Nonmyeloablative Conditioning for Mismatched Hematopoietic Stem Cell Transplantation for Severe Sickle Cell Disease

NCT02678143 | Terminated Phase 1 DMC FDA Drug FDA Device

• 1 other identifier: 201602019
• Study Type: interventional
• Target: 1
• Locations: 1 country
• Sites: 1

Brief Summary

The aim of this study is to evaluate the overall safety and feasibility of using haploidentical or one antigen mismatch unrelated hematopoietic stem cell transplant (HSCT) for adult patients with severe sickle cell disease (SCD) who undergo a non-myeloablative preparative regimen consisting of total body irradiation (TBI), cyclophosphamide and alemtuzumab (and fludarabine for haplo-SCT only) and graft vs. host disease (GvHD) prophylaxis consisting of post-transplant cyclophosphamide (PT-Cy), mycophenolate mofetil (MMF), and sirolimus. The investigators anticipate that this approach will expand the donor pool and offer a safe and less toxic curative intervention.

Conditions

Sickle Cell Disease

Outcome Measures

Primary Outcomes (1)

• Safety and tolerability of treatment regimen as measured by grade 3, 4, and 5 toxicities

  -The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting.

  From time of consent through Day 180 (estimated to be 6 months)

Secondary Outcomes (10)

• Feasibility of treatment regimen as measured by accrual

  Completion of study accrual (up to 10 years)

• Feasibility of treatment regimen as measured by patient compliance to treatment and follow-up

  Up to 2 years

• Rate of engraftment

  Day 100

• Incidence of acute graft-versus-host disease

  Up to Day 140

• Incidence of transplant related mortality

  Up to 2 years

Study Arms (1)

Recipients

EXPERIMENTAL

* The recipient of one antigen mismatch unrelated HSCT will begin the preparative regimen on Day -7. Alemtuzumab on Days -7, -6, -5, -4, and -3, cyclophosphamide on Days -4 and -3, and 300 cGy of total body irradiation (TBI) on Day -2. * The recipient of haplo-SCT will begin the preparative regimen on Day -7. Alemtuzumab on Days -7, -6, -5, -4, and -3, fludarabine on Days -7, -6, -5, -4, and -3, cyclophosphamide on Days -4 and -3, and 400 cGy of TBI on Day -2. * For both types of HSCT, the frozen peripheral blood stem cells will be thawed and infused on Day 0 per institutional guidelines. GVHD prophylaxis will consist of cyclophosphamide on Days +3 and + 4, mycophenolate mofetil (MMF) three times a day on Days +5 through +35 then tapered off over 1 week provided there is no evidence of GVHD, and sirolimus starting on Day +5 and continuing for one year. Sirolimus can be tapered at one year only if donor T-cell chimerism reaches more than 50% in the absence of GVHD.

Drug: Alemtuzumab; Drug: Cyclophosphamide; Drug: Mycophenolate mofetil; Drug: Sirolimus; Drug: Fludarabine; Radiation: Total body irradiation; Procedure: Hematopoietic stem cell transplant

Interventions

Alemtuzumab DRUG

Also known as: Campath

Recipients

Cyclophosphamide DRUG

Also known as: Revimmune, Clafen, Cytoxan, Neosar

Recipients

Mycophenolate mofetil DRUG

Also known as: CellCept

Recipients

Sirolimus DRUG

Also known as: Rapamune

Recipients

Fludarabine DRUG

Also known as: Oforta, Fludara

Recipients

Total body irradiation RADIATION

Also known as: TBI

Recipients

Hematopoietic stem cell transplant PROCEDURE

Recipients

Eligibility Criteria

• Age: 19 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age greater than or equal to 19 years.
• Diagnosis of sickle cell disease (HB SS, SC, or SBeta-thal(0)); confirmed by hemoglobin electrophoresis, high-performance liquid chromatography, DNA testing when necessary or both.
• At high risk for disease-related morbidity or mortality, defined by having at least one of the following manifestations (A-E):
• A: Clinically significant neurologic event (stroke) or any neurological deficit lasting \> 24 hours.
• B: History of two or more episodes of acute chest syndrome (ACS) in the 2-year period preceding enrollment despite the institution of supportive care measures including hydroxyurea.
• C: Three or more pain crises per year in the 2-year period preceding referral (required intravenous pain management in the outpatient or inpatient hospital setting) despite the institution of supportive care measures including hydroxyurea.
• D: Administration of regular RBC transfusion therapy, defined as receiving 8 or more transfusions per year for ≥ 1 year to prevent vaso-occlusive clinical complications (i.e. pain, stroke, acute chest syndrome, and priapism).
• E: Pulmonary hypertension (defined as tricuspid regurgitant jet velocity (TRV) ≥2.5 m/s at baseline (without vaso-occlusive crisis)
• Any one of the below complications not ameliorated by hydroxyurea at the maximum tolerated dose for at least 6 months:
• Vaso-occlusive crises with more than 1 hospital admission per year while on maximal tolerated dose of hydroxyurea
• Acute chest syndrome occurring while on hydrox\*Eyurea
• Age greater than or equal to 19 years.
• Availability of one antigen mismatched unrelated or haploidentical related donor
• Cerebral MRI/MRA within 30 days prior to initiation of transplant conditioning. If there is clinical or radiologic evidence of a recent neurologic event (such as stroke or transient ischemic attack) subjects will be deferred for at least 6 months with repeat cerebral MRI/MRA to ensure stabilization of the neurologic event prior to proceeding to transplantation.
• Ability to comprehend and willing to sign an informed consent

You may not qualify if:

• Detectable antibody to ABO, Rh, or other red blood cell antigen of their donors
• Presence of donor specific antibodies detected by donor specific antibody screen (if using product from a haploidentical donor).
• Karnofsky/Lansky performance score \< 60
• Evidence of uncontrolled bacterial, viral, or fungal infections (currently taking medication and progression of clinical symptoms) within one month prior to starting the conditioning regimen. Patients with fever or suspected minor infection should await resolution of symptoms before starting the conditioning regimen.
• Poor cardiac function defined as left ventricular ejection fraction \< 40%.
• Poor pulmonary function defined as FEV1 and FVC \< 40% predicted or diffusing capacity of the lung for carbon monoxide (DLCO) \< 40% (corrected for hemoglobin)
• Poor liver function defined as direct bilirubin \> 2x upper limit of normal for age and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \> 5 times upper limit of normal.
• Poor kidney function defined by creatinine clearance \< 70mL/min.
• HIV-positive.
• Unwillingness to use approved contraception method from time of biologic assignment until discontinuation of all immunosuppressive medications.
• Demonstrated lack of compliance with prior medical care (determined by referring physician).
• Pregnant or breastfeeding.
• Diagnosis of any debilitating medical or psychiatric illness that would preclude giving informed consent or receiving optimal treatment and follow-up.
• Donor Selection:
• Must be one antigen mismatched unrelated donor or first-degree relative who shares at least one HLA haplotype with the recipient.

Sponsors & Collaborators

• Washington University School of Medicine: lead

Study Sites (1)

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Related Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

MeSH Terms

Conditions

Anemia, Sickle Cell

Interventions

Alemtuzumab; Cyclophosphamide; Mycophenolic Acid; Sirolimus; fludarabine; fludarabine phosphate; Whole-Body Irradiation; Stem Cell Transplantation

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids; Macrolides; Lactones; Radiotherapy; Therapeutics; Investigative Techniques; Cell Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Transplantation; Surgical Procedures, Operative

Study Officials

• Mark A Schroeder, M.D.

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

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

Study Record Dates

• First Submitted: February 4, 2016
• First Posted: February 9, 2016
• Study Start: April 26, 2016
• Primary Completion: April 3, 2020
• Study Completion: November 16, 2021
• Last Updated: February 14, 2022

Record last verified: 2022-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)