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Study of Safety and Efficacy of a Sequential Regimen Consisting of Three Cycles of Fludarabine Followed by Tositumomab and Iodine I 131 Tositumomab

This study has been completed.
Sponsor:
Information provided by:
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT00933335
First received: July 2, 2009
Last updated: February 9, 2012
Last verified: February 2012
History of Changes
Results First Received: December 1, 2011  
Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Single Group Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Conditions: Lymphoma, Non-Hodgkin
Non-Hodgkin's Lymphoma
Intervention: Biological: Tositumomab and Iodine I 131 Tositumomab

  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
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Participants received fludarabine in the first study phase. Upon completion of this phase, if they met the appropriate criteria, they began the first of 2 phases of radioimmunotherapy: Phase 1, dosimetric dose (DD), administered 6 weeks after Day 1 of the third fludarabine cycle; Phase 2, therapeutic dose, administered 7-14 days after the DD.

Reporting Groups
  Description
Received Less Than 3 Cycles of Fludarabine Participants received less than 3 cycles of intravenous (IV) fludarabine monophosphate (25 milligrams/meter^2/day [mg/m^2/day]) for 5 days every 5 to 6 weeks.
Fludarabine (3 Cycles); TST and Iodine I 131 TST Participants (par.) received 3 cycles of IV fludarabine (FL) monophosphate (25 mg/m^2/day) for 5 days every 5-6 weeks. After receiving FL, par. meeting criteria received the dosimetric dose (DD), administered 6-8 weeks after the 3rd cycle of FL. IV administration of unlabeled tositumomab (TST) (450 mg) was infused over 1 hour (hr) prior to a 30 minute infusion of 35 mg TST trace labeled with 5 millicurie (mCi) iodine I 131. Par. received >=3 doses (4 drops by mouth [DBM], 3 times a day [TID]) of a saturated solution of potassium iodide (KI), 3 doses (20 DBM, TID) of Lugol’s solution, or KI tablets (130 mg BM, once a day) >=24 hrs prior to administration of the DD and continued daily for 14 days after the therapeutic dose (TD), administered 7-14 days after the DD. The TD was an IV infusion of 450 mg TST over 1 hr, followed by infusion of 35 mg of TST radiolabeled with iodine I 131 to deliver the appropriate total body dose of 75, 65, or 45 centigray (cGy) over 20 minutes.

Participant Flow:   Overall Study
    Received Less Than 3 Cycles of Fludarabine     Fludarabine (3 Cycles); TST and Iodine I 131 TST  
STARTED     2     36 [1]
COMPLETED     0     20  
NOT COMPLETED     2     16  
Lost to Follow-up                 1                 3  
Withdrawal by Subject                 0                 1  
Progressive Disease                 0                 11  
Didn't Meet Criteria for TST/I 131 TST                 0                 1  
Co-morbid Illness                 1                 0  
[1] 35/36 participants who received 3 cycles of fludarabine later received a DD and TD of TST/I 131 TST.



  Baseline Characteristics
  Hide Baseline Characteristics

Reporting Groups
  Description
Received Less Than 3 Cycles of Fludarabine Participants received less than 3 cycles of intravenous (IV) fludarabine monophosphate (25 milligrams/meter^2/day [mg/m^2/day]) for 5 days every 5 to 6 weeks.
Fludarabine (3 Cycles); TST and Iodine I 131 TST Participants (par.) received 3 cycles of IV fludarabine (FL) monophosphate (25 mg/m^2/day) for 5 days every 5-6 weeks. After receiving FL, par. meeting criteria received the dosimetric dose (DD), administered 6-8 weeks after the 3rd cycle of FL. IV administration of unlabeled tositumomab (TST) (450 mg) was infused over 1 hour (hr) prior to a 30 minute infusion of 35 mg TST trace labeled with 5 millicurie (mCi) iodine I 131. Par. received >=3 doses (4 drops by mouth [DBM], 3 times a day [TID]) of a saturated solution of potassium iodide (KI), 3 doses (20 DBM, TID) of Lugol’s solution, or KI tablets (130 mg BM, once a day) >=24 hrs prior to administration of the DD and continued daily for 14 days after the therapeutic dose (TD), administered 7-14 days after the DD. The TD was an IV infusion of 450 mg TST over 1 hr, followed by infusion of 35 mg of TST radiolabeled with iodine I 131 to deliver the appropriate total body dose of 75, 65, or 45 centigray (cGy) over 20 minutes.
Total Total of all reporting groups

