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Agatolimod Sodium, Rituximab, and Yttrium Y 90 Ibritumomab Tiuxetan in Treating Patients With Recurrent or Refractory Non-Hodgkin Lymphoma

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ClinicalTrials.gov Identifier: NCT00438880
Recruitment Status : Completed
First Posted : February 22, 2007
Results First Posted : September 1, 2014
Last Update Posted : February 4, 2016
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Mayo Clinic

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Adult Non-Hodgkin Lymphoma
Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue
Nodal Marginal Zone Lymphoma
Recurrent Adult Diffuse Large Cell Lymphoma
Recurrent Grade 1 Follicular Lymphoma
Recurrent Grade 2 Follicular Lymphoma
Recurrent Grade 3 Follicular Lymphoma
Recurrent Mantle Cell Lymphoma
Recurrent Marginal Zone Lymphoma
Recurrent Small Lymphocytic Lymphoma
Splenic Marginal Zone Lymphoma
Waldenstrom Macroglobulinemia
Interventions Drug: Agatolimod Sodium
Radiation: Indium In-111 Ibritumomab Tiuxetan
Other: Laboratory Biomarker Analysis
Procedure: Radionuclide Imaging
Biological: Rituximab
Procedure: Single Photon Emission Computed Tomography
Radiation: Yttrium Y-90 Ibritumomab Tiuxetan
Enrollment 38
Recruitment Details Phase I of this study opened 10/20/2004 and accrued 30 patients before closing 10/29/2007. Eight patients were accrued to the Phase II portion at the maximum tolerated dose established in Phase I.
Pre-assignment Details  
Arm/Group Title Phase I Phase II
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Phase I patients will receive the following treatment:

  • 250 mg/m^2 Rituximab IV on days 1, 8, and 15 of a 27 day cycle
  • 5 mCi (Indium-111), 1.6 mg Ibritumomab IV on day 1
  • 10 mCi (Indium-111), 1.6 mg Ibritumomab IV on day 8
  • CpG 7909 (Agatolimod Sodium) doses will be assigned in groups of 6 patients. Dose levels will escalate in each group until maximum tolerability is attained (starting at 0.08 mg/kg and sequentially escalating to 0.16 mg/kg, 0.32 mg/kg, 0.48 mg/kg). Doses will be taken day 6, 13, 20, and 27 of a 27 day cycle.
  • 0.4 mCi/kg Yttrium-90 Zevalin IV on day 15

Phase II patients will receive the following treatment:

  • 250 mg/m^2 Rituximab IV on days 1, 8, and 15 of a 27 day cycle
  • 5 mCi (Indium-111), 1.6 mg Ibritumomab IV on day 8
  • 0.48 mg/kg CpG 7909 (Agatolimod Sodium) doses will be taken day 6, 13, 20, and 27 of a 27 day cycle.
  • 0.4 mCi/kg Yttrium-90 Zevalin IV on day 15
Period Title: Overall Study
Started 30 8
Completed 30 8
Not Completed 0 0
Arm/Group Title Phase I Phase II Total
Hide Arm/Group Description

Phase I patients will receive the following treatment:

  • 250 mg/m^2 Rituximab IV on days 1, 8, and 15 of a 27 day cycle
  • 5 mCi (Indium-111), 1.6 mg Ibritumomab IV on day 1
  • 10 mCi (Indium-111), 1.6 mg Ibritumomab IV on day 8
  • CpG 7909 (Agatolimod Sodium) doses will be assigned in groups of 6 patients. Dose levels will escalate in each group until maximum tolerability is attained (starting at 0.08 mg/kg and sequentially escalating to 0.16 mg/kg, 0.32 mg/kg, 0.48 mg/kg). Doses will be taken day 6, 13, 20, and 27 of a 27 day cycle.
  • 0.4 mCi/kg Yttrium-90 Zevalin IV on day 15

Phase II patients will receive the following treatment:

  • 250 mg/m^2 Rituximab IV on days 1, 8, and 15 of a 27 day cycle
  • 5 mCi (Indium-111), 1.6 mg Ibritumomab IV on day 8
  • 0.48 mg/kg CpG 7909 (Agatolimod Sodium) doses will be taken day 6, 13, 20, and 27 of a 27 day cycle.
  • 0.4 mCi/kg Yttrium-90 Zevalin IV on day 15
Total of all reporting groups
Overall Number of Baseline Participants 30 8 38
Hide Baseline Analysis Population Description
All participants accrued to this study were analyzed for baseline characteristics
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 30 participants 8 participants 38 participants
60.5
(36 to 80)
68.5
(42 to 83)
62.5
(36 to 83)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 30 participants 8 participants 38 participants
Female
13
  43.3%
4
  50.0%
17
  44.7%
Male
17
  56.7%
4
  50.0%
21
  55.3%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 30 participants 8 participants 38 participants
30 8 38
1.Primary Outcome
Title Maximum Tolerated Dose of CpG 7909 as Determined Using the Number of Participants With a DLT at Each Dose Level
Hide Description

