HLA-Mismatched Unrelated Donor Bone Marrow Transplantation With Post-Transplantation Cyclophosphamide

Summary

This is a multi-center, single arm Phase II study of hematopoietic cell transplantation (HCT) using human leukocyte antigen (HLA)-mismatched unrelated bone marrow transplantation donors and post-transplantation cyclophosphamide (PTCy), sirolimus and mycophenolate mofetil (MMF) for graft versus host disease (GVHD) prophylaxis in patients with hematologic malignancies.

Conditions

• Myelodysplastic Syndrome (MDS)
• Chronic Lymphocytic Leukemia (CLL)
• Chemotherapy-sensitive Lymphoma
• Acute Lymphoblastic Leukemia (ALL)/T Lymphoblastic Lymphoma
• Acute Myelogenous Leukemia (AML)
• Acute Biphenotypic Leukemia (ABL)
• Acute Undifferentiated Leukemia (AUL)

Interventions

DRUG

Fludarabine

* Fludarabine 30 mg/m2/day (adjusted for renal function) is administered over a 30-60 minute IV infusion on Days -6 through -2 (maximum cumulative dose, 150 mg/m2). * The body surface area (BSA) for fludarabine dosing is based on adjusted ideal body weight (IBW) (Appendix K). * creatinine clearance may change during the days fludarabine is given. Adjustment in fludarabine dose due to creatinine changes during conditioning is permitted.

DRUG

Cyclophosphamide 14.5 mg/kg/day IV on Days -6, -5

* Cy 14.5 mg/kg/day is administered as a 1-2 hour IV infusion on Days -6 and -5 after hydration. * Use of Mesna and dosing will be done according to institutional standards. A recommended approach is as follows: Mesna IV dose of ≥ 80% of the total daily dose of Cy and given in divided doses 30 minutes before and at 3, 6, and 8-9 hours after completion of Cy. * Hydration prior to Cy may be given according to institutional guideline. * Cy and mesna are dosed according to adjusted IBW (Appendix K), unless the subject weighs less than IBW, in which case these drugs will be dosed according to actual weight.

RADIATION

Total Body Irradiation (TBI) 200cGy on Day -1

* 200 cGy TBI is administered in a single fraction on Day -1. * Radiation sources, dose rates, and shielding follow institutional practice.

PROCEDURE

Infusion of non-T-cell depleted bone marrow on Day 0

* On Day 0, the harvested bone marrow is infused. * Donor bone marrow will be harvested with a target yield of 4 x 108 nucleated cells/kg recipient weight. * The lowest acceptable nucleated cells yield is 1.5 x 108 cells/kg recipient weight.

DRUG

Busulfan

* Busulfan ≥ 9mg/kg total dose (IV or PO) on Days -6, -5, -4, -3 (PK monitoring required to achieve a daily area under the curve (AUC) target of 4800-5300 μM\*min (Perkins et al., 2012)) * Busulfan dosing is based on adjusted IBW (Appendix K)

DRUG

Cyclophosphamide 50mg/kg/day IV on Days -2,-1

* Cy 50mg/kg/day is administered as a 1-2 hour IV infusion on Days -2 and -1 after hydration. * Use of Mesna and dosing will be done according to institutional standards. A recommended approach is as follows: Mesna IV dose of ≥ 80% of the total daily dose of Cy and given in divided doses 30 minutes before and at 3, 6, and 8-9 hours after completion of Cy. * Hydration prior to Cy may be given according to institutional guideline. * Cy and mesna are dosed according to adjusted IBW (Appendix K), unless the subject weighs less than IBW, in which case these drugs will be dosed according to actual weight.

DRUG

Cyclophosphamide 50mg/kg/day IV on Days -5,-4

* Cy 50mg/kg/day is administered as a 1-2 hour IV infusion on Days -5 and -4 after hydration. * Use of Mesna and dosing will be done according to institutional standards. A recommended approach is as follows: Mesna IV dose of ≥ 80% of the total daily dose of Cy and given in divided doses 30 minutes before and at 3, 6, and 8-9 hours after completion of Cy. * Hydration prior to Cy may be given according to institutional guideline. * Cy and mesna are dosed according to adjusted IBW (Appendix K), unless the subject weighs less than IBW, in which case these drugs will be dosed according to actual weight.

RADIATION

Total Body Irradiation (TBI) 200cGy twice a day on Days -3, -2, -1

* 200cGy TBI is administered in twice daily on Days -3, -2, and -1. * Radiation sources, dose rates, and shielding follow institutional practice.

DRUG

Post-HCT Cyclophosphamide 50mg/kg IV on Day+3, +4

* Cy 50mg/kg IV, over 1-2 hours (depending on volume), is given on Day+3 (ideally between 60 and 72 hours after bone marrow infusion) and on Day+4 (approximately 24 hours after Day+3 Cy). * Hydration with Cy, management of volume status, and monitoring for hemorrhagic cystitis will follow institutional standards. * Mesna is required. Mesna IV dose must be ≥ 80% of the total daily dose of Cy and given in divided doses 30 minutes before and at 3, 6, and 8-9 hours after completion of Cy. * Cy is dosed according to IBW, unless the subject weighs less than IBW, in which case these drugs will be dosed according to actual body weight.

DRUG

Sirolimus

* Sirolimus dosing is based on adjusted IBW (Appendix K). * Sirolimus prophylaxis is discontinued after the last dose on Day+180, or may be continued if there is GVHD. For subjects ≥ 18 years old: * A one-time sirolimus loading dose, 6 mg PO, is given on Day+5, at least 24 hours after Cy completion. * Sirolimus is then continued at a maintenance dose (starting dose 2 mg PO QD), with dose adjustments to maintain a trough of 5 - 15 ng/mL as measured by high performance liquid chromatography (HPLC) or immunoassay. For subjects \< 18 years old: * A one-time sirolimus loading dose, 3 mg/m2 PO with the dose not to exceed 6 mg, is given on Day+5, at least 24 hours after Cy completion. * Sirolimus is then continued at a maintenance dose (starting dose 1 mg/m2 PO QD, maximum 2 mg PO QD), with dose adjustments to maintain a trough of 5 - 15 ng/mL as measured by HPLC or immunoassay.

DRUG

Mycophenolate mofetil

MMF begins on Day+5, at least 24 hours after completion of PTCy. MMF dose is 15 mg/kg PO TID (adjusted IBW (Appendix K)) with total daily dose not to exceed 3 grams (i.e. maximum 1 g PO TID). An equivalent IV dose (1:1 conversion) may instead be given. MMF prophylaxis is discontinued after the last dose on Day+35, or may be continued if there is GVHD.

DRUG

G-CSF

Granulocyte-colony stimulating factor (G-CSF): filgrastim or a biosimilar begins on Day+5 at a dose of 5 mcg/kg/day (actual body weight) IV or subcutaneously (SC) (rounding to the nearest vial dose is allowed), until the absolute neutrophil count (ANC) is ≥ 1,000/mm3 over the course of 3 consecutive days. Additional G-CSF may be administered as warranted.

DRUG

Pre-HCT Mesna on Days -6 and -5

Use of Mesna and dosing will be done according to institutional standards. A recommended approach is as follows: Mesna IV dose of ≥ 80% of the total daily dose of Cy and given in divided doses 30 minutes before and at 3, 6, and 8-9 hours after completion of Cy. Mesna is dosed according to adjusted IBW (Appendix K), unless the subject weighs less than IBW, in which case Mesna will be dosed according to actual weight.

DRUG

Pre-HCT Mesna on Days -2 and -1

Use of Mesna and dosing will be done according to institutional standards. A recommended approach is as follows: Mesna IV dose of ≥ 80% of the total daily dose of Cy and given in divided doses 30 minutes before and at 3, 6, and 8-9 hours after completion of Cy. Mesna is dosed according to adjusted IBW (Appendix K), unless the subject weighs less than IBW, in which case Mesna will be dosed according to actual weight.

DRUG

Pre-HCT Mesna on Days -5 and -4

Use of Mesna and dosing will be done according to institutional standards. A recommended approach is as follows: Mesna IV dose of ≥ 80% of the total daily dose of Cy and given in divided doses 30 minutes before and at 3, 6, and 8-9 hours after completion of Cy. Mesna is dosed according to adjusted IBW (Appendix K), unless the subject weighs less than IBW, in which case Mesna will be dosed according to actual weight.

DRUG

Post-HCT Mesna

Mesna is required. Mesna IV dose must be ≥ 80% of the total daily dose of Cy and given in divided doses 30 minutes before and at 3, 6, and 8-9 hours after completion of Cy on Day+3 and Day+4. Mesna is dosed according to IBW, unless the subject weighs less than IBW, in which case Mesna will be dosed according to actual body weight.

Sponsors & Collaborators

• National Marrow Donor Program

  collaborator OTHER

• Center for International Blood and Marrow Transplant Research

  lead NETWORK

Principal Investigators

• Javier Bolaños Meade, MD · Sidney Kimmel Comprehensive Cancer Centre at Johns Hopkins

• Bronwen E. Shaw, MD, PhD · CIBMTR/Medical College of Wisconsin

Study Design

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Min Age

15 Years

Max Age

70 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2016-12-31

Primary Completion

2020-03-31

Completion

2020-03-31

Countries

• United States

Study Locations