Yttrium-90 Ibritumomab Tiuxetan Plus High-Dose BEAM Followed By ASCT For Relapsed B-Cell Non-Hodgkin Lymphoma

• ClinicalTrials.gov Identifier: NCT00695409
• Recruitment Status: Completed
• First Posted: June 11, 2008
• Results First Posted: July 6, 2018
• Last Update Posted: July 6, 2018
• Sponsor: City of Hope Medical Center
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): City of Hope Medical Center

Study Description

Brief Summary:

This phase II clinical trial studies how well yttrium Y 90 ibritumomab tiuxetan, rituximab, and high-dose chemotherapy followed by peripheral blood stem cell transplant in treating patients with relapsed B-cell non-Hodgkin lymphoma. Monoclonal antibodies, such as yttrium Y 90 ibritumomab tiuxetan and 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 can find tumor cells and carry tumor-killing substances to them without harming normal cells. Giving monoclonal antibody therapy, radioimmunotherapy (RIT), and high-dose combination chemotherapy before a peripheral blood stem cell transplant may be an effective treatment for non-Hodgkin lymphoma.

Condition or disease	Intervention/treatment	Phase
Lymphoma	Biological: rituximab; Drug: carmustine; Drug: cytarabine; Drug: etoposide; Drug: melphalan; Procedure: ASCT; Radiation: yttrium Y 90 ibritumomab tiuxetan	Phase 2

Detailed Description:

PRIMARY OBJECTIVE:

I. To estimate the 2-year progression free survival.

SECONDARY OBJECTIVES:

II. To estimate the 2-year overall survival.

III. To estimate the 2-year cumulative incidence of progression.

IV. To estimate time to hematopoietic recovery, using absolute neutrophil and platelet engraftment.

V. To estimate incidence of grade 3-4 toxicities by Bearman Scale, Day 0 to Day 100.

VI. To estimate the response rate (CR/PR).

VII. To estimate 100-day treatment related mortality.

VIII. To estimate incidence of myelodysplasia and therapy related acute myeloid leukemia (AML).

IX. To descriptively compare the outcomes of patients treated on this protocol to a comparable patient population treated with chemotherapy alone.

OUTLINE: RADIOIMMUNOTHERAPY: Patients receive yttrium Y 90 ibritumomab tiuxetan intravenously (IV) following rituximab IV on day -14.

HIGH-DOSE COMBINATION CHEMOTHERAPY: Patients receive carmustine IV on days -7 and -6; etoposide IV over 1 hour twice daily (BID) and cytarabine IV over 2 hours BID on days -5 to -2; and melphalan IV on day -1.

STEM CELL TRANSPLANTATION: Patients undergo autologous peripheral blood stem cell transplant on day 0. Patients also receive rituximab on day 8*. NOTE: * Some patients may also receive rituximab on day -1. Treatment continues in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up periodically.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 122 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Yttrium-90-Labeled Anti-CD20 Monoclonal Antibody in Combination With High-Dose Beam Followed by Autologous Stem Cell Transplantation for Poor Risk/Relapsed B-Cell Lymphoma
• Actual Study Start Date: March 18, 2008
• Actual Primary Completion Date: March 27, 2017
• Actual Study Completion Date: March 27, 2017

Arms and Interventions

Arm

Intervention/treatment

Experimental: Treatment (RIT, ZBEAM, ASCT); RADIOIMMUNOTHERAPY: Patients receive yttrium Y 90 ibritumomab tiuxetan IV following rituximab IV on day -14. HIGH-DOSE COMBINATION CHEMOTHERAPY: Patients receive carmustine IV on days -7 and -6; etoposide IV over 1 hour twice daily and cytarabine IV over 2 hours twice daily on days -5 to -2; and melphalan IV on day -1. STEM CELL TRANSPLANTATION: Patients undergo autologous peripheral blood stem cell transplant on day 0. Patients also receive rituximab on day 8*. NOTE: * Some patients may also receive rituximab on day -1. Treatment continues in the absence of disease progression or unacceptable toxicity.

Biological: rituximab; Given IV; Other Names: IDEC-C2B8; IDEC-C2B8 monoclonal antibody; Mabthera; MOAB IDEC-C2B8; Rituxan; Drug: carmustine; Given IV; Other Names: BCNU; BiCNU; bis-chloronitrosourea; Drug: cytarabine; Given IV; Other Names: ARA-C; arabinofuranosylcytosine; arabinosylcytosine; Cytosar-U; cytosine arabinoside; Drug: etoposide; Given IV; Other Names: EPEG; VP-16; VP-16-213; Drug: melphalan; Given IV; Other Names: Alkeran; CB-3025; L-PAM; L-phenylalanine mustard; L-Sarcolysin; Procedure: ASCT; Undergo autologous peripheral blood stem cell transplant; Other Name: Autologous Stem Cell Transplantation; Radiation: yttrium Y 90 ibritumomab tiuxetan; Given IV; Other Names: 90Y ibritumomab tiuxetan; IDEC Y2B8; Y90 Zevalin; Y90-labeled ibritumomab tiuxetan

Outcome Measures

Primary Outcome Measures :

1. 2-Year Progression-Free Survival [ Time Frame: From peripheral stem cell infusion (Day0 ASCT) to first observation of progressive disease or death due to any cause, whichever comes first, assessed up to 5 years ]
   Progression-free survival (PFS) was defined as time from peripheral stem cell infusion to recurrence, progression or death. In a clinical trial, measuring the progression-free survival is one way to see how well a new treatment works. Progression-free survival was estimated using the Kaplan-Meier method; the 95% confidence interval was calculated using Greenwood's formula [Breslow NE, Day NE. Statistical methods in cancer research: volume II, the design and analysis of cohort studies. IARC Sci Publ 1987;82:1-406.]

Secondary Outcome Measures :

1. 2-Year Overall Survival [ Time Frame: From peripheral stem cell infusion (Day0 ASCT) to death due to any cause, assessed up to 5 years ]
   Overall survival (OS) was measured from peripheral stem cell infusion to death from any cause. It was estimated using the Kaplan-Meier method; the 95% confidence interval was calculated using Greenwood's formula. [Breslow NE, Day NE. Statistical methods in cancer research: volume II, the design and analysis of cohort studies. IARC Sci Publ 1987;82:1-406.]
2. 2-Year Cumulative Incidence of Progression [ Time Frame: From peripheral stem cell infusion (Day0 ASCT) to date of first observation of progressive disease or relapsed disease, assessed up to 5 years ]
   The cumulative incidence was estimated after taking into account the competing risk of early death.
3. Number of Patients With Active Disease at ASCT Achieving CR/PR by Day 100 After ASCT [ Time Frame: Up to Day 100 post-ASCT ]
   Responses are assessed using the Revised Criteria for Malignant Lymphoma Response Definitions for Clinical Trials (Cheson et al. 2007). Complete Response (CR) defined as disappearance of all evidence of disease. Partial Response (PR) defined as regression of measurable disease and no new sites.
4. Number of Patients With Grade 3-4 Bearman Toxicities. [ Time Frame: From initial of study treatment to Day 100 post-ASCT ]
   Toxicities were recorded using the modified Bearman Scale for non-hematologic adverse events.
5. 100-Day Treatment-Related Mortality [ Time Frame: From peripheral stem cell infusion (Day0 ASCT) to death due to any couse, assessed up to 5 years ]
   The cumulative incidence was estimated after taking into account the competing risk of relapse post-ASCT.
6. Time to Neutrophil Recovery [ Time Frame: From peripheral stem cell infusion (Day0 ASCT) till the first of 3 consecutive days of an absolute neutrophil count ≥ 500/µL.) ]
   Neutrophil recovery was defined as the first of 3 consecutive days of an absolute neutrophil count ≥ 500/µL.
7. Time to Platelet Recovery [ Time Frame: From peripheral stem cell infusion (Day0 ASCT) till the first of 7 consecutive days with a platelet count ≥ 20,000/µL with no transfusions ]
   Platelet recovery was defined as the first of 7 consecutive days with a platelet count ≥ 20,000/µL with no transfusions.
8. Number of Patients With RIT/ZBEAM Developing Therapy Induced MDS and AML [ Time Frame: From peripheral stem cell infusion (Day0 ASCT) to onset of therapy induced MDS/AML, assessed up to 5 years ]
   Patient receiving the full treatment of RIT/ZBEAM developed therapy induced MDS or AML.

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• All patients must have biopsy proven diagnosis of low- and intermediate-grade non-Hodgkin lymphoma (NHL) working formulation B, C,D, E, F, and G; including mantle cell lymphoma; patients with transformed lymphoma are also eligible
• Demonstrated monoclonal CD20 positive b-cell population in lymph nodes and/or bone marrow
• Patients must have relapsed after achieving a complete or partial response to prior therapy, have never responded to prior therapy or have poor risk disease
• Patients with prior bone marrow involvement must have bone marrow aspiration and biopsy within 60 days prior to stem cell collection which shows =< 10% lymphomatous involvement of total cellularity; alternatively, patients with prior bone marrow involvement should have a normal bone marrow study which shows =< 10% lymphomatous involvement within 28 days before salvage chemotherapy
• Normal renal function test with serum creatinine of < upper limit of normal (ULN), and a creatinine clearance of >= 60 ml/min (measured or calculated)
• Adequate pulmonary function as measured by forced expiratory volume in 1 second (FEV1) > 60% of predicted measured, or a diffusion capacity of carbon monoxide (DLCO) >= 50% of predicted measured
• Cardiac ejection fraction of > 50% by echocardiogram or multi gated acquisition (MUGA) scan; the left ventricular ejection fraction (LVEF) from the prestudy echocardiogram (ECHO) or MUGA may be used for eligibility purposes, even if the prestudy stress test indicated a lower LVEF
• Adequate liver function tests with a bilirubin of =< 1.5 x ULN and serum glutamic oxaloacetic transaminase (SGOT) or serum glutamic pyruvic transaminase (SGPT) =< 2 x ULN
• Negative human immunodeficiency virus antibody
• Eastern Cooperative Oncology Group (ECOG) performance status = 0 or 1; karnofsky performance status (KPS) >= 80
• No active central nervous system (CNS) disease or prior history of CNS disease
• Patients must have recovered from last therapy and should be at least four weeks from prior radiation or systemic chemotherapy on the day of administration of Y2B8
• After the last systemic therapeutic chemotherapy (Cytoxan, administered only for stem cell mobilization is not considered therapeutic) and prior to initiation of high dose treatment, the patient should have a baseline computed tomography (CT) scan and positron emission tomography (PET) scan done; an fluorodeoxyglucose-computed tomography (FDG/CT) scan is sufficient, however, is clinically indicated, an additional diagnostic CT may be ordered; exception: if scans were done and were negative for disease just prior to priming chemotherapy (therapeutic or nontherapeutic) and subsequent stem cell harvest, they do not need to be repeated prior to initiation of high dose treatment

Exclusion Criteria:

• Presence of human anti-Zevalin antibody (HAZA)
• Prior radioimmunotherapy
• Failure to collect adequate number of CD34+ cells >= 3 x 10^6/kg
• Abnormal cytogenetic study not related to the underlying lymphoma on the bone marrow aspirate sample prior to stem cell collection; if cytogenetics were not performed on the marrow aspirate prior to stem cell collection, cytogenetics on the peripheral blood may be performed
• Prior bone marrow transplantation

• Prior malignancy except for:

  • Adequately treated basal cell or squamous cell skin cancer
  • Adequately treated noninvasive carcinoma
  • Other cancer from which the patient has been disease-free for at least five years
• Active evidence of Hepatitis B or C infection; Hepatitis B surface antigen positive
• Patients who have had prior radiation to the lung will be excluded from the study, although mediastinal irradiation will be permitted if minimal lung is in the treatment volume
• Patients who have received > 500cGy radiation to the kidneys will be excluded from the study
• Patients who are pregnant or lactating

Contacts and Locations

Locations

United States, California

City of Hope Medical Center

Duarte, California, United States, 91010-3000

Sponsors and Collaborators

City of Hope Medical Center

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Amrita Y. Krishnan, MD; City of Hope Medical Center

  Study Documents (Full-Text)

Documents provided by City of Hope Medical Center:

Study Protocol and Statistical Analysis Plan  [PDF] December 15, 2014

More Information

• Responsible Party: City of Hope Medical Center
• ClinicalTrials.gov Identifier: NCT00695409
• Other Study ID Numbers: 07076; P01CA030206 ( U.S. NIH Grant/Contract ); P30CA033572 ( U.S. NIH Grant/Contract ); CHNMC-07076; CDR0000597569 ( Registry Identifier: NCI PDQ ); NCI-2010-01231 ( Registry Identifier: NCI CTPR )
• First Posted: June 11, 2008
• Results First Posted: July 6, 2018
• Last Update Posted: July 6, 2018
• Last Verified: June 2018

Keywords provided by City of Hope Medical Center:

recurrent mantle cell lymphoma; stage III mantle cell lymphoma; stage IV mantle cell lymphoma; recurrent adult diffuse large cell lymphoma; stage III adult diffuse large cell lymphoma; stage IV adult diffuse large cell lymphoma; recurrent grade 1 follicular lymphoma; recurrent grade 2 follicular lymphoma; recurrent grade 3 follicular lymphoma; stage III grade 1 follicular lymphoma; stage III grade 2 follicular lymphoma; stage III grade 3 follicular lymphoma; stage IV grade 1 follicular lymphoma; stage IV grade 2 follicular lymphoma; stage IV grade 3 follicular lymphoma; stage III adult immunoblastic large cell lymphoma; stage IV adult immunoblastic large cell lymphoma; recurrent adult immunoblastic large cell lymphoma

Additional relevant MeSH terms:

Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Cytarabine; Rituximab; Etoposide; Etoposide phosphate; Melphalan; Carmustine; Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antiviral Agents; Anti-Infective Agents; Immunosuppressive Agents; Antineoplastic Agents, Alkylating