HuMax-CD20 in B-Cell Chronic Lymphocytic Leukemia (B-CLL) Patients Failing Fludarabine and Alemtuzumab

This study has been completed.

Sponsor:

Information provided by (Responsible Party):

GlaxoSmithKline

ClinicalTrials.gov Identifier:

NCT00349349

First received: July 6, 2006

Last updated: May 9, 2013

Last verified: September 2012

History of Changes

Results First Received: October 20, 2011

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Single Group Assignment; Masking: Open Label; Primary Purpose: Treatment
Condition:	Leukaemia, Lymphocytic, Chronic
Intervention:	Drug: ofatumumab

Participant Flow

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Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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Reporting Groups

	Description
2000 mg Ofatumumab + DR	Ofatumumab intravenous (iv) infusion was initiated at 300 milligrams (mg), followed by seven weekly 2000 mg infusions and then four monthly infusions of 2000 mg for a duration of 24 weeks. The independent endpoint review committee (IRC) classified these participants as double refractory (DR), defined as participants who were enrolled in the study and were refractory to both fludarabine and alemtuzumab.
2000 mg Ofatumumab + BFR	Ofatumumab iv infusion was initiated at 300 mg, followed by seven weekly 2000 mg infusions and then four monthly infusions of 2000 mg for a duration of 24 weeks. The IRC classified these participants as bulky fludarabine refractory (BFR), defined as participants who were enrolled in the study and were refractory to fludarabine with bulky lymphadenopathy.
2000 mg Ofatumumab + Other	Ofatumumab iv infusion was initiated at 300 mg, followed by seven weekly 2000 mg infusions and then four monthly infusions of 2000 mg for a duration of 24 weeks. The IRC classified these participants as "other," defined as participants who were enrolled in the study but did not meet criteria for DR or BFR.

Participant Flow: Overall Study

	2000 mg Ofatumumab + DR	2000 mg Ofatumumab + BFR	2000 mg Ofatumumab + Other
STARTED	95	112	16
COMPLETED	42	50	10
NOT COMPLETED	53	62	6
Adverse Event	5	6	2
Withdrawal by Subject	5	2	1
Withdrawn due to Disease Progression	27	37	1
Death	13	10	1
Other Treatment Selected	2	0	0
Participant Reduced General Condition	0	1	0
Physician Decision	1	2	1
No Response	0	3	0
New Malignancy (Bladder Cancer)	0	1	0

Baseline Characteristics

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Reporting Groups

	Description
2000 mg Ofatumumab + DR	Ofatumumab iv infusion was initiated at 300 mg, followed by seven weekly 2000 mg infusions and then four monthly infusions of 2000 mg for a duration of 24 weeks. The IRC classified these participants as DR, defined as participants who were enrolled in the study and were refractory to both fludarabine and alemtuzumab.
2000 mg Ofatumumab + BFR	Ofatumumab iv infusion was initiated at 300 mg, followed by seven weekly 2000 mg infusions and then four monthly infusions of 2000 mg for a duration of 24 weeks. The IRC classified these participants as BFR, defined as participants who were enrolled in the study and were refractory to fludarabine with bulky lymphadenopathy.
2000 mg Ofatumumab + Other	Ofatumumab iv infusion was initiated at 300 mg, followed by seven weekly 2000 mg infusions and then four monthly infusions of 2000 mg for a duration of 24 weeks. The IRC classified these participants as "other,"defined as participants who were enrolled in the study but did not meet criteria for DR or BFR.
Total	Total of all reporting groups

Baseline Measures

	2000 mg Ofatumumab + DR	2000 mg Ofatumumab + BFR	2000 mg Ofatumumab + Other	Total
Number of Participants [units: participants]	95	112	16	223
Age [units: Years] Mean ± Standard Deviation	63.2 ± 8.4	64.4 ± 9.3	64.5 ± 7.4	63.9 ± 8.8
Gender [units: Participants]
Female	24	31	5	60
Male	71	81	11	163
Race/Ethnicity, Customized [units: participants]
Asian	1	0	1	2
Black or African American	2	1	0	3
Hispanic or Latino	1	0	0	1
White	88	111	15	214
Arab	1	0	0	1
Yemenite	1	0	0	1
Middle Eastern	1	0	0	1