Baseline Measures
    Received Less Than 3 Cycles of Fludarabine     Fludarabine (3 Cycles); TST and Iodine I 131 TST     Total  
Number of Participants  
[units: participants]
 		  2     36     38  
Age  
[units: Years]
Mean ± Standard Deviation 		  61.0  ± 11.3     51.2  ± 13.4     51.7  ± 13.4  
Gender  
[units: Participants]
 		     
Female     1     16     17  
Male     1     20     21  
Race/Ethnicity, Customized  
[units: participants]
 		     
White     2     34     36  
Hispanic     0     1     1  
Black     0     1     1  



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Number of Participants With Any Adverse Event (AE)   [ Time Frame: First day of fludarabine cycle 1 to day prior to TST and iodine I 131 TST dosimetric dose (DD) (Week -16 to Week 1); Day of TST and iodine I 131 TST DD to database release (Week 1 to Week 520) ]
  Show Outcome Measure 1

2.  Primary:   Number of Participants With Any Treatment-related Adverse Event (TRAE)   [ Time Frame: First day of fludarabine cycle 1 to day prior to TST and iodine I 131 TST DD (Week -16 to Week 1); Day of TST and iodine I 131 TST DD to database release (Week 1 to Week 520) ]
  Show Outcome Measure 2

3.  Primary:   Number of Participants With Any Grade 3 or Grade 4 Adverse Event   [ Time Frame: First day of fludarabine cycle 1 to day prior to TST and iodine I 131 TST DD (Week -16 to Week 1); Day of TST and iodine I 131 TST DD to database release (Week 1 to Week 520) ]
  Show Outcome Measure 3

4.  Primary:   Number of Participants With Any Treatment-related Grade 3 or Grade 4 Adverse Event   [ Time Frame: First day of fludarabine cycle 1 to day prior to TST and iodine I 131 TST DD (Week -16 to Week 1); Day of TST and iodine I 131 TST DD to database release (Week 1 to Week 520) ]
  Show Outcome Measure 4

5.  Primary:   Number of Participants With Any Serious Adverse Event (SAE)   [ Time Frame: First day of fludarabine cycle 1 to day prior to TST and iodine I 131 TST DD (Week -16 to Week 1); Day of TST and iodine I 131 TST DD to database release (Week 1 to Week 520) ]
  Show Outcome Measure 5

6.  Primary:   Number of Participants With Any Treatment-related SAE   [ Time Frame: First day of fludarabine cycle 1 to day prior to TST and iodine I 131 TST DD (Week -16 to Week 1); Day of TST and iodine I 131 TST DD to database release (Week 1 to Week 520) ]
  Show Outcome Measure 6

7.  Primary:   Number of Participants With the Indicated Grade 3 and Grade 4 AEs   [ Time Frame: First day of fludarabine cycle 1 to day prior to TST and iodine I 131 TST DD (Week -16 to Week 1); Day of TST and iodine I 131 TST DD to database release (Week 1 to Week 520) ]
  Show Outcome Measure 7

8.  Primary:   Number of Participants With the Indicated Treatment-related AEs Experienced by at Least 10% of Participants in the Combined Regimen   [ Time Frame: First day of fludarabine cycle 1 to day prior to TST and iodine I 131 TST DD (Week -16 to Week 1); Day of TST and iodine I 131 TST DD to database release (Week 1 to Week 520) ]
  Show Outcome Measure 8

9.  Primary:   Number of Participants Who Were Negative for Human Anti-murine Antibodies (HAMA) at Baseline (Study Entry) But Positive or Negative at Weeks 12 and 25 and at Months 12, 18, and 24   [ Time Frame: Day 1 to Day 730 (24 Months) after receiving the dosimetric dose ]
  Show Outcome Measure 9

