CpG 7909, Rituximab, and Yttrium Y 90 Ibritumomab Tiuxetan in Treating Patients With Non-Hodgkin's Lymphoma That is Recurrent or Did Not Respond to Previous Treatment

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Mayo Clinic
ClinicalTrials.gov Identifier:
NCT00438880
First received: February 20, 2007
Last updated: August 20, 2014
Last verified: August 2014

February 20, 2007
August 20, 2014
October 2004
October 2010   (final data collection date for primary outcome measure)
  • Maximum Tolerated Dose of CpG 7909 as Determined Using the Number of Participants With a DLT at Each Dose Level [ Time Frame: at least 10 weeks post treatment up to 3 months. ] [ Designated as safety issue: Yes ]

    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.

  • Tumor Response [ Time Frame: Evaluations occur every three months up to a year ] [ Designated as safety issue: No ]

    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.

  • Toxicity
  • Immunostimulation (optimal immunological dose)
  • Change in fraction of injected activity
Complete list of historical versions of study NCT00438880 on ClinicalTrials.gov Archive Site
  • Progression-free Survival [ Time Frame: Up to 1 year from treatment start date ] [ Designated as safety issue: No ]
    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.
  • Duration of Response [ Time Frame: Up to 1 year from treatment start date ] [ Designated as safety issue: No ]
    Duration of response (DoR) will be calculated from the documentation of response until the date of progression in the subset of patients who respond.
  • Response rate (complete response [CR], CR unconfirmed, partial response)
  • Human antimouse antibodies and human antichimeric antibodies
Not Provided
Not Provided
 
CpG 7909, Rituximab, and Yttrium Y 90 Ibritumomab Tiuxetan in Treating Patients With Non-Hodgkin's Lymphoma That is Recurrent or Did Not Respond to Previous Treatment
A Phase I/II Trial of CpG 7909, Rituximab Immunotherapy, and Y-90 Zevalin Radioimmunotherapy for Patients With Previously Treated CD20+ Non-Hodgkin Lymphoma

RATIONALE: Biological therapies, such as CpG 7909, may stimulate the immune system in different ways and stop cancer cells from growing. Monoclonal antibodies, such as rituximab and yttrium Y-90 ibritumomab tiuxetan, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Giving CpG 7909 together with monoclonal antibodies may kill more cancer cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of CpG 7909 when given together with rituximab and yttrium Y-90 ibritumomab tiuxetan and to see how well it works in treating patients with non-Hodgkin's lymphoma that is recurrent or did not respond to previous treatment.

OBJECTIVES:

Primary

  • Determine the maximum tolerated dose of CpG 7909 when administered in combination with rituximab and yttrium-90 ibritumomab in patients with CD20+ recurrent or refractory non-Hodgkin's lymphoma. (Phase I [closed to accrual as of 10/29/07])
  • Assess the toxicity of this regimen in these patients. (Phase I [closed to accrual as of 10/29/07])

Secondary

  • Determine the response rate (complete response [CR], CR unconfirmed, and partial response [PR]) in patients treated with this regimen. (Phase I [closed to accrual as of 10/29/07])
  • Compare the biodistribution of indium (In-111) ibritumomab tiuxetan radioimmunoconjugate scans before and after treatment with CpG 7909. (Phase I [closed to accrual as of 10/29/07])
  • Determine the human antimouse antibody and/or human antichimeric antibody rate in patients treated with this regimen. (Phase I [closed to accrual as of 10/29/07])
  • Determine if CpG 7909, when given in combination with rituximab and yttrium (Y-90) ibritumomab tiuxetan, can stimulate immune effector cells in the blood and tumor tissue of these patients. (Phase I [closed to accrual as of 10/29/07])
  • Assess the overall response rate (CR and PR) in patients with relapsed diffuse large B cell lymphoma treated with this regimen. (Phase II)
  • Assess the toxicity of this regimen in patients with relapsed diffuse large B cell lymphoma. (Phase II)
  • Assess the time to progression and duration of response in patients with relapsed diffuse large B cell lymphoma. (Phase II)

OUTLINE: This is a multicenter, phase I, dose-escalation study of CpG 7909 followed by a phase II study. (Phase I closed to accrual as of 10/29/07.)

  • Phase I (patients with relapsed, refractory, or residual CD20+ non-Hodgkin lymphoma [closed to accrual as of 10/29/07]): Patients receive rituximab IV on days 1, 8, and 15, CpG 7909 IV over 2 hours on days 6, 13, 20, and 27, and yttrium (Y-90) ibritumomab tiuxetan* IV over 10 minutes on day 15 in the absence of disease progression or unacceptable toxicity.

Cohorts of 6 patients receive escalating doses of CpG 7909 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity. Twelve additional patients are treated at the MTD.

NOTE: *Patients receive indium (In-111) ibritumomab tiuxetan IV over 10 minutes on days 1 and 8. Patients undergo whole-body gamma camera imaging, single-photon emission computed tomography/CT scans, and blood sampling after each dose of indium (In-111) ibritumomab tiuxetan to determine biodistribution. If biodistribution is acceptable, patients receive yttrium (Y-90) ibritumomab tiuxetan.