Outcome Measures

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1. Primary:

Number of Participants (Par.) Classified as Responders and Non-responders for Objective Response as Assessed by an Independent Endpoint Review Committee (IRC) in Accordance With the National Cancer Institute Working Group (NCIWG) 1996 Guidelines [ Time Frame: Start of treatment (Week 0 of Visit 2) until Week 24 ]

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Measure Type	Primary
Measure Title	Number of Participants (Par.) Classified as Responders and Non-responders for Objective Response as Assessed by an Independent Endpoint Review Committee (IRC) in Accordance With the National Cancer Institute Working Group (NCIWG) 1996 Guidelines
Measure Description	Par. with complete remission (CR), nodular partial remission (nPR), and partial remission (PR) were classified as responders, while those with stable disease (SD) and progressive disease (PD) were classified as non-responders. Per the NCIWG guideline (1996): CR; no lymphadenopathy/hepatomegaly/splenomegaly/constitutional symptoms, normal hematology, bone marrow sample as normocellular for age, <30% lymphocytes (LC), no lymphoid nodule; PR: a >=50% decrease in LC/lymphadenopathy; nPR: persistent nodules in bone marrow; PD: new lesion or increase by >=50% from baseline; SD: no CR, PR, or PD.
Time Frame	Start of treatment (Week 0 of Visit 2) until Week 24
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full Analysis Set (FAS): all participants who had been exposed to study drug irrespective of their compliance to the planned course of treatment. Participants not evaluable (NE) were due to patient withdraw, refusal, non-trial drug related AEs, and death

Reporting Groups

	Description
2000 mg Ofatumumab + DR	Ofatumumab iv infusion was initiated at 300 mg, followed by seven weekly 2000 mg infusions and then four monthly infusions of 2000 mg for a duration of 24 weeks. The IRC classified these participants as DR, defined as participants who were enrolled in the study and were refractory to both fludarabine and alemtuzumab.
2000 mg Ofatumumab + BFR	Ofatumumab iv infusion was initiated at 300 mg, followed by seven weekly 2000 mg infusions and then four monthly infusions of 2000 mg for a duration of 24 weeks. The IRC classified these participants as BFR, defined as participants who were enrolled in the study and were refractory to fludarabine with bulky lymphadenopathy.
2000 mg Ofatumumab + Other	Ofatumumab iv infusion was initiated at 300 mg, followed by seven weekly 2000 mg infusions and then four monthly infusions of 2000 mg for a duration of 24 weeks. The IRC classified these participants as "other,"defined as participants who were enrolled in the study but did not meet criteria for DR or BFR.

Measured Values

	2000 mg Ofatumumab + DR	2000 mg Ofatumumab + BFR	2000 mg Ofatumumab + Other
Number of Participants Analyzed [units: participants]	95	112	16
Number of Participants (Par.) Classified as Responders and Non-responders for Objective Response as Assessed by an Independent Endpoint Review Committee (IRC) in Accordance With the National Cancer Institute Working Group (NCIWG) 1996 Guidelines [units: participants]
Responders with CR	0	2	0
Responders with nPR	0	0	1
Responders with PR	47	46	9
Non-responders with SD	33	52	4
Non-responders with PD	5	9	1
NE	10	3	1

Statistical Analysis 1 for Number of Participants (Par.) Classified as Responders and Non-responders for Objective Response as Assessed by an Independent Endpoint Review Committee (IRC) in Accordance With the National Cancer Institute Working Group (NCIWG) 1996 Guidelines

Groups ^[1]	2000 mg Ofatumumab + DR
Method ^[2]	Two-sided exact binomial test
P Value ^[3]	<0.0001
percentage of responders ^[4]	0.49
95.3% Confidence Interval	( 0.39 to 0.60 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	The p value is testing the hypothesis that the response rate is equal to 15% versus the response rate is not equal to 15%.
[4]	Other relevant estimation information:
	Two-sided 95.3% exact confidence intervals were calculated based on the binomial distribution.

Statistical Analysis 2 for Number of Participants (Par.) Classified as Responders and Non-responders for Objective Response as Assessed by an Independent Endpoint Review Committee (IRC) in Accordance With the National Cancer Institute Working Group (NCIWG) 1996 Guidelines

Groups ^[1]	2000 mg Ofatumumab + BFR
Method ^[2]	Two-sided exact binomial test
P Value ^[3]	<0.0001
percentage of responders ^[4]	0.43
95.3% Confidence Interval	( 0.33 to 0.53 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	The p value is testing the hypothesis that the response rate is equal to 15% versus the response rate is not equal to 15%.
[4]	Other relevant estimation information:
	Two sided 95.3% exact confidence intervals were calculated based on the binomial distribution.

Statistical Analysis 3 for Number of Participants (Par.) Classified as Responders and Non-responders for Objective Response as Assessed by an Independent Endpoint Review Committee (IRC) in Accordance With the National Cancer Institute Working Group (NCIWG) 1996 Guidelines

Groups ^[1]	2000 mg Ofatumumab + Other
Method ^[2]	Two-sided exact binomial test
P Value ^[3]	<0.001
percentage of responders ^[4]	0.63
95.3% Confidence Interval	( 0.35 to 0.85 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	The p value is testing the hypothesis that the response rate is equal to 15% versus the response rate is not equal to 15%.
[4]	Other relevant estimation information:
	Two-sided 95.3% exact confidence intervals were calculated based on the binomial distribution.

2. Secondary:

Duration of Response [ Time Frame: Start of treatment (Week 0 of Visit 2) until Week 24 ]

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3. Secondary:

Progression-Free Survival (PFS) [ Time Frame: Start of treatment (Week 0 of Visit 2) until Week 24 ]

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4. Secondary:

Time to Next Chronic Lymphocytic Leukemia (CLL) Treatment [ Time Frame: Time from randomization (Week 0 of Visit 2) until the time of first administration of a CLL treatment other than ofatumumab (assessed for a median of 8.7 weeks currently [or up to 13.3 months]) ]

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5. Secondary:

Overall Survival [ Time Frame: Start of randomization (Week 0 of Visit 2) until death (up to a median of 17.1 weeks) ]

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6. Secondary:

Percent Change From Baseline to Week 7 in Peripheral CD5+CD19+ Cell Counts [ Time Frame: Baseline (Visit 2) until Week 7 (Visit 9) ]

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7. Secondary:

Percent Change From Baseline to Week 7 in Peripheral CD5+CD20+ Cell Counts [ Time Frame: Baseline (Visit 2) until Week 7 (Visit 9) ]

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8. Secondary:

Median Percent Change of Tumor Size (Sum of Products Dimensions [SPD]) From Baseline (Visit 2) to Week 24 (Visit 14) [ Time Frame: Baseline (Visit 2) until Week 24 (Visit 14) ]

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9. Secondary:

Number of Participants With Complete Resolution of Constitutional Symptoms at Week 24 [ Time Frame: Baseline (Visit 2) and Week 24 ]

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10. Secondary:

Number of Participants With Complete Resolution of Lymphadenopathy [ Time Frame: Baseline (Visit 2) to end of study (up to Week 24) ]

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11. Secondary:

Number of Participants With Improvement on the Eastern Cooperative Oncology Group (ECOG) Performance Status Scale at Week 24 [ Time Frame: Baseline (Visit 2) and Week 24 ]

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12. Secondary:

Number of Participants Who Were Positive, Negative, or Had Missing Data for the Indicated Fluorescence in Situ Hybridization (FISH) Prognostic Factors at Screening [ Time Frame: Screening (Visit 1, <=14 days prior to Visit 2) ]

