapy. These techniques might help prevent or minimize the problems.
Prevention
1. Minimize hand and nail trauma.
2. Avoid repeated hand washing or soaking, for example, wear waterproof gloves 
when washing dishes.
3. Avoid nail polish and solvents.
4. Avoid using instruments to dig under nails.
5. Avoid exposing nails to direct sunlight (this has been a problem with a different 
chemotherapy. In that case, avoiding the sunlight helped).
6. Wear gloves in the winter and sunscreen (containing titanium or iron oxide) on nails in 
the summer.
7. Dry hand/nails thoroughly whenever they become wet. Some patients find a blow dryer 
is very helpful to dry the nails.
8. Wear gloves when gardening or in situations that your nails might be exposed to dirt or 
solvents.
Treatment 
1. Signs of infections include nail discoloration, pus forming under the nail, or pus 
draining from the nail. If possible, the pus should be sent for “culture” to 
determine if any bacteria are present. This can be done by your local doctor or by 
the staff at the NIH.
2. If you have an infection you can clean your nails with either hydrogen peroxide or 
dilute vinegar. You can put the solution in a small bowl and soak your fingertips 
for a few minutes, twice a day. Dry thoroughly when done.
3. Some patients have found that trimming their nails very short has helped the 
infections clear more quickly.
4. You may need antibiotics to treat the infection.

ICF_001.pdf: 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
INSTITUTE: 
National Cancer Institute 
STUDY NUMBER: 
09-C-0037 
PRINCIPAL INVESTIGATOR: Tito Fojo, M.D., Ph.D 
STUDY TITLE:  
A Phase II Clinical Trial of Ixabepilone (Ixempra®, BMS–247550, NSC 710428), an 
Epothilone B Analog, in Cervical Cancer 
Continuing Review Approved by the IRB on 04/09/12 
Amendment Approved by the IRB on 02/16/12 (H) 
Date posted to web:04/21/12 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent (1) 
 
 
INTRODUCTION 
We invite you to take part in a research study at the National Institutes of Health (NIH). 
First, we want you to know that: 
Taking part in NIH research is entirely voluntary. 
You may choose not to take part, or you may withdraw from the study at any time.  In 
either case, you will not lose any benefits to which you are otherwise entitled.  However, 
to receive care at the NIH, you must be taking part in a study or be under evaluation for 
study participation. 
You may receive no benefit from taking part.  The research may give us knowledge that 
may help people in the future. 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of 
medical or research treatments they would want to receive (such as blood transfusions).  If you 
have such beliefs, please discuss them with your NIH doctors or research team before you agree 
to the study. 
Now we will describe this research study.  Before you decide to take part, please take as much 
time as you need to ask any questions and discuss this study with anyone at NIH, or with family, 
friends or your personal physician or other health professional.   
 
DESCRIPTION OF RESEARCH STUDY 
 
This is a Phase II study for the experimental treatment of cervical cancer.  A Phase II study is 
one that begins the process of examining whether a specific drug might be useful in a particular 
type of cancer.  It follows Phase I studies that are conducted to determine the amount of a drug 
that can be safely administered.  The drug to be examined in this study is ixabepilone.  The 
purpose of this Phase II study is to determine whether ixabepilone administered every day for 
five consecutive days is effective in the treatment of cervical cancer.  To determine if 
ixabepilone is effective in the treatment of cervial cancer, up to 76 patients will be enrolled in 
this study.  Ixabepilone is a member of the epothilone class of drugs.  The epothilones are drugs 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
09-C-0037 
CONTINUATION: page 2 of 14 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
that interfere with the ability of cancer cells to divide.  In the way they kill cells, they are very 
similar to a class of compounds known as the taxanes.  The taxane class of drugs include the 
drug taxol.  Taxol has been used extensively in a wide variety of cancers and is effective in the 
treatment of several forms of cancer, including cancer of the breast, cancer of the ovary and 
cancer of the lung.  The epothilones are similar to taxol, but also have other characteristics that 
may make them better.  The latter include the ability to work in cells that are resistant to taxol.  
 
