Tandem Auto-Allo Transplant for Lymphoma

NCT ID: NCT01181271

Last Updated: 2017-03-09

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 42 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-08-31
• Study Completion Date: 2016-02-29

Brief Summary

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.

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.

Conditions

Diffuse, Large B-Cell, Lymphoma; Lymphoma, Low-Grade; T-Cell Lymphoma; Mantle-Cell Lymphoma; Hodgkin's Lymphoma; Chronic Lymphocytic Leukemia; Lymphoma, Small Lymphocytic

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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).

Group Type: EXPERIMENTAL

Busulfan (conditioning for AUTO transplant)

Intervention Type: DRUG

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

Etoposide (conditioning for AUTO transplant)

Intervention Type: DRUG

Etoposide 30 mg/kg IV bolus every day (QD) on day -4. The total daily dose of etoposide will be 30 mg/kg.

Cyclophosphamide (conditioning for AUTO transplant)

Intervention Type: DRUG

Cyclophosphamide 60 mg/kg IV bolus QD on days -3 and -2. The total daily dose of cyclophosphamide will be 60 mg/kg.

Mesna (prior to AUTO transplant)

Intervention Type: DRUG

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

autologous (auto) peripheral blood stem cell transplantation

Intervention Type: OTHER

Infusion of autologous peripheral blood stem cells on Day 0.

Neupogen

Intervention Type: DRUG

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

Fludarabine (conditioning for ALLO Transplant)

Intervention Type: DRUG

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.

Busulfan (conditioning for ALLO Transplant)

Intervention Type: DRUG

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

non-myeloablative allogeneic (allo) transplant

Intervention Type: OTHER

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

Tacrolimus

Intervention Type: DRUG

Tacrolimus (FK506) will be given orally at a dose of 0.05 mg/kg orally (PO) twice a day (BID) starting day -3.

Sirolimus

Intervention Type: DRUG

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

Methotrexate

Intervention Type: DRUG

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

Interventions

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

Intervention Type: 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.

Intervention Type: 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.

Intervention Type: 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

Intervention Type: DRUG

autologous (auto) peripheral blood stem cell transplantation

Infusion of autologous peripheral blood stem cells on Day 0.

Intervention Type: OTHER

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

Intervention Type: 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.

Intervention Type: 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

Intervention Type: DRUG

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

Intervention Type: OTHER

Tacrolimus

Tacrolimus (FK506) will be given orally at a dose of 0.05 mg/kg orally (PO) twice a day (BID) starting day -3.

Intervention Type: 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

Intervention Type: 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

Intervention Type: DRUG

Other Intervention Names

Busulfex; VP-16; Cytoxan; G-CSF; Fludara; Busulfex; FK506; Rapamycin

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Dana-Farber Cancer Institute

OTHER

Sponsor Role: collaborator

Massachusetts General Hospital

OTHER

Sponsor Role: lead

Responsible Party

Yi-Bin A. Chen, MD

MD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Yi-Bin A Chen, MD

Role: PRINCIPAL_INVESTIGATOR

Massachusetts General Hospital

Locations

Massachusetts General Hospital

Boston, Massachusetts, United States

Dana Farber Cancer Institute

Boston, Massachusetts, United States

Countries

United States

References

Chen YB, Li S, Fisher DC, Driscoll J, Del Rio C, Abramson J, Armand P, Barnes J, Brown J, Cutler C, El-Jawahri A, Ho VT, Hochberg E, McAfee S, Takvorian R, Spitzer TR, Antin JH, Soiffer R, Jacobsen E. Phase II Trial of Tandem High-Dose Chemotherapy with Autologous Stem Cell Transplantation Followed by Reduced-Intensity Allogeneic Stem Cell Transplantation for Patients with High-Risk Lymphoma. Biol Blood Marrow Transplant. 2015 Sep;21(9):1583-8. doi: 10.1016/j.bbmt.2015.05.016. Epub 2015 May 22.

Reference Type: RESULT

PMID: 26009261 (View on PubMed)

Other Identifiers

10-057

Identifier Type: -

Identifier Source: org_study_id