Calcineurin Inhibitor-Free GVHD Prevention Regimen After Related Haplo PBSCT

Phase 1

Completed

• Conditions: Non-Hodgkin's Lymphoma; Acute Leukemia in Remission; Hodgkin Lymphoma; Chronic Myeloid Leukemia; Chronic Myelomonocytic Leukemia; Multiple Myeloma; Primary Myelofibrosis; Myelodysplastic Syndromes
• Interventions: Drug: Fludarabine; Drug: Busulfan; Drug: Cyclophosphamide; Radiation: Total body irradiation (TBI); Procedure: Peripheral Blood Hematopoietic Cell Transplantation (HCT); Drug: Sirolimus (SIR); Drug: Mycophenolate mofetil (MMF); Drug: Granulocyte-colony stimulating factor (G-CSF)

• Registration Number: NCT03018223
• Lead Sponsor: H. Lee Moffitt Cancer Center and Research Institute

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2017-01-10
• Study First Submitted QC: 2017-01-10
• Study First Posted: 2017-01-11
• Study Start: 2017-01-31
• Primary Completion: 2018-12-15
• Results First Submitted: 2019-12-06
• Results First Submitted QC: 2020-01-10
• Results First Posted: 2020-01-21
• Study Completion: 2021-03-18
• Status Verified: 2021-09
• Last Update Submitted: 2021-09-14
• Last Update Posted: 2021-09-16

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 32

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.

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Conditioning/HCT/GVHD Prophylaxis	Busulfan	Pre-HCT Conditioning, HCT, GVHD Prophylaxis. 1. 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. 2. Peripheral blood hematopoietic cell transplantation 3. Graft vs. Host Disease (GVHD) prevention treatment: cyclophosphamide, mycophenolate mofetil, sirolimus. 4. Growth factor support: G-CSF
Conditioning/HCT/GVHD Prophylaxis	Total body irradiation (TBI)	Pre-HCT Conditioning, HCT, GVHD Prophylaxis. 1. 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. 2. Peripheral blood hematopoietic cell transplantation 3. Graft vs. Host Disease (GVHD) prevention treatment: cyclophosphamide, mycophenolate mofetil, sirolimus. 4. Growth factor support: G-CSF
Conditioning/HCT/GVHD Prophylaxis	Peripheral Blood Hematopoietic Cell Transplantation (HCT)	Pre-HCT Conditioning, HCT, GVHD Prophylaxis. 1. 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. 2. Peripheral blood hematopoietic cell transplantation 3. Graft vs. Host Disease (GVHD) prevention treatment: cyclophosphamide, mycophenolate mofetil, sirolimus. 4. Growth factor support: G-CSF
Conditioning/HCT/GVHD Prophylaxis	Sirolimus (SIR)	Pre-HCT Conditioning, HCT, GVHD Prophylaxis. 1. 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. 2. Peripheral blood hematopoietic cell transplantation 3. Graft vs. Host Disease (GVHD) prevention treatment: cyclophosphamide, mycophenolate mofetil, sirolimus. 4. Growth factor support: G-CSF
Conditioning/HCT/GVHD Prophylaxis	Mycophenolate mofetil (MMF)	Pre-HCT Conditioning, HCT, GVHD Prophylaxis. 1. 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. 2. Peripheral blood hematopoietic cell transplantation 3. Graft vs. Host Disease (GVHD) prevention treatment: cyclophosphamide, mycophenolate mofetil, sirolimus. 4. Growth factor support: G-CSF
Conditioning/HCT/GVHD Prophylaxis	Granulocyte-colony stimulating factor (G-CSF)	Pre-HCT Conditioning, HCT, GVHD Prophylaxis. 1. 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. 2. Peripheral blood hematopoietic cell transplantation 3. Graft vs. Host Disease (GVHD) prevention treatment: cyclophosphamide, mycophenolate mofetil, sirolimus. 4. Growth factor support: G-CSF
Conditioning/HCT/GVHD Prophylaxis	Fludarabine	Pre-HCT Conditioning, HCT, GVHD Prophylaxis. 1. 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. 2. Peripheral blood hematopoietic cell transplantation 3. Graft vs. Host Disease (GVHD) prevention treatment: cyclophosphamide, mycophenolate mofetil, sirolimus. 4. Growth factor support: G-CSF
Conditioning/HCT/GVHD Prophylaxis	Cyclophosphamide	Pre-HCT Conditioning, HCT, GVHD Prophylaxis. 1. 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. 2. Peripheral blood hematopoietic cell transplantation 3. Graft vs. Host Disease (GVHD) prevention treatment: cyclophosphamide, mycophenolate mofetil, sirolimus. 4. Growth factor support: G-CSF

Primary Outcome Measures

Name	Time	Method
Incidence of Grade II-IV Acute Graft vs. Host Disease (GVHD)	100 days post hematopoietic cell transplant (HCT)	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

Name	Time	Method
Overall Survival (OS)	Up to 1 year post HCT	Overall survival is defined as time from transplant to death or last follow-up, and is reported as percentage of surviving participants.
Incidence of Chronic GVHD	1 year post HCT	Cumulative incidence of chronic GVHD by 1 year. Chronic GVHD diagnosis follow National Institutes of Health (NIH) Consensus guidelines.
Progression Free Survival (PFS)	Up to 1 year post HCT	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.

Trial Locations

Locations (1)

H. Lee Moffitt Cancer Center and Research Institute; 🇺🇸 Tampa, Florida, United States