You will be expected to stay in the area for about 7 to 8 days in the first treatment cycle.  In 
subsequent cycles you will need to be in the area for the five days during which the drug is 
administered.  The amount of drug you receive in the first cycle will be that administered to all 
patients.  In subsequent cycles the dose may be adjusted according to how well your body 
responds to the chemotherapy. The dose will not be increased, but it may be decreased, if 
necessary. Each cycle lasts 21 days.  The first 5 days of a cycle are the days you receive 
ixabepilone and the next 16 days are the rest period before the next cycle begins.  During the 16 
day rest period you will return to your home.  You will need to have your blood tested at home 
twice a week during the first two cycles and then once a week during later cycles.  The results of 
these blood tests will be sent to us to help monitor your safety. 
 
Ixabepilone will be administered by vein.  Ixabepilone will be administered over a 60-minute 
period, every day for 5 days in a row.  The number of cycles of experimental therapy you receive 
will depend on your clinical situation. We plan to use x-rays (CT scans) and other studies if 
necessary, to determine if your tumor is responding to the treatment. The CT before the first 
cycle will be the ‘baseline CT’.  CTs will be done following cycle 2, cycle 4 etc and compared to 
the baseline CT as well as the previous CT.  In making decisions as to whether to continue 
treatment we will be guided by information from the CT and other studies as well, as the 
physical examination and reports from you on how you are tolerating the treatment.  The 
experimental therapy will be stopped if you have worsening of your disease or significant 
toxicity.   
 
During cycle one tumor biopsies will be obtained on two separate days, if you are willing and 
able to undergo a biopsy procedure. The first biopsy will be obtained prior to the first dose of 
ixabepilone.  This can happen during the day(s) before ixabepilone begins, or the morning of the 
first dose.  The second biopsy will be obtained either on the 4th or 5th day of ixabepilone, after 
you have received the infusion that day. The purpose of these biopsies is to analyze structures 
within the tumor cells for evidence that the chemotherapy is penetrating the tumor and causing 
disruption to its structure.  One specimen will be of the tumor without chemotherapy and the 
other will be of the tumor with chemotherapy.  These biopsies are optional. You can still be 
treated on this study, even if you refuse the biopsies. They will not benefit you, but will help our 
research.  The following section explains the procedure for obtaining biopsies. 
A physician may perform simple biopsies in an examining room using local anesthesia.  Other 
biopsies will be performed in the radiology suite with the help of special equipment such as a CT 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
09-C-0037 
CONTINUATION: page 3 of 14 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
scan or an ultrasound.  These will be performed under local anesthesia by an experienced 
radiologist.  A needle will be used to obtain the tumor sample.  It will pass through your skin and 
some of the internal tissues between the surface of your skin and the tumor.  We will use this 
tissue sample to examine some of the proteins that are important in how cancer cells react to 
drugs such as ixabepilone.  Part of this sample will be saved and may be used for additional 
investigations at the conclusion of the study.  We want to emphasize that the biopsy will be 
performed exclusively for research purposes.  You will not derive any personal benefit from this.  
We would also emphasize that we consider it an important part of the study, because we hope it 
will help us understand why the drug works, if it does, or why it did not work against the cancer 
if it does not.  Furthermore, the results of tissue (specimen) bank research may help find new 
ways to learn about, prevent, or treat cancer and other diseases. In the following section you will 
be asked if you would be willing have these biopsies done for research.  Even if you sign “yes” 
to the biopsies you can change your mind later and not have the biopsies.  
 