  • Phase II (patients with relapsed, refractory, or residual diffuse large B-cell lymphoma): Patients receive CPG 7909 at the MTD as determined in phase I. Patients also receive rituximab and yttrium (Y-90) ibritumomab tiuxetan as in phase I.

NOTE: *Patients receive indium (In-111) ibritumomab tiuxetan IV over 10 minutes on day 8. Patients undergo whole-body gamma camera imaging and blood sampling after each dose of indium (In-111) ibritumomab tiuxetan to determine biodistribution.

Blood samples are collected at baseline and periodically during treatment and follow up. Samples are evaluated for immunology correlates by flow cytometry and immunoenzyme techniques and biomarkers.

After the completion of study treatment, patients are followed periodically for up to 5 years.

PROJECTED ACCRUAL: A total of 63 patients will be accrued for this study.

Interventional
Phase 1
Phase 2
Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Lymphoma
  • Biological: rituximab
  • Drug: agatolimod sodium
    Other Name: CpG 7909
  • Radiation: indium In 111 ibritumomab tiuxetan
  • Radiation: yttrium Y 90 ibritumomab tiuxetan
Experimental: Treatment

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 millicurie (mCi) of (Indium-111), 1.6 mg Ibritumomab IV on day 1
  • 10 mCi (Indium-111), 1.6 mg Ibritumomab IV on day 8
  • CpG 7909 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 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
Interventions:
  • Biological: rituximab
  • Drug: agatolimod sodium
  • Radiation: indium In 111 ibritumomab tiuxetan
  • Radiation: yttrium Y 90 ibritumomab tiuxetan
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
38
June 2011
October 2010   (final data collection date for primary outcome measure)

DISEASE CHARACTERISTICS:

  • Histologically confirmed non-Hodgkin's lymphoma, including the following subtypes:

    • Small lymphocytic lymphoma*
    • Lymphoplasmacytoid lymphoma*
    • Grade 1, 2, or 3 follicular lymphoma*
    • Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue*
    • Nodal marginal zone B-cell lymphoma*
    • Splenic marginal zone B-cell lymphoma*
    • Mantle cell lymphoma*
    • Diffuse large cell lymphoma
    • Transformed lymphoma NOTE: *Closed to accrual as of 10/29/07
  • Recurrent, refractory, or residual disease
  • CD20-positive disease
  • Bidimensionally measurable disease (≥ 1 lesion that has a single diameter of ≥ 2 cm)
  • Must have < 25% bone marrow involvement of cellular marrow with lymphoma, as determined by bilateral bone marrow aspirate and biopsy
  • No marrow cellularity ≤ 15% (as determined on all bone marrow samples)
  • No prior failed stem cell collection
  • No CNS lymphoma
  • No lymphoma related to HIV or AIDS
  • No myelodysplastic syndromes or marrow chromosomal changes suggesting myelodysplasia

PATIENT CHARACTERISTICS:

  • ECOG performance status 0-2
  • Life expectancy ≥ 3 months
  • Absolute neutrophil count ≥ 1,500/mm³
  • Platelet count ≥ 150,000/mm³
  • Lymphocyte count < 5,000/mm³ (only for patients with small lymphocytic lymphoma)
  • Hemoglobin ≥ 8 g/dL
  • Total bilirubin ≤ 2 times upper limit of normal (ULN) OR direct bilirubin ≤ 1.5 times ULN
  • Creatinine ≤ 2 mg/dL
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • No serious nonmalignant disease (e.g., active infection) or other condition that would preclude study participation
  • No other active primary malignancy
  • No known human antimouse antibodies or human antichimeric antibodies
  • No skin rash (e.g., Stevens-Johnson's syndrome or toxic epidermal necrolysis) after receiving rituximab
  • No pre-existing clinical autoimmune or antibody-mediated diseases*, including any of the following:

    • Systemic lupus erythematosus
    • Rheumatoid arthritis
    • Multiple sclerosis
    • Sjögren's syndrome
    • Autoimmune thrombocytopenia
  • NOTE: *If no clinical symptoms, but only previously detected antibodies, then not excluded.

PRIOR CONCURRENT THERAPY:

  • More than 1 week since prior filgrastim (G-CSF) or sargramostim (GM-CSF) (3 weeks for pegfilgrastim)
  • More than 3 weeks since prior myelosuppressive chemotherapy (6 weeks for nitrosoureas or mitomycin C)
  • More than 4 weeks since prior major surgery, except for diagnostic surgery
  • More than 6 weeks since prior rituximab
  • No prior external-beam radiotherapy to > 25% of active bone marrow
  • No prior myeloablative therapies with autologous or allogeneic bone marrow transplantation or peripheral blood stem cell support
  • No prior radioimmunotherapy, including yttrium Y 90 ibritumomab tiuxetan, tositumomab, or iodine I 131 monoclonal antibody Lym-1
  • No concurrent myelosuppressive chemotherapy
  • No concurrent corticosteroid therapy, except prednisone (< 20 mg) for benign causes
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00438880
LS0382, LS0382, 703-04, LS0382
Yes
Mayo Clinic
Mayo Clinic
Not Provided
Study Chair: Thomas E. Witzig, MD Mayo Clinic
Mayo Clinic
August 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP