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

NCT02167958 | Completed Phase 1 DMC

• 1 other identifier: 13-131
• Study Type: interventional
• Target: 28
• Locations: 1 country
• Sites: 1

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.

Conditions

Leukemia; MDS; Myelofibrosis; Lymphoma

Outcome Measures

Primary Outcomes (4)

• Acute GvHD

  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.

  Day +84

• Chronic Graft-versus-Host Disease

  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.

  1 year

• Nonrelapse Mortality (NRM)

  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.

  1 year

• Relapse of Malignancy

  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.

  1 year

Secondary Outcomes (7)

• Neutrophil Recovery

  Up to day +84

• Primary graft failure

  Day +84

• Secondary graft failure

  Up to 1 year

• Platelet recovery

  Up to day +84

• Donor Cell Engraftment

  Day +28, Day >= +84

Study Arms (1)

Treatment

EXPERIMENTAL

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; Drug: Cyclophosphamide; Drug: Mesna; Radiation: Total Body Irradiation; Other: Hematopoietic stem cell infusion; Drug: Tacrolimus; Drug: Mycophenolate; Drug: G-CSF

Interventions

Fludarabine DRUG

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.

Also known as: Fludara

Treatment

Cyclophosphamide DRUG

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. .

Treatment

Mesna DRUG

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.

Also known as: Mesnex

Treatment

Total Body Irradiation RADIATION

200 cGy will be administered in a single fraction on Day -1 via linear accelerator.

Treatment

Hematopoietic stem cell infusion OTHER

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.

Also known as: PBSC

Treatment

Tacrolimus DRUG

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.

Also known as: Astagraf XL, Hecoria, Prograf

Treatment

Mycophenolate DRUG

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.

Also known as: CellCept, Myfortic

Treatment

G-CSF DRUG

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.

Also known as: Granulocyte - Colony Stimulating Factor, Filgrastim, Neupogen®

Treatment

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subject
• Age\< 70.
• 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.
• 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

You may not qualify if:

• Subject
• HLA-matched donor able to donate.
• Pregnancy or breast-feeding.
• Current uncontrolled bacterial, viral or fungal infection (currently taking medication with evidence of progression of clinical symptoms or radiologic findings).
• Donor
• \) Positive anti-donor HLA antibody.

Sponsors & Collaborators

• Rafic Farah, MD: lead

Study Sites (1)

UPMC Hillman Cancer Center

Pittsburgh, Pennsylvania, 15232, United States

Location

MeSH Terms

Conditions

Leukemia; Primary Myelofibrosis; Lymphoma

Interventions

fludarabine; fludarabine phosphate; Cyclophosphamide; Mesna; Whole-Body Irradiation; Stem Cell Transplantation; Tacrolimus; Mycophenolic Acid; Granulocyte Colony-Stimulating Factor; Filgrastim

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Myeloproliferative Disorders; Bone Marrow Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Sulfhydryl Compounds; Sulfur Compounds; Sulfonic Acids; Sulfur Acids; Radiotherapy; Therapeutics; Investigative Techniques; Cell Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Transplantation; Surgical Procedures, Operative; Macrolides; Lactones; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Study Officials

• Rafic J Farah, MD

  University of Pittsburgh

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Professor of Medicine

Study Record Dates

• First Submitted: June 17, 2014
• First Posted: June 19, 2014
• Study Start: February 11, 2015
• Primary Completion: September 21, 2019
• Study Completion: September 21, 2019
• Last Updated: October 15, 2019

Record last verified: 2019-10

Locations

US (1)