Busulfan, Melphalan, and Thiotepa in Treating Patients Who Are Undergoing an Autologous Stem Cell Transplant for Hodgkin's or Non-Hodgkin's Lymphoma

A Phase II Study to Evaluate the Safety and Efficacy of IV Busulfan, Melphalan, and Thiotepa (BuMelTT) Followed By Autologous PBSC Infusion for Patients With Hodgkin's Disease and Non-Hodgkin's Lymphoma

RATIONALE: Chemotherapy, such as busulfan, melphalan, and thiotepa, may destroy cancerous blood-forming cells (stem cells) in the blood and bone marrow. Giving the patient their healthy stem cells will help their bone marrow make new stem cells that become red blood cells, white blood cells, and platelets.

PURPOSE: This phase II trial is studying how well busulfan, melphalan, and thiotepa work in treating patients who are undergoing an autologous stem cell transplant for Hodgkin's or non-Hodgkin's lymphoma.

Study Overview

• Status: Completed
• Conditions: Lymphoma
• Intervention / Treatment: Biological: filgrastim; Drug: busulfan; Drug: melphalan; Drug: thiotepa; Procedure: bone marrow ablation with stem cell support; Procedure: peripheral blood stem cell transplantation

Detailed Description

OBJECTIVES:

• Determine the therapeutic efficacy of a myeloablative preparative regimen comprising busulfan, melphalan, and thiotepa followed by autologous peripheral blood stem cell (PBSC) transplantation in patients with Hodgkin's or non-Hodgkin's lymphoma.
• Determine the toxic effects of this preparative regimen in these patients.

OUTLINE:

• Myeloablative preparative regimen: Patients receive busulfan IV over 3 hours on days -8 to -6, melphalan IV over 15-30 minutes on days -5 and -4, and thiotepa IV over 2 hours on days -3 and -2.
• Peripheral blood stem cell (PBSC) transplantation: Patients undergo PBSC transplantation on day 0 followed by filgrastim (G-CSF) IV over 30 minutes beginning on day 5 and continuing until blood counts recover.
• Intrathecal chemotherapy: Patients with a history of treated Central Nervous System (CNS) disease or at high-risk for CNS relapse receive methotrexate and cytarabine intrathecally (IT) for 2 doses each within 10 days prior to transplantation and 4-6 doses each beginning on day 32 post-transplantation.
• Consolidation therapy: Patients with residual bulk disease at 80-100 days post-transplantation that is > 2.5 cm by CT scan may undergo local radiotherapy to residual scar/disease provided it can be encompassed in a single radiation port and the volume of lung to be irradiated is ≤ 20%.

After completion of study treatment, patients are followed weekly for 1 month, monthly for 6 months, every 3 months for 6 months, every 6 months for 1 year, and then annually thereafter.

PROJECTED ACCRUAL: A total of 30 patients will be accrued for this study.

• Study Type: Interventional
• Enrollment (Actual): 37
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Oregon
    • Portland, Oregon, United States, 97239-3098
      • Knight Cancer Institute At Oregon Health and Science University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 70 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Diagnosis of 1 of the following:

  • Intermediate- or high-grade non-Hodgkin's lymphoma (NHL), meeting 1 of the following criteria:

    • In first complete remission (CR) AND at high-risk for relapse, as defined by all of the following criteria:

      • High age-adjusted International Prognostic Index category AND meets the following criteria at diagnosis:

        • Stage III or IV disease
        • Lactic dehydrogenase abnormal
        • Eastern Cooperative Oncology Group (ECOG) score 0-2
      • Mantle cell histology
    • Primary refractory disease
    • Beyond first CR

  • Low-grade NHL

    • Beyond second relapse

  • Hodgkin's lymphoma

    • Primary refractory disease OR beyond first CR

• Must have an adequate number of stored autologous peripheral blood stem cells (PBSCs) (i.e., 2.0 x 10^6 hematopoietic progenitor cell antigen (CD34)-positive cells/kg)

  • Patients who are not able to mobilize a sufficient number of PBSCs may use bone marrow instead
• No active CNS disease NOTE: A new classification scheme for adult non-Hodgkin's lymphoma has been adopted by PDQ. The terminology of "indolent" or "aggressive" lymphoma will replace the former terminology of "low", "intermediate", or "high" grade lymphoma. However, this protocol uses the former terminology.

PATIENT CHARACTERISTICS:

Age

• 0 to 70

Performance status

• ECOG 0-2

Life expectancy

• Not specified

Hematopoietic

• Not specified

Hepatic

• Bilirubin < 2 times upper limit of normal (ULN)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 times ULN

Renal

• Creatinine ≤ 2.0 mg/dL
• Creatinine clearance ≥ 50 mL/min

Pulmonary

• No significant pulmonary dysfunction, defined as Diffusing Capacity the Lung for Carbon monoxide (DLCO) < 60% of predicted

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception for ≥ 2 months before and during study participation
• HIV negative
• No significant active infection that would preclude PBSC transplantation

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No prior transplantation
• No other concurrent blood products during PBSC transplantation

Chemotherapy

• Not specified

Endocrine therapy

• Not specified

Radiotherapy

• More than 60 days since prior local or regional radiotherapy

Surgery

• Not specified

Other

• More than 30 days since prior investigational drugs
• No concurrent amphotericin

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: Filgrastim/Melphalan/Thiotepa; Biological/Vaccine: filgrastim 5mcg/kg intravenous piggyback (IVPB) will be administered beginning on day +5 and continued until absolute neutrophil count (ANC) > 1500 for 2 consecutive days. Drug: busulfan 3.2mg/kg/day for 3 days starting on day -8. Each dose of intravenous busulfan will be mixed in a concentration of 0.54 mg/ml of 0.9% saline and infused over 3 hours. Drug: melphalan 50mg/m2/day/iv, infused over 30 minutes on days -5 and -4. The reconstituted melphalan is diluted in 250cc normal saline to a concentration not greater than 0.4 mg/ml. Drug: thiotepa 250 mg/m2/day/iv on days -3 and -2 Procedure/Surgery: bone marrow ablation with stem cell support The transplant therapy should begin within 2 weeks of registration, but no sooner then 30 days after the last dose of chemotherapy. Procedure/Surgery: peripheral blood stem cell transplantation Performed 36-48 hours following last chemotherapy dose.

