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Calcineurin Inhibitor-Free GVHD Prevention Regimen After Related Haplo PBSCT

Primary Purpose

Non-Hodgkin's Lymphoma, Acute Leukemia in Remission, Chronic Myeloid Leukemia

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Fludarabine
Busulfan
Cyclophosphamide
Total body irradiation (TBI)
Peripheral Blood Hematopoietic Cell Transplantation (HCT)
Sirolimus (SIR)
Mycophenolate mofetil (MMF)
Granulocyte-colony stimulating factor (G-CSF)
Sponsored by
H. Lee Moffitt Cancer Center and Research Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Non-Hodgkin's Lymphoma focused on measuring Acute leukemia in CR, Chronic myeloid leukemia, Non-Hodgkin lymphoma in high risk, Graft vs. Host Disease, GVHD, Hematopoietic cell transplant (HCT)

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

Patient Participants:

  • Age: Must be older than 18 years, no upper age limit.
  • Karnofsky performance status: Full intensity conditioning, 80-100%; reduced intensity conditioning, 60-100%.
  • Vital organ function: a) Cardiac: Left ventricular ejection fraction must be > 45% assessed by multigated acquisition (MUGA) scan or echocardiogram. No myocardial infarction within 6 months of transplant evaluation. b) Pulmonary: forced expiratory volume at one second (FEV1), forced vital capacity (FVC), and adjusted diffusing capacity of the lungs for carbon monoxide (DLCO) must be ≥ 50% of predicted values. c) Liver: Transaminases (AST, ALT) less than 2 times upper limit of normal values. d) Kidney: Estimated creatinine clearance ≥ 50 cc/min.
  • Signed informed consent.
  • Included disease conditions and remission status: a) Acute leukemia in First Complete Remission (CR1) or second/subsequent CR. b) Chronic myeloid leukemia, primary myelofibrosis, chronic myelomonocytic leukemia. c) Int-2 or high risk myelodysplastic syndrome (MDS). d) Hodgkin lymphoma beyond CR1 with chemosensitive disease, Stable Disease (SD) may be included if no mass >3 cm. e) Non-Hodgkin lymphoma in high risk CR1 or subsequent CR (by clinical, cytogenetic or molecular criteria), primary induction failure (PIF) or relapsed with chemosensitive disease. SD may be included if no mass >3 cm. f) Multiple myeloma in CR/Very Good Partial Response (VGPR).

Donor Participants:

  • Per Moffitt Cancer Center (MCC) Blood and Marrow Transplant (BMT) program practices, an allele level matched (8/8 HLA A, B, C and DR) sibling or unrelated donor is preferred. If a matched donor is not found, mismatched unrelated or haploidentical donors may be considered.
  • If a haploidentical donor is considered, parents, children, full siblings and in selected cases, extended family, will have high resolution typing at the MCC HLA laboratory. A familiar haploidentical donor is chosen among those who share at least one HLA-A, B, C, DRB1 and DQB1 haplotype with the patient.
  • Patient will be screened for antibodies targeting mismatched HLA antigens in potential haploidentical donors (donor specific antibodies, DSA). Antibody screen and confirmatory testing using Luminex single antigen-bead test will be done.
  • Among several potential donors, will choose in order of priority: a) Matched cytomegalovirus (CMV) immunoglobulin G (IgG) serologic status between donor and recipient. b) ABO blood group system-matched donor preferred, then minor ABO mismatch, then major ABO mismatch. c) Younger donor preferred: child, then sibling, and then parent. d) For male recipient, male donor will be preferred. Avoid mother as a donor unless no other choices.

Exclusion Criteria:

Patient Participants:

  • Uncontrolled active bacterial, viral, fungal infection.
  • Prior allogeneic HCT.
  • Unwilling to comply with study requirements.
  • Active, progressive or advanced disease based on diagnosis.

Sites / Locations

  • H. Lee Moffitt Cancer Center and Research Institute

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Conditioning/HCT/GVHD Prophylaxis

Arm Description

Pre-HCT Conditioning, HCT, GVHD Prophylaxis. Conditioning regimen: To reduce heterogeneity, two commonly used myeloablative (MAC) and reduced intensity (RIC) regimens are permitted on this trial. Myeloablative conditioning: fludarabine, busulfan. Reduced intensity conditioning: fludarabine, cyclophosphamide, total body irradiation. Peripheral blood hematopoietic cell transplantation Graft vs. Host Disease (GVHD) prevention treatment: cyclophosphamide, mycophenolate mofetil, sirolimus. Growth factor support: G-CSF

Outcomes

Primary Outcome Measures

Incidence of Grade II-IV Acute Graft vs. Host Disease (GVHD)
Cumulative incidence of grade II-IV acute GVHD by day 100 after HCT. Acute GVHD organ staging and assessment of overall grade will use standard consensus criteria. The cumulative incidence of acute and chronic GVHD will be estimated, considering malignancy relapse and non-relapse death as competing risk events.

Secondary Outcome Measures

Incidence of Chronic GVHD
Cumulative incidence of chronic GVHD by 1 year. Chronic GVHD diagnosis follow National Institutes of Health (NIH) Consensus guidelines.
Overall Survival (OS)
Overall survival is defined as time from transplant to death or last follow-up, and is reported as percentage of surviving participants.
Progression Free Survival (PFS)
Progression-free survival defined by the time interval from transplant to relapse/recurrence, to death or to last follow-up. Reported as percentage of participants who are disease free one year post HCT.

Full Information

First Posted
January 10, 2017
Last Updated
September 14, 2021
Sponsor
H. Lee Moffitt Cancer Center and Research Institute
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1. Study Identification

Unique Protocol Identification Number
NCT03018223
Brief Title
Calcineurin Inhibitor-Free GVHD Prevention Regimen After Related Haplo PBSCT
Official Title
A Calcineurin Inhibitor-Free GVHD Prevention Regimen After Related Haploidentical Peripheral Blood Stem Cell Transplantation
Study Type
Interventional

2. Study Status

Record Verification Date
September 2021
Overall Recruitment Status
Completed
Study Start Date
January 31, 2017 (Actual)
Primary Completion Date
December 15, 2018 (Actual)
Study Completion Date
March 18, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
H. Lee Moffitt Cancer Center and Research Institute

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
The purpose of this study is to find out if a combination of drugs (these are called: cyclophosphamide, sirolimus, and mycophenolate mofetil) will protect participants better against graft vs. host disease (GVHD) after receiving a hematopoietic cell transplant from a related partially matched (haploidentical) donor. As part of the treatment for their blood cancer, participants need a hematopoietic cell transplantation (HCT) to improve their chances of cure. In any HCT, after the stem cell infusion is given, a combination of drugs is needed to prevent GVHD and facilitate acceptance of the graft.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Non-Hodgkin's Lymphoma, Acute Leukemia in Remission, Chronic Myeloid Leukemia, Primary Myelofibrosis, Chronic Myelomonocytic Leukemia, Myelodysplastic Syndromes, Hodgkin Lymphoma, Multiple Myeloma
Keywords
Acute leukemia in CR, Chronic myeloid leukemia, Non-Hodgkin lymphoma in high risk, Graft vs. Host Disease, GVHD, Hematopoietic cell transplant (HCT)