Participants will be treated in cohorts of 6 patients at each dose level of CpG 7909 (0.08 mg/kg, 0.16 mg/kg, 0.32 mg/kg, 0.48 mg/kg) and observed for at least 10 weeks post treatment. If at most one of the 6 patients experiences a dose limiting toxicity (DLT), a new cohort of 6 patients will be treated at the next higher dose level. A DLT for this study is defined as patients with one of the following:

  • Absolute neutrophil counts or platelet counts below 10*10^9/L for 14 days
  • Absolute neutrophil counts greater than 0.5 or less than 1*10^9/L
  • Platelet counts greater than 10 or less than 50*10^9/L for 28 days.
  • Any grade 3 non-hematologic toxicity not explainable by another obvious cause as assessed using the Common Terminology Criteria for Adverse Events (CTCAE) v3.0.

We are reporting the number of DLTs at each of the dose levels. The maximum tolerated dose will be 0.48 mg/kg or the largest dose level where 1 or fewer participants reports a dose limiting toxicity.

Time Frame at least 10 weeks post treatment up to 3 months.
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Only participants accrued to the Phase I portion of this study were used to determine the maximum tolerated dose.
Arm/Group Title Phase I Phase II
Hide Arm/Group Description:

Phase I patients will receive the following treatment:

  • 250 mg/m^2 Rituximab IV on days 1, 8, and 15 of a 27 day cycle
  • 5 mCi (Indium-111), 1.6 mg Ibritumomab IV on day 1
  • 10 mCi (Indium-111), 1.6 mg Ibritumomab IV on day 8
  • CpG 7909 (Agatolimod Sodium) doses will be assigned in groups of 6 patients. Dose levels will escalate in each group until maximum tolerability is attained (starting at 0.08 mg/kg and sequentially escalating to 0.16 mg/kg, 0.32 mg/kg, 0.48 mg/kg). Doses will be taken day 6, 13, 20, and 27 of a 27 day cycle.
  • 0.4 mCi/kg Yttrium-90 Zevalin IV on day 15

Phase II patients will receive the following treatment:

  • 250 mg/m^2 Rituximab IV on days 1, 8, and 15 of a 27 day cycle
  • 5 mCi (Indium-111), 1.6 mg Ibritumomab IV on day 8
  • 0.48 mg/kg CpG 7909 (Agatolimod Sodium) doses will be taken day 6, 13, 20, and 27 of a 27 day cycle.
  • 0.4 mCi/kg Yttrium-90 Zevalin IV on day 15
Overall Number of Participants Analyzed 30 0
Measure Type: Number
Unit of Measure: participants
Dose Level 1: (.08 mg/kg), n=6 0
Dose Level 2: (.16 mg/kg), n=6 1
Dose Level 3: (.32 mg/kg), n=6 0
Dose Level 4: (.48 mg/kg), n=12 1
2.Primary Outcome
Title Tumor Response
Hide Description

Complete Response (CR):

  • No measurable or nonmeasurable disease.
  • No symptoms of Lymphoma.
  • Non-palpable spleen, if palpable at baseline.
  • Histologically negative bone marrow, if positive at baseline.
  • All nodes <1.5 cm in transverse diameter.

Partial Response (PR):

  • greater than 50% decrease from baseline in the sum of the products of the longest perpendicular diameters of the six largest dominant lesions.
  • No new lesions

We are reporting the number of participants that attained a status of CR or PR.

Time Frame Evaluations occur every three months up to a year
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participants accrued to the Phase I portion of this study were not used to analyze the Phase II primary endpoint.
Arm/Group Title Phase I Phase II
Hide Arm/Group Description:

Phase I patients will receive the following treatment:

  • 250 mg/m^2 Rituximab IV on days 1, 8, and 15 of a 27 day cycle
  • 5 mCi (Indium-111), 1.6 mg Ibritumomab IV on day 1
  • 10 mCi (Indium-111), 1.6 mg Ibritumomab IV on day 8
  • CpG 7909 (Agatolimod Sodium) doses will be assigned in groups of 6 patients. Dose levels will escalate in each group until maximum tolerability is attained (starting at 0.08 mg/kg and sequentially escalating to 0.16 mg/kg, 0.32 mg/kg, 0.48 mg/kg). Doses will be taken day 6, 13, 20, and 27 of a 27 day cycle.
  • 0.4 mCi/kg Yttrium-90 Zevalin IV on day 15

Phase II patients will receive the following treatment:

  • 250 mg/m^2 Rituximab IV on days 1, 8, and 15 of a 27 day cycle
  • 5 mCi (Indium-111), 1.6 mg Ibritumomab IV on day 8
  • 0.48 mg/kg CpG 7909 (Agatolimod Sodium) doses will be taken day 6, 13, 20, and 27 of a 27 day cycle.
  • 0.4 mCi/kg Yttrium-90 Zevalin IV on day 15
Overall Number of Participants Analyzed 0 8
Measure Type: Number
Unit of Measure: participants
Complete Response (CR) 1
Partial Response (PR) 0
3.Secondary Outcome
Title Progression-free Survival
Hide Description The Progression-free survival (PFS) is defined as the time from registration to progression or death due to any cause. The distribution of PFS will be estimated using the method of Kaplan-Meier.
Time Frame Up to 1 year from treatment start date
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Only participants accrued to the Phase II portion of the study were evaluated for this endpoint.
Arm/Group Title Phase I Phase II
Hide Arm/Group Description:

Phase I patients will receive the following treatment:

  • 250 mg/m^2 Rituximab IV on days 1, 8, and 15 of a 27 day cycle
  • 5 mCi (Indium-111), 1.6 mg Ibritumomab IV on day 1
  • 10 mCi (Indium-111), 1.6 mg Ibritumomab IV on day 8
  • CpG 7909 (Agatolimod Sodium) doses will be assigned in groups of 6 patients. Dose levels will escalate in each group until maximum tolerability is attained (starting at 0.08 mg/kg and sequentially escalating to 0.16 mg/kg, 0.32 mg/kg, 0.48 mg/kg). Doses will be taken day 6, 13, 20, and 27 of a 27 day cycle.
  • 0.4 mCi/kg Yttrium-90 Zevalin IV on day 15

Phase II patients will receive the following treatment:

  • 250 mg/m^2 Rituximab IV on days 1, 8, and 15 of a 27 day cycle
  • 5 mCi (Indium-111), 1.6 mg Ibritumomab IV on day 8
  • 0.48 mg/kg CpG 7909 (Agatolimod Sodium) doses will be taken day 6, 13, 20, and 27 of a 27 day cycle.
  • 0.4 mCi/kg Yttrium-90 Zevalin IV on day 15
Overall Number of Participants Analyzed 0 8
Median (95% Confidence Interval)
Unit of Measure: months
1.57
(1.22 to 3.42)
4.Secondary Outcome
Title Duration of Response
Hide Description Duration of response (DoR) will be calculated from the documentation of response until the date of progression in the subset of patients who respond.
Time Frame Up to 1 year from treatment start date
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The duration of response was not analyzed due to a lack of more than one response.
Arm/Group Title Phase I Phase II
Hide Arm/Group Description:

Phase I patients will receive the following treatment:

  • 250 mg/m^2 Rituximab IV on days 1, 8, and 15 of a 27 day cycle
  • 5 mCi (Indium-111), 1.6 mg Ibritumomab IV on day 1
  • 10 mCi (Indium-111), 1.6 mg Ibritumomab IV on day 8
  • CpG 7909 (Agatolimod Sodium) doses will be assigned in groups of 6 patients. Dose levels will escalate in each group until maximum tolerability is attained (starting at 0.08 mg/kg and sequentially escalating to 0.16 mg/kg, 0.32 mg/kg, 0.48 mg/kg). Doses will be taken day 6, 13, 20, and 27 of a 27 day cycle.
  • 0.4 mCi/kg Yttrium-90 Zevalin IV on day 15

Phase II patients will receive the following treatment:

  • 250 mg/m^2 Rituximab IV on days 1, 8, and 15 of a 27 day cycle
  • 5 mCi (Indium-111), 1.6 mg Ibritumomab IV on day 8
  • 0.48 mg/kg CpG 7909 (Agatolimod Sodium) doses will be taken day 6, 13, 20, and 27 of a 27 day cycle.
  • 0.4 mCi/kg Yttrium-90 Zevalin IV on day 15
Overall Number of Participants Analyzed 0 0
No data displayed because Outcome Measure has zero total analyzed.
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Phase I Phase II
Hide Arm/Group Description

Phase I patients will receive the following treatment:

  • 250 mg/m^2 Rituximab IV on days 1, 8, and 15 of a 27 day cycle
  • 5 mCi (Indium-111), 1.6 mg Ibritumomab IV on day 1
  • 10 mCi (Indium-111), 1.6 mg Ibritumomab IV on day 8
  • CpG 7909 (Agatolimod Sodium) doses will be assigned in groups of 6 patients. Dose levels will escalate in each group until maximum tolerability is attained (starting at 0.08 mg/kg and sequentially escalating to 0.16 mg/kg, 0.32 mg/kg, 0.48 mg/kg). Doses will be taken day 6, 13, 20, and 27 of a 27 day cycle.
  • 0.4 mCi/kg Yttrium-90 Zevalin IV on day 15