10.  Primary:   Time to HAMA Positivity From the First TST/I 131 TST Dosimetric Dose for the Participants Achieving HAMA Positivity   [ Time Frame: Day 1 to Day 730 (24 Months) after receiving the dosimetric dose ]
  Show Outcome Measure 10

11.  Primary:   Number of Participants With Elevated Thyroid-Stimulating Hormone (TSH) Levels at Baseline (Study Entry) and Weeks 25, 52, 78, 104, 130, 156, 182, 208, 234, 260, 286, 312, 364, 416, 468, and 512   [ Time Frame: Baseline (Week -16) and Weeks 25, 52, 78, 104, 130, 156, 182, 208, 234, 260, 286, 312, 364, 416, 468, and 512 ]
  Show Outcome Measure 11

12.  Primary:   Number of Participants With Thyroid Medication Use Prior to the Therapeutic Dose   [ Time Frame: Baseline (study entry; Week -16) and Week 2 to Week 3 (prior to the therapeutic dose) ]
  Show Outcome Measure 12

13.  Primary:   Time to Nadir for Hematological Parameters: Absolute Neutrophil Count (ANC), Hemoglobin, and Platelets   [ Time Frame: up to 120 days following the therapeutic dose (or dosimetric dose for participants who did not receive the therapeutic dose) ]
  Show Outcome Measure 13

14.  Primary:   Nadir Values for Absolute Neutrophil Count (ANC)   [ Time Frame: up to 120 days following the therapeutic dose (or dosimetric dose for participants who did not receive the therapeutic dose) ]
  Show Outcome Measure 14

15.  Primary:   Nadir Values for Hemoglobin   [ Time Frame: up to 120 days following the therapeutic dose (or dosimetric dose for participants who did not receive the therapeutic dose) ]
  Show Outcome Measure 15

16.  Primary:   Nadir Values for Platelet Count   [ Time Frame: up to 120 days following the therapeutic dose (or dosimetric dose for participants who did not receive the therapeutic dose) ]
  Show Outcome Measure 16

17.  Primary:   Number of Participants With Any Grade 3 or Grade 4 Toxicity (AE) for Hematological Parameters (Absolute Neutrophil Count [ANC], Hemoglobin, and Platelets)   [ Time Frame: First day of fludarabine cycle 1 to day prior to TST and iodine I 131 TST dosimetric dose (DD) (Week -16 to Week 1); Day of TST and iodine I 131 TST DD to database release (Week 1 to Week 520) ]
  Show Outcome Measure 17

18.  Primary:   Duration of Any Grade 3 or Grade 4 Toxicity for Hematological Parameters: Absolute Neutrophil Count (ANC), Hemoglobin, and Platelets   [ Time Frame: First day of fludarabine cycle 1 to day prior to TST and iodine I 131 TST dosimetric dose (DD) (Week -16 to Week 1); Day of TST and iodine I 131 TST DD to database release (Week 1 to Week 520) ]
  Show Outcome Measure 18

19.  Primary:   Number of Participants With Any Infection at Week 16 Post-Fludarabine Treatment and Week 13 Post-TST Treatment Detected by Laboratory Culture of Participant Sample or Investigator Report   [ Time Frame: Week 16 Post-Fludarabine Treatment (Week -16 to Week 0); Week 13 Post-TST Treatment (Week 1 to Week 13) ]
  Show Outcome Measure 19

20.  Primary:   Number of the Indicated Type of Infection Reported by Investigator Based on Laboratory Testing at Week 16 Post-Fludarabine (Fl) Treatment and Week 13 Post-TST Treatment   [ Time Frame: Week 16 Post-Fludarabine Treatment (Week -16 to Week 0); Week 13 Post-TST Treatment (Week 1 to Week 13) ]
  Show Outcome Measure 20

21.  Primary:   Number of Participants With a Culture Obtained for Infection at Week 16 Post-Fludarabine (Fl) Treatment and Week 13 Post-TST Treatment   [ Time Frame: Week 16 Post-Fludarabine Treatment (Week -16 to Week 0); Week 13 Post-TST Treatment (Week 1 to Week 13) ]
  Show Outcome Measure 21

