Tandem Auto-Allo Transplant for Lymphoma

Chronic Lymphocytic Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01181271
• Other study ID #: DFCI Protocol No.: 10-057
• Status: Active, not recruiting
• Phase: Phase 2
• First received: August 12, 2010
• Last updated: July 28, 2015
• Start date: August 2010
• Est. completion date: February 2016

Study information

• Verified date: July 2015
• Source: Massachusetts General Hospital
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 40
• Est. completion date: February 2016
• Est. primary completion date: February 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 75 Years

Eligibility

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 Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chronic Lymphocytic Leukemia
• Diffuse, Large B-Cell, Lymphoma
• Hodgkin Disease
• Hodgkin's Lymphoma
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid
• Lymphoma
• Lymphoma, Large B-Cell, Diffuse
• Lymphoma, Low-Grade
• Lymphoma, Mantle-Cell
• Lymphoma, Non-Hodgkin
• Lymphoma, Small Lymphocytic
• Lymphoma, T-Cell
• Mantle-Cell Lymphoma
• T-Cell Lymphoma

Intervention

Drug:
• Busulfan
0.8 mg/kg IV bolus 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
Etoposide 30 mg/kg IV bolus QD on day -4. The total daily dose of etoposide will be 30 mg/kg.
• Cyclophosphamide
Cyclophosphamide 60 mg/kg IV bolus QD on days -3 and -2. The total daily dose of cyclophosphamide will be 60 mg/kg.
• Mesna
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 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
• Phenytoin
Phenytoin 200 mg BID orally given on days -8, -7, -6, -5, and -4 for seizure prophylaxis.
• Ursodiol
Ursodiol 300 mg TID orally given starting on day -8 and continuing daily until discharge for hepatic veno-occlusive disease (VOD) prophylaxis.

Other:
• Infusion of autologous peripheral blood stem cells
Infusion of autologous peripheral blood stem cells on Day 0.

Drug:
• Neupogen
Neupogen 5 mcg/kg SQ daily starting on day +1 until ANC is greater than or equal to 1000 per micro liter on two separate occasions or greater than 5000 per micro liter once
• Fludarabine
Fludarabine 30 mg/m2/d will be administered as a bolus infusion over approximately 30 minutes for 4 days on days -5, -4, -3, -2.
• Busulfan
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:
• Peripheral blood stem cell transplant
Donor 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 PO BID starting day -3.
• 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
• 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

Locations

Country	Name	City	State
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
Massachusetts General Hospital	Dana-Farber Cancer Institute

Country where clinical trial is conducted

United States, 

References & Publications (1)

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 A — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Donor stem cell engraftment	Assessment of donor stem cell engraftment such that = 80% of hematopoietic elements are donor-derived as determined by chimerism assays from peripheral blood prior to day 60 after non-myeloablative allogeneic stem cell transplantation.	60 days post allogeneic transplant	No