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Precursor Cell Lymphoblastic Leukemia-Lymphoma

Lymphoma, Non-Hodgkin

Leukemia, Lymphocytic, Chronic, B-Cell

Lymphoma, Mantle-Cell

Lymphoma, Follicular

Lymphoma, B-Cell, Marginal Zone

Lymphoma, Large B-Cell, Diffuse

Lymphoma, B-Cell

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Diffuse Large B-Cell Lymphoma

Lymphoma, Large-cell, Immunoblastic

All Drugs and Chemicals

Antineoplastic Agents

Antirheumatic Agents

Antibodies

Antibodies, Monoclonal

Rituximab

Immunoglobulins

Antineoplastic Agents, Immunological

Immunologic Factors

rituximab

agatolimod sodium

Christos E. Emmanouilides, MD

RATIONALE: Monoclonal antibodies such as rituximab can locate cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. Biological therapies such as CpG 7909 use different ways to stimulate the immune system and stop cancer cells from growing. Combining CpG 7909 with rituximab may kill more cancer cells.

PURPOSE: Phase I trial to study the effectiveness of CpG 7909 plus rituximab in treating patients who have relapsed or refractory non-Hodgkin's lymphoma.

OBJECTIVES:

* Determine the maximum tolerated dose of subcutaneous and IV CpG 7909 when administered with rituximab in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma.
* Determine the safety and tolerability of this regimen in these patients.
* Determine the disease response in patients treated with this regimen.

OUTLINE: This is a multicenter, dose-escalation study of CpG 7909. Patients are sequentially assigned to 1 of 2 treatment groups.

* Group A: Patients receive rituximab IV over 4-5 hours followed by CpG 7909 IV over 2 hours on day 1. Courses repeat weekly for 4 weeks.
* Group B: Patients receive rituximab as above followed by CpG 7909 subcutaneously on day 1. Courses repeat weekly for 4 weeks.

Cohorts of 3-6 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 at least 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

Patients are followed at 4 weeks.

PROJECTED ACCRUAL: A total of 6-48 patients (3-24 per treatment group) will be accrued for this study.

Biological Therapy Plus Monoclonal Antibody Therapy in Treating Patients With Relapsed or Refractory Non-Hodgkin's Lymphoma

A Multi-Center, Phase I, Open Label, Two Arm, Non-Randomized, Dose-Escalation, Study Of The Safety And Tolerability Of CPG 7909 In Patients Receiving Rituxan For Relapsed Or Refractory B-Cell Non-Hodgkin's Lymphoma

National Cancer Institute (NCI)

Jonsson Comprehensive Cancer Center

Heart and Blood Diseases

Waldenstrom Macroglobulinemia

Leukemia

Disease Attributes

Leukemia, B-Cell

Leukemia, Lymphoid

Hematologic Diseases

Chronic Disease

Neoplasms, Plasma Cell

Hemostatic Disorders

Blood Coagulation Disorders

Vascular Diseases

Paraproteinemias

Blood Protein Disorders

Hemorrhagic Disorders

Chronic Graft Versus Host Disease

Immunomodulating Agents

Immunoglobulins, Intravenous

Agatolimod Sodium

Indium In-111 Ibritumomab Tiuxetan

Laboratory Biomarker Analysis

Radionuclide Imaging

Single Photon Emission Computed Tomography

Yttrium Y-90 Ibritumomab Tiuxetan

Thomas Witzig

RATIONALE: Biological therapies, such as agatolimod sodium, may stimulate the immune system in different ways and stop cancer cells from growing. Monoclonal antibodies, such as rituximab, 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. Radiolabeled monoclonal antibodies, such as yttrium Y 90 ibritumomab tiuxetan, can find cancer cells and carry cancer-killing substances to them without harming normal cells. Giving agatolimod sodium together with rituximab and yttrium Y 90 ibritumomab tiuxetan may kill more cancer cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of agatolimod sodium when given together with rituximab and yttrium Y 90 ibritumomab tiuxetan and to see how well it works in treating patients with recurrent or refractory non-Hodgkin lymphoma.

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose of CpG 7909 that can be delivered in four doses (days 6, 13, 20, 27) for patients with relapsed CD20+ non-Hodgkin's lymphoma. (Phase I) II. To assess the toxicity of CpG 7909 when combined with rituximab and Y-90 Zevalin in patients with lymphoma. (Phase I) III. To assess the overall response rate (CR + PR) of this regimen in relapsed diffuse large B cell lymphoma. (Phase II) IV. To assess the toxicity of the treatment regimen in patients with relapsed diffuse large B cell lymphoma. (Phase II) V. To assess the time to progression and duration of response in patients with relapsed diffuse large B cell lymphoma. (Phase II)

SECONDARY OBJECTIVES:

I. To report the response rate (complete remission + complete remission unconfirmed + partial remission) in this patient population after CpG 7909, rituximab, and Y-90 Zevalin. (Phase I) II. To compare the biodistribution of In-111 Zevalin radioimmunoconjugate scans before and after CpG 7909. (Phase I) III. To determine the HAMA/HACA rate in patients treated with this regimen. (Phase I) IV. To determine if CpG 7909 when given in the context of rituximab and Y-90 Zevalin can stimulate immune effector cells in the blood and tumor tissue. (Phase I)

OUTLINE:

This is a dose escalation study of agatolimod sodium followed by a phase II study.

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, agatolimod sodium 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 and unacceptable toxicity.

\*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 agatolimod sodium at the MTD as determined in phase I. Patients 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.

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

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

A Phase I/II Trial of CpG 7909, Rituximab Immunotherapy, and Y-90 Zevalin Radioimmunotherapy for Patients With Previously Treated CD20+ Non-Hodgkin Lymphoma

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.

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.

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 (DoR) will be calculated from the documentation of response until the date of progression in the subset of patients who respond.

Mayo Clinic

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 I

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

Phase II

Total

Age, Continuous

Sex: Female, Male

United States

Region of Enrollment

All participants accrued to this study were analyzed for baseline characteristics

Thomas E. Witzig, M.D.

Dose Level 1: (.08 mg/kg), n=6

Dose Level 2: (.16 mg/kg), n=6

Dose Level 3: (.32 mg/kg), n=6

Dose Level 4: (.48 mg/kg), n=12

Only participants accrued to the Phase I portion of this study were used to determine the maximum tolerated dose.

Maximum Tolerated Dose of CpG 7909 as Determined Using the Number of Participants With a DLT at Each Dose Level

Complete Response (CR)

Partial Response (PR)

Participants accrued to the Phase I portion of this study were not used to analyze the Phase II primary endpoint.

Tumor Response

Only participants accrued to the Phase II portion of the study were evaluated for this endpoint.

Progression-free Survival

The duration of response was not analyzed due to a lack of more than one response.

Duration of Response

Overall Study

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Biological Therapy Plus Monoclonal Antibody Therapy in Treating Patients With Relapsed or Refractory Non-Hodgkin's Lymphoma	NCT00040950	Lymphoma	rituximab agatolimod sodi...	18 Years -	National Cancer Institute (NCI)
Biological Therapy Plus Monoclonal Antibody Therapy in Treating Patients With Relapsed or Refractory Non-Hodgkin's Lymphoma	NCT00040950	Lymphoma	rituximab agatolimod sodi...	18 Years -	National Cancer Institute (NCI)
Agatolimod Sodium, Rituximab, and Yttrium Y 90 Ibritumomab Tiuxetan in Treating Patients With Recurrent or Refractory Non-Hodgkin Lymphoma	NCT00438880	Adult Non-Hodgk... Extranodal Marg... Nodal Marginal ... Recurrent Adult... Recurrent Grade... Recurrent Grade... Recurrent Grade... Recurrent Mantl... Recurrent Margi... Recurrent Small... Splenic Margina... Waldenstrom Mac...	Agatolimod Sodi... Indium In-111 I... Laboratory Biom... Radionuclide Im... Rituximab Single Photon E... Yttrium Y-90 Ib...	18 Years -	Mayo Clinic
Agatolimod Sodium, Rituximab, and Yttrium Y 90 Ibritumomab Tiuxetan in Treating Patients With Recurrent or Refractory Non-Hodgkin Lymphoma	NCT00438880	Adult Non-Hodgk... Extranodal Marg... Nodal Marginal ... Recurrent Adult... Recurrent Grade... Recurrent Grade... Recurrent Grade... Recurrent Mantl... Recurrent Margi... Recurrent Small... Splenic Margina... Waldenstrom Mac...	Agatolimod Sodi... Indium In-111 I... Laboratory Biom... Radionuclide Im... Rituximab Single Photon E... Yttrium Y-90 Ib...	18 Years -	Mayo Clinic

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