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

Phase 1

Completed

• Conditions: Leukemia; MDS; Lymphoma; Myelofibrosis
• Interventions: Drug: Fludarabine; Drug: Cyclophosphamide; Drug: Mesna; Radiation: Total Body Irradiation; Other: Hematopoietic stem cell infusion; Drug: Tacrolimus; Drug: Mycophenolate; Drug: G-CSF

• Registration Number: NCT02167958
• Lead Sponsor: Rafic Farah, MD

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.

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.

Study Timeline

• Study First Submitted: 2014-06-17
• Study First Submitted QC: 2014-06-17
• Study First Posted: 2014-06-19
• Study Start: 2015-02-11
• Primary Completion: 2019-09-21
• Study Completion: 2019-09-21
• Status Verified: 2019-10
• Last Update Submitted: 2019-10-11
• Last Update Posted: 2019-10-15

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 28

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment	Total Body Irradiation	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
Treatment	Hematopoietic stem cell infusion	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
Treatment	Fludarabine	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
Treatment	Cyclophosphamide	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
Treatment	Mesna	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
Treatment	Tacrolimus	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
Treatment	Mycophenolate	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
Treatment	G-CSF	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

Primary Outcome Measures

Name	Time	Method
Chronic Graft-versus-Host Disease	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.
Acute GvHD	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.
Nonrelapse Mortality (NRM)	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.
Relapse of Malignancy	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

Name	Time	Method
Primary graft failure	Day +84	Primary graft failure \< 5% donor CD3 chimerism
Secondary graft failure	Up to 1 year	Initial recovery followed by neutropenia with \< 5% donor chimerism.
Neutrophil Recovery	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.
Platelet recovery	Up to day +84	The first day of a sustained platelet count \>20,000/mm3 with no platelet transfusions in the preceding seven days.
Donor Cell Engraftment	Day +28, Day >= +84	Donor chimerism \>= 50% on day \>= 84 after transplantation. Donor engraftment also should be tested on day +28.
Progression-free Survival	Up to 1 year	Progression-free survival is the minimum time interval to relapse/recurrence, to death or to last follow-up.
Infections	Date of onset	Infections will be reported by anatomic site, date of onset, organism and resolution, if any.

Trial Locations

Locations (1)

UPMC Hillman Cancer Center; 🇺🇸 Pittsburgh, Pennsylvania, United States