Ixabepilone in Treating Patients With Relapsed or Refractory Aggressive Non-Hodgkin's Lymphoma

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00058019
• Collaborator: (none)
• Enrollment: 51
• Locations: 2
• Arm: 1
• Duration (Months): 90
• Patients Per Site: 25.5
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This phase II trial is studying how well ixabepilone works in treating patients with relapsed or refractory aggressive non-Hodgkin's lymphoma. Drugs used in chemotherapy, such as ixabepilone, work in different ways to stop cancer cells from dividing so they stop growing or die.

Condition or Disease	Intervention/Treatment	Phase
Anaplastic Large Cell Lymphoma; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma	Drug: ixabepilone	Phase 2

Detailed Description

OBJECTIVES:

1. Determine the objective overall response rate of patients with relapsed or refractory aggressive non-Hodgkin's lymphoma treated with BMS-247550 (ixabepilone).

2. Determine the safety and toxicity of this drug in these patients. III. Determine the duration of response, overall survival, and time to progression in patients treated with this drug.

OUTLINE: This is a multi-center study.

Patients receive ixabepilone intravenously (IV) over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression, unacceptable toxicity, or if the patient becomes a candidate for stem cell transplantation.

Patients are followed every 8 weeks until disease progression.

Study Design

• Study Type: Interventional
• Actual Enrollment: 51 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Epothilone B Analog BMS-247550 (NSC 710428) in Patients With Relapsed Aggressive Non-Hodgkin's Lymphomas
• Study Start Date: Feb 1, 2003
• Actual Primary Completion Date: Aug 1, 2010
• Actual Study Completion Date: Aug 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (chemotherapy) Patients receive ixabepilone IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression, unacceptable toxicity, or if the patient becomes a candidate for stem cell transplantation.	Drug: ixabepilone; Given IV; Other Names: BMS-247550 epothilone B lactam Ixempra

Outcome Measures

Primary Outcome Measures

1. Objective Overall Response Rate [up to 3 years]

   The 1999 international response criteria (http://www.ncbi.nlm.nih.gov/pubmed/10561185) as published by Cheson was used for the definition of target lesions and CT scans were used for response assessment. CR(complete response)/CRu(unconfirmed complete response) requires disappearance of all target lesions; PR (partial response) requires >=50% decrease in the sum of the products of the greatest diameters; Overall Response (OR)=CR/CRu+PR.

2. Safety and Toxicity of Ixabepilone [up to 3 years]

   Number of patients experiencing adverse event grade 3 or above. Grade was determined by the National Cancer Institute Common Toxicity Criteria (CTC) version 2.0. Adverse events possibly, probably, or definitely attributed to use of ixabepilone.

Secondary Outcome Measures

1. Duration of Response [up to 3 years]

   Duration of response was measured from the time measurement criteria are met for CR(complete response)/CRu(unconfirmed complete response)/PR(partial response), whichever was first recorded, until the first date that PD(progressive disease) was objectively documented. According to the 1999 international response criteria as published by Cheson, CR/CRu is defined as the disappearance of all target lesions; PR is defined as >=50% decrease in the sum of the products of the greatest diameters; PD is defined as >=50% increase from nadir in the sum of the products of the greatest diameters of any previously identified abnormal node for PRs or nonresponders, or appearance of any new lesion during or at the end of therapy.

2. Overall Survival [up to 3 years]

   Defined as the time from the first day of therapy to the date of death. If the patient was lost to follow-up, survival was censored on the last date the patient was known to be alive.

