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

NCT ID: NCT00989586

Last Updated: 2017-02-06

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 35 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-09-30
• Study Completion Date: 2015-09-30

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.

Conditions

Lymphoma

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Phase I

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.

Group Type: EXPERIMENTAL

milatuzumab

Intervention Type: BIOLOGICAL

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.

veltuzumab

Intervention Type: BIOLOGICAL

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.

Correlative/Special Studies

Intervention Type: PROCEDURE

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.

Quantitative T-, B-, and NK cell subsets

Intervention Type: PROCEDURE

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.

Pharmacokinetics

Intervention Type: PROCEDURE

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).

Pharmacokinetics

Intervention Type: PROCEDURE

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.

Human Anti-Human Antibodies

Intervention Type: PROCEDURE

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.

Phase II

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.

Group Type: EXPERIMENTAL

veltuzumab and milatuzumab

Intervention Type: BIOLOGICAL

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.

Interventions

milatuzumab

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.

Intervention Type: BIOLOGICAL

veltuzumab

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.

Intervention Type: BIOLOGICAL

Correlative/Special Studies

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.

Intervention Type: PROCEDURE

Quantitative T-, B-, and NK cell subsets

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.

Intervention Type: PROCEDURE

Pharmacokinetics

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).

Intervention Type: PROCEDURE

Pharmacokinetics

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.

Intervention Type: PROCEDURE

Human Anti-Human Antibodies

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.

Intervention Type: PROCEDURE

veltuzumab and milatuzumab

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.

Intervention Type: BIOLOGICAL

Other Intervention Names

monoclonal antibody; monoclonal antibody; blood samples; blood samples; blood samples; blood samples; blood samples; monoclonal antibody

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Gilead Sciences

INDUSTRY

Sponsor Role: collaborator

Beth Christian

OTHER

Sponsor Role: lead

Responsible Party

Beth Christian

Principal Investigator

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Beth Christian, MD

Role: PRINCIPAL_INVESTIGATOR

Ohio State University

Locations

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, United States

Countries

United States

References

Christian BA, Poi M, Jones JA, Porcu P, Maddocks K, Flynn JM, Benson DM Jr, Phelps MA, Wei L, Byrd JC, Wegener WA, Goldenberg DM, Baiocchi RA, Blum KA. The combination of milatuzumab, a humanized anti-CD74 antibody, and veltuzumab, a humanized anti-CD20 antibody, demonstrates activity in patients with relapsed and refractory B-cell non-Hodgkin lymphoma. Br J Haematol. 2015 Jun;169(5):701-10. doi: 10.1111/bjh.13354. Epub 2015 Apr 7.

Reference Type: RESULT

PMID: 25847298 (View on PubMed)

Related Links

http://cancer.osu.edu

Jamesline

Other Identifiers

NCI-2011-03150

Identifier Type: REGISTRY

Identifier Source: secondary_id

OSU-09024

Identifier Type: -

Identifier Source: org_study_id