Calcineurin Inhibitor-Free GVHD Prevention Regimen After Related Haplo PBSCT

NCT ID: NCT03018223

Last Updated: 2021-09-16

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 32 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-01-31
• Study Completion Date: 2021-03-18

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.

Conditions

Non-Hodgkin's Lymphoma; Acute Leukemia in Remission; Chronic Myeloid Leukemia; Primary Myelofibrosis; Chronic Myelomonocytic Leukemia; Myelodysplastic Syndromes; Hodgkin Lymphoma; Multiple Myeloma

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: PREVENTION
• Blinding Strategy: NONE

Study Groups

Conditioning/HCT/GVHD Prophylaxis

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

Group Type: EXPERIMENTAL

Fludarabine

Intervention Type: DRUG

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.

Busulfan

Intervention Type: DRUG

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).

Cyclophosphamide

Intervention Type: DRUG

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.

Total body irradiation (TBI)

Intervention Type: RADIATION

Reduced intensity conditioning: 200 centigray (cGy) on day -1.

Peripheral Blood Hematopoietic Cell Transplantation (HCT)

Intervention Type: PROCEDURE

On day 0, patients will receive a peripheral blood hematopoietic cell graft.

Sirolimus (SIR)

Intervention Type: DRUG

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.

Mycophenolate mofetil (MMF)

Intervention Type: DRUG

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.

Granulocyte-colony stimulating factor (G-CSF)

Intervention Type: DRUG

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.

Interventions

Fludarabine

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

Busulfan

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

Cyclophosphamide

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: DRUG

Total body irradiation (TBI)

Reduced intensity conditioning: 200 centigray (cGy) on day -1.

Intervention Type: RADIATION

Peripheral Blood Hematopoietic Cell Transplantation (HCT)

On day 0, patients will receive a peripheral blood hematopoietic cell graft.

Intervention Type: PROCEDURE

Sirolimus (SIR)

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

Mycophenolate mofetil (MMF)

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

Granulocyte-colony stimulating factor (G-CSF)

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.

Intervention Type: DRUG

Other Intervention Names

Fludara, Oforta; Busulfex, Myleran; Cytoxan; radiotherapy; cell graft; Rapamune; CellCept; Neupogen, Filgrastim

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

H. Lee Moffitt Cancer Center and Research Institute

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Nelli Bejanyan, M.D.

Role: PRINCIPAL_INVESTIGATOR

H. Lee Moffitt Cancer Center and Research Institute

Locations

H. Lee Moffitt Cancer Center and Research Institute

Tampa, Florida, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 33635333 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

MCC-18766

Identifier Type: -

Identifier Source: org_study_id