Veltuzumab and Milatuzumab in Treating Patients With Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma

Study Overview
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Brief Summary
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A phase I dose escalation study of veltuzumab and milatuzumab in relapsed and refractory B-cell NHL. The phase I study will be followed by a pilot phase II study.

Detailed Description
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A phase I/II study of veltuzumab combined with milatuzumab in relapsed and refractory non-Hodgkin's lymphoma. Both agents are well-tolerated in early phase clinical testing with infusion reactions as the primary observed toxicity. Preclinical testing in vitro and in vivo have demonstrated single agent activity for both veltuzumab and milatuzumab. In mantle cell lymphoma cell lines and SCID mouse models, synergist effects were observed when milatuzumab was combined with rituximab. Veltuzumab has several advantages over rituximab including slower off-rates, shorter infusion times, higher potency, and improved therapeutic responses in animal models. Previous and ongoing clinical investigations support the concept of combining monoclonal antibodies in NHL.

Official Title
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A Phase I/II Study of Veltuzumab (IMMU-106, hA20), a Humanized Anti-CD20 Monoclonal Antibody, Combined With Milatuzumab (IMMU-115, hLL1), a Humanized Anti-CD74 Monoclonal Antibody, in Relapsed and Refractory B-cell Non-Hodgkin's Lymphoma

Conditions
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Lymphoma

Intervention / Treatment
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* Biological: milatuzumab
* Biological: veltuzumab
* Procedure: Correlative/Special Studies
* Procedure: Quantitative T-, B-, and NK cell subsets
* Procedure: Pharmacokinetics
* Procedure: Pharmacokinetics
* Procedure: Human Anti-Human Antibodies
* Biological: veltuzumab and milatuzumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed B-cell non-Hodgkin lymphoma (NHL), including any of the following: Marginal zone lymphoma Waldenstrom macroglobulinemia (lymphoplasmacytic lymphoma) Follicular lymphoma Mantle cell lymphoma Relapsed or refractory disease after ≥ 1 prior therapy Patients with rituximab-refractory disease (defined as having less than a partial response to the prior rituximab-containing regimen) or rituximab-sensitive disease (defined as having a complete response or partial response to the last rituximab-containing regimen [provided it has been ≥ 3 months since the last dose of rituximab]) are eligible. Age >18 years. Eastern Cooperative Oncology Group (ECOG)performance status 0-2. Patients must have normal organ and marrow function as defined below: Absolute neutrophil count ≥ 1000/μL Platelets ≥ 75,000/μL Total bilirubin ≤ 2.0 X institutional upper limit of normal AST(SGOT)/ALT(SGPT) ≤ 2.5 X institutional upper limit of normal Creatinine ≤ 2.0 mg/dL Patients who have relapsed after stem cell transplant are eligible for this trial. Patients with active Hepatitis B infection are not eligible. Non-pregnant and non-nursing. Women of child bearing potential and men must agree to use contraception prior to study entry and for duration of study participation. Must possess the ability to understand and the willingness to sign a written informed consent document. Phase II -Must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension >10 mm or in the case of Waldenstrom's macroglobulinemia, the presence of an IgM paraprotein level 2x the upper limit of normal. Exclusion Criteria: Must be recovered from all toxicities from prior therapy or radiation (excluding alopecia). No known CNS lymphoma. History of documented human anti-globulin antibodies. No uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations. HIV-positive patients. Pregnant women. Patients with secondary malignancies with exception of non-melanomatous skin cancers.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I<br>Phase I portion of the study, a standard 3+3 dose escalation schema will be followed. Patients will receive veltuzumab IV weekly on day 1 for 4 doses and milatuzumab weekly on for 4 total doses during induction therapy. Induction therapy will be defined as the first 4 weeks of study therapy. During week 1 of induction therapy, patients will receive veltuzumab alone on day 1 and milatuzumab alone on day 2 to prevent overlapping infusion reactions. Starting week 2, veltuzumab will be given on day 1 and milatuzumab will be given on day 4. | Biological: milatuzumab<br>* Patient will receive milatuzumab weekly for 4 total doses during induction therapy. Induction therapy will be defined as the first 4 weeks of study therapy. During week 1 of induction therapy, patients will receive milatuzumab on day 2. Starting in week 2, milatuzumab will be given on day 4. Provided the patient does not experience excessive toxicity or disease progression during induction therapy, the patient may continue treatment with extended induction therapy, consisting of veltuzumab day 1 and milatuzumab day 4 of weeks 12, 20, 28, and 36.<br>* Other names: monoclonal antibody;Biological: veltuzumab<br>* Patient will receive veltuzumab weekly for 4 total doses during induction therapy. Induction therapy will be defined as the first 4 weeks of study therapy. Provided the patient does not experience excessive toxicity or disease progression during induction therapy, the patient may continue treatment with extended induction therapy, consisting of veltuzumab day 1 and milatuzumab day 4 of weeks 12, 20, 28, and 36.<br>* Other names: monoclonal antibody;Procedure: Correlative/Special Studies<br>* To correlate Fcγ receptor polymorphisms with response to treatment with the combination of veltuzumab and milatuzumab. Whole blood will be collected pre-treatment on day 1.<br>* Other names: blood samples;Procedure: Quantitative T-, B-, and NK cell subsets<br>* Quantitative T-, B-, and NK- cell subsets will be assessed using flow cytometry to quantify the percentage and absolute number of cells expressing CD4, CD8, CD56, CD16, CD19, and CD20 pre-treatment on day 1, after induction (week 5, day 1), and prior to the start of therapy on day 1 week 12, day 1 week 36, and then every 4 months for one year.<br>* Other names: blood samples;Procedure: Pharmacokinetics<br>* To assess the pharmacokinetics of veltuzumab in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma. Pharmacokinetics will be assessed with blood samples collected at the following time points: immediately pre- and post-infusion on day 1 of weeks 1, 2, 4, 12 and 36. One additional sample will be collected each of weeks 5 through 10 (sample may be collected any day during each of these weeks).<br>* Other names: blood samples;Procedure: Pharmacokinetics<br>* To assess the pharmacokinetics of milatuzumab in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma. Pharmacokinetics will be assessed with blood samples collected at the following time points: immediately pre- and post-infusion on day 2 of week 1 and day 1 of weeks 2, 4, 12 and 36. Additional samples will be collected days 3 through 6 of week 1.<br>* Other names: blood samples;Procedure: Human Anti-Human Antibodies<br>* To monitor for the development of human anti-veltuzumab antibodies and human anti-milatuzumab antibodies (HAHA) in patients receiving treatment with veltuzumab and milatuzumab. Patients will be monitored for the development of HAHA at the following timepoints: pre-treatment on day 1 of week 1, pre-treatment on day 1 of week 4, pre-treatment on day 1 of week 12, and pre-treatment on day 1 of week 36.<br>* Other names: blood samples;|
| Experimental: Phase II<br>Patients will receive veltuzumab IV weekly for 4 doses and milatuzumab IV weekly on day 2 of week 1 and on day 4 of weeks 2-4 for 4 total doses during induction therapy. Patients may continue on therapy to receive extended induction therapy provided they do not experience significant toxicity or rapid disease progression during the initial 4 week induction. | Biological: veltuzumab and milatuzumab<br>* Patient will receive veltuzumab and milatuzumab weekly for 4 total doses during induction therapy. Induction therapy will be defined as the first 4 weeks of study therapy. During week 1 of induction therapy, patients will receive veltuzumab on day 1 and milatuzumab on day 2. Starting in week 2, veltuxumab will be given on day 1 and milatuzumab will be given on day 4. Provided the patient does not experience excessive toxicity or disease progression during induction therapy, the patient may continue treatment with extended induction therapy, consisting of veltuzumab day 1 and milatuzumab day 4 of weeks 12, 20, 28, and 36.<br>* Other names: monoclonal antibody;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Limiting Toxicity (DLT) for Phase I Patients | Dose-limiting toxicity was assessed during induction therapy for phase I. | up to 2 years | 
| Maximum Tolerated Dose (MTD)for Phase I Patients | Patients received a fixed dose of Veltuzumab IV 200 mg/m2 and Milatuzumab was dose escalated | up to 2 years | 
| Overall Objective Response Rate | Per International Response Criteria (Cheson JCO 2007) for target lesions and assessed by CT, MRI or PET: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=50% decrease in sum of the product of the diameters (SPD) of up to six of the largest dominant nodes or nodal masses; Overall Response (OR) = CR + PR. | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | Progression is defined using International Response Criteria (Cheson JCO 2007), as a >= 50% increase from nadir in the SPD of any previously involved nodes, or in a single involved node, or at least a 50% increase in the longest diameter of any single previously identified node more than 1 cm in its short axis, or the size of other lesions (eg, splenic or hepatic nodules), or the appearance of new lesions. | up to 2 years | 
| Fcγ-receptor Polymorphism Response to Treatment | The relationship between overall response rate (ORR) and Fcy receptor status. A two-sided chi-square test or exact test with α = 0.05 will be used to test the homogeneity of the ORR among the three genotypes. | up to 2 years | 
| Quantitative T-, B-, and NK-cell Subsets Using Flow Cytometry | Quantitative T-, B-, and NK- cell subsets will be assessed using flow cytometry to quantify the percentage and absolute number of cells expressing CD4, CD8, CD56, CD16, CD19, and CD20 at screening, after induction, and prior to the start of therapy on day 1 week 12, day 1 week 28, and then every 4 months for one year. | up to 1 year | 
| Access Pharmacokinetics Through AUC0-∞ (Area Under Curve) | Evaluation of pharmacokinetics (Pk) of veltuzumab and milatuzumab was performed for patients included in the trial. Statistically, descriptive data of PK parameters will be computed. Relationships between such parameters as dose and AUC, volume of distribution, clearance, and others will be evaluated, but be preliminary due to the small sample size. | 0, 24, 48, 72, 96 and 120 hours post-does | 
| Access Pharmacokinetics Through Cmax | Evaluation of pharmacokinetics of veltuzumab and milatuzumab was performed for patients included in the trial. Statistically, descriptive data of PK parameters will be computed. Relationships between such parameters as dose and AUC, volume of distribution, clearance, and others will be evaluated, but be preliminary due to the small sample size. | 0, 24, 48, 72, 96 and 120 hours post-dose | 
| Monitor Human Anti-veltuzumab Antibodies and Human Anti-milatuzumab (HAHA) | Patients will be monitored for the development of human anti-veltuzumab antibodies and human anti-milatuzumab antibodies (HAHA). | up to 36 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent mantle cell lymphoma, recurrent grade 1 follicular lymphoma, recurrent grade 2 follicular lymphoma, recurrent grade 3 follicular lymphoma, MALT lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone lymphoma, recurrent marginal zone lymphoma, Waldenstrom macroglobulinemia