It will also be necessary to draw a small amount of blood five times during the first cycle of 
chemotherapy.  These blood draws will coincide with the biopsies, if you have biopsies.  If you 
do not have biopsies, the blood tests will not be done.   This will allow us to see how your body 
is handling ixabepilone.  Less than two teaspoons of blood will be drawn for each sample.  The 
blood samples will be collected on Day One, prior to the ixabepilone drug infusion and then at 1, 
8 and 24 hours after the drug is given. An additional blood sample will be collected within 1 
hour of the biopsy on either Day 4 or Day 5.  
 
Please read each sentence below and think about your choice. After reading each sentence, circle 
and initial the answer that is right for you.  No matter what you decide to do, it will not affect 
your care. 
1. I agree to have the two tumor biopsies for the research tests as specified in this study. 
 
 
 
Yes 
       No 
Initials_________ 
2. I also agree to have the five blood samples collected at the time of the biopsies. 
 
 
 
Yes 
      No  
Initials_________ 
 
 
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
09-C-0037 
CONTINUATION: page 4 of 14 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Optional Studies 
We would like to keep some of the specimens and data that are collected for future research.  
These specimens and data will be identified by a number and not your name.  The use of your 
specimens and data will be for research purposes only and will not benefit you.  It is also 
possible that the stored specimens and/or data may never be used.  Results of research done on 
your specimens and/or data will not be available to you or your doctor.  It might help people who 
have cancer and other diseases in the future.   
If you decide now that specimens and data can be kept for research, you can change your mind at 
any time. Just contact us and let us know that you do not want us to use your specimens and data. 
Then specimens that remain will be destroyed and your data will not be used for future research.  
3. My specimens and data may be kept for use in research to learn about, prevent, or treat cancer.  
 
 
 
 
Yes              No               Initials_________ 
4. My specimens and data may be kept for use in research to learn about, prevent or treat other 
health problems (for example: diabetes, Alzheimer's disease, or heart disease).  
 
 
 
 
Yes              No               Initials_________ 
5. Someone may contact me in the future to ask permission to use my specimens and/or data in 
new research not included in this consent.  
 
 
 
 
Yes              No               Initials_________ 
 
If your tumor grows while you are being treated with ixabepilone, your experimental treatment 
will be stopped.  In addition, your doctor can stop treatment at any time if in his/her opinion your 
continued participation would be detrimental to your health or the side effects are unmanageable.  
You may decide to stop the experimental treatment and withdraw from the study at any time.  
Upon completion of this study, you may be given the option of participating in additional 
research protocols that may be appropriate for you, if such protocols exist.  If they do not, you 
will be returned to the care of your referring physician.  
Your tumor may shrink or become undetectable by the CT scans.  If this were to happen, you 
would continue to receive ixabepilone for several more cycles until the physicians agree you 
have achieved the best response possible.  At that time, you would stop receiving ixabepilone, 
but continue to be monitored by us.  You will continue to have CT scans and physical exams 
every 6 weeks, then possibly extending to every 3 to 4 months.  You may have these visits done 
here at the NIH Clinical Center, or at your local physician’s office.  If you have scans done at 
your local office, we will request a copy of the scan and physician’s notes for your records here 
in the trial.  


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
09-C-0037 
CONTINUATION: page 5 of 14 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
ALTERNATIVE APPROACHES OR TREATMENTS 
 
It is important to stress that participation in this protocol does not constitute promise of long-
term care here at the NIH Clinical Center. 
 
If there is no research study that is suitable for you and your state of disease, you will be returned 
to the care of your referring doctor or institution or to alternate sources of care closer to home. 
 
It is conceivable that participation in this study may make you ineligible to participate in certain 
other research protocols because the requirements for entry into these protocols may disallow 
patients who have been on certain drugs. 
 
You may decide now not to receive treatment in this protocol or you may choose at any point in 
time to stop the drug and withdraw from the protocol; in either case you would be returned to the 
care of you referring physician. 
 
Because of the type and extent of your tumor, chemotherapy is an option other than surgery or 
radiation.   
 
Alternative approaches that could be used may include: 
1. 
Radiation treatment that sometimes can control tumor growth in local areas such as 
lymph nodes, bones, lung and bowel.  However, this approach will not effectively treat 
disease that has spread beyond small areas, as in your case. 
 
2. 
Surgery that can be used to remove disease from local areas such as lymph nodes, lung 
and bowel but is not useful for long term control when the disease has spread. 
 
3. 
Another option is  
• Getting no treatment. 
• Getting comfort care, also called palliative care. This type of care helps reduce 
pain, tiredness, appetite problems, and other problems caused by cancer. It does 
not treat the cancer directly, but instead tries to improve how you feel. Comfort 
care tries to keep you as active and comfortable as possible. 
 
4. 
FDA-approved chemotherapy or drug treatment. 
 
5. 
Other experimental therapies. 
 
RISKS OR DISCOMFORTS OF PARTICIPATION 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
09-C-0037 
CONTINUATION: page 6 of 14 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Local anesthesia will be used when biopsies of tumor masses are performed.  The risks 
associated with these procedures are pain, bleeding and local infection.  These risks will be 
individually explained to you at the time of the procedure.  We would also emphasize that if we 
are unsuccessful in our attempts to obtain a sample of your tumor, you will not be disqualified 
from participating in the study.  That is to say, if we feel that you are eligible for the study, and 
that a sample of tumor can be obtained without surgery, you will be eligible to enroll on study 
even if we are not successful in our attempt to obtain a sample of your tumor. 
 
If biopsies are performed, they will be obtained for experimental purposes including 
performance of tests on your tumor that may help us understand why it responds or does not 
respond to treatment.  As indicated above, biopsies requiring major surgery (opening the chest or 
abdomen), or those requiring general anesthesia will only be obtained if necessary for your 
medical care and will not be obtained for experimental purposes.  It is important for you to 
understand that the biopsies of tumor will be performed for experimental purposes, so that we 
can try to determine why tumors become resistant to chemotherapy.  You will not derive any 
personal benefit from these biopsies. 
 
This research study involves exposure to radiation from up to 2 CT-directed biopsies.  This 
radiation exposure is not required for your medical care and is for research purposes only. 
The amount of radiation you will receive in this study is 0.26 rem which is below the 
guideline of 5 rem (or 0.5 rem in children) per year allowed for research subjects by the 
NIH Radiation Safety Committee.  The average person in the United States receives a 
radiation exposure of 0.3 rem per year from natural sources, such as the sun, outer space, 
and the earth's air and soil.  If you would like more information about radiation, please ask 
the investigator for a copy of the pamphlet, An Introduction to Radiation for NIH Research 
Subjects. 
 
While there is no direct evidence that the amount of exposure received from participating in 
this study is harmful, there is indirect evidence it may not be completely safe.  There may 
be a very slight increase in the risk of cancer.  
 
Please tell your doctor if you have had any radiation exposure in the past year, either from 
other research studies or from medical tests or care, so we can make sure that you will not 
receive too much radiation. Radiation exposure includes x-rays taken in radiology 
departments, cardiac catheterization, and fluoroscopy as well as nuclear medicine scans in 
which radioactive materials were injected into your body.  
If you are pregnant you will not be permitted to participate in this research study. If you are 
breast feeding and the protocol involves injection of radioactive material you will not be 
permitted to participate.  It is best to avoid radiation exposure to unborn or nursing infants since 
they are more sensitive to radiation than adults. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
09-C-0037 
CONTINUATION: page 7 of 14 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
Blood samples will be obtained at five time points during cycle one. A heparin-lock device may 
be placed during this time to prevent repeated use of needles.  This is placement of a temporary 
needle in your arm and using heparin in small amounts to prevent blood from clotting in the 
needle.  Alternately if you have a device that has been inserted to allow access to your veins (a 
central venous catheter), such as a ‘port’ or ‘picc’, blood can be drawn from these devices.  Since 
chemotherapy will result in decreased ability to make new red blood cells, the drawing of blood 
may increase the risk of anemia and the need for a blood transfusion, or treatment with a drug to 
increase your red blood cell count. 
 
To receive this experimental therapy you can have a central venous catheter placed.  This is a 
catheter that is placed under the skin of your chest, neck or arm and enters a major vein.  This 
catheter is used for administration of chemotherapy and drawing of blood.  These catheters are 
called ‘ports’ or ‘piccs’. A surgeon in the operating room using local anesthesia inserts the port 
catheter. Piccs are inserted by specially trained nurses in our procedure area.  The risks 
associated with these procedures include pain, bleeding, infection, and development of air in the 
chest.  Air in the chest outside the lung would require temporary placement of a chest tube by the 
surgeon. Other risks of the catheter include infection and clotting of your veins, which could 
require removal of the catheter for treatment. These risks will be explained to you in more detail 
at the time of insertion. 
 
The purpose of this phase II study is to determine whether ixabepilone is effective against 
cervical cancer. Ixabepilone is approved by the Food and Drug Administration (FDA) for the 
treatment of metastatic breast cancer. Although it is an approved drug, we are still studying 
ixabepilone to see if it might be useful in other cancers beside breast cancer.  For this reason, the 
study is considered experimental, because we do not know if ixabepilone will be effective 
against cervical cancer.  
All patients enrolled in the current study will be observed carefully for the development of any 
side effects and these will be recorded.  Blood tests will be monitored frequently and you will 
also undergo periodic physical examinations, and be asked to report any side effects you might 
have experienced.  Should any side effects other than those listed here become apparent during 
the course of the study, you will be advised of these at the time of study entry, or at any time 
during the course of the study.   We would also caution you not to take St. John’s Wort while 
receiving ixabepilone, since this may lead to a drug interaction that could be serious. You will 
need to report all prescription, over-the-counter medicines, and herbal remedies to the study team 
so we can review them for potential drug interactions.  This includes medicines and herbs taken 
in the month before you begin the study and also any new medicines or herbs you would like to 
start during the study.  Your study team must review the medicines and herbs before you begin to 
take them.  
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
09-C-0037 
CONTINUATION: page 8 of 14 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Anticipated side effects from Ixabepilone may include but are not limited to the following: 
 
Likely: 
• Lack of enough red blood cells (anemia) 
• Diarrhea 
• Nausea or the urge to vomit 
• Vomiting 
• Fatigue or tiredness 
• Increased blood level of a liver or bone enzyme (alkaline phosphatase) 
• Decreased number of a type of white blood cell (neutrophil/granulocyte) 
• Decreased number of a type of blood cell that help to clot blood (platelet) 
• Decrease in the total number of white blood cells (leukocytes) 
• Muscle pain 
• Inflammation (swelling and redness) or degeneration of the peripheral nerves (those 
nerves outside of brain and spinal cord) causing numbness, tingling, burning 
• Hair loss 
 
Less Likely: 
• Fever associated with dangerously low levels of a type of white blood cell (neutrophils) 
• Abnormally fast irregular heartbeat involving the upper chambers of the heart (atria) 
• Abnormally fast regular heartbeat involving the upper chambers of the heart (atria) 
• Period of very rapid and regular heartbeats that begins and ends suddenly 
• Slow heartbeat; regular rhythm 
• Fast heartbeat; regular rhythm 
• Fast heartbeat usually originating in an area located above the ventricles 
• Excessive tearing in the eyes 
• Belly pain 
• Irritation or sores in the lining of the anus 
• Constipation 
• Irritation or sores in the lining of the mouth 
• Irritation or sores in the lining of the rectum 
• Irritation or sores in the lining of the small bowel 
• Fever 
• Pain 
• Abnormal reaction of the body to substances, called allergens, that are contacted through 
the skin, inhaled into the lungs, swallowed, or injected (allergic reaction) 
• Infection 
• Inflammation (swelling and redness) of the skin caused by drugs after radiation therapy 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
09-C-0037 
CONTINUATION: page 9 of 14 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
• Increased blood level of a liver enzyme (ALT/SGPT) 
• Increased blood level of a liver enzyme (AST/SGOT) 
• Increased blood level of a liver pigment (bilirubin) often a sign of liver problems 
• Increased blood level of creatinine (a substance normally eliminated by the kidneys into 
the urine) 
• Increased INR (measure of the ability of the blood to clot properly) which increases the 
risk of bleeding 
• Loss of appetite 
• Dehydration (when your body does not have as much water and fluid as it should) 
• Joint pain 
• Muscle weakness of the whole body 
• Leg and/or arm pain 
• Pain in the area of the tumor 
• Dizziness (or sensation of lightheadedness, unsteadiness, giddiness, spinning or rocking) 
• Taste changes 
• Speech problems 
• Headache or head pain 
• Nerve pain 
• Weakness or paralysis (loss of muscle function) caused by damage to peripheral nerves 
(those nerves outside of brain and spinal cord) 
• Fainting 
• Difficulty sleeping or falling asleep 
• Difficulty emptying the bladder 
• Cough 
• Shortness of breath 
• Hiccups 
• Decrease in the oxygen supply to a tissue 
• Irritation or sores in the lining of the voice box 
• Irritation or sores in the lining of the throat 
• Inflammation (swelling and redness) of the lungs 
• Irritation or sores in the lining of the windpipe 
• Loss of some or all of the finger or toenails 
• Itching 
• Skin rash with the presence of macules (flat discolored area) and papules (raised bump) 
• Sudden reddening of the face and/or neck 
• Low blood pressure 
Rare but Serious: 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
09-C-0037 
CONTINUATION: page 10 of 14 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
• Partial or complete blockage of the small and/or large bowel.  Ileus is a functional rather 
than actual blockage of the bowel. 
• Build up of a large amount of fluid between the layers of tissue that line the lungs and 
chest cavity 
• Severe reaction of the skin and gut lining that may include rash and shedding or death of 
tissue 
• Swelling and redness of the skin on the palms of the hands and soles of the feet 
• Increase in the number and size of the pores in the capillaries (small blood vessels) which 
causes leakage of fluid from the blood to the tissue spaces, resulting in dangerously low 
blood pressure, swelling and multiple organ failure 
• Ixabepilone is dissolved in a solution that contains a compound called cremophor EL.  
Because some patients have had allergic reactions to the cremophor EL, you will receive 
two medications prior to the administration of ixabepilone, in order to prevent an allergic 
reaction.  The two medications will be diphenhydramine (Benadryl) and ranitidine 
(Zantac).  Although the likelihood a serious side effect will occur from receiving these 
drugs is low, you should be aware they have potential side effects.  Despite receiving 
premedications, you may still develop an allergic reaction.  If that happens the infusion 
will be stopped and additional diphenhydramine, ranitidine and a third medication, 
dexamethasone (Decadron), may be added to treat the reaction.  This is a rare occurrence.  
 
If you have received prior radiation therapy, you may experience cystitis or obstruction of the 
bladder after receiving ixabepilone.  Cystitis is an inflammation of bladder.  It may cause 
pain when trying to urinate.  The wall of the bladder may become thicker causing the 
opening of the bladder to become narrower, making it more difficult to urinate.  If you 
experience any of these changes please notify your study team immediately. 
 
1. 
For diphenhydramine (Benadryl), these include sedation, sleepiness, dizziness, 
difficulty with coordination, abdominal pain, dry mouth, flushing, and temporary 
difficulties passing urine.  Diphenhydramine may impair your ability to drive and 
you may need to seek transportation to and from clinic visits. 
  
2. 
For ranitidine (Zantac) potential side effects you may experience include 
headache, fatigue, dizziness, mild diarrhea, temporary confusion and a rash. 
 
3. 
For dexamethasone (Decadron) potential side effects you may experience include 
increased susceptibility to infection, lower values of calcium, potassium, sodium 
in your blood, high blood pressure and change in mood.  This medication would 
only be given for a few days during a cycle.  
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
09-C-0037 
CONTINUATION: page 11 of 14 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
4. 
Finally, there is evidence that some drugs that you may be taking for other 
reasons may affect the ability of your body to eliminate ixabepilone.  If you are 
taking any of these drugs the investigators will discuss the options available 
including substituting other similar drugs or withholding their administration for 
a defined period.   
These drugs include the following:  ketoconazole, itraconazole, clarithromycin, 
atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, amprenavir, 
indinavir, nelfinavir, delavirdine, voriconazole, and St. John’s Wort.  Please 
discuss all medications and herbs with your study team prior to taking them. 
 
5.  
You should not drink grapefruit juice while on this study, because it can interact 
with other medications. 
 
Pregnancy 
 
Patients with childbearing potential should use adequate birth control measures while on study, 
and for two months after discontinuing therapy.  Pregnant and breast-feeding patients will not be 
allowed on study due to the experimental nature of the protocol and the possibility of 
jeopardizing the health of the child.  If you or partner become pregnant while on study contact 
your NIH doctors immediately. 
 
POTENTIAL BENEFITS OF PARTICIPATION 
This is an experimental study.   While we hope this will be of some benefit to you, it is 
impossible to predict whether ixabepilone will be effective against cervical cancer.  It is also 
impossible to predict any side effects with certainty. 
 
RESEARCH SUBJECT’S RIGHTS 
Any complication arising from this treatment will receive full and prompt medical attention.  
However, neither the National Cancer Institute, the Federal Government, nor the Clinical Center, 
can provide financial compensation for injury or long-term medical treatment for such injuries, 
except as may be provided through whatever remedies are normally available under law.  Any 
significant new findings that relate to your treatment will be discussed with you. 
 
PAYMENT 
You will not be paid for taking part in this study.  Your medical care and the costs of the 
laboratory and radiographic studies done at the Clinical Center, NIH will be at no expense to 
you.  If the blood tests needed to monitor the effects of treatment are to be done by your local 
physician, you can be reimbursed for the costs if your insurance does not cover this expense; 
your NIH physician must obtain permission for this in advance.  The NIH cannot, however, 
reimburse you for the costs of other types of medical care delivered outside the NIH, even if you 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
09-C-0037 
CONTINUATION: page 12 of 14 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
are seeking medical attention as a result of side effects from treatment given here, unless 
permission for this is secured in advance by your NIH physician.  Similarly, we do not ordinarily 
reimburse the costs of diagnostic radiology tests (such as CT scans, MRI, or chest X-rays) done 
outside the NIH, even if they are done for the purpose of this study.  The upper limit of 
reimbursement is $5,000 per patient. 
 
What Happens after This Treatment is completed? 
This depends on how you have responded to the experimental therapy.  If all evidence of disease 
has disappeared, we will schedule periodic visits to the Clinical Center for follow-up 
examination and tests.  If the disease does not disappear entirely or if it should recur after having 
disappeared for a period of time, then you may need further therapy.  At that time you will be 
given the opportunity of participating in additional research protocols that may be appropriate for 
you.  If no such protocols are available, you will be returned to the care of your local physician.  
It is important to stress that participation in this protocol does not constitute a promise of long-
term medical care here at the Clinical Center.  If there is no research study that is suitable for you 
and your stage of disease, you will be returned to the care of your private doctor or to a clinic in 
your local community.  It is conceivable that participation in this study may make you ineligible 
to participate in certain other research protocols because the requirements for entry onto these 
protocols may disallow patients who have already been treated with certain drugs or who have 
had certain side effects from previous treatment.  You may decide now not to receive treatment 
on this protocol, or you may choose at any point in time to stop the treatment and withdraw from 
the protocol; in either case you will be returned to the care of your referring physician. 
 
