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

Phase 3TerminatedNCT02366663

City of Hope Medical Center3 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Interventions

90-Yttrium Ibritumomab tiuxetanRADIATION

0.4 mCi/kg given IV

CarmustineDRUG

Given IV

EtoposideDRUG

Given IV

CytarabineDRUG

Given IV

MelphalanDRUG

Given IV

Autologous Hematopoietic Stem Cell TransplantPROCEDURE

Autologous Hematopoietic Stem Cell Transplantation (ASCT)

RituximabBIOLOGICAL

Given IV

Eligibility

Sex: ALLMin age: 18 YearsMax age: 70 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Patients with CD20 positive diffuse large B-cell lymphoma as confirmed by a pathological biopsy report. 2. Patients who are candidates for autologous stem-cell transplantation due to primary refractory or first relapse of disease. 3. Patients must have chemo-sensitive disease achieving at least partial response (Cheson 2007 criteria) to last chemotherapy. 4. Patients with adequate autologous stem cell collection for transplantation (target \>= 2.5 x 10\^6 CD34+ cells/kg). 5. Patients must sign written informed consent. 6. Adequate birth control in fertile patients. 7. All prior chemotherapy completed at least three weeks before study treatment. 8. Marrow involvement less than 25% at transplantation, no limitation on blood counts (low platelet count allowed). 9. Negative HIV antibody. Exclusion Criteria: 1. Chemo-refractory disease as determined by less than partial response (Cheson 2007 Criteria) to last chemotherapy. 2. Two or more relapses after initial response to induction chemotherapy. 3. 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. 4. Bilirubin \> 3.0 mg/dl, transaminases \> 3 times upper normal limit. 5. Creatinine \> 2.0 mg/dl. 6. KPS \< 70. 7. Uncontrolled infection. 8. Pregnancy or lactation. 9. Abnormal lung diffusion capacity (DLCO \< 40% predicted). 10. Severe cardiovascular disease; New York Heart Association (NYHA) Functional Classification ≥2. 11. Active CNS disease involvement. 12. 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. 13. Pleural effusion or ascites \> 1 liter. 14. Known hypersensitivity to rituximab. 15. Psychiatric conditions/disease that impair the ability to give informed consent or to adequately co-operate. 16. Prior radioimmunotherapy. 17. Prior autologous or allogeneic HSCT. 18. Active evidence of Hepatitis B or C infection; Hepatitis B surface antigen positive. 19. 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. 20. Patients who have received \>500cGy radiation to the kidneys will be excluded from the study.

Outcomes

Primary Outcomes

Overall Survival

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 Outcomes

Progression-free Survival

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

Time to Progression

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

Time frame: Up to 5 years

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 frame: Day 0 to Day +30 post-HCT

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.

Time frame: Day 0 to Day 100 post-HCT

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.

Time frame: Day 0 to Day +100 post-HCT

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.

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

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 frame: Up to 5 years

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.

Time frame: Day 0 to Day 100 post-HCT

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.

Time frame: Day -21 to Day +100 post-HCT

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.

Time frame: Day 0 to Year 5 post-HCT

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

Overview

Conditions

Interventions

Eligibility

Locations (2)

Outcomes

Primary Outcomes

Secondary Outcomes