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Nonmyeloablative Hematopoietic Cell Transplantation (HCT) for Patients With Hematologic Malignancies Using Related, HLA-Haploidentical Donors: A Pilot Trial of Peripheral Blood Stem Cells (PBSC) as the Donor Source

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ClinicalTrials.gov Identifier: NCT02167958
Recruitment Status : Recruiting
First Posted : June 19, 2014
Last Update Posted : August 14, 2018
Sponsor:
Information provided by (Responsible Party):
Rafic Farah, MD, University of Pittsburgh

Brief Summary:
The purpose of this study is to determine whether stem cells collected from a donor's blood stream will be as safe and effective as using bone marrow collected from a donor's pelvic bone.

Condition or disease Intervention/treatment Phase
Leukemia MDS Myelofibrosis Lymphoma Drug: Fludarabine Drug: Cyclophosphamide Drug: Mesna Radiation: Total Body Irradiation Other: Hematopoietic stem cell infusion Drug: Tacrolimus Drug: Mycophenolate Drug: G-CSF Phase 1

Detailed Description:
This is a pilot study to assess the safety and potential efficacy of haploidentical peripheral blood stem cell transplantation using a nonmyeloablative preparative regimen and post-transplant cyclophosphamide. The overall objective of this study is to collect the efficacy and safety data to provide the basis to decide whether a larger study of clinical efficacy is warranted in this setting.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Nonmyeloablative Hematopoietic Cell Transplantation (HCT) for Patients With Hematologic Malignancies Using Related, HLA-Haploidentical Donors: A Pilot Trial of Peripheral Blood Stem Cells (PBSC) as the Donor Source
Study Start Date : November 2014
Estimated Primary Completion Date : July 2019
Estimated Study Completion Date : July 2020


Arm Intervention/treatment
Experimental: Treatment

Day -6, -5 Fludarabine 30 mg/M2 IV over 30-60 minutes Cyclophosphamide 14.5 mg/kg IV over 1-2 hours*, Mesna 14.5 mg/kg IV in 4 divided doses

Day -4 through -2 Fludarabine 30 mg/M2 IV over 30-60 minutes

Day -1 Total Body Irradiation 200 cGy, donor apheresis

Day 0 T cell replete PBSC

Days 3, 4 Cyclophosphamide 50 mg/kg IV Mesna 50 mg/kg IV in 4 divided doses

Day 5 Begin tacrolimus ,mycophenolate, and G-CSF

Drug: Fludarabine

Fludarabine 30 mg/m2/day will be administered over 30-60 minutes intravenous infusion on Days -6 through -2. Fludarabine will be dosed according to the recipient's Adjusted Ideal Body Weight (AIBW) unless AIBW is less than Ideal Body Weight (IBW).

For decreased creatinine clearance (< 61 mL/min) determined by the Cockcroft Formula:

Cockcroft-Gault CrCl = (140-age) * (Wt in kg) * (0.85 if female) / (72 * Cr)

Fludarabine dosage should be reduced per standard of care.

Other Name: Fludara

Drug: Cyclophosphamide

Pre-transplant

Cy 14.5 mg/kg/day will be administered as a 1-2 hour intravenous infusion with a high volume fluid flush on Days -6 and -5. Cy will be dosed according to the recipient's actual body weight unless the patient weighs more than 125% of IBW, in which case the drug will be dosed according to the adjusted IBW

Post-transplant

Hydration prior to cyclophosphamide may be given according to Standard Practice Guidelines.

Cyclophosphamide [50mg/kg] will be given on Day 3 post-transplant (between 60 and 72 hours after marrow infusion) and on Day 4 post-transplant (approximately 24 hours after Day 3 cyclophosphamide). Cy will be dosed according to the recipient's actual body weight unless the patient weighs more than 125% of IBW, in which case the drug will be dosed according to the adjusted IBW. Cyclophosphamide will be given as an IV infusion over 1-2 hours.

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Drug: Mesna

Pre-transplant

Mesna should be given in divided doses IV 30 min pre- and at 3, 6, and 8 hours post-cyclophosphamide. Mesna dose will be based on the cyclophosphamide dose being given. The total daily dose of mesna is equal to 100% of the total daily dose of cyclophosphamide.

Post-transplant

Mesna should be given in divided doses IV 30 min pre- and at 3, 6, and 8 hours post-cyclophosphamide. Mesna dose will be based on the cyclophosphamide dose being given. The total daily dose of mesna is equal to 100% of the total daily dose of cyclophosphamide.

Other Name: Mesnex

Radiation: Total Body Irradiation
200 cGy will be administered in a single fraction on Day -1 via linear accelerator.

Other: Hematopoietic stem cell infusion
Donors who consent to PBSC donation will receive 5 daily doses of G-CSF, 10 μg/kg/day by subcutaneous injection commencing on day -5. PBSC's will be collected in the afternoon of day -1, stored at 4C overnight, and infused as soon as possible on day 0. If the collection on day -1 contains less than 5.0 X 106 CD34+ cells per kg recipient weight, a second collection will be performed the following morning and infused on day 0. Quantitation of CD34 and CD3 cells will be performed by the Cellular Therapy Lab. For all patients, the target number of CD34 cells to be infused should be 5-6 X 106 cells per kg recipient weight. PBSC in excess of 6.0 x 106 CD34 cells/kg recipient weight may be cryopreserved.
Other Name: PBSC

Drug: Tacrolimus
Tacrolimus will be given at a dose of .03 mg/kg IV over 24 hours. Tacrolimus will be changed to a PO dosing schedule once a therapeutic level is achieved and the patient is tolerating PO. Whole bloodblood levels of tacrolimus will be measured around Day 7 and then should be checked at least weekly thereafter and the dose adjusted accordingly to maintain a level of 5-10 ng/mL. Tacrolimus will be discontinued after the last dose around Day 180, or may be continued if active GVHD is present. Cyclosporine (target concentration 200-400 ng/ml) may be substituted for tacrolimus if the patient is intolerant of tacrolimus.
Other Names:
  • Astagraf XL
  • Hecoria
  • Prograf

Drug: Mycophenolate
Either the sodium salt of mycophenolate or mycophenolate mofetil (MMF) may be used as prophylaxis of GvHD and will be dosed by actual bodyweight. Only MMF is available as IV formulation. Sodium mycophenolate will be given at a dose of 10mg/kg PO TID rounded to the nearest number of 180mg tablets. MMF will be given at a dose of 15 mg/kg PO TID. The maximum total daily dose should not exceed 2160 mg (sodium salt) or 3 grams (mofetil). Mycophenolate prophylaxis will be discontinued after the last dose on Day 35, or may be continued if active GVHD is present.
Other Names:
  • CellCept
  • Myfortic

Drug: G-CSF
G-CSF will be given beginning on Day 5 at a dose of 5 mcg/kg/day (rounding to the nearest vial dose is allowed), until the absolute neutrophil count (ANC) is > 1,000/mm3 for three consecutive days.
Other Names:
  • Granulocyte - Colony Stimulating Factor
  • Filgrastim
  • Neupogen®




Primary Outcome Measures :
  1. Acute GvHD [ Time Frame: Day +84 ]
    The cumulative incidence of grades III/IV acute GvHD at day +84 will be assessed. The first day of acute GvHD onset will be used to calculate a cumulative incidence curve by certain grade. An overall cumulative incidence curve will be computed along with a 90% CI with graft failure, relapse/progression, and death as competing risks.

  2. Chronic Graft-versus-Host Disease [ Time Frame: 1 year ]
    The cumulative incidence of chronic GvHD at one year will be assessed. An overall cumulative incidence curve will be computed along with a 90% CI with graft failure, relapse/progression, and death as competing risks.

  3. Nonrelapse Mortality (NRM) [ Time Frame: 1 year ]
    The cumulative incidence of NRM at 1 year will be assessed. An overall cumulative incidence curve will be computed along with a 90% CI with relapse/progression as competing risk.

  4. Relapse of Malignancy [ Time Frame: 1 year ]
    The cumulative incidence of relapse at 1 year will be assessed. An overall cumulative incidence curve will be computed along with a 90% CI with NRM as competing risk.


Secondary Outcome Measures :
  1. Neutrophil Recovery [ Time Frame: Up to day +84 ]
    Achievement of an ANC ≥ 500/mm3 for three consecutive measurements on different days. The first of the three days will be designated the day of neutrophil recovery.

  2. Primary graft failure [ Time Frame: Day +84 ]
    Primary graft failure < 5% donor CD3 chimerism

  3. Secondary graft failure [ Time Frame: Up to 1 year ]
    Initial recovery followed by neutropenia with < 5% donor chimerism.

  4. Platelet recovery [ Time Frame: Up to day +84 ]
    The first day of a sustained platelet count >20,000/mm3 with no platelet transfusions in the preceding seven days.

  5. Donor Cell Engraftment [ Time Frame: Day +28, Day >= +84 ]
    Donor chimerism >= 50% on day >= 84 after transplantation. Donor engraftment also should be tested on day +28.

  6. Progression-free Survival [ Time Frame: Up to 1 year ]
    Progression-free survival is the minimum time interval to relapse/recurrence, to death or to last follow-up.

  7. Infections [ Time Frame: Date of onset ]
    Infections will be reported by anatomic site, date of onset, organism and resolution, if any.



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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Subject

  1. Age< 70.
  2. Molecular based HLA typing will be performed for the HLA-A, -B, -Cw, DRB1 and -DQB1 loci to the resolution adequate to establish haplo identity. A minimum match of 5/10 is required. An unrelated donor search is not required for a patient to be eligible for this protocol if the clinical situation dictates an urgent transplant. Clinical urgency is defined as 6-8 weeks from referral or low-likelihood of finding a matched, unrelated donor.
  3. Subjects must meet one of the disease classifications listed below:

    Acute leukemias (includes T lymphoblastic lymphoma). Remission is defined as < 5% blasts with no morphological characteristics of acute leukemia (e.g., Auer Rods) in a bone marrow with > 20% cellularity, peripheral blood counts showing ANC >1000/ul, including patients in CRp.

    Acute Lymphoblastic Leukemia in high risk CR1 as defined by at least one of the following:

    Adverse cytogenetics such as t(9;22), t(1;19), t(4;11), MLL rearrangements White blood cell counts >30,000/mcL Patients over 30 years of age Time to complete remission >4 weeks Presence of extramedullary disease

    Acute Myelogeneous Leukemia in high risk CR1 as defined by at least one of the following:

    Greater than 1 cycle of induction therapy required to achieve remission Preceding myelodysplastic syndrome (MDS) Presence of Flt3 abnormalities FAB M6 or M7 leukemia or

    Adverse cytogenetics for overall survival such as:

    those associated with MDS Complex karyotype (≥ 3 abnormalities) Any of the following: inv(3) or t(3;3), t(6;9), t(6;11), + 8 [alone or with other abnormalities except for t(8;21), t(9;11), inv(16) or t(16;16)], t(11;19)(q23;p13.1)

    Acute Leukemias in 2nd or subsequent remission

    Biphenotypic/Undifferentiated Leukemias in 1st or subsequent CR.

    High-risk MDS status-post cytotoxic chemotherapy

    Myelofibrosis

    Burkitt's lymphoma: second or subsequent CR.

    Lymphoma.

    Chemotherapy-sensitive (complete or partial response; see response criteria Appendix C) large cell, Mantle Cell or Hodgkin's lymphomas that have failed at least 1 prior regimen of multi-agent chemotherapy and are ineligible for an autologous transplant or relapsed/progressed after autologous stem cell transplant.

    Marginal zone B-cell lymphoma or follicular lymphoma that has progressed after at least two prior therapies (excluding single agent Rituxan) and are ineligible for an autologous transplant or relapsed/progressed after autologous stem cell transplant..

  4. Patients with adequate physical function as measured by:

    Cardiac: left ventricular ejection fraction at rest must be ≥ 35%.

    Hepatic: bilirubin ≤ 2.5 mg/dL; and ALT, AST, and Alkaline Phosphatase < 5 x ULN.

    Renal: serum creatinine within normal range for age, or if serum creatinine outside normal range for age, then renal function(creatinine clearance or GFR) > 40 mL/min/1.73m2.

    Pulmonary: FEV1, FVC, DLCO (diffusion capacity) ≥ 40% predicted (corrected for hemoglobin); if unable to perform pulmonary function tests, then O2 saturation > 92% on room air.

    Performance status: Karnofsky/Lansky score ≥ 60%.

  5. Patients who have received a prior allogeneic HSCT and who have either rejected their grafts or who have become tolerant of their grafts with no active GVHD requiring immunosuppressive therapy.

Donor

  1. Donors must be HLA-haploidentical first-degree or second degree relatives of the patient.
  2. Age ≥ 18 years
  3. Weight ≥ 40 kg

Exclusion Criteria:

Subject

  1. HLA-matched donor able to donate.
  2. Pregnancy or breast-feeding.
  3. Current uncontrolled bacterial, viral or fungal infection (currently taking medication with evidence of progression of clinical symptoms or radiologic findings).

Donor

1) Positive anti-donor HLA antibody.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02167958


Contacts
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Contact: Rafic J Farah, MD 412-235-1020 farahr@upmc.edu

Locations
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United States, Pennsylvania
UPMC Hillman Cancer Center Recruiting
Pittsburgh, Pennsylvania, United States, 15232
Contact: Rita Johnson, RN    412-647-8571    Johnsonr1@upmc.edu   
Sub-Investigator: Annie P Im, MD         
Sub-Investigator: Alison R Sehgal, MD         
Sub-Investigator: Mounzer E Agha, MD         
Sub-Investigator: Jing-Zhou Hou, MD         
Sub-Investigator: Mounzer Agha, MD         
Sub-Investigator: Kathleen Dorritie, MD         
Sub-Investigator: Anastasios Raptis, MD         
Sponsors and Collaborators
Rafic Farah, MD
Investigators
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Principal Investigator: Rafic J Farah, MD University of Pittsburgh

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Responsible Party: Rafic Farah, MD, Assistant Professor of Medicine, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT02167958     History of Changes
Other Study ID Numbers: 13-131
First Posted: June 19, 2014    Key Record Dates
Last Update Posted: August 14, 2018
Last Verified: August 2018

Additional relevant MeSH terms:
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Primary Myelofibrosis
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Cyclophosphamide
Tacrolimus
Fludarabine phosphate
Fludarabine
Mycophenolic Acid
Sargramostim
Vidarabine
Mesna
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Calcineurin Inhibitors
Enzyme Inhibitors
Antimetabolites, Antineoplastic
Antimetabolites
Antiviral Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antibiotics, Antitubercular
Antitubercular Agents