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

Phase 1

Completed

Conditions: Lymphoma

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

Registration Number: NCT00989586

Lead Sponsor: Beth Christian

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 35

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Phase I	milatuzumab	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.
Phase I	Human Anti-Human Antibodies	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.
Phase I	Quantitative T-, B-, and NK cell subsets	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.
Phase I	veltuzumab	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.
Phase I	Correlative/Special Studies	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.
Phase I	Pharmacokinetics	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.
Phase II	veltuzumab and milatuzumab	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.

Primary Outcome Measures

Name	Time	Method
Dose Limiting Toxicity (DLT) for Phase I Patients	up to 2 years	Dose-limiting toxicity was assessed during induction therapy for phase I.
Maximum Tolerated Dose (MTD)for Phase I Patients	up to 2 years	Patients received a fixed dose of Veltuzumab IV 200 mg/m2 and Milatuzumab was dose escalated
Overall Objective Response Rate	Up to 2 years	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.

Secondary Outcome Measures

Name	Time	Method
Progression-free Survival (PFS)	up to 2 years	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.
Fcγ-receptor Polymorphism Response to Treatment	up to 2 years	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.
Quantitative T-, B-, and NK-cell Subsets Using Flow Cytometry	up to 1 year	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.
Access Pharmacokinetics Through Cmax	0, 24, 48, 72, 96 and 120 hours post-dose	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.
Monitor Human Anti-veltuzumab Antibodies and Human Anti-milatuzumab (HAHA)	up to 36 weeks	Patients will be monitored for the development of human anti-veltuzumab antibodies and human anti-milatuzumab antibodies (HAHA).
Access Pharmacokinetics Through AUC0-∞ (Area Under Curve)	0, 24, 48, 72, 96 and 120 hours post-does	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.