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Hematopoietic Stem Cell Transplant for Sickle Cell Disease

This study is currently recruiting participants. (see Contacts and Locations)
Verified December 2016 by Case Comprehensive Cancer Center
Sponsor:
Information provided by (Responsible Party):
Case Comprehensive Cancer Center
ClinicalTrials.gov Identifier:
NCT02065596
First received: February 14, 2014
Last updated: December 5, 2016
Last verified: December 2016
  Purpose
This is a phase I/II study of patients with sickle cell disease. It aims to find out if people with sickle cell disease can be cured by changing their immune system before they have blood stem cell transplants. Doctors will give patients a new drug (fludarabine) to see if this drug changes patients immune system and reduces the patient's cells (host) from rejecting donor cells (graft) after the patient gets a Hematopoietic (blood) stem cell transplant.

Condition Intervention Phase
Sickle Cell Disease
Sickle Cell Anemia
SCD
Drug: Fludarabine
Procedure: Hematopoietic Stem Cell Transplant (HSCT)
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Hematopoietic Stem Cell Transplant for Sickle Cell Disease

Resource links provided by NLM:


Further study details as provided by Case Comprehensive Cancer Center:

Primary Outcome Measures:
  • Probability of Engraftment [ Time Frame: 42 Days after transplant ] [ Designated as safety issue: No ]
    The number of patients with engraftment (as defined as recovery of ANC to 500 cells per cubic mm) compared to the total number of patients treated as a function of the patient's age.


Secondary Outcome Measures:
  • Mean time to engraftment [ Time Frame: 42 Days ] [ Designated as safety issue: No ]
    The average time to for engraftment (as defined as recovery of ANC to 500 cells per cubic mm) to occur estimated using a Kaplan-Meier curve as a function of the patient's age.

  • Disease Progression [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    The average time (in days) to disease progression estimated using a Kaplan-Meier curve

  • Overall Survival [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    The average time (in days) patients are alive after treatment estimated using a Kaplan-Meier curve

  • Follicular Stimulating Hormone Levels [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    Estimated difference in changes in Follicular Stimulating Hormone Levels after transplant, among patients with matched sibling donors compared to patients with alternate donors.

  • Luteinizing Hormone Levels [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    Estimated difference in changes in Luteinizing hormone Levels after transplant, among patients with matched sibling donors compared to patients with alternate donors.

  • Testosterone Levels [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    Estimated difference in changes in Testosterone Levels after transplant, among male patients with matched sibling donors compared to patients with alternate donors.

  • Graft versus Host Disease [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
    The number patients with Grade III-IVGraft versus Host Disease as defined by CTCAE v4.0 in matched sibling compared to alternate-donor graft recipients

  • Cerebral Vasculopathy [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    Vasculopathy may clinically manifest as a history of stroke. The difference in number of strokes before and after transplantation will be evaluated with paired statistical tests (t-test or McNemar).

  • Renal Vasculopathy [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    Vasculopathy may clinically manifest as macroalbuminuria (≥300mg/g urinary albumin-to-creatinine ratio) or as a depressed estimated glomerular flow rate (eGFR). Evidence of renal vasculopathy before and after transplantation will be evaluated with paired statistical tests (t-test or McNemar).

  • Pulmonary Vasculopathy [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    Vasculopathy may clinically manifest as pulmonary arterial systolic pressure (PASP) by echo. Difference in PASP levels before and after transplantation will be evaluated with paired statistical tests (t-test or McNemar).

  • Hematopoiesis [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    Levels of stress hematopoiesis will be assessed by measuring telomere lengths with PCR before and after transplantation. These levels will be evaluated with paired statistical tests (t-test or McNemar).

  • Erythropoiesis [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    Levels of stress erythropoiesis will be assessed by measuring telomere lengths with PCR before and after transplantation. These levels will be evaluated with paired statistical tests (t-test or McNemar).


Estimated Enrollment: 25
Study Start Date: April 2015
Estimated Primary Completion Date: June 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Immunomodulation with Fludarabine prior to HSCT
Fludarabine given beginning at 25mgm/m2 three times per day. Patients may be escalated up to 25mgm/m2 five times per day depending on dose-limiting toxicity
Drug: Fludarabine
the study will begin with enrollment of an initial safety cohort of at least 10 subjects at the lowest dose, after which enrollment will pause until the dose-limiting toxicity (DLT) period has been completed. If a patient experiences DLT, defined as failure to engraft. In which case, the patient may be advanced to two higher doses.
Other Name: Fludarabine monophosphate
Procedure: Hematopoietic Stem Cell Transplant (HSCT)
Three weeks after Immunomodulation patients will be infused with matched bone marrow from a sibling, unrelated donor, haploidentical donor, or cord blood. Patients will be followed for the following year.

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have one of the following inherited hemoglobin gene disorders:

    • a. Hemoglobin SS
    • b. Hemoglobin SC
    • c. Hemoglobin S-Beta-zero-Thalassemia or
    • d. Hemoglobin S-Beta-plus Thalassemia with an episode of multi-organ failure within 5 years of eligibility
  • Low Risk (Red Light. Stop and consider therapy closely): Must have matched sibling donor grafts, failed conventional therapy as determined by the PI, and evidence for morbid disease (one of the following):

    • a. 2 or more painful episode/year (requiring Emergency Department or inpatient care) x 2 years or
    • b. 1 or more diagnoses of Acute Chest Syndrome within 5 years, or
    • c. 2-year mortality 5-10% or
    • d. Baseline LDH>600 IU or
    • e. History of sepsis, with or without a WBC>13.5, or
    • f. On chronic transfusions
  • Moderate Risk (Yellow Light. Reasonable to proceed, but with caution): May have alternate donor grafts (haploidentical or matched unrelated donor), if MSD is not available. Must have history of high-level vasculopathy, as defined by at least one of the criteria below:

    • a. Urine Albumin to Creatinine Ratio of >300mg/g or eGFR 50-90 ml/min x 2 evaluations within 3 months or
    • b. History of overt clinical stroke, or progressive cerebral vasculopathy radiographically or
    • c. 2 or more diagnoses of Acute Chest Syndrome within 5 years, or
    • d. Excessively morbid disease manifest as VOCs at a rate of 2 or more per year x 2-years or uncontolled retinal disease attributed to SCD. These patients can be considered for moderate-risk alternate donor transplants. The palliative nature of the transplant will be explicit in the consent.
    • e. 2-year mortality >10-15%
    • f. Baseline WBC>13.5 and on chronic transfusions or baseline LDH>600 or age >35 years old, or
    • g. Baseline TRV ≥3 m/s, or
    • h. Chronic transfusion therapy and age >35 years old or male gender, or
    • i. Baseline LDH>600 and age >35 years old or history of sepsis or
    • j. History of sepsis and age >35 years old or male gender. or
    • k. History of multi-organ failure
  • High Risk (Green light, proceