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BEAM vs. 90-Yttrium Ibritumomab Tiuxetan (Zevalin®)/BEAM With ASCT for Relapsed DLBCL (SPINOZA)

Primary Purpose

Recurrent Diffuse Large B-Cell Lymphoma, Refractory Diffuse Large B-Cell Lymphoma

Status

Terminated

Phase

Phase 3

Locations

United States

Study Type

Interventional

Intervention

90-Yttrium Ibritumomab tiuxetan

Carmustine

Etoposide

Cytarabine

Melphalan

Autologous Hematopoietic Stem Cell Transplant

Rituximab

About this trial

This is an interventional treatment trial for Recurrent Diffuse Large B-Cell Lymphoma focused on measuring Non-Hodgkin's lymphoma, autologous stem cell transplantation, radioimmunotherapy, Zevalin, Lymphoma, Lymphoma, Large B-Cell, Diffuse, Lymphoma, Non-Hodgkin, Immune System Diseases, Immunoproliferative Disorders, Lymphatic Diseases, Lymphoma, B-Cell, Lymphoproliferative Disorders, Neoplasms, Neoplasms by Histologic Type, Antibodies, Monoclonal, Immunologic Factors, Pharmacologic Actions, Physiological Effects of Drugs

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Patients with CD20 positive diffuse large B-cell lymphoma as confirmed by a pathological biopsy report.
Patients who are candidates for autologous stem-cell transplantation due to primary refractory or first relapse of disease.
Patients must have chemo-sensitive disease achieving at least partial response (Cheson 2007 criteria) to last chemotherapy.
Patients with adequate autologous stem cell collection for transplantation (target >= 2.5 x 10^6 CD34+ cells/kg).
Patients must sign written informed consent.
Adequate birth control in fertile patients.
All prior chemotherapy completed at least three weeks before study treatment.
Marrow involvement less than 25% at transplantation, no limitation on blood counts (low platelet count allowed).
Negative HIV antibody.

Exclusion Criteria:

Chemo-refractory disease as determined by less than partial response (Cheson 2007 Criteria) to last chemotherapy.
Two or more relapses after initial response to induction chemotherapy.
High-grade transformation from earlier diagnosis of low-grade lymphoma. Patients with "De Novo" Transformed DLBCL, defined as DLBCL only on lymph node biopsy and a discordant marrow with para-trabecular small cells at first diagnosis of lymphoma, are eligible if adherent to all other selection criteria.
Bilirubin > 3.0 mg/dl, transaminases > 3 times upper normal limit.
Creatinine > 2.0 mg/dl.
KPS < 70.
Uncontrolled infection.
Pregnancy or lactation.
Abnormal lung diffusion capacity (DLCO < 40% predicted).
Severe cardiovascular disease; New York Heart Association (NYHA) Functional Classification ≥2.
Active CNS disease involvement.
Presence of any other malignancy or history of prior malignancy within 5 years of study entry. Within 5 years, patients treated for Stage I or II cancers are eligible provided they have a life expectancy > 5 years in relation to this prior malignance. The 5-year exclusion rule does not apply to-non melanoma skin tumors and in situ cervical cancer.
Pleural effusion or ascites > 1 liter.
Known hypersensitivity to rituximab.
Psychiatric conditions/disease that impair the ability to give informed consent or to adequately co-operate.
Prior radioimmunotherapy.
Prior autologous or allogeneic HSCT.
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.

Sites / Locations

City of Hope Medical Center
Memorial Sloan Kettering Cancer Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Arm I (ZBEAM)

Arm II (BEAM)

Arm Description

Patients receive rituximab IV on days -21 and -14, and 90-yttrium ibritumomab tiuxetan IV on day -14. Patients also receive BEAM comprising carmustine IV over 4 hours on day -6; cytarabine IV over 2 hours BID on days -5 to -2; etoposide IV over 1 hour BID or QD on days -5 to -2; and melphalan IV on day -1. Patients then undergo autologous hematopoietic stem cell transplant on day 0.

Patients receive BEAM comprising carmustine IV over 4 hours on day -6; cytarabine IV over 2 hours BID on days -5 to -2; etoposide IV over 1 hour BID or QD on days -5 to -2; and melphalan IV on day -1. Patients then undergo autologous hematopoietic stem cell transplant on day 0.

Outcomes

Primary Outcome Measures

Overall Survival

Survival estimates will be calculated using the Kaplan-Meier method

Secondary Outcome Measures

Progression-free Survival

Survival estimates will be calculated using the Kaplan-Meier method

Time to Progression

Time-to-event will be measured from the date of ASCT.

Number of Patients With Complete or Partial Response at Day 30

Definition of disease status is based on the article of Revised Response Criteria for Malignant Lymphoma Response Definitions for Clinical Trials (Cheson et al, 2007). Tests used for evaluation of disease status would be physical examination, laboratory testing, bone marrow testing, bone marrow biopsy and aspirate, PET scan, and CT scans of neck, chest, abdomen and pelvis as indicated.

Time to Neutrophil Engraftment

Time to neutrophil engraftment will be compared between treatment arms using a log-rank test, and the cumulative incidence curves will be estimated.

Incidence of Infection

Microbiologically documented infections will be reported by site of disease, date of onset, severity, and resolution, if any. The incidence of definite and probable viral, fungal and bacterial infections will be tabulated for each patient. The proportion of patients developing infections will be compared between treatment arms.

Incidence of Non-relapse Mortality (NRM) Defined as Death Occurring in a Patient From Causes Other Than Relapse or Progression

The cumulative incidence of NRM will be estimated using the method described by Gooley et al. Differences between cumulative incidence curves in the presence of a competing risk will be tested using the Gray method.

Cumulative Incidence of Secondary Malignancies

Incidence of myelodysplastic syndrome (MDS), and secondary acute Myelogenous leukemia (AML) will be compared between the treatment arms using Gray's test.

Time to Platelet Engraftment

Time to platelet engraftment will be compared between treatment arms using a log-rank test, and the cumulative incidence curves will be estimated.

Number of Patients With Grade 3-5 Toxicities Graded by the NCI CTCAE Version 4.0

Observed toxicities will be summarized in terms of type and severity. In accordance with the secondary study objectives, descriptive analyses on these data will be performed.

Cumulative Incidence of New, Abnormal Cytogenetics

The cumulative incidence of therapy related new, abnormal cytogenetics will be estimated for both groups taking into account the competing risk of death among patients who do not develop a second malignancy.

Full Information

NCT ID

NCT02366663

First Posted

February 9, 2015

Last Updated

February 12, 2018

Sponsor

City of Hope Medical Center

Collaborators

National Cancer Institute (NCI)

1. Study Identification

Unique Protocol Identification Number

NCT02366663

Brief Title

BEAM vs. 90-Yttrium Ibritumomab Tiuxetan (Zevalin®)/BEAM With ASCT for Relapsed DLBCL

Acronym

SPINOZA

Official Title

SPINOZA / שפינוזה. Study With Preparatory INduction Of Zevalin in Aggressive Lymphoma. A Randomized Phase 3 Study of BEAM Versus 90Yttrium Ibritumomab Tiuxetan (Zevalin) / BEAM in Patients Requiring ASCT for Relapsed DLBCL

Study Type

Interventional

2. Study Status

Record Verification Date

February 2018

Overall Recruitment Status

Terminated

Why Stopped

Withdrawal of sponsor support

Study Start Date

January 2015 (undefined)

Primary Completion Date

October 2016 (Actual)

Study Completion Date

October 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

City of Hope Medical Center

Collaborators

National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

This randomized phase III trial studies 90-yttrium ibritumomab tiuxetan and combination chemotherapy compared with combination chemotherapy alone before stem cell transplant in treating patients with diffuse large b-cell non-Hodgkin lymphoma that has returned after a period of improvement. Radioactive substances linked to monoclonal antibodies, such as 90-yttrium ibritumomab tiuxetan, can bind to cancer cells and give off radiation which may help kill cancer cells. Drugs used in chemotherapy, such as carmustine, etoposide phosphate, cytarabine, and melphalan (BEAM), work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether 90-yttrium ibritumomab tiuxetan and BEAM before a stem cell transplant are more effective than BEAM alone in treating patients with diffuse large b-cell non-Hodgkin lymphoma.

Detailed Description

PRIMARY OBJECTIVES: I. To compare overall survival (OS) between the two transplant arms, with at least a two year of follow-up. SECONDARY OBJECTIVES: I. To compare progression-free survival (PFS), complete response (CR) and partial response (PR) proportion at day 100, time to hematopoietic recovery, incidence of infection, grade III-IV toxicities, treatment-related mortality, incidence of myelodysplastic syndrome (MDS), and secondary acute myelogenous leukemia (AML). OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive rituximab intravenously (IV) on days -21 and -14, and 90-yttrium ibritumomab tiuxetan IV on day -14. Patients also receive BEAM comprising carmustine IV over 4 hours on day -6; cytarabine IV over 2 hours twice daily (BID) on days -5 to -2; etoposide IV over 1 hour BID or once daily (QD) on days -5 to -2; and melphalan IV on day -1. Patients then undergo peripheral blood stem cell (PBSC) transplant on day 0. ARM II: Patients receive BEAM as in Arm I and undergo PBSC transplant on day 0. After completion of study treatment, patients are followed up weekly for 30 days, 100 days, 6 months, 1 year, every 3 months for 1 year, and then annually for 3 years.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Recurrent Diffuse Large B-Cell Lymphoma, Refractory Diffuse Large B-Cell Lymphoma

Keywords

Non-Hodgkin's lymphoma, autologous stem cell transplantation, radioimmunotherapy, Zevalin, Lymphoma, Lymphoma, Large B-Cell, Diffuse, Lymphoma, Non-Hodgkin, Immune System Diseases, Immunoproliferative Disorders, Lymphatic Diseases, Lymphoma, B-Cell, Lymphoproliferative Disorders, Neoplasms, Neoplasms by Histologic Type, Antibodies, Monoclonal, Immunologic Factors, Pharmacologic Actions, Physiological Effects of Drugs

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

3 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm I (ZBEAM)

Arm Type

Experimental

Arm Description

Arm Title

Arm II (BEAM)

Arm Type

Active Comparator

Arm Description

Intervention Type

Radiation

Intervention Name(s)

90-Yttrium Ibritumomab tiuxetan

Other Intervention Name(s)

IDEC Y2B8, Zevalin

Intervention Description

0.4 mCi/kg given IV

Intervention Type

Drug

Intervention Name(s)

Carmustine

Other Intervention Name(s)

BiCNU, FDA 0345

Intervention Description

Given IV

Intervention Type

Drug

Intervention Name(s)

Etoposide

Other Intervention Name(s)

VP-16, Lastet

Intervention Description

Given IV

Intervention Type

Drug

Intervention Name(s)

Cytarabine

Other Intervention Name(s)

Cytosar-U, CHX-3311, U-19920

Intervention Description

Given IV

Intervention Type

Drug

Intervention Name(s)

Melphalan

Other Intervention Name(s)

Alkeran

Intervention Description

Given IV

Intervention Type

Procedure

Intervention Name(s)

Autologous Hematopoietic Stem Cell Transplant

Other Intervention Name(s)

Autologous Stem Cell Transplant

Intervention Description

Autologous Hematopoietic Stem Cell Transplantation (ASCT)

Intervention Type

Biological

Intervention Name(s)

Rituximab

Other Intervention Name(s)

MOAB IDEC-C2B8

Intervention Description

Given IV

Primary Outcome Measure Information:

Title

Overall Survival

Description

Survival estimates will be calculated using the Kaplan-Meier method

Time Frame

Measured from randomization to date of death or last follow up date, whichever occurs first, for up to 5 years post randomization

Secondary Outcome Measure Information:

Title

Progression-free Survival

Description

Survival estimates will be calculated using the Kaplan-Meier method

Time Frame

Measured from randomization until death, relapse/progression, receipt of anti-lymphoma therapy, or last follow up whichever comes first, for up to 5 years post randomization

Title

Time to Progression

Description

Time-to-event will be measured from the date of ASCT.

Time Frame

Up to 5 years

Title

Number of Patients With Complete or Partial Response at Day 30

Description

Time Frame

Day 0 to Day +30 post-HCT

Title

Time to Neutrophil Engraftment

Description

Time to neutrophil engraftment will be compared between treatment arms using a log-rank test, and the cumulative incidence curves will be estimated.

Time Frame

Day 0 to Day 100 post-HCT

Title

Incidence of Infection

Description

Time Frame

Day 0 to Day +100 post-HCT

Title

Incidence of Non-relapse Mortality (NRM) Defined as Death Occurring in a Patient From Causes Other Than Relapse or Progression

Description

Time Frame

From randomization until non-disease related death, or last follow-up, whichever comes first, assessed up to 5 years

Title

Cumulative Incidence of Secondary Malignancies

Description

Incidence of myelodysplastic syndrome (MDS), and secondary acute Myelogenous leukemia (AML) will be compared between the treatment arms using Gray's test.

Time Frame

Up to 5 years

Title

Time to Platelet Engraftment

Description

Time to platelet engraftment will be compared between treatment arms using a log-rank test, and the cumulative incidence curves will be estimated.

Time Frame

Day 0 to Day 100 post-HCT

Title

Number of Patients With Grade 3-5 Toxicities Graded by the NCI CTCAE Version 4.0

Description

Observed toxicities will be summarized in terms of type and severity. In accordance with the secondary study objectives, descriptive analyses on these data will be performed.

Time Frame

Day -21 to Day +100 post-HCT

Title

Cumulative Incidence of New, Abnormal Cytogenetics

Description

Time Frame

Day 0 to Year 5 post-HCT

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Patients with CD20 positive diffuse large B-cell lymphoma as confirmed by a pathological biopsy report. Patients who are candidates for autologous stem-cell transplantation due to primary refractory or first relapse of disease. Patients must have chemo-sensitive disease achieving at least partial response (Cheson 2007 criteria) to last chemotherapy. Patients with adequate autologous stem cell collection for transplantation (target >= 2.5 x 10^6 CD34+ cells/kg). Patients must sign written informed consent. Adequate birth control in fertile patients. All prior chemotherapy completed at least three weeks before study treatment. Marrow involvement less than 25% at transplantation, no limitation on blood counts (low platelet count allowed). Negative HIV antibody. Exclusion Criteria: Chemo-refractory disease as determined by less than partial response (Cheson 2007 Criteria) to last chemotherapy. Two or more relapses after initial response to induction chemotherapy. High-grade transformation from earlier diagnosis of low-grade lymphoma. Patients with "De Novo" Transformed DLBCL, defined as DLBCL only on lymph node biopsy and a discordant marrow with para-trabecular small cells at first diagnosis of lymphoma, are eligible if adherent to all other selection criteria. Bilirubin > 3.0 mg/dl, transaminases > 3 times upper normal limit. Creatinine > 2.0 mg/dl. KPS < 70. Uncontrolled infection. Pregnancy or lactation. Abnormal lung diffusion capacity (DLCO < 40% predicted). Severe cardiovascular disease; New York Heart Association (NYHA) Functional Classification ≥2. Active CNS disease involvement. Presence of any other malignancy or history of prior malignancy within 5 years of study entry. Within 5 years, patients treated for Stage I or II cancers are eligible provided they have a life expectancy > 5 years in relation to this prior malignance. The 5-year exclusion rule does not apply to-non melanoma skin tumors and in situ cervical cancer. Pleural effusion or ascites > 1 liter. Known hypersensitivity to rituximab. Psychiatric conditions/disease that impair the ability to give informed consent or to adequately co-operate. Prior radioimmunotherapy. Prior autologous or allogeneic HSCT. 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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Amrita Y. Krishnan MD, MD

Organizational Affiliation

City of Hope Medical Center

Official's Role

Principal Investigator

Facility Information:

Facility Name

City of Hope Medical Center

City

Duarte

State/Province

California

ZIP/Postal Code

91010

Country

United States

Facility Name

Memorial Sloan Kettering Cancer Center

City

New York

State/Province

New York

ZIP/Postal Code

10065

Country

United States

12. IPD Sharing Statement

Learn more about this trial

BEAM vs. 90-Yttrium Ibritumomab Tiuxetan (Zevalin®)/BEAM With ASCT for Relapsed DLBCL

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