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13. Secondary:

Number of Participants With Improvement in Hemoglobin [ Time Frame: Baseline (Visit 2) to Week 28 ]

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14. Secondary:

Number of Participants With Improvement in Thrombocytopenia (Thromb.) [ Time Frame: Baseline (Visit 2) to Week 28 ]

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15. Secondary:

Number of Participants With Improvement in Neutropenia [ Time Frame: Baseline (Visit 2) to Week 28 ]

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16. Secondary:

Number of Participants With Complete Resolution of Hepatomegaly [ Time Frame: Baseline (Visit 2) until Week 24 ]

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17. Secondary:

Number of Participants Who Experienced Any Adverse Event [ Time Frame: From first infusion (Visit 2/Week 0) to Visit 21 (Month 24 of follow-up [up to Month 48]) or time of withdrawal (treatment and follow-up) ]

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18. Secondary:

Number of Participants With Complete Resolution of Splenomegaly [ Time Frame: Baseline (Visit 2) until Week 24 ]

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19. Secondary:

Cmax and Ctrough at Dose 1 (Visit 2, Week 0), Dose 8 (Visit 9, Week 7), and Dose 12 (Visit 14, Week 24) [ Time Frame: Visit 2 (Week 0), Visit 9 (Week 7), and Visit 14 (Week 24) ]

Show Outcome Measure 19

20. Secondary:

AUC (0-inf) and AUC(0-tau) at Dose 8 (Visit 9, Week 7) and Dose 12 (Visit 14, Week 24) [ Time Frame: Visit 9 (Week 7) and Visit 14 (Week 24) ]

Show Outcome Measure 20

21. Secondary:

Half-life (t1/2) at Dose 8 (Visit 9, Week 7) and at Dose 12 (Visit 14, Week 24) [ Time Frame: Visit 9 (Week 7) and Visit14 (Week 24) ]

Show Outcome Measure 21

22. Secondary:

Clearance (CL) After Dose 8 (Visit 9, Week 7) and Dose 12 (Visit 14, Week 24) [ Time Frame: Visit 9 (Week 7) and Visit 14 (Week 24) ]

Show Outcome Measure 22

23. Secondary:

Volume of Distribution at Steady State (Vss) at Dose 8 (Visit 9, Week 7) and at Dose 12 (Visit 14, Week 24) [ Time Frame: Visit 9 (Week 7) and Visit 14 (Week 24) ]

Show Outcome Measure 23

Serious Adverse Events

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Other Adverse Events

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More Information

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Certain Agreements:

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

There IS 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.

The agreement is:

	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.
	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 more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.

Results Point of Contact:

Name/Title: GSK Response Center
Organization: GlaxoSmithKline
phone: 866-435-7343

No publications provided by GlaxoSmithKline

Publications automatically indexed to this study:

Wierda WG, Padmanabhan S, Chan GW, Gupta IV, Lisby S, Osterborg A; Hx-CD20-406 Study Investigators. Ofatumumab is active in patients with fludarabine-refractory CLL irrespective of prior rituximab: results from the phase 2 international study. Blood. 2011 Nov 10;118(19):5126-9. Epub 2011 Aug 19.

Wierda WG, Kipps TJ, Mayer J, Stilgenbauer S, Williams CD, Hellmann A, Robak T, Furman RR, Hillmen P, Trneny M, Dyer MJ, Padmanabhan S, Piotrowska M, Kozak T, Chan G, Davis R, Losic N, Wilms J, Russell CA, Osterborg A; Hx-CD20-406 Study Investigators. Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol. 2010 Apr 1;28(10):1749-55. Epub 2010 Mar 1.

Responsible Party:	GlaxoSmithKline
ClinicalTrials.gov Identifier:	NCT00349349 History of Changes
Other Study ID Numbers:	111773, Hx-CD20-406
Study First Received:	July 6, 2006
Results First Received:	October 20, 2011
Last Updated:	May 9, 2013
Health Authority:	United States: Food and Drug Administration

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