COMMUNICATION 
The NCI physicians involved in your case are available to answer all of your questions 
concerning this protocol.  If you have any concerns or questions, you may contact Dr. Tito 
Fojo, the Principal Investigator (301-402-1357), and/or Maureen Edgerly, R.N., the Research 
Nurse at 301-435-5604.  The NIH patient’s rights representative (301-496-2626) will be 
available to answer questions you may have concerning your involvement in this study or your 
rights as a research subject.  Officials of the Food and Drug Administration, the NCI, and the 
drug manufacturer (Bristol Myers Squibb) may review your patient records during this study, 
confidentially.  A copy of this informed consent is on file with Institutional Review Board of 
the National Cancer Institute and a copy is available to you when you sign it and at any further 
time.  Your participation in this protocol is entirely voluntary and you may refuse to participate 
or withdraw from this protocol at any time. 
 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER:09-C-0037 
CONTINUATION: page 13 of 14 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
OTHER PERTINENT INFORMATION 
 
1. Confidentiality.  When results of an NIH research study are reported in medical journals or 
at scientific meetings, the people who take part are not named and identified.  In most cases, 
the NIH will not release any information about your research involvement without your 
written permission.  However, if you sign a release of information form, for example, for an 
insurance company, the NIH will give the insurance company information from your medical 
record.  This information might affect (either favorably or unfavorably) the willingness of the 
insurance company to sell you insurance. 
 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, 
you should know that the Act allows release of some information from your medical record 
without your permission, for example, if it is required by the Food and Drug Administration 
(FDA), members of Congress, law enforcement officials, or authorized hospital accreditation 
organizations. 
 
2. Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-term 
medical care for any injury resulting from your participation in research here.  In general, no 
long-term medical care or financial compensation for research-related injuries will be 
provided by the National Institutes of Health, the Clinical Center, or the Federal Government.  
However, you have the right to pursue legal remedy if you believe that your injury justifies 
such action. 
 
3. Payments.  The amount of payment to research volunteers is guided by the National 
Institutes of Health policies.  In general, patients are not paid for taking part in research 
studies at the National Institutes of Health.  Reimbursement of travel and subsistence will be 
offered consistent with NIH guidelines. 
 
4. Problems or Questions.  If you have any problems or questions about this study, or about 
your rights as a research participant, or about any research-related injury, contact the 
Principal Investigator, Tito Fojo, M.D.;  Bldg 10, Rm 12N226, 10 Center Drive, Bethesda, 
MD 20892; Telephone: 301-402-1357.  Other researchers you may call are: Maureen 
Edgerly, R.N., Telephone: 301-435-5604. If you have any questions about the use of your 
specimens and data for future research studies, please contact the Office of the Clinical 
Director, Telephone: 301-496-4251. 
 
You may also call the Clinical Center Patient Representative at 301-496-2626. 
 
5. Consent Document.  Please keep a copy of this document in case you want to read it again. 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER:09-C-0037 
CONTINUATION: page 14 of 14 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient. 
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions.  I hereby consent to 
take part in this study. 
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions.  I hereby give 
permission for my child to take part in this 
study.   
(Attach NIH 2514-2, Minor’s Assent, if 
applicable.) 
 
  
  
 
 
 
Signature of Adult Patient/ 
Legal Representative 
Date 
Signature of Parent(s)/ Guardian Date 
 
 
Print Name 
 
 
Print Name 
C. Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to 
participate in the study. 
 
  
  
 
Signature of Parent(s)/Guardian 
Date 
Print Name 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM APRIL 9, 2012 THROUGH APRIL 8, 2013.  
 
 
 
 
 
 
 
 
 
Signature of Investigator 
Date 
Signature of Witness 
Date 
 
 
Print Name 
 
 
Print Name