Calcineurin Inhibitor-Free GVHD Prevention Regimen After Related Haplo PBSCT

NCT03018223 | Completed Phase 1 Results FDA Drug

• 1 other identifier: MCC-18766
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 1

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

Keywords

Acute leukemia in CR; Chronic myeloid leukemia; Non-Hodgkin lymphoma in high risk; Graft vs. Host Disease; GVHD; Hematopoietic cell transplant (HCT)

Outcome Measures

Primary Outcomes (1)

• 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.

  100 days post hematopoietic cell transplant (HCT)

Secondary Outcomes (3)

• Incidence of Chronic GVHD

  1 year post HCT

• Overall Survival (OS)

  Up to 1 year post HCT

• Progression Free Survival (PFS)

  Up to 1 year post HCT

Study Arms (1)

Conditioning/HCT/GVHD Prophylaxis

EXPERIMENTAL

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

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)

Interventions

Fludarabine 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.

Also known as: Fludara, Oforta

Conditioning/HCT/GVHD Prophylaxis

Busulfan 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).

Also known as: Busulfex, Myleran

Conditioning/HCT/GVHD Prophylaxis

Cyclophosphamide 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.

Also known as: Cytoxan

Conditioning/HCT/GVHD Prophylaxis

Total body irradiation (TBI) RADIATION

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

Also known as: radiotherapy

Conditioning/HCT/GVHD Prophylaxis

Peripheral Blood Hematopoietic Cell Transplantation (HCT) PROCEDURE

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

Also known as: cell graft

Conditioning/HCT/GVHD Prophylaxis

Sirolimus (SIR) 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.

Also known as: Rapamune

Conditioning/HCT/GVHD Prophylaxis

Mycophenolate mofetil (MMF) 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.

Also known as: CellCept

Conditioning/HCT/GVHD Prophylaxis

Granulocyte-colony stimulating factor (G-CSF) 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.

Also known as: Neupogen, Filgrastim

Conditioning/HCT/GVHD Prophylaxis

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• H. Lee Moffitt Cancer Center and Research Institute: lead

Study Sites (1)

H. Lee Moffitt Cancer Center and Research Institute

Tampa, Florida, 33612, United States

Location

Related Publications (1)

• 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.

  PMID: 33635333 DERIVED

Related Links

• Moffitt Cancer Center Clinical Trials website

MeSH Terms

Conditions

Lymphoma, Non-Hodgkin; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Primary Myelofibrosis; Leukemia, Myelomonocytic, Chronic; Myelodysplastic Syndromes; Hodgkin Disease; Multiple Myeloma; Graft vs Host Disease

Interventions

fludarabine; fludarabine phosphate; Busulfan; Cyclophosphamide; Whole-Body Irradiation; Radiotherapy; Sirolimus; Mycophenolic Acid; Granulocyte Colony-Stimulating Factor; Filgrastim

Condition Hierarchy (Ancestors)

Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, Myeloid; Leukemia; Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Myelodysplastic-Myeloproliferative Diseases; Neoplasms, Plasma Cell; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hemorrhagic Disorders

Intervention Hierarchy (Ancestors)

Butylene Glycols; Glycols; Alcohols; Organic Chemicals; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Hydrocarbons; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Therapeutics; Investigative Techniques; Macrolides; Lactones; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Results Point of Contact

• Title: Nelli Bejanyan, MD
• Organization: Moffitt Cancer Center

Nellie.Bejanyan@moffitt.org

813-745-7208

Study Officials

• Nelli Bejanyan, M.D.

  H. Lee Moffitt Cancer Center and Research Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 10, 2017
• First Posted: January 11, 2017
• Study Start: January 31, 2017
• Primary Completion: December 15, 2018
• Study Completion: March 18, 2021
• Last Updated: September 16, 2021
• Results First Posted: January 21, 2020

Record last verified: 2021-09

Locations

US (1)