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

Myelodysplastic Syndrome (MDS) Clinical Trial

Official title:

A Multi-Center, Phase II Trial of HLA-Mismatched Unrelated Donor Bone Marrow Transplantation With Post-Transplantation Cyclophosphamide for Patients With Hematologic Malignancies

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02793544
• Other study ID #: 15-MMUD
• Status: Completed
• Phase: Phase 2
• Start date: December 2016
• Est. completion date: March 2020

Study information

• Verified date: November 2020
• Source: Center for International Blood and Marrow Transplant Research
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 80
• Est. completion date: March 2020
• Est. primary completion date: March 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 15 Years to 70 Years

Eligibility

Inclusion Criteria:

1. Age = 15 years and < 71 years at the time of signing the informed consent form

2. Partially HLA-mismatched unrelated donor: HLA typing will be performed at high resolution (allele level) for the HLA-A, -B, -C, and -DRB1 loci; a minimum match of 4/8 at HLA-A, -B, -C, and -DRB1 is required

3. Product planned for infusion is bone marrow

4. Disease and disease status:

1. Acute Leukemias or T lymphoblastic lymphoma in 1st or subsequent complete remission (CR): Acute lymphoblastic leukemia (ALL)/T lymphoblastic lymphoma; acute myelogenous leukemia (AML); acute biphenotypic leukemia (ABL); acute undifferentiated leukemia (AUL)

2. Myelodysplastic Syndrome (MDS), fulfilling the following criteria: Subjects with de novo MDS who have or have previously had Intermediate-2 or High risk disease as determined by the International Prognostic Scoring System (IPSS). Current Intermediate-2 or High risk disease is not a requirement; Subjects must have < 20% bone marrow blasts, assessed within 60 days of informed consent; Subjects may have received prior therapy for the treatment of MDS prior to enrollment

3. Chronic Lymphocytic Leukemia (CLL) in CR if RIC is to be used; in CR or partial response (PR) if FIC is to be used

4. Chronic myeloid leukemia (CML) in 1st or subsequent chronic phase characterized by <10% blasts in the blood or bone marrow.

5. Chemotherapy-sensitive lymphoma in status other than 1st CR

5. Performance status: Karnofsky or Lansky score = 60% (Appendix A)

6. Adequate organ function defined as:

1. Cardiac: left ventricular ejection fraction (LVEF) at rest = 35% (RIC cohort) or LVEF at rest = 40% (FIC cohort), or left ventricular shortening fraction (LVFS) = 25%

2. Pulmonary: diffusing capacity of the lungs for carbon monoxide (DLCO), forced expiratory volume (FEV1), forced vital capacity (FVC) = 50% predicted by pulmonary function tests (PFTs)

3. Hepatic: total bilirubin = 2.5 mg/dL, and alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) < 5 x upper limit of (ULN) (unless disease related)

4. Renal: serum creatinine (SCr) within normal range for age (see table 2.3). If SCr is outside normal range for age, creatinine clearance (CrCl) > 40 mL/min/1.73m2 must be obtained (measured by 24-hour (hr) urine specimen or nuclear glomerular filtration rate (GFR), or calculated GFR (by Cockcroft-Gault formula for those aged = 18 years; by Original Schwartz estimate for those < 18 years))

7. Subjects = 18 years of age must have the ability to give informed consent according to applicable regulatory and local institutional requirements. Legal guardian permission must be obtained for subjects < 18 years of age. Pediatric subjects will be included in age appropriate discussion in order to obtain assent.

8. Subjects with documentation of confirmed HIV-1 infection (i.e. HIV-positive), and a

hematologic malignancy who meets all other eligibility requirements must:

1. Receive only RIC regimen (i.e. Regimen A)

2. Be willing to comply with effective antiretroviral therapy (ARV)

3. Have achieved a sustained virologic response for 12 weeks after cessation of hepatitis C antiviral treatment (in HIV-positive subjects with hepatitis C)

Exclusion Criteria:

1. HLA-matched related or 8/8 allele matched (HLA-A, -B, -C, -DRB1) unrelated donor available. This exclusion does not apply to HIV-positive subjects who have a CCR5delta32 homozygous donor.

2. Autologous HCT < 3 months prior to the time of signing the informed consent form

3. Females who are breast-feeding or pregnant

4. HIV-positive subjects:

1. Acquired immunodeficiency syndrome (AIDS) related syndromes or symptoms that may pose an excessive risk for transplantation-related morbidity as determined by the Treatment Review Committee (see Appendix D).

2. Untreatable HIV infection due to multidrug ARV resistance. Subjects with a detectable or standard viral load > 750 copies/mL should be evaluated with an HIV drug resistance test (HIV-1 genotype). The results should be included as part of the ARV review (described in Appendix D).

3. May not be currently prescribed ritonavir, cobacistat and/or zidovudine

5. Current uncontrolled bacterial, viral or fungal infection (currently taking medication with evidence of progression of clinical symptoms or radiologic findings)

6. Prior allogeneic HCT

7. History of primary idiopathic myelofibrosis

8. MDS subjects may not receive RIC and must be < 50 years of age at the time of signing the informed consent form

Related Conditions & MeSH terms

• Acute Biphenotypic Leukemia (ABL)
• Acute Lymphoblastic Leukemia (ALL)/T Lymphoblastic Lymphoma
• Acute Myelogenous Leukemia (AML)
• Acute Undifferentiated Leukemia (AUL)
• Chemotherapy-sensitive Lymphoma
• Chronic Lymphocytic Leukemia (CLL)
• Leukemia
• Leukemia, Biphenotypic, Acute
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Myeloid, Acute
• Lymphoma
• Myelodysplastic Syndrome (MDS)
• Myelodysplastic Syndromes
• Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Preleukemia

Intervention

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.
• 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)
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Locations

Country	Name	City	State
United States	The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Baltimore	Maryland
United States	University of Maryland Greenebaum Cancer Center	Baltimore	Maryland
United States	University of North Carolina Hospitals	Chapel Hill	North Carolina
United States	Ohio State Medical Center, James Cancer Center	Columbus	Ohio
United States	Karmanos Cancer Institute	Detroit	Michigan
United States	Shands HealthCare & University of Florida	Gainesville	Florida
United States	University of Miami	Miami	Florida
United States	Froedtert Memorial Lutheran Hospital	Milwaukee	Wisconsin
United States	Memorial Sloan Kettering Cancer Center - Adults	New York	New York
United States	Virginia Commonwealth University Massey Cancer Center Bone Marrow Transplant Program	Richmond	Virginia
United States	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida

Sponsors (2)

Lead Sponsor	Collaborator
Center for International Blood and Marrow Transplant Research	National Marrow Donor Program

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival		1 year post transplant
Secondary	Progression-free survival		180 days and 365 days post-transplant
Secondary	Transplant-related mortality		100 days, 180 days, and 365 days post-transplant
Secondary	Cumulative incidence of neutrophil recovery		1 year post transplant
Secondary	Cumulative incidence of platelet recovery		1 year post transplant
Secondary	Cumulative incidence of primary graft failure		56 days post-transplant
Secondary	Donor Chimerism	Peripheral blood chimerism (% of donor chimerism) in whole blood (unsorted)	28 days, 56 days, 100 days, 180 days, and 365 days post-transplant
Secondary	Peripheral blood chimerism	The percentage of subjects with peripheral blood (unsorted) chimerism>95%	56 days post-transplant
Secondary	Cumulative incidence of acute GVHD		100 days post-transplant
Secondary	Cumulative incidence of chronic GVHD		180 days and 365 days post-transplant
Secondary	Cumulative incidences of viral reactivations and infections		100 days, 180 days and 365 days post-transplant
Secondary	Cumulative incidence of relapse/progression		180 days and 365 days post-transplant
Secondary	Cumulative incidences of thrombotic microangiopathy (TMA) and hepatic veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS)		1 year post transplant
Secondary	Proportion of subjects proceeding to transplant		1 year post transplant
Secondary	Donor Selection Characteristics	number of mismatches at HLA-A, -B, -C, -DRB1, -DQB1, -DPB1, donor age, donor-recipient CMV serostatus match, donor weight, donor-recipient sex match and donor-recipient ABO group match	1 year post transplant
Secondary	Time from search to donor identification		1 year post transplant
Secondary	Subgroup analysis of HIV-positive subjects	If CCR5delta32 homozygous donors are successfully found and used for one or more HIV-positive subjects, a descriptive analysis of baseline characteristics and outcomes for those HIV-positive subjects will be conducted, including the viral load detected over time obtained from collected samples.	1 year post transplant
Secondary	Donor clonal hematopoiesis	The proportion of subjects developing donor clonal hematopoiesis	100 days and 365 days post-transplant