Biological: filgrastim; 5mcg/kg IVPB will be administered beginning on day +5 and continued until ANC> 1500 for 2 consecutive days.; Drug: busulfan; 3.2mg/kg/day for 3 days starting on day -8. Each dose of intravenous busulfan will be mixed in a concentration of 0.54 mg/ml of 0.9% saline and infused over 3 hours.; Drug: melphalan; 50mg/m2/day/iv, infused over 30 minutes on days -5 and -4. The reconstituted melphalan is diluted in 250cc normal saline to a concentration not greater than 0.4 mg/ml.; Drug: thiotepa; 250 mg/m2/day/iv on days -3 and -2; Procedure: bone marrow ablation with stem cell support; The transplant therapy should begin within 2 weeks of registration, but no sooner then 30 days after the last dose of chemotherapy.; Procedure: peripheral blood stem cell transplantation; Performed 36-48 hours following last chemotherapy dose.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease-Free Survival	The data presented below represents the total number of subjects (out of 36) that reached disease-free survival status during Months 3, 6, 9, 12, 18, and 24 time points.	3, 6, 9, 12, 18, and 24 months post transplantation
Therapy-Related Toxicities	The table presented below reflects how many participants (out of 36 total) presented an adverse event related to the treatment regimen within each toxicity category. To review specific adverse events, both related and unrelated to study treatment, please refer to Adverse Events Section.	Through 24 months post transplantation

Collaborators and Investigators

• Sponsor: OHSU Knight Cancer Institute
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Richard Maziarz, MD, OHSU Knight Cancer Institute

Study record dates

Study Major Dates

• Study Start: March 1, 2005
• Primary Completion (Actual): August 1, 2015
• Study Completion (Actual): December 1, 2016

Study Registration Dates

• First Submitted: October 12, 2005
• First Submitted That Met QC Criteria: October 12, 2005
• First Posted (Estimate): October 13, 2005

Study Record Updates

• Last Update Posted (Actual): September 27, 2017
• Last Update Submitted That Met QC Criteria: September 25, 2017
• Last Verified: September 1, 2017

More Information

Terms related to this study

• Keywords: stage III adult diffuse large cell lymphoma; stage III adult immunoblastic large cell lymphoma; stage III adult Burkitt lymphoma; stage IV grade 3 follicular lymphoma; stage IV adult diffuse large cell lymphoma; stage IV adult immunoblastic large cell lymphoma; stage IV adult Burkitt lymphoma; recurrent grade 3 follicular lymphoma; recurrent adult diffuse large cell lymphoma; recurrent adult immunoblastic large cell lymphoma; recurrent adult Burkitt lymphoma; stage III childhood small noncleaved cell lymphoma; stage IV childhood small noncleaved cell lymphoma; stage IV childhood large cell lymphoma; recurrent childhood small noncleaved cell lymphoma; recurrent childhood large cell lymphoma; recurrent adult Hodgkin lymphoma; recurrent/refractory childhood Hodgkin lymphoma; recurrent adult diffuse small cleaved cell lymphoma; recurrent adult diffuse mixed cell lymphoma; stage III grade 3 follicular lymphoma; stage III adult diffuse small cleaved cell lymphoma; stage III adult diffuse mixed cell lymphoma; stage IV adult diffuse small cleaved cell lymphoma; stage IV adult diffuse mixed cell lymphoma; stage III mantle cell lymphoma; stage IV mantle cell lymphoma; recurrent grade 1 follicular lymphoma; recurrent grade 2 follicular lymphoma; recurrent marginal zone lymphoma; recurrent small lymphocytic lymphoma; extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue; nodal marginal zone B-cell lymphoma; splenic marginal zone lymphoma; recurrent adult lymphoblastic lymphoma; recurrent mantle cell lymphoma; stage III cutaneous T-cell non-Hodgkin lymphoma; stage IV cutaneous T-cell non-Hodgkin lymphoma; recurrent cutaneous T-cell non-Hodgkin lymphoma; stage III adult lymphoblastic lymphoma; stage IV adult lymphoblastic lymphoma; stage III childhood large cell lymphoma; stage III childhood lymphoblastic lymphoma; stage IV childhood lymphoblastic lymphoma; stage IV childhood Hodgkin lymphoma; recurrent childhood lymphoblastic lymphoma; stage III childhood Hodgkin lymphoma; childhood grade III lymphomatoid granulomatosis; recurrent childhood anaplastic large cell lymphoma; stage III childhood anaplastic large cell lymphoma; stage IV childhood anaplastic large cell lymphoma
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Lymphoma, Non-Hodgkin; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Melphalan; Thiotepa; Busulfan
• Other Study ID Numbers: IRB00000248; P30CA069533 (U.S. NIH Grant/Contract); OHSU-HEM-04083-L; OHSU-IRB-248