22.  Primary:   Number of Participants With Positive Culture Results for Infections at Week 16 Post-Fludarabine (Fl) Treatment and Week 13 Post-TST Treatment   [ Time Frame: Week 16 Post-Fludarabine Treatment (Week -16 to Week 0); Week 13 Post-TST Treatment (Week 1 to Week 13) ]
  Show Outcome Measure 22

23.  Primary:   Number of Participants With an Anti-infective Administered at Week 16 Post-Fludarabine (Fl) Treatment and Week 13 Post-TST Treatment   [ Time Frame: Week 16 Post-Fludarabine Treatment (Week -16 to Week 0); Week 13 Post-TST Treatment (Week 1 to Week 13) ]
  Show Outcome Measure 23

24.  Primary:   Number of Participants Who Received Any Supportive Care After Fludarabine Treatment and After TST Treatment   [ Time Frame: First day of fludarabine cycle 1 to day prior to TST and iodine I 131 TST DD (Week -16 to Week 1); Day of TST and iodine I 131 TST DD to database release (Week 1 to Week 520) ]
  Show Outcome Measure 24

25.  Primary:   Number of Participants Receiving the Indicated Type of Supportive Care After Fludarabine Treatment and After TST Treatment   [ Time Frame: First day of fludarabine cycle 1 to day prior to TST/I 131 TST dosimetric dose (Week -16 to Week 1); Day of TST/I 131 TST dosimetric dose to database release (Week 1 to Week 520) ]
  Show Outcome Measure 25

26.  Secondary:   Number of Participants With the Investigator-assessed Confirmed Responses of Complete Response (CR), Clinical Complete Response (CCR), and Partial Response (PR)   [ Time Frame: First day of fludarabine cycle 1 to day prior to TST/I 131 TST dosimetric dose (Week -16 to Week 1); Day of TST/I 131 TST dosimetric dose to database release (Week 1 to Week 520) ]
  Show Outcome Measure 26

27.  Secondary:   Number of Participants With the Investigator-assessed Unconfirmed Responses of Complete Response (CR), Clinical Complete Response (CCR), and Partial Response (PR)   [ Time Frame: First day of fludarabine cycle 1 to day prior to TST/I 131 TST dosimetric dose (Week -16 to Week 1); Day of TST/I 131 TST dosimetric dose to database release (Week 1 to Week 520) ]
  Show Outcome Measure 27

28.  Secondary:   Number of Participants With Progression of Disease   [ Time Frame: First day of fludarabine cycle 1 to day prior to TST/I 131 TST dosimetric dose (Week -16 to Week 1); Day of TST/I 131 TST dosimetric dose to database release (Week 1 to Week 520) ]
  Show Outcome Measure 28

29.  Secondary:   Duration of Response for All Confirmed Responders   [ Time Frame: First day of fludarabine cycle 1 to day prior to TST/I 131 TST dosimetric dose (Week -16 to Week 1); Day of TST/I 131 TST dosimetric dose to database release (Week 1 to Week 520) ]
  Show Outcome Measure 29

30.  Secondary:   Number of Participants With Progressive Disease (PD)   [ Time Frame: First day of fludarabine cycle 1 to day prior to TST/I 131 TST dosimetric dose (Week -16 to Week 1); Day of TST/I 131 TST dosimetric dose to database release (Week 1 to Week 520) ]
  Show Outcome Measure 30

31.  Secondary:   Time to Disease Progression or Death   [ Time Frame: First day of fludarabine cycle 1 to day prior to TST/I 131 TST dosimetric dose (Week -16 to Week 1); Day of TST/I 131 TST dosimetric dose to database release (Week 1 to Week 520) ]
  Show Outcome Measure 31

32.  Secondary:   Number of Participants With a Treatment Failure   [ Time Frame: First day of fludarabine cycle 1 to day prior to TST/I 131 TST dosimetric dose (Week -16 to Week 1); Day of TST/I 131 TST dosimetric dose to database release (Week 1 to Week 520) ]
  Hide Outcome Measure 32

