BMT and High Dose Post-Transplant Cyclophosphamide for Chimerism Induction and Renal Allograft Tolerance

NCT02029638 | Terminated Phase 2 Results DMC

• 2 other identifiers: DAIT ITN054STACCEPTOR
• Study Type: interventional
• Target: 4
• Locations: 1 country
• Sites: 1

Brief Summary

The primary objective of this study is to assess the ability of bone marrow transplantation (BMT) and high-dose post-transplantation cyclophosphamide (PT/Cy) to induce renal allograft tolerance and thus enable discontinuation of immunosuppressive therapy in haploidentical living related donor renal transplant recipients.

Conditions

Kidney Transplantation

Keywords

renal transplantation; conditioning regimen; BMT; high dose post-transplant cyclophosphamide (PT/Cy); renal allograft tolerance; immunosuppression withdrawal

Outcome Measures

Primary Outcomes (1)

• Percent of Participants Who Achieved Operational Tolerance

  Operational tolerance is defined as remaining off all immunosuppression 52 weeks after completion of immunosuppression withdrawal, with no evidence of biopsy-proven allograft rejection and, with acceptable renal function defined as a serum creatinine that has increased no more than 25% above baseline at the primary endpoint visit. Baseline creatinine is defined as the average of the lowest three creatinine values during 2 to 4 weeks post-transplant, excluding days on dialysis. The endpoint is summarized with a two-sided, 95% exact binomial confidence interval.

  Transplantation through 52 Weeks after Discontinuation of All Immunosuppression

Secondary Outcomes (19)

• Number of Participants Experiencing an Incidence of Graft-versus-Host Disease Post-Transplant

  Transplant to Two Years Post-Transplant

• Severity of Graft-versus-Host Disease in Transplanted Participants

  Transplant to Two Years Post-Transplant

• Duration in Days of Graft-versus-Host Disease in Transplanted Participants

  Transplant to Two Years Post-Transplant

• Number of Transplanted Participants With Engraftment Syndrome

  Transplant to End of Study (Up to 25 months After Enrollment)

• Duration in Days of Engraftment Syndrome in Transplanted Participants

  Transplant to End of Study (Up to 25 months After Enrollment)

Study Arms (1)

RICG, BMT and high dose PT/Cy+SOC

EXPERIMENTAL

Reduced-intensity conditioning regimen (RICG), bone marrow transplantation (BMT), high dose post-transplant cyclophosphamide (PT/Cy) and Standard of Care (SOC). Participants will receive: ATG (pre-transplant), pre-medicated with acetaminophen, diphenhydramine; steroid taper of methylprednisolone; fludarabine (2-6 days before transplant), and low-dose cyclophosphamide (pre- transplant); total body irradiation the day before transplant. Participants will receive a living renal transplant followed by BMT. High-dose cyclophosphamide will be given on days 3 and 4 post-transplant with MESNA. Filgrastim will be given on day 5 post-transplant and continue until absolute neutrophil recovery. Standard immunosuppression of tacrolimus, MMF, and prednisone will begin on day 5 post-transplant and be given ≥26 weeks post-transplant. Eligible participants will be gradually withdrawn from medication over a period of 24-40 weeks.

Biological: anti-thymocyte globulin; Drug: Fludarabine; Drug: Cyclophosphamide; Radiation: Total Body Irradiation; Drug: acetaminophen; Drug: diphenhydramine; Drug: methylprednisolone; Biological: bone marrow transplant; Drug: MESNA; Drug: mycophenolate mofetil; Drug: prednisone; Drug: filgrastim

Interventions

anti-thymocyte globulin BIOLOGICAL

An initial dose of 0.5 mg/kg IV will be administered over 6 hours on Day -9. Thereafter the daily dose will be increased to 2 mg/kg IV given over 4 hours on Days -8 and -7. No more than 150 mg of ATG may be administered per day.

Also known as: ATG, Thymoglobulin

RICG, BMT and high dose PT/Cy+SOC

Fludarabine DRUG

Fludarabine at dose 30 mg/m\^2 will be administered daily by intravenous infusion over 30 minutes on Day -6 to Day -2.

RICG, BMT and high dose PT/Cy+SOC

Cyclophosphamide DRUG

1. Low dose pre-transplant cyclophosphamide will be administered intravenously (IV) over 1- 2 hours, (depending on volume) on Days -6 and -5. The dose of pre-transplant cyclophosphamide is 14.5 mg/kg/day. 2. High dose cyclophosphamide \[50mg/kg (Ideal Body Weight)\] will be administered on Day 3 post-transplant (within 60 to 72 hours of marrow infusion) and on Day 4 post-transplant. Cyclophosphamide will be given IV over 1-2 hours depending on volume.

Also known as: cytoxan

RICG, BMT and high dose PT/Cy+SOC

Total Body Irradiation RADIATION

Total body irradiation, consisting of 200 centigray (cGy) Anterior-Posterior/Posterior-Anterior (AP/PA) with 4 Megavolts (MV) or 6 MV photons at 8-12 cGy/min at the point of prescription will be administered in a single day on Day -1.

Also known as: TBI

RICG, BMT and high dose PT/Cy+SOC

acetaminophen DRUG

650 mg orally prior to antithymocyte globulin infusion.

Also known as: Tylenol

RICG, BMT and high dose PT/Cy+SOC

diphenhydramine DRUG

25mg diphenhydramine orally prior to antithymocyte globulin infusion.

Also known as: benadryl

RICG, BMT and high dose PT/Cy+SOC

methylprednisolone DRUG

On Days -9 to -7 methylprednisolone 1mg/kg IV 1 hour prior ATG. This dose may be repeated once 3 hours after the first dose of steroids. On Day -6 and -5, methylprednisolone 0.75 mg/kg/ IV as a single dose; on Days -4 and -3, methylprednisolone 0.5 mg/kg/ IV as a single dose; on Day -2 methylprednisolone 0.25 mg/kg/ IV as a single dose.

RICG, BMT and high dose PT/Cy+SOC

bone marrow transplant BIOLOGICAL

Unprocessed, unmanipulated bone marrow will be harvested from the donor and infused into the recipient on Day 0.

Also known as: bone marrow transfusion, BMT

RICG, BMT and high dose PT/Cy+SOC

MESNA DRUG

A series of MESNA doses will be administered for each dose of high dose, post-transplant cyclophosphamide. The total daily dose of MESNA is equal to 80% of the total daily dose of cyclophosphamide.

Also known as: Mesnex

RICG, BMT and high dose PT/Cy+SOC

mycophenolate mofetil DRUG

MMF will be administered at a dose of 15 mg/kg orally three times per day based upon actual body weight, with the maximum of 3 grams a day from Day 5 to 35. The dose will then be reduced to the standard 1 g twice daily thereafter.

Also known as: MMF, CellCept

RICG, BMT and high dose PT/Cy+SOC

prednisone DRUG

Prednisone will be administered at a dose of 10 mg orally daily from Day 5 for 12 weeks. Thereafter the dose will be reduced to 5 mg orally daily.

RICG, BMT and high dose PT/Cy+SOC

filgrastim DRUG

All recipients will receive 5 microgram/kg per day of filgrastim as a single, subcutaneous injection from Day 5 post-transplant until the absolute neutrophil count is greater than 1000/µl on three consecutive measurements over at least 2 days.

Also known as: neupogen

RICG, BMT and high dose PT/Cy+SOC

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Recipient participants must meet all of the following criteria to be eligible for this study:
• Recipient of a first renal allograft from an Human Leukocyte Antigen (HLA)-haploidentical, living related donor. The donor and recipient must be HLA identical for at least one allele (using high resolution DNA based typing) at the following genetic loci: HLA-A, HLA-B, HLA-C and HLA-DRB1. Fulfillment of this criterion shall be considered sufficient evidence that the donor and recipient share one HLA haplotype.
• Age 18 to 65 years.
• Single solid organ recipients (kidney only).
• Blood Group System (ABO) compatibility with donor.
• Donor-Specific Antibody (DSA) will be assessed by the local laboratory 30 days or less prior to transplant using solid phase micro particle technology (by Luminex® phenotype panel or Luminex single antigen bead test.) The following criteria apply:
• Participants without detectable DSA will be deemed eligible if they meet other entry criteria.
• Participants with detectable DSA and a positive flow cytometric crossmatch may undergo de-sensitization per standard of care if they are cytotoxic crossmatch negative. Such participants must demonstrate a negative flow cytometric crossmatch by day -9 in order to receive the first dose of study therapy (ATG). Participants who do not demonstrate an acceptable response to de-sensitization by day -9 will be considered screen failures and will be terminated from the study.
• Participants with a positive cytotoxicity crossmatch will be excluded.
• No known history of anti-HLA antibodies. Recipients with low- level anti-HLA antibodies not considered to be clinically significant may be eligible, following consultation with the Protocol Chairs, the local HLA Laboratory Director, the NIAID Medical Monitor and the ITN Clinical Trial Physician.
• Negative T and B cell flow crossmatches with the designated donor; as assessed by local laboratories. If one or more of the crossmatches is positive, the participant will be considered a screen failure unless combined results of antibody and cross match testing implicate a non-HLA antibody as the cause of the positive flow crossmatch. In this case, the Protocol Chair must approve the participant as a screening success after consultation with the local HLA Laboratory Director.
• Normal estimated left ventricular ejection fraction and no history of ischemic heart disease requiring revascularization, unless cleared by a cardiologist.
• Forced expiratory volume (FEV1) and forced vital capacity (FVC) \> 40% of predicted at the screening visit.
• Serological evidence of prior Epstein-Barr virus (EBV) infection as documented by positive IgG and negative IgM antibodies against EBV.
• For women of childbearing potential, a negative serum or urine pregnancy test with sensitivity less than 50 Milli-International unit (mIU)/m within 72 hours before the start of study medication.

You may not qualify if:

• Recipient subjects who meet any of the following criteria will not be eligible for this study:
• Underlying renal disease with a high risk of disease recurrence in the transplanted kidney, including:
• Focal segmental glomerulosclerosis (FSGS).
• Type I or II membranoproliferative glomerulonephritis.
• Hemolytic-uremic syndrome/thrombotic thrombocytopenic purpura.
• Clinically important genital/urinary tract dysfunction.
• Body mass index (BMI) \> 40.
• Women who are breastfeeding.
• History of cancer within the last 5 years, except for nonmelanoma skin cancer, stage 1 renal cell carcinoma, stage 1 prostate cancers cured by local resection and any curatively treated carcinomas in situ.
• History of positive HIV-1 or HIV-2 serologies or nucleic acid test.
• Evidence of prior hepatitis B infection as evaluated by hepatitis B surface antigen (HBsAg), total hepatitis B core antibody (anti-HBc IgM and IgG) and Hepatitis B surface antibody (anti-HBsAb).
• Subjects demonstrating any one of the following will be excluded:
• Positive hepatitis B surface antigen (HBsAg) or
• Positive anti-HBc IgM.
• Positive anti-HBc IgG.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead
• Immune Tolerance Network (ITN): collaborator

Study Sites (1)

Johns Hopkins University

Baltimore, Maryland, 21205, United States

Location

Related Publications (1)

• Solez K, Colvin RB, Racusen LC, Haas M, Sis B, Mengel M, Halloran PF, Baldwin W, Banfi G, Collins AB, Cosio F, David DS, Drachenberg C, Einecke G, Fogo AB, Gibson IW, Glotz D, Iskandar SS, Kraus E, Lerut E, Mannon RB, Mihatsch M, Nankivell BJ, Nickeleit V, Papadimitriou JC, Randhawa P, Regele H, Renaudin K, Roberts I, Seron D, Smith RN, Valente M. Banff 07 classification of renal allograft pathology: updates and future directions. Am J Transplant. 2008 Apr;8(4):753-60. doi: 10.1111/j.1600-6143.2008.02159.x. Epub 2008 Feb 19.

  PMID: 18294345 BACKGROUND

Related Links

• National Institute of Allergy and Infectious Diseases website
• Division of Allergy, Immunology, and Transplantation (DAIT) website
• Immune Tolerance Network (ITN) website

MeSH Terms

Interventions

Antilymphocyte Serum; thymoglobulin; fludarabine; Cyclophosphamide; Whole-Body Irradiation; Acetaminophen; Diphenhydramine; Methylprednisolone; Bone Marrow Transplantation; Mesna; Mycophenolic Acid; Prednisone; Filgrastim

Intervention Hierarchy (Ancestors)

Immune Sera; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Biological Products; Complex Mixtures; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Radiotherapy; Therapeutics; Investigative Techniques; Acetanilides; Anilides; Amides; Aniline Compounds; Amines; Ethylamines; Benzhydryl Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Prednisolone; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Tissue Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Transplantation; Surgical Procedures, Operative; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Sulfhydryl Compounds; Sulfur Compounds; Sulfonic Acids; Sulfur Acids; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids; Pregnadienediols; Granulocyte Colony-Stimulating Factor; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Biological Factors

Limitations and Caveats

Due to slow accrual and a current assessment of risks related to the study, the study was closed to enrollment in December 2016. Participants actively screening did not move forward in the study and those on trial completed safety follow-up.

Results Point of Contact

• Title: Director, Clinical Research Operations Program
• Organization: DAIT/NIAID

DAITClinicalTrialsGov@niaid.nih.gov

301-594-7669

Study Officials

• Lode Swinnen, MD

  Johns Hopkins University

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 30, 2013
• First Posted: January 8, 2014
• Study Start: January 7, 2014
• Primary Completion: September 6, 2017
• Study Completion: September 6, 2017
• Last Updated: September 24, 2018
• Results First Posted: September 19, 2018

Record last verified: 2018-09

Locations

US (1)