Tandem Auto-Allo Transplant for Lymphoma

January 19, 2017 updated by: Yi-Bin A. Chen, MD, Massachusetts General Hospital

Sequential Myeloablative Autologous Stem Cell Transplantation Followed by Allogeneic Non-Myeloablative Stem Cell Transplantation for Patients With Poor Risk Lymphomas

Relapse remains a principle cause of treatment failure for patients with aggressive lymphoma after autologous transplantation. Non-myeloablative allogeneic transplantation allows patients to receive an infusion of donor cells in an attempt to induce a graft versus lymphoma effect. This study will assess the feasibility, safety and efficacy of the combination of autologous stem cell transplantation followed by non-myeloablative transplantation for patients with poor-risk aggressive lymphoma.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

This is a phase II clinical trial investigating the feasibility, and efficacy of sequential autologous stem cell transplant followed by non-myeloablative allogeneic transplant for patients with poor risk lymphoma. Patients will be enrolled onto the trial when eligible and undergo standard high-dose chemotherapy with the combination with busulfan, cyclophosphamide, and etoposide followed by autologous stem cell transplant. After recovery of counts and clinical status, patients will then proceed to non-myeloablative allogeneic stem cell transplant using a fully matched related or unrelated donor.

Study Type

Interventional

Enrollment (Actual)

42

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Massachusetts
      • Boston, Massachusetts, United States, 02114
        • Massachusetts General Hospital
      • Boston, Massachusetts, United States, 02115
        • Dana Farber Cancer Institute

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Patients with high-risk diffuse large B cell or transformed low grade lymphoma defined as:

    • Residual disease after at least 6 cycles of anthracycline-based chemotherapy (with residual disease defined as persistent bone marrow involvement and/or persistent measurable lymph node or solid organ masses that are PET or gallium avid)
    • Progressive disease after at least 2 cycles of anthracycline-based chemotherapy
    • Patients with an initial complete response but subsequent relapse within 6 months after completion of anthracycline-based chemotherapy

  • Patients with any T-cell non-Hodgkin's lymphoma as defined as:

    • Peripheral T-cell lymphoma (ALK negative PTCL-U) including PTCL-NOS, HSGD (hepato-splenic gamma-delta TCL), AITL (angioimmunoblastic T-cell lymphoma), EATL (enteropathy associated T-cell lymphoma), ALK-negative anaplastic large cell lymphoma
    • Any T-cell histology (except LGL) with residual disease after at least 4 cycles of anthracycline-based chemotherapy (with residual disease defined as persistent bone marrow involvement and/or persistent measurable lymph node or solid organ masses that are PET or gallium avid)
  • Patients with mantle cell lymphoma at any time in therapy
  • Patients with "double-hit" lymphoma as characterized by the presence of concurrent overexpression of Bcl-2 and c-myc

  • Patients with Hodgkin's lymphoma that is

    • Refractory to first-line therapy and at least one second line chemotherapy regimen
    • Relapsed Hodgkin's lymphoma which is refractory to at least one salvage chemotherapy regimen.
  • Patients with CLL/SLL with 17p- cytogenetic abnormality
  • Age 18 years and greater
  • ECOG performance status 0-2
  • Ability to understand and the willingness to sign a written informed consent document.

  • Responsive disease to last therapy as determined by at least one of the following:

    • At least PR by Revised Response Criteria
    • At least PR by traditional Cheson Criteria
    • < 10% of overall cellularity involved with disease on bone marrow biopsy for patients with involvement of the bone marrow
  • Minimum of 2 x 106 CD34+ cells / kg already collected and frozen. These stem cells may have been collected from PBSC pheresis, bone marrow harvest, or the combination.

Exclusion Criteria:

Patients will be re-evaluated after autologous transplant prior to proceeding to non-myeloablative transplant

  • Pregnancy
  • Evidence of HIV infection
  • Heart failure uncontrolled by medications or ejection fraction less than 45%
  • Active involvement of the CNS by lymphoma
  • Inability to provide informed consent
  • Previous autologous or allogeneic stem cell transplant
  • Creatinine greater than 2 gm/dL or 24 hour urine creatinine clearance < 50 cc/minute (does not have to satisfy both)
  • Total bilirubin greater than 2 times the upper limit of normal except when due to Gilbert's syndrome or hemolysis.
  • Transaminases greater than 3 times the upper limit of normal
  • FVC or DLCO of less than 50% of predicted (DLCO corrected for hemoglobin level)
  • Already known to not possess suitably HLA-matched related or unrelated donor

Eligibility to proceed to allogeneic transplant Cannot be admitted for allogeneic transplant earlier than 40 days and no later than 180 days after autologous stem cell transplant.

  • HLA identical (A, B, C and DR) related or unrelated donor available. HLA typing of class I loci (HLA- A, B, C) will be based on complement dependent cytotoxicity assay or PCR of sequence specific oligonucleotide primers (SSOP). Typing of HLA class II (DRB1) will be based on PCR of sequence specific oligonucleotide primers (SSOP).
  • No need for intravenous hydration in the previous 2 weeks
  • Resolved mucositis

  • Renal, cardiac, pulmonary, and hepatic function meet standard criteria for nonmyeloablative SCT as listed below:

    • Serum Cr < 2 gm/dL
    • LV ejection fraction > 30% and no uncontrolled symptoms of congestive heart failure
    • DLCO > 50% of predicted value (corrected for hemoglobin)
    • Transaminases < 5X the institution upper limit of normal
    • Bilirubin < 3X the institution upper limit of normal except when Gilbert's Syndrome or hemolysis is present
    • ECOG PS ≤ 2
  • No intravenous antimicrobials within 2 weeks
  • No evidence of progressive disease, defined as a 25% increase from nadir in the sum of the product of the diameters (SPD) of any lymph node previously identified as abnormal prior to autologous transplant or the appearance of any new lymph node greater than 1.5 cm in greatest diameter, new bone marrow involvement, or new solid organ nodule greater than 1 cm in diameter. This restaging study will be performed at least 28 days after the autologous transplant and within 60 days prior to admission for allogeneic transplant. Status of stable disease (SD) is acceptable to proceed to allogeneic transplant.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Autologous then Allogeneic transplant

All patients will receive conditioning with busulfan, etoposide, and cyclophosphamide (with mesna) and then will undergo autologous (auto) peripheral blood stem cell transplantation.

Patients will be re-evaluated after autologous transplant prior to proceeding to non-myeloablative allogeneic (allo) transplant. If eligible to proceed, allogenic transplantation will take place no earlier than 40 days and no later than 180 days after autologous stem cell transplantation.

Conditioning for the allogeneic transplant will consist of fludarabine and busulfan. Participants will receive tacrolimus and sirolimus as prophylaxis against graft versus host disease (GVHD).
Drug: Busulfan (conditioning for AUTO transplant)
0.8 mg/kg intravenous (IV) bolus every six hours (Q6H) on days -8,-7,-6,-5 (total of 14 doses). The total daily dose of busulfan will be 3.2 mg/kg on days -8,-7, and -6 and 1.6 mg/kg on day -5
Other Names:
  • Busulfex
Drug: Etoposide (conditioning for AUTO transplant)
Etoposide 30 mg/kg IV bolus every day (QD) on day -4. The total daily dose of etoposide will be 30 mg/kg.
Other Names:
  • VP-16
Drug: Cyclophosphamide (conditioning for AUTO transplant)
Cyclophosphamide 60 mg/kg IV bolus QD on days -3 and -2. The total daily dose of cyclophosphamide will be 60 mg/kg.
Other Names:
  • Cytoxan
Drug: Mesna (prior to AUTO transplant)
Mesna 15 mg/kg IV bolus on days -3 and -2 infused over 15 minutes and given 15 minutes prior to cyclophosphamide administration. This is followed by Mesna given 15 mg/kg IV bolus three times daily (TID) on days -3 and -2 infused over 15 minutes at 3, 6, and 9 hours after completion of cyclophosphamide infusion. Total daily dose of Mesna should be equivalent to daily dose of cyclophosphamide. Lastly, Mesna will be given at 15 mg/kg IV bolus QD on day -1. This makes a total of 9 doses of Mesna
Other: autologous (auto) peripheral blood stem cell transplantation
Infusion of autologous peripheral blood stem cells on Day 0.
Drug: Neupogen
Neupogen 5 mcg/kg subcutaneous (SQ) daily starting on day +1 until absolute neutrophil count (ANC) is greater than or equal to 1000 per micro liter on two separate occasions or greater than 5000 per micro liter once
Other Names:
  • G-CSF
Drug: Fludarabine (conditioning for ALLO Transplant)
Fludarabine 30 mg/m2/day will be administered as a bolus infusion over approximately 30 minutes for 4 days on days -5, -4, -3, -2.
Other Names:
  • Fludara
Drug: Busulfan (conditioning for ALLO Transplant)
Busulfan will be administered by IV infusion over approximately 3 hours on days -5, -4, -3, -2. The dose of busulfan will be 0.8 mg/kg/day
Other Names:
  • Busulfex
Other: non-myeloablative allogeneic (allo) transplant
Donor peripheral blood stem cells (PBSC) will be infused intravenously beginning on Day 0. The minimum total CD34+ cell dose will be 2 x 10^6 CD34+cells/kg of recipient's actual body weight with a maximum dose of 8 x 10^6/kg of recipient's actual body weight
Drug: Tacrolimus
Tacrolimus (FK506) will be given orally at a dose of 0.05 mg/kg orally (PO) twice a day (BID) starting day -3.
Other Names:
  • FK506
Drug: Sirolimus
Sirolimus (rapamycin) will be given orally at a dose of 12 mg times one on day -3 and then the dose shall be 4 mg by mouth daily starting on day -2. The dose may then be adjusted according to serum levels at the discretion of the treating physician
Other Names:
  • Rapamycin
Drug: Methotrexate
Methotrexate will be administered once daily on days 1, 3, and 6 as an IV bolus over 15 minutes at a dose of 5 mg/m2

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Peripheral Blood All-cell Donor Chimerism
Time Frame: 100 days post allogeneic transplant
Successful donor stem cell engraftment is defined as when ≥ 80% of hematopoietic elements are donor-derived as determined by chimerism assays from peripheral blood at day 100 after non-myeloablative allogeneic stem cell transplantation.
100 days post allogeneic transplant

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Days After Allogeneic Transplant Until Absolute Neutrophil Count Was Equal to or Greater Than 500/uL
Time Frame: within 28 days after allogeneic transplant
within 28 days after allogeneic transplant
Cumulative Incidence of Grades II to IV Acute Graft Versus Host Disease (GVHD)
Time Frame: within 200 days after allogeneic transplant
Grade I GVHD is characterized as mild disease, grade II GVHD as moderate, grade III as severe, and grade IV life-threatening.
within 200 days after allogeneic transplant
Cumulative Incidence of Extensive Chronic Graft-versus-host-disease
Time Frame: 1-year after allogeneic transplant
Extensive chronic graft versus-host-disease (GVHD) was defined as GVHD that required systemic immunosuppression.
1-year after allogeneic transplant
Cumulative Incidence of Non-relapse Mortality
Time Frame: 2-years after allogeneic transplant
Non-relapse mortality is defined as participants who die from causes other than their underlying disease relapse, such as infection or graft versus host disease
2-years after allogeneic transplant
Cumulative Incidence of Disease Relapse
Time Frame: 2-years after allogeneic transplant
2-years after allogeneic transplant
Estimated Two Year Progression Free Survival Rate for Participants Undergoing Both Autologous and Allogeneic Transplants
Time Frame: 2 years after allogeneic transplant
2 years after allogeneic transplant
Estimated Two Year Overall Survival Rate for Participants Undergoing Both Autologous and Allogeneic Transplants
Time Frame: Two-years after Allogeneic Transplant
Two-years after Allogeneic Transplant
Estimated Two Year Progression Free Survival Rate for All Participants
Time Frame: 2 years
2 years
Estimated Two Year Overall Survival Rate for All Participants
Time Frame: 2 years
2 years
Estimated Two Year Progression Free Survival Rate for Participants Undergoing Only Autologous Transplant
Time Frame: Two Years
Two Years
Estimated Two Year Overall Survival Rate for Participants Undergoing Only Autologous Transplant
Time Frame: two years
two years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Massachusetts General Hospital

Collaborators

Dana-Farber Cancer Institute

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

August 1, 2010

Primary Completion (Actual)

February 1, 2014

Study Completion (Actual)

February 1, 2016

Study Registration Dates

First Submitted

August 12, 2010

First Submitted That Met QC Criteria

August 12, 2010

First Posted (Estimate)

August 13, 2010

Study Record Updates

Last Update Posted (Actual)

March 9, 2017

Last Update Submitted That Met QC Criteria

January 19, 2017

Last Verified

January 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 10-057

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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