Belinostat and Yttrium Y 90 Ibritumomab Tiuxetan in Patients W/Relapsed Aggressive B-Cell NHL

A Phase II Exploratory Study of PXD-101(Belinostat) Followed by Zevalin in Patients With Relapsed Aggressive High-Risk Lymphoma

This study looks at what effects (good and bad) a drug called PXD-101 (belinostat) in combination with the radioactive drug Zevalin (yttrium Y 90 ibritumomab tiuxetan) has on patients with relapsed aggressive (high-risk) non-Hodgkin lymphoma. Studies in the laboratory suggest that drugs such as PXD101 can act upon specific cancer cell processes to cause either death of the cancer cells or prevention of their growth. In human studies with a small number of patients with this lymphoma, PXD-101 has shown the ability to shrink and slow tumor growth. When Zevalin is delivered directly to the tumor, the lymphoma cells are destroyed and this may result in the disappearance of the tumor (remission)

Study Overview

• Status: Completed
• Conditions: Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Mantle Cell Lymphoma; Anaplastic Large Cell Lymphoma
• Intervention / Treatment: Biological: rituximab; Radiation: yttrium Y 90 ibritumomab tiuxetan; Drug: belinostat

Detailed Description

PRIMARY OBJECTIVES:

I. To document the complete response rate and overall response for patients with relapsed aggressive high-risk non-Hodgkin's lymphoma treated with two cycles PXD-101 followed by one cycle of Zevalin.

SECONDARY OBJECTIVES:

I. To estimate 2-year progression-free survival in patients with relapsed aggressive high-risk non-Hodgkin's lymphoma treated with two cycles PXD-101 followed by one cycle of Zevalin.

II. To evaluate the toxicity of two cycles PXD-101 and one cycle of Zevalin in patients with relapsed aggressive high-risk non-Hodgkin's lymphoma.

OUTLINE:

Patients receive belinostat intravenously (IV) over 30-60 minutes on days 1-5. Treatment with belinostat repeats every 21 days for 2 courses. Patients then receive rituximab IV on days 1 and either 7, 8, or 9, and yttrium Y 90 ibritumomab tiuxetan IV over 10 minutes on day 50. Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Tucson, Arizona, United States, 85724-5024
      • University of Arizona Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Biopsy confirmed, CD20 positive diffuse large B-cell lymphoma, primary mediastinal b-cell lymphoma, mantel cell lymphoma, transformed indolent lymphoma, high grade-B-cell lymphoma; AND bone marrow must show =< 20% CD20+ B-cells with >= 15% cellularity within 42 days of study registration
• Any stage disease

• Patients must have been previously treated:

  • >= 3rd line if bone marrow transplant (BMT) candidate OR
  • >= 2nd line if not BMT candidate OR
  • >= 2nd relapse for BMT candidate OR
  • >= 1st relapse for non- BMT candidate
• Must have a diagnostic quality CT scan of the chest, abdomen and pelvis OR baseline PET-CT scan performed within 28 days prior to registration
• Must have bidimensionally measurable disease with lesions at least 1.5 cm in one dimension ALL measurable disease must be assessed within 28 days of registration
• To determine prior drug regimens: radiation therapy counts as 1 treatment, BMT including induction counts as one treatment, radioimmunotherapy is not considered a chemotherapy regimen, rituximab alone is not considered a treatment; all prior therapy must have been completed at least 30 days prior to registration; patients should not have taken valproic acid, or any other histone deacetylase inhibitor (eg., vorinostat, romidepsin), for at least 30 days prior to registration; patients must have recovered from any toxicities related to therapies prior to registration
• No clinical evidence of CNS involvement by lymphoma, any lab (eg., LDH or radiographic tests performed to access CNS involvement must be negative and must be performed within 42 days prior to registration
• Unilateral or bilateral bone marrow biopsy performed within 42 days prior to registration
• Life expectancy of greater than 3 months
• Karnofsky performance status >= 60%
• Leukocytes >= 3,000/mcL
• Absolute neutrophil count >= 1,500/mcL
• Platelets >= 100,000/mcL
• AST (SGOT)/ALT(SGPT) =< 2.5 X institutional upper limit of normal
• Total bilirubin =< 1.5 X institutional upper limit of normal (unless associated with Gilbert's syndrome)
• Serum creatinine < 2 x institutional upper limit of normal OR
• Measured creatinine clearance >= 60 mL/min
• LDH < 1.50 X institutional upper limit of normal
• EKG with no significant abnormalities within 28 days prior to registration
• Women of child-bearing potential and men must agree to use adequate contraception

Exclusion Criteria:

• Patients who have had chemotherapy or radiotherapy within 30 days (6 weeks for nitrosoureas or mitomycin C) prior to study screening or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
• Prior radioimmunotherapy
• Pregnant or nursing
• Clinical evidence of CNS involvement by lymphoma
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to PXD-101 or Zevalin or other agents used in the study
• Concomitant medication that may cause Torsade de Pointes, i.e. prolongation of the QT interval > 500 msec
• Significant cardiovascular disease including unstable angina pectoris, uncontrolled hypertension, congestive heart failure related to primary cardiac disease, any condition requiring anti-arrhythmic therapy, ischemic or valvular heart disease, or a myocardial infarction within the past 6 months
• Current long QT syndrome or baseline prolongation of QT/QTcF interval, i.e. demonstration of a QTcF interval > 450 msec
• Clinical evidence of severe peripheral vascular disease, diabetic ulcers or venous stasis ulcers, or history of deep venous or arterial thrombosis within 3 months prior to screening
• Known to be human immunodeficiency virus (HIV) positive or with known acquired immunodeficiency syndrome (AIDS) syndrome
• Patients may not be receiving any other investigational agents

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Belinostat Yttrium Ibritumomab Tiuxetan; Patients receive belinostat IV over 30-60 minutes on days 1-5. Treatment with belinostat repeats every 21 days for 2 courses. Patients then receive rituximab IV on days 1 and either 7, 8, or 9, and yttrium Y 90 ibritumomab tiuxetan IV over 10 minutes on day 50. Treatment continues in the absence of disease progression or unacceptable toxicity.

Biological: rituximab; Given IV; Other Names: Rituxan; Mabthera; IDEC-C2B8; IDEC-C2B8 monoclonal antibody; MOAB IDEC-C2B8; Radiation: yttrium Y 90 ibritumomab tiuxetan; Given IV; Other Names: 90Y ibritumomab tiuxetan; IDEC Y2B8; Y90 Zevalin; Y90-labeled ibritumomab tiuxetan; Drug: belinostat; Given IV; Other Names: PXD101

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete Response Rate	To document the complete response rate for patients with relapsed aggressive high-risk non-Hodgkin's lymphoma (NHL) treated with two cycles PXD-101 followed by one cycle of the Zevalin regimen.	Up to 5 years
Overall Response	To document the overall response for patients with relapsed aggressive high-risk non-Hodgkin's lymphoma (NHL) treated with two cycles PXD-101 followed by one cycle of the Zevalin regimen.	Up to 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival	Will be estimated using a Kaplan-Meier estimate. The observed 2-year progression-free survival rate will be estimated (with a 95% confidence interval) from the Kaplan-Meier curve.	2 years
Occurrence of Adverse Events and Serious Adverse Events	The proportion of patients with a given adverse event will be tabulated and the 95% confidence interval computed.	Up to 30 days after patient receives last dose of study drug

Collaborators and Investigators

• Sponsor: University of Arizona
• Collaborators: National Cancer Institute (NCI)

Publications and helpful links

General Publications

• Puvvada SD, Guillen-Rodriguez JM, Rivera XI, Heard K, Inclan L, Schmelz M, Schatz JH, Persky DO. A Phase II Exploratory Study of PXD-101 (Belinostat) Followed by Zevalin in Patients with Relapsed Aggressive High-Risk Lymphoma. Oncology. 2017;93(6):401-405. doi: 10.1159/000479230. Epub 2017 Sep 5.

Study record dates

Study Major Dates

• Study Start (Actual): August 31, 2012
• Primary Completion (Actual): February 9, 2016
• Study Completion (Actual): November 9, 2017

Study Registration Dates

• First Submitted: September 12, 2012
• First Submitted That Met QC Criteria: September 12, 2012
• First Posted (Estimate): September 17, 2012

Study Record Updates

• Last Update Posted (Actual): August 28, 2018
• Last Update Submitted That Met QC Criteria: July 30, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Lymphoma, B-Cell; Lymphoma, T-Cell; Lymphoma; Lymphoma, Large B-Cell, Diffuse; Recurrence; Lymphoma, Non-Hodgkin; Lymphoma, Mantle-Cell; Lymphoma, Large-Cell, Anaplastic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Histone Deacetylase Inhibitors; Rituximab; Antibodies, Monoclonal; Belinostat
• Other Study ID Numbers: 12-0288-04; P30CA023074 (U.S. NIH Grant/Contract); NCI-2012-01131 (Other Identifier: CTRP (Clinical Trial Reporting Program)); 1200000288 (Other Identifier: UofA IRB #)