Measure Type Secondary
Measure Title Number of Participants With a Treatment Failure
Measure Description Treatment failure is defined as the occurrence of treatment withdrawal, a decision to seek additional therapy, study removal, progression, alternative therapy for lymphoma, or death.
Time Frame First day of fludarabine cycle 1 to day prior to TST/I 131 TST dosimetric dose (Week -16 to Week 1); Day of TST/I 131 TST dosimetric dose to database release (Week 1 to Week 520)  
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.
ITT-Exposed Population

Reporting Groups
  Description
TST and Iodine I 131 TST The dosimetric dose (DD) was administered 6 to 8 weeks after the third cycle of fludarabine. IV administration of unlabeled tositumomab (TST) (450 mg) was infused over 1 hour (hr) prior to a 30 minute infusion of 35 mg TST trace labeled with 5 millicurie (mCi) iodine I 131. Participants received at least 3 doses (4 drops by mouth, 3 times a day [TID]) of a saturated solution of potassium iodide (KI), 3 doses (20 drops by mouth, TID) of Lugol’s solution, or KI tablets (130 mg by mouth, once a day) 24 hrs or more prior to administration of the DD and continued daily for 14 days following the therapeutic dose (TD). The TD was administered 7 to 14 days after the dosimetric dose. The TD was an IV infusion of 450 mg TST over 1 hour, followed by infusion of 35 mg of TST radiolabeled with iodine I 131 to deliver the appropriate total body dose of 75, 65, or 45 centigray (cGy) over 20 minutes.
Fludarabine/TST and Iodine I 131 TST (Combined Regimen) Participants received 3 cycles of IV fludarabine monophosphate (25 mg/m^2/day) for 5 days every 5 to 6 weeks. The DD was administered 6 to 8 weeks after the third cycle of fludarabine. IV administration of unlabeled TST (450 mg) was infused over 1 hr prior to a 30 minute infusion of 35 mg TST trace labeled with 5 mCi iodine I 131. Participants received at least 3 doses (4 drops by mouth, TID) of a saturated solution KI, 3 doses (20 drops by mouth, TID) of Lugol's solution, or KI tablets (130 mg by mouth, once a day) 24 hrs or more prior to administration of the DD and continued daily for 14 days following the TD. The TD was administered 7 to 14 days after the dosimetric dose. The TD was an IV infusion of 450 mg TST over 1 hour, followed by infusion of 35 mg of TST radio labeled with iodine I 131 to deliver the appropriate total body dose of 75, 65, or 45 cGy over 20 minutes.

Measured Values
    TST and Iodine I 131 TST     Fludarabine/TST and Iodine I 131 TST (Combined Regimen)  
Number of Participants Analyzed  
[units: participants]
 		  35     38  
Number of Participants With a Treatment Failure  
[units: participants]
 		  20     23  

No statistical analysis provided for Number of Participants With a Treatment Failure



33.  Secondary:   Time to Treatment Failure   [ Time Frame: First day of fludarabine cycle 1 to day prior to TST/I 131 TST dosimetric dose (Week -16 to Week 1); Day of TST/I 131 TST dosimetric dose to database release (Week 1 to Week 520) ]
  Show Outcome Measure 33

34.  Secondary:   Number of Participants Who Died During Their Participation in the Study   [ Time Frame: Day of TST/I 131 TST dosimetric dose to date of database release (Week 1 to Week 520); First day of fludarabine cycle 1 to date of database release (Week -16 to Week 520) ]
  Show Outcome Measure 34

35.  Secondary:   Time to Death of Participants During Their Participation in the Study   [ Time Frame: Day of TST/I 131 TST dosimetric dose to date of database release (Week 1 to Week 520); First day of fludarabine cycle 1 to date of database release (Week -16 to Week 520) ]
  Show Outcome Measure 35


  Serious Adverse Events
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  Other Adverse Events
  Show Other Adverse Events


  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:
unchecked 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.
unchecked 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.


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


Publications of Results:


Responsible Party: Cheri Hudson; Clinical Disclosure Advisor, GSK Clinical Disclosure
ClinicalTrials.gov Identifier: NCT00933335     History of Changes
Other Study ID Numbers: 393229/023, CP-98-025
Study First Received: July 2, 2009
Results First Received: December 1, 2011
Last Updated: February 9, 2012
Health Authority: United States: Food and Drug Administration