Phase II patients will receive the following treatment:

  • 250 mg/m^2 Rituximab IV on days 1, 8, and 15 of a 27 day cycle
  • 5 mCi (Indium-111), 1.6 mg Ibritumomab IV on day 8
  • 0.48 mg/kg CpG 7909 (Agatolimod Sodium) doses will be taken day 6, 13, 20, and 27 of a 27 day cycle.
  • 0.4 mCi/kg Yttrium-90 Zevalin IV on day 15
All-Cause Mortality
Phase I Phase II
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Phase I Phase II
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   14/30 (46.67%)      5/8 (62.50%)    
Blood and lymphatic system disorders     
Febrile neutropenia  1  1/30 (3.33%)  1 0/8 (0.00%)  0
Gastrointestinal disorders     
Constipation  1  0/30 (0.00%)  0 1/8 (12.50%)  1
Investigations     
Leukocyte count decreased  1  7/30 (23.33%)  7 0/8 (0.00%)  0
Neutrophil count decreased  1  10/30 (33.33%)  11 1/8 (12.50%)  1
Platelet count decreased  1  12/30 (40.00%)  20 4/8 (50.00%)  7
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Tumor pain  1  0/30 (0.00%)  0 1/8 (12.50%)  1
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 6
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Phase I Phase II
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   30/30 (100.00%)      8/8 (100.00%)    
Blood and lymphatic system disorders     
Hemoglobin decreased  1  19/30 (63.33%)  40 8/8 (100.00%)  15
Cardiac disorders     
Arrhythmia  1  0/30 (0.00%)  0 1/8 (12.50%)  1
Gastrointestinal disorders     
Abdominal pain  1  1/30 (3.33%)  1 0/8 (0.00%)  0
Diarrhea  1  0/30 (0.00%)  0 1/8 (12.50%)  1
Nausea  1  1/30 (3.33%)  1 0/8 (0.00%)  0
General disorders     
Chills  1  1/30 (3.33%)  1 0/8 (0.00%)  0
Fatigue  1  2/30 (6.67%)  5 1/8 (12.50%)  1
Localized edema  1  1/30 (3.33%)  1 0/8 (0.00%)  0
Pain  1  1/30 (3.33%)  1 0/8 (0.00%)  0
Infections and infestations     
Abdominal infection  1  0/30 (0.00%)  0 1/8 (12.50%)  1
Sinusitis  1  3/30 (10.00%)  3 0/8 (0.00%)  0
Investigations     
Alanine aminotransferase increased  1  0/30 (0.00%)  0 1/8 (12.50%)  1
Blood bilirubin increased  1  0/30 (0.00%)  0 1/8 (12.50%)  1
Leukocyte count decreased  1  26/30 (86.67%)  63 4/8 (50.00%)  7
Neutrophil count decreased  1  23/30 (76.67%)  37 4/8 (50.00%)  5
Platelet count decreased  1  26/30 (86.67%)  34 5/8 (62.50%)  7
Metabolism and nutrition disorders     
Anorexia  1  0/30 (0.00%)  0 1/8 (12.50%)  1
Blood glucose increased  1  1/30 (3.33%)  1 0/8 (0.00%)  0
Musculoskeletal and connective tissue disorders     
Neck pain  1  1/30 (3.33%)  1 0/8 (0.00%)  0
Nervous system disorders     
Neurological disorder NOS  1  1/30 (3.33%)  1 0/8 (0.00%)  0
Syncope vasovagal  1  0/30 (0.00%)  0 1/8 (12.50%)  1
Skin and subcutaneous tissue disorders     
Petechiae  1  1/30 (3.33%)  1 0/8 (0.00%)  0
Rash desquamating  1  4/30 (13.33%)  4 0/8 (0.00%)  0
Sweating  1  1/30 (3.33%)  1 0/8 (0.00%)  0
Vascular disorders     
Hypotension  1  1/30 (3.33%)  1 1/8 (12.50%)  1
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 6
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Name/Title: Thomas E. Witzig, M.D.
Organization: Mayo Clinic Cancer Center
Responsible Party: Mayo Clinic
ClinicalTrials.gov Identifier: NCT00438880     History of Changes
Other Study ID Numbers: LS0382
NCI-2009-01275 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
LS0382 ( Other Identifier: Mayo Clinic )
P30CA015083 ( U.S. NIH Grant/Contract )
First Submitted: February 20, 2007
First Posted: February 22, 2007
Results First Submitted: May 20, 2014
Results First Posted: September 1, 2014
Last Update Posted: February 4, 2016