3. Time to Progression [up to 3 years]

   Defined as the time from the first day of treatment until the date PD(progressive disease) or death is first reported. Patients who died without a reported prior progression was considered to have progressed on the day of their death. Patients who did not progress was censored at the day of their last tumor assessment. According to the 1999 international response criteria as published by Cheson, progression/progressive disease is defined as >=50% increase from nadir in the sum of the products of the greatest diameters of any previously identified abnormal node for PRs or nonresponders, or appearance of any new lesion during or at the end of therapy.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Histologically confirmed aggressive non-Hodgkin's lymphoma of 1 of the following cellular types:

• Grade III follicular center

• Diffuse large B-cell

• Mantle cell

• Primary mediastinal B-cell

• Burkitt's

• High-grade B-cell (Burkitt-like)

• Anaplastic large cell of 1 of the following subtypes:

• CD30-positive

• T-cell

• Null cell

• Hodgkin's-like

• Relapsed or refractory disease after prior standard chemotherapy, meeting criteria for 1of the following cohorts:

• Cohort 1 (relapsed but chemosensitive): Prior complete response (CR) or partial response (PR) lasting at least 4 weeks after the most recent prior therapy

• Cohort 2 (refractory): Stable disease or less than a PR after the most recent prior therapy

• No progressive disease after the most recent prior therapy

• Measurable disease

• At least 1 bidimensionally measurable lesion at least 10 mm by conventional techniques or clinical exam

• Ineligible for or unwilling to undergo hematopoietic stem cell transplantation

• Patients requiring debulking prior to transplant allowed

• No known CNS involvement by lymphoma

• Prior CNS disease that has been successfully treated in patients with relapsed disease exclusively outside of the CNS may be allowed by the principal investigator

• Performance status - ECOG 0-2

• More than 3 months

• WBC at least 3,000/mm^3

• Absolute neutrophil count at least 1,200/mm^3

• Platelet count at least 100,000/mm^3

• Bilirubin no greater than 1.5 mg/dL

• AST/ALT no greater than 2.5 times upper limit of normal

• Creatinine no greater than 1.5 mg/dL

• Creatinine clearance at least 60 mL/min

• No symptomatic congestive heart failure

• No unstable angina pectoris

• No cardiac arrhythmia

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• No prior allergic reaction or hypersensitivity to compounds containing Cremophor EL or agents of similar chemical or biological composition to BMS-247550

• No peripheral neuropathy grade 2 or greater

• No other currently active malignancy except nonmelanoma skin cancer or carcinoma in situ of the cervix (previously treated malignancy allowed if considered to be at less than 30% risk of relapse)

• No ongoing or active infection

• No psychiatric illness or social situation that would preclude study compliance

• No other concurrent uncontrolled illness

• No colony-stimulating factors (CSFs) within 24 hours of study chemotherapy

• No CSFs during first course of study therapy

• No concurrent filgrastim-SD/01

• No concurrent immunotherapy

• See Disease Characteristics

• At least 4 weeks since prior cytotoxic chemotherapy (6 weeks for nitrosoureas or mitomycin)

• No other concurrent chemotherapy

• No concurrent hormonal therapy

• At least 4 weeks since prior radiotherapy

• No concurrent therapeutic radiotherapy

• At least 4 weeks since prior surgery

• Recovered from prior therapy

• At least 7 days since prior cimetidine

• No concurrent cimetidine

• No concurrent combination antiretroviral therapy for HIV-positive patients

• No other concurrent investigational agents

• No other concurrent anticancer medications

• No concurrent unconventional therapies, food, or vitamin supplements containing Hypericum perforatum

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Chicago	Chicago	Illinois	United States	60637
2	M D Anderson Cancer Center	Houston	Texas	United States	77030

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Sonali Smith, University of Chicago

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00058019
• Other Study ID Numbers: NCI-2009-00031; NCI-2009-00031; NCI-5913; UCCRC-NCI-5913; CDR0000285683; UCCRC-11965B; 11965B; 5913; P30CA014599; N01CM62202; N01CM62201; NCT01660269
• First Posted: Apr 9, 2003
• Last Update Posted: May 23, 2014
• Last Verified: Oct 1, 2011

• Additional relevant MeSH terms: Burkitt Lymphoma; Lymphoma; Lymphoma, Non-Hodgkin; Lymphoma, Mantle-Cell; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Large-Cell, Anaplastic; Recurrence; Epothilones; Epothilone B

Study Results

Participant Flow

Pre-assignment Detail	One patient never received treatment and was excluded from analysis.

Arm/Group Title	Cohort 1 (Chemosensitive)	Cohort 2 (Chmoresistant)
Arm/Group Description	Ixabepilone was administered intravenously at a dose of 20 mg/m^2 over 1 hour weekly on days 1,8, and 15 of a 28-day cycle. Cohort 1(Chemosensitive) enrolled patients with a complete response or partial response lasting at least 4 weeks to their most recent therapy.	Ixabepilone was administered intravenously at a dose of 20 mg/m^2 over 1 hour weekly on days 1,8, and 15 of a 28-day cycle. Cohort 2(Chemoresistant) enrolled patients with stable disease but less than a partial response to their most recent therapy.
Period Title: Overall Study
STARTED	39	12
COMPLETED	39	12
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Cohort 1 (Chemosensitive)	Cohort 2 (Chmoresistant)	Total
Arm/Group Description	Ixabepilone was administered intravenously at a dose of 20 mg/m^2 over 1 hour weekly on days 1,8, and 15 of a 28-day cycle. Cohort 1(Chemosensitive) enrolled patients with a complete response or partial response lasting at least 4 weeks to their most recent therapy.	Ixabepilone was administered intravenously at a dose of 20 mg/m^2 over 1 hour weekly on days 1,8, and 15 of a 28-day cycle. Cohort 2(Chemoresistant) enrolled patients with stable disease but less than a partial response to their most recent therapy.	Total of all reporting groups
Overall Participants	39	12	51
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	64	73	66
Sex: Female, Male (Count of Participants)
Female	12 30.8%	5 41.7%	17 33.3%
Male	27 69.2%	7 58.3%	34 66.7%
Race/Ethnicity, Customized (Number) [Number]
Caucasian	34 87.2%	12 100%	46 90.2%
African American	1 2.6%	0 0%	1 2%
Hispanic	4 10.3%	0 0%	4 7.8%
LDH elevation (Number) [Number]
Yes	16 41%	6 50%	22 43.1%
No	23 59%	6 50%	29 56.9%
Prior therapies (Number) [Number]
1	10 25.6%	4 33.3%	14 27.5%
2-3	17 43.6%	5 41.7%	22 43.1%
4 or more	12 30.8%	3 25%	15 29.4%
Prior rituximab (Number) [Number]
Yes	34 87.2%	11 91.7%	45 88.2%
No	5 12.8%	1 8.3%	6 11.8%

Outcome Measures

1. Primary Outcome

Title	Objective Overall Response Rate
Description	The 1999 international response criteria (http://www.ncbi.nlm.nih.gov/pubmed/10561185) as published by Cheson was used for the definition of target lesions and CT scans were used for response assessment. CR(complete response)/CRu(unconfirmed complete response) requires disappearance of all target lesions; PR (partial response) requires >=50% decrease in the sum of the products of the greatest diameters; Overall Response (OR)=CR/CRu+PR.
Time Frame	up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort 1 (Chemosensitive)	Cohort 2 (Chmoresistant)
Arm/Group Description	Ixabepilone was administered intravenously at a dose of 20 mg/m^2 over 1 hour weekly on days 1,8, and 15 of a 28-day cycle. Cohort 1(Chemosensitive) enrolled patients with a complete response or partial response lasting at least 4 weeks to their most recent therapy.	Ixabepilone was administered intravenously at a dose of 20 mg/m^2 over 1 hour weekly on days 1,8, and 15 of a 28-day cycle. Cohort 2(Chemoresistant) enrolled patients with stable disease but less than a partial response to their most recent therapy.
Measure Participants	39	12
Number [participants]	14 35.9%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 (Chemosensitive), Cohort 2 (Chmoresistant)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.022
	Comments
	Method	Fisher Exact
	Comments

2. Primary Outcome

Title	Safety and Toxicity of Ixabepilone
Description	Number of patients experiencing adverse event grade 3 or above. Grade was determined by the National Cancer Institute Common Toxicity Criteria (CTC) version 2.0. Adverse events possibly, probably, or definitely attributed to use of ixabepilone.
Time Frame	up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort 1 (Chemosensitive)	Cohort 2 (Chmoresistant)
Arm/Group Description	Ixabepilone was administered intravenously at a dose of 20 mg/m^2 over 1 hour weekly on days 1,8, and 15 of a 28-day cycle. Cohort 1(Chemosensitive) enrolled patients with a complete response or partial response lasting at least 4 weeks to their most recent therapy.	Ixabepilone was administered intravenously at a dose of 20 mg/m^2 over 1 hour weekly on days 1,8, and 15 of a 28-day cycle. Cohort 2(Chemoresistant) enrolled patients with stable disease but less than a partial response to their most recent therapy.
Measure Participants	39	12
Number [participants]	27 69.2%	8 66.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 (Chemosensitive), Cohort 2 (Chmoresistant)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.00
	Comments
	Method	Fisher Exact
	Comments

3. Secondary Outcome

Title	Duration of Response
Description	Duration of response was measured from the time measurement criteria are met for CR(complete response)/CRu(unconfirmed complete response)/PR(partial response), whichever was first recorded, until the first date that PD(progressive disease) was objectively documented. According to the 1999 international response criteria as published by Cheson, CR/CRu is defined as the disappearance of all target lesions; PR is defined as >=50% decrease in the sum of the products of the greatest diameters; PD is defined as >=50% increase from nadir in the sum of the products of the greatest diameters of any previously identified abnormal node for PRs or nonresponders, or appearance of any new lesion during or at the end of therapy.
Time Frame	up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort 1 (Chemosensitive)	Cohort 2 (Chmoresistant)
Arm/Group Description	Ixabepilone was administered intravenously at a dose of 20 mg/m^2 over 1 hour weekly on days 1,8, and 15 of a 28-day cycle. Cohort 1(Chemosensitive) enrolled patients with a complete response or partial response lasting at least 4 weeks to their most recent therapy.	Ixabepilone was administered intravenously at a dose of 20 mg/m^2 over 1 hour weekly on days 1,8, and 15 of a 28-day cycle. Cohort 2(Chemoresistant) enrolled patients with stable disease but less than a partial response to their most recent therapy.
Measure Participants	14	0
Median (95% Confidence Interval) [Days]	291

4. Secondary Outcome

Title	Overall Survival
Description	Defined as the time from the first day of therapy to the date of death. If the patient was lost to follow-up, survival was censored on the last date the patient was known to be alive.
Time Frame	up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort 1 (Chemosensitive)	Cohort 2 (Chmoresistant)
Arm/Group Description	Ixabepilone was administered intravenously at a dose of 20 mg/m^2 over 1 hour weekly on days 1,8, and 15 of a 28-day cycle. Cohort 1(Chemosensitive) enrolled patients with a complete response or partial response lasting at least 4 weeks to their most recent therapy.	Ixabepilone was administered intravenously at a dose of 20 mg/m^2 over 1 hour weekly on days 1,8, and 15 of a 28-day cycle. Cohort 2(Chemoresistant) enrolled patients with stable disease but less than a partial response to their most recent therapy.
Measure Participants	39	12
Median (95% Confidence Interval) [Days]	501	98

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 (Chemosensitive), Cohort 2 (Chmoresistant)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.695
	Comments
	Method	Log Rank
	Comments

5. Secondary Outcome

Title	Time to Progression
Description	Defined as the time from the first day of treatment until the date PD(progressive disease) or death is first reported. Patients who died without a reported prior progression was considered to have progressed on the day of their death. Patients who did not progress was censored at the day of their last tumor assessment. According to the 1999 international response criteria as published by Cheson, progression/progressive disease is defined as >=50% increase from nadir in the sum of the products of the greatest diameters of any previously identified abnormal node for PRs or nonresponders, or appearance of any new lesion during or at the end of therapy.
Time Frame	up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort 1 (Chemosensitive)	Cohort 2 (Chmoresistant)
Arm/Group Description	Ixabepilone was administered intravenously at a dose of 20 mg/m^2 over 1 hour weekly on days 1,8, and 15 of a 28-day cycle. Cohort 1(Chemosensitive) enrolled patients with a complete response or partial response lasting at least 4 weeks to their most recent therapy.	Ixabepilone was administered intravenously at a dose of 20 mg/m^2 over 1 hour weekly on days 1,8, and 15 of a 28-day cycle. Cohort 2(Chemoresistant) enrolled patients with stable disease but less than a partial response to their most recent therapy.
Measure Participants	39	12
Median (95% Confidence Interval) [Days]	112	84

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 (Chemosensitive), Cohort 2 (Chmoresistant)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.55
	Comments
	Method	Log Rank
	Comments

Adverse Events

Adverse Event Reporting Description	Adverse events possibly, probably, or definitely attributed to use of ixabepilone. The Adverse event report includes all patients experiencing adverse events with any grade while one of the primary outcomes (safety and toxicity of Ixabepilone) targeted patients experiencing adverse event grade 3 or above.
Arm/Group Title	Ixabeilone for Relapsed Aggressive NHL
Arm/Group Description
All Cause Mortality
	Ixabeilone for Relapsed Aggressive NHL
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Ixabeilone for Relapsed Aggressive NHL
	Affected / at Risk (%)	# Events
Total	11/51 (21.6%)
Cardiac disorders
Palpitations	1/51 (2%)
Gastrointestinal disorders
Diarrhea	1/51 (2%)
Vomiting	1/51 (2%)
Infections and infestations
Infections and infestations - Other, specify	2/51 (3.9%)
Lung infection	1/51 (2%)
Investigations
Neutrophil count decreased	2/51 (3.9%)
Metabolism and nutrition disorders
Dehydration	2/51 (3.9%)
Hypokalemia	1/51 (2%)
Musculoskeletal and connective tissue disorders
Myalgia	1/51 (2%)
Nervous system disorders
Peripheral motor neuropathy	1/51 (2%)
Peripheral sensory neuropathy	1/51 (2%)
Syncope	1/51 (2%)
Vascular disorders
Thromboembolic event	1/51 (2%)
Other (Not Including Serious) Adverse Events
	Ixabeilone for Relapsed Aggressive NHL
	Affected / at Risk (%)	# Events
Total	48/51 (94.1%)
Blood and lymphatic system disorders
Anemia	26/51 (51%)
Gastrointestinal disorders
Nausea	24/51 (47.1%)
Diarrhea	18/51 (35.3%)
Constipation	12/51 (23.5%)
Vomiting	9/51 (17.6%)
General disorders
Fatigue	31/51 (60.8%)
Edema limbs	3/51 (5.9%)
Pain	4/51 (7.8%)
Fever	4/51 (7.8%)
Injection site reaction	4/51 (7.8%)
Infections and infestations
Infections and infestations - Other, specify	5/51 (9.8%)
Investigations
White blood cell decreased	30/51 (58.8%)
Platelet count decreased	19/51 (37.3%)
Neutrophil count decreased	21/51 (41.2%)
Lymphocyte count decreased	13/51 (25.5%)
Aspartate aminotransferase increased	9/51 (17.6%)
Alanine aminotransferase increased	6/51 (11.8%)
Weight loss	4/51 (7.8%)
Alkaline phosphatase increased	3/51 (5.9%)
Creatinine increased	3/51 (5.9%)
Metabolism and nutrition disorders
Hyperglycemia	8/51 (15.7%)
Anorexia	15/51 (29.4%)
Hypocalcemia	4/51 (7.8%)
Hypoalbuminemia	3/51 (5.9%)
Hyponatremia	3/51 (5.9%)
Hyperkalemia	4/51 (7.8%)
Dehydration	4/51 (7.8%)
Musculoskeletal and connective tissue disorders
Myalgia	13/51 (25.5%)
Arthralgia	5/51 (9.8%)
Bone pain	3/51 (5.9%)
Generalized muscle weakness	3/51 (5.9%)
Nervous system disorders
Peripheral sensory neuropathy	32/51 (62.7%)
Dizziness	6/51 (11.8%)
Peripheral motor neuropathy	7/51 (13.7%)
Dysgeusia	5/51 (9.8%)
Respiratory, thoracic and mediastinal disorders
Cough	3/51 (5.9%)
Dyspnea	6/51 (11.8%)
Skin and subcutaneous tissue disorders
Alopecia	11/51 (21.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.