Phase II Study of Ixabepilone in Metastatic Breast Cancer and Its Effects on the Ultrastructure of Neurons

• Sponsor: Weill Medical College of Cornell University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00627978
• Collaborator: Bristol-Myers Squibb (Industry)
• Enrollment: 15
• Location: 1
• Arms: 2
• Duration (Months): 38
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

Primary Objectives

• Assess ultrastructure changes in dermal myelinated nerves of patients who receive ixabepilone chemotherapy

• Detailed characterization of peripheral neuropathy in patients who receive ixabepilone

Secondary Objectives

• Clinical benefit rate

• Time to progression ( TTP)

• Toxicity

• Exploratory studies:

• Relation of MDR 1 and TRKA polymorphisms to evolution of ultrastructural neurologic changes observed in neurons.

• Relation of NGF, IL8, and IL10 to the development of clinical symptoms and ultrastructural changes in neurons.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Breast Cancer	Drug: ixabepilone	Phase 2

Detailed Description

Eligible patient population:

• Stage 4 breast cancer

• Resolution from toxicity of prior therapy to ≤ CTC grade 1 ( except alopecia)

• No limit on prior number of therapies to treat cancer

• Adequate organ function

• Life expectancy greater than 3 months

Treatment: ixabepilone 40 mg/m2 Q3w over 3 hours

Evaluation on Study:

I. Efficacy evaluation:

• Baseline CT chest, abdomen and pelvis and bone scan within 4 weeks of starting therapy

• Evaluation of disease every 2 cycles of chemotherapy

• Ongoing toxicity evaluation using NCI CTC 3.

II. Neurological evaluation:

• Detailed neurologic exam using Neuropathy Assessment Instrument (represents a standard neurological exam)

• Serum NGF, IL 8,10, prior to starting therapy and prior to each cycle of ixabepilone

• DNA for assessment of TRK A and MDR1 polymorphisms

• Punch biopsy of skin prior to starting therapy and after every 2 cycles. Laboratory evaluation of peripheral nerve biopsies will be conducted at Rockefeller University under the direction of Dr. Carlson in Dr. Strickland's Lab.

Study Design

• Study Type: Interventional
• Actual Enrollment: 15 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study of Ixabepilone in Patients With Metastatic Breast Cancer and a Prospective Evaluation of Its Effects on the Ultrastructure of Neurons
• Study Start Date: Nov 1, 2007
• Actual Primary Completion Date: Jan 1, 2011
• Actual Study Completion Date: Jan 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ixabepilone Participants are treated with Ixabepilone.	Drug: ixabepilone; ixabepilone 40 mg/m2 Q3w over 3 hours
No Intervention: Control

Outcome Measures

Primary Outcome Measures

1. Axons With Abnormal Morphology [Baseline and Over 7 cycles of treatment, approximately 21 weeks]

   Digital photographs for morphometry were captured at a magnification of 8000-16,000x and the photos were uploaded onto an imaging platform of transmission electron microscope (iTEM) (Olympus, Mu¨nster, Germany). The figures were enlarged by 50%, and an individual linear array was used to measure the axonal diameter (cross-sectional area) and the number of unmyelinated axons per Remak Schwann cell was enumerated according to the established methodology.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria

• Ability to understand and the willingness to sign a written informed consent document.

• Histologic or cytologic diagnosis of adenocarcinoma originating in the breast.

• Evidence that the cancer is metastatic or locally advanced and not curable by local measures (i.e., surgery, radiation).

NOTE: There is no limit on number of prior chemotherapy regimens received.

• Karnofsky performance status (KPS) score of 70 - 100; (Appendix 1).

• Life expectancy of at least 12 weeks.

• Adequate recovery of drug related toxicities from prior systemic therapy (recovery to < = Grade 1 except for Grade 2 fatigue and alopecia).

• Adequate recovery from recent surgery and radiation therapy. At least one week must have elapsed from the time of a minor surgery and/or focal/palliative radiation therapy; at least 3 weeks for major surgery and other radiation therapy.

• Women or Men, age > = 18 years.

• Patients must have normal organ and marrow function as defined below:

• Hematologic function with absolute neutrophils ≥ 1,500/mm3 and/or platelets > 125,000/mm3

• Hepatic function with serum bilirubin less than 1.5 times the upper institutional limits of normal, ALT ≤ 2.5 times the upper institutional limits of normal (≤ 5 times the upper institutional limits of normal if documented hepatic metastases are present)

• Renal function with serum creatinine ≤ 1.5 times the upper limit of normal

• Women of childbearing potential (WOCBP) and men with partners who are of childbearing potential must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 4 weeks after the study in such a manner that the risk of pregnancy is minimized.

WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea > = 12 consecutive months; or women on hormone replacement therapy (HRT) with documented serum follicle stimulating hormone (FSH) level > 35 mIU/mL). Even women who are using oral, implanted or injectable contraceptive hormones or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy or practicing abstinence or where partner is sterile (e.g., vasectomy), should be considered to be of child bearing potential.

• WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of study medication.

Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.

Exclusion Criteria

• Patients with known and active brain and/or leptomeningeal metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.

• CTC Grade 2 or greater neuropathy (motor or sensory) at study entry.

• Prior treatment with ixabepilone.

• Serious intercurrent infections, or nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the complications of this therapy, including, but not limited to: ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

• Known history of HIV infection.

• Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.

• Patients may not be receiving any other concurrent chemotherapy, hormonal therapy, immunotherapy regimens or radiation therapy, standard or investigational.

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to ixabepilone.

• Known prior severe hypersensitivity reactions to agents containing CremophorEL.

• Patients may not be receiving any prohibited therapies and/or medications.

• Pregnant and lactating women are excluded from the study because the risks to an unborn fetus or potential risks in nursing infants are unknown.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Weill Medical College of Cornell University	New York	New York	United States	10021

Sponsors and Collaborators

• Weill Medical College of Cornell University
• Bristol-Myers Squibb

Investigators

• Principal Investigator: Linda Vahdat, MD, Weill Medical College of Cornell University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Weill Medical College of Cornell University
• ClinicalTrials.gov Identifier: NCT00627978
• Other Study ID Numbers: 0707009284
• First Posted: Mar 4, 2008
• Last Update Posted: Jun 26, 2018
• Last Verified: May 1, 2018

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Weill Medical College of Cornell University: breast
• Additional relevant MeSH terms: Breast Neoplasms

Study Results

Participant Flow

Arm/Group Title	Ixabepilone	Control
Arm/Group Description	Participants are treated with Ixabepilone. ixabepilone: ixabepilone 40 mg/m2 Q3w over 3 hours	No treatment with Ixabepilone
Period Title: Overall Study
STARTED	10	5
COMPLETED	10	5
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Ixabepilone	Control	Total
Arm/Group Description	Participants are treated with Ixabepilone. ixabepilone: ixabepilone 40 mg/m2 Q3w over 3 hours	Participants receive no intervention.	Total of all reporting groups
Overall Participants	10	5	15
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	8 80%	5 100%	13 86.7%
>=65 years	2 20%	0 0%	2 13.3%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	55.8	51	54.4
Sex: Female, Male (Count of Participants)
Female	10 100%	5 100%	15 100%
Male	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	10 100%	5 100%	15 100%

Outcome Measures

1. Primary Outcome

Title	Axons With Abnormal Morphology
Description	Digital photographs for morphometry were captured at a magnification of 8000-16,000x and the photos were uploaded onto an imaging platform of transmission electron microscope (iTEM) (Olympus, Mu¨nster, Germany). The figures were enlarged by 50%, and an individual linear array was used to measure the axonal diameter (cross-sectional area) and the number of unmyelinated axons per Remak Schwann cell was enumerated according to the established methodology.
Time Frame	Baseline and Over 7 cycles of treatment, approximately 21 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ixabepilone	Control
Arm/Group Description	Participants are treated with Ixabepilone. ixabepilone: ixabepilone 40 mg/m2 Q3w over 3 hours	No treatment with Ixabepilone
Measure Participants	10	5
Axons grade 0 (normal) or 1 morphology baseline	52	82
Axons grade 0 (normal) or 1 morphology Cycle 7	2	NA
Axons grade 3 or 4 morphology baseline	24	15.5
Axons grade 3 or 4 morphology Cycle 7	79	NA

Adverse Events

Adverse Event Reporting Description	Serious and Other [Not Including Serious] Adverse Events were not collected/assessed.
Arm/Group Title	Ixabepilone		Control
Arm/Group Description	Participants are treated with Ixabepilone. ixabepilone: ixabepilone 40 mg/m2 Q3w over 3 hours		Participants are not treated with Ixabepilone.
All Cause Mortality
	Ixabepilone		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Ixabepilone		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)
Other (Not Including Serious) Adverse Events
	Ixabepilone		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.