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
32 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Conditioning/HCT/GVHD Prophylaxis
Arm Type
Experimental
Arm Description
Pre-HCT Conditioning, HCT, GVHD Prophylaxis. Conditioning regimen: To reduce heterogeneity, two commonly used myeloablative (MAC) and reduced intensity (RIC) regimens are permitted on this trial. Myeloablative conditioning: fludarabine, busulfan. Reduced intensity conditioning: fludarabine, cyclophosphamide, total body irradiation. Peripheral blood hematopoietic cell transplantation Graft vs. Host Disease (GVHD) prevention treatment: cyclophosphamide, mycophenolate mofetil, sirolimus. Growth factor support: G-CSF
Intervention Type
Drug
Intervention Name(s)
Fludarabine
Other Intervention Name(s)
Fludara, Oforta
Intervention Description
Myeloablative conditioning: 40 mg/m^2 daily for 4 days. Dose will be adjusted for estimated creatinine clearance. Reduced intensity conditioning: 30 mg/m^2 daily on days -6, -5, -4, -3 and -2. Dose will be adjusted for estimated creatinine clearance.
Intervention Type
Drug
Intervention Name(s)
Busulfan
Other Intervention Name(s)
Busulfex, Myleran
Intervention Description
Myeloablative conditioning: IV dosing targeted for a daily total area under curve (AUC) 5300 mmol*min/L for 4 days. Busulfan AUC will be pharmacokinetically targeted. An AUC 3500 mmol*min/l may be considered in patients over 60 years of age or with multiple comorbidities. Chemotherapy may start on day -6 or day -5 depending on the day of admission (-6 for Wednesday admission, -5 for Sunday admission).
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
Cytoxan
Intervention Description
Reduced intensity conditioning: 14.5 mg/kg/day on days -6, -5. GVHD prophylaxis: 50 mg/kg ideal body weight (IBW) daily dose will be given on days +3 and +4 post-transplant as an IV infusion over 1-2 hours.
Intervention Type
Radiation
Intervention Name(s)
Total body irradiation (TBI)
Other Intervention Name(s)
radiotherapy
Intervention Description
Reduced intensity conditioning: 200 centigray (cGy) on day -1.
Intervention Type
Procedure
Intervention Name(s)
Peripheral Blood Hematopoietic Cell Transplantation (HCT)
Other Intervention Name(s)
cell graft
Intervention Description
On day 0, patients will receive a peripheral blood hematopoietic cell graft.
Intervention Type
Drug
Intervention Name(s)
Sirolimus (SIR)
Other Intervention Name(s)
Rapamune
Intervention Description
GVHD prophylaxis: SIR will be administered as a 9 mg oral loading dose on day +5, followed by maintenance. SIR levels will be monitored and maintenance dosing adjusted as needed for a target trough level 8 to 14 ng/ml, per Moffitt BMT program standard practice. In the absence of acute GVHD, sirolimus taper will start on day +90 (+/- 10 days) and it is suggested to finish by day +180.
Intervention Type
Drug
Intervention Name(s)
Mycophenolate mofetil (MMF)
Other Intervention Name(s)
CellCept
Intervention Description
GVHD prophylaxis: MMF will start on day +5 at a dose of 15 mg/kg every 8 hours IV with the maximum daily dose not to exceed 3 gm. MMF will be changed to orally (PO) and discontinued on day +35 (without taper) in the absence of acute GVHD.
Intervention Type
Drug
Intervention Name(s)
Granulocyte-colony stimulating factor (G-CSF)
Other Intervention Name(s)
Neupogen, Filgrastim
Intervention Description
Growth factor support: G-CSF will be given beginning on day 5 at a dose of 5 mcg/kg/day (rounding to the nearest vial dose), until absolute granulocyte count (ANC) is > 1,000/mm^3 for three consecutive days. G-CSF may be given IV or subcutaneously.
Primary Outcome Measure Information:
Title
Incidence of Grade II-IV Acute Graft vs. Host Disease (GVHD)
Description
Cumulative incidence of grade II-IV acute GVHD by day 100 after HCT. Acute GVHD organ staging and assessment of overall grade will use standard consensus criteria. The cumulative incidence of acute and chronic GVHD will be estimated, considering malignancy relapse and non-relapse death as competing risk events.
Time Frame
100 days post hematopoietic cell transplant (HCT)
Secondary Outcome Measure Information:
Title
Incidence of Chronic GVHD
Description
Cumulative incidence of chronic GVHD by 1 year. Chronic GVHD diagnosis follow National Institutes of Health (NIH) Consensus guidelines.
Time Frame
1 year post HCT
Title
Overall Survival (OS)
Description
Overall survival is defined as time from transplant to death or last follow-up, and is reported as percentage of surviving participants.
Time Frame
Up to 1 year post HCT
Title
Progression Free Survival (PFS)
Description
Progression-free survival defined by the time interval from transplant to relapse/recurrence, to death or to last follow-up. Reported as percentage of participants who are disease free one year post HCT.
Time Frame
Up to 1 year post HCT

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Patient Participants: Age: Must be older than 18 years, no upper age limit. Karnofsky performance status: Full intensity conditioning, 80-100%; reduced intensity conditioning, 60-100%. Vital organ function: a) Cardiac: Left ventricular ejection fraction must be > 45% assessed by multigated acquisition (MUGA) scan or echocardiogram. No myocardial infarction within 6 months of transplant evaluation. b) Pulmonary: forced expiratory volume at one second (FEV1), forced vital capacity (FVC), and adjusted diffusing capacity of the lungs for carbon monoxide (DLCO) must be ≥ 50% of predicted values. c) Liver: Transaminases (AST, ALT) less than 2 times upper limit of normal values. d) Kidney: Estimated creatinine clearance ≥ 50 cc/min. Signed informed consent. Included disease conditions and remission status: a) Acute leukemia in First Complete Remission (CR1) or second/subsequent CR. b) Chronic myeloid leukemia, primary myelofibrosis, chronic myelomonocytic leukemia. c) Int-2 or high risk myelodysplastic syndrome (MDS). d) Hodgkin lymphoma beyond CR1 with chemosensitive disease, Stable Disease (SD) may be included if no mass >3 cm. e) Non-Hodgkin lymphoma in high risk CR1 or subsequent CR (by clinical, cytogenetic or molecular criteria), primary induction failure (PIF) or relapsed with chemosensitive disease. SD may be included if no mass >3 cm. f) Multiple myeloma in CR/Very Good Partial Response (VGPR). Donor Participants: Per Moffitt Cancer Center (MCC) Blood and Marrow Transplant (BMT) program practices, an allele level matched (8/8 HLA A, B, C and DR) sibling or unrelated donor is preferred. If a matched donor is not found, mismatched unrelated or haploidentical donors may be considered. If a haploidentical donor is considered, parents, children, full siblings and in selected cases, extended family, will have high resolution typing at the MCC HLA laboratory. A familiar haploidentical donor is chosen among those who share at least one HLA-A, B, C, DRB1 and DQB1 haplotype with the patient. Patient will be screened for antibodies targeting mismatched HLA antigens in potential haploidentical donors (donor specific antibodies, DSA). Antibody screen and confirmatory testing using Luminex single antigen-bead test will be done. Among several potential donors, will choose in order of priority: a) Matched cytomegalovirus (CMV) immunoglobulin G (IgG) serologic status between donor and recipient. b) ABO blood group system-matched donor preferred, then minor ABO mismatch, then major ABO mismatch. c) Younger donor preferred: child, then sibling, and then parent. d) For male recipient, male donor will be preferred. Avoid mother as a donor unless no other choices. Exclusion Criteria: Patient Participants: Uncontrolled active bacterial, viral, fungal infection. Prior allogeneic HCT. Unwilling to comply with study requirements. Active, progressive or advanced disease based on diagnosis.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Nelli Bejanyan, M.D.
Organizational Affiliation
H. Lee Moffitt Cancer Center and Research Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
H. Lee Moffitt Cancer Center and Research Institute
City
Tampa
State/Province
Florida
ZIP/Postal Code
33612
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
33635333
Citation
Bejanyan N, Pidala JA, Wang X, Thapa R, Nishihori T, Elmariah H, Lazaryan A, Khimani F, Davila ML, Mishra A, Faramand R, Jain MD, Ochoa L, Perez LE, Liu H, Alsina M, Kharfan-Dabaja MA, Fernandez H, Nieder ML, Locke FL, Anasetti C, Ayala E. A phase 2 trial of GVHD prophylaxis with PTCy, sirolimus, and MMF after peripheral blood haploidentical transplantation. Blood Adv. 2021 Mar 9;5(5):1154-1163. doi: 10.1182/bloodadvances.2020003779.
Results Reference
derived
Links:
URL
https://moffitt.org/clinical-trials-research/
Description
Moffitt Cancer Center Clinical Trials website

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Calcineurin Inhibitor-Free GVHD Prevention Regimen After Related Haplo PBSCT

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