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Haploidentical Transplantation With Pre-Transplant Immunosuppressive Therapy for Patients With Sickle Cell Disease

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ClinicalTrials.gov Identifier: NCT03279094
Recruitment Status : Recruiting
First Posted : September 12, 2017
Last Update Posted : April 24, 2020
Sponsor:
Information provided by (Responsible Party):
City of Hope Medical Center

Tracking Information
First Submitted Date  ICMJE September 6, 2017
First Posted Date  ICMJE September 12, 2017
Last Update Posted Date April 24, 2020
Actual Study Start Date  ICMJE February 2, 2018
Estimated Primary Completion Date February 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 8, 2017)
Rate of unacceptable adverse events that are defined as any of the following events that occur from start of pre-transplant immunosuppressive therapy to the first 100 days post HCT: [ Time Frame: 190 days ]
  • Rate of death of any causes
  • Rate of study discontinuation or early withdrawal
  • Rate of graft failure • Primary graft failure is defined as failure to achieve a neutrophil count of 0.5 x 109/L before day +42 or mixed chimerism with failure to achieve <30% Hgb S on electrophoresis after day +180. Secondary graft failure is defined as recovery followed by a sustained loss of initial graft.
  • Rate of grade 4 non-hematological toxicities per NCI CTCAE v4.03 that last more than 21 days
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 8, 2017)
  • Time to donor neutrophil engraftment [ Time Frame: 24 months ]
    Day of Neutrophil Engraftment: The first of three consecutive days on which the ANC is ≥0.5x109/L
  • Time to donor platelets engraftment [ Time Frame: 24 months ]
    Day of Platelet engraftment: The first documented day on which the platelet count is >20x109/L unsupported by platelet transfusions for 7 days
  • Rate of graft failure [ Time Frame: 24 months ]
    Primary graft failure is defined as failure to achieve a neutrophil count of 0.5 x 109/L before day +42 or mixed chimerism with failure to achieve <30% Hgb S on electrophoresis after day +180. Secondary graft failure is defined as recovery followed by a sustained loss of initial graft.
  • Incidence of acute GvHD (grade II - IV) during the first 100 days after transplantation [ Time Frame: 100 days after transplantation ]
  • Incidence of chronic GvHD [ Time Frame: 24 months ]
  • Overall survival rate [ Time Frame: 24 months ]
    • Overall survival: the time from start of PTIS to death, or last follow-up, whichever comes first.
  • Event-free survival rate [ Time Frame: 24 months ]
    • Event-free survival: the time from start of PTIS to death, the unacceptable events, or last follow-up, whichever comes first.
  • Disease free survival rate [ Time Frame: 24 months ]
    • Disease free survival: the time from HCT to death, secondary graft failure, or last follow-up, whichever comes first.
  • Immune reconstitution at day 100, 180 and 365 [ Time Frame: 24 months ]
    • Immune reconstitution: measurement of CD3, CD4, CD8, CD11b, CD14, CD56, CD20/19, FoxP3+ Treg, and memory subsets.
  • Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v4.0 from start of pre-transplant immunosuppressive therapy to 24 months post transplant [ Time Frame: 24 months post-transplant ]
  • Percent of donor chimerism at 12 and 24 months after HCT [ Time Frame: 12 and 24 months after HCT ]
  • Change From Baseline in Pain Scores using Numerical Rating Scale or Faces Pain Rating Scale at 100 days, 6 months and 12 months post-transplant [ Time Frame: 100 days, 6 months and 12 months post-transplant ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Haploidentical Transplantation With Pre-Transplant Immunosuppressive Therapy for Patients With Sickle Cell Disease
Official Title  ICMJE A Pilot Study of Pre-transplant Immunosuppressive Therapy for Haploidentical Transplants in Patients With Sickle Cell Disease
Brief Summary

This is a study to evaluate the safety and toxicity of a treatment regimen consisting of 2 cycles of pre-transplant immunosuppressive therapy followed by myeloablative preparative regimen and allogeneic hematopoietic stem cell transplantation from a haploidentical donor in patients with sickle cell disease.

The overall goal of this study is to expand the donor pool for hematopoietic stem cell transplantation in sickle cell disease using haploidentical donors, and to develop a non-toxic, myeloablative regimen, with the goal of achieving a consistent donor chimerism utilizing pre-transplant immunosuppressive therapy.

Detailed Description

All patients will receive an haploidentical hematopoietic stem cell transplant with the following conditioning and GvHD prevention:

Pre-transplant immunosuppressive therapy:

2 cycles of Fludarabine and Dexamethasone x 5 days each cycle

Conditioning regimen:

rATG daily x 3 days, Fludarabine daily x 6 days and Busulfan daily x 4 days

GVHD prophylaxis:

Cyclophosphamide day +3 and +4, Tacrolimus and Mycophenolate mofetil

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Sickle Cell Disease
Intervention  ICMJE Biological: Hematopoietic stem cell transplantation
Haploidentical stem cell transplantation with pre-transplant immunosuppressive therapy
Study Arms  ICMJE Experimental: Haploidentical stem cell transplantation
Intervention: Biological: Hematopoietic stem cell transplantation
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: September 8, 2017)
15
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE February 2023
Estimated Primary Completion Date February 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion criteria

  • Diagnosis: Patients with sickle cell anemia (Hgb SS or SB° Thalassemia) with baseline Hgb S more than 60%.
  • Disease status:
  • Significant neurologic event (stroke) or any neurological deficit lasting > 24 hours; or increased transcranial Doppler velocity (>200 m/s).
  • History of one or more episodes of acute chest syndrome (ACS) in the 2-year period preceding enrollment despite the institution of supportive care measures (i.e. asthma therapy and/or hydroxyurea).
  • History of one or more severe vaso-occlusive pain crises per year in the 2-year period preceding enrollment despite the institution of supportive care measures (i.e. a pain management plan and/or treatment with hydroxyurea).
  • Recurrent priapism requiring medical therapy.
  • Osteonecrosis of two or more joints despite the institution of supportive care measures.
  • Prior treatment with 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, and acute chest syndrome)
  • Echocardiograph finding of tricuspid valve regurgitation jet (TRJ) velocity ≥ 2.5 m/sec.
  • Ages 1 to 30.
  • Child Bearing Potential- Transplantation could be teratogenic and/or lethal to the developing fetus. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for six months following duration of study participation. Should a woman become pregnant or suspect that she is pregnant while participating on the trial, she should inform her treating physician immediately.
  • Informed Consent/Assent: All subjects must have the ability to understand and the willingness to sign a written informed consent.
  • The recipient must have a related donor who is genotypically haploidentical on HLA-A, B, C and DRB1 loci.
  • No HLA matched sibling or 10/10 matched unrelated donor is available.

Exclusion criteria:

  • Any uncontrolled illness including ongoing or active bacterial, viral or fungal infection.
  • Patients may not be receiving any other investigational agents, or concurrent biological, chemotherapy, or radiation therapy.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to any in the pre- or post-transplant regimen.
  • Pregnant women are excluded from this study.
  • Patients with any active malignancy are ineligible for this study, other than non-melanoma skin cancers.
  • Medical problem or neurologic/psychiatric dysfunction which would impair patient ability to be compliant with the medical regimen and to tolerate transplantation or would prolong hematologic recovery which in the opinion of the principal investigator would place the recipient at unacceptable risk.
  • Prior autologous or allogeneic transplant.
  • Fully HLA-matched related or unrelated donor is available to donate.
  • Non-Compliance: Subjects, who in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 1 Year to 30 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Anna B. Pawlowska, MD 626-218-8442 apawlowska@coh.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03279094
Other Study ID Numbers  ICMJE 17136
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party City of Hope Medical Center
Study Sponsor  ICMJE City of Hope Medical Center
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Anna B. Pawlowska, MD City of Hope Medical Center
PRS Account City of Hope Medical Center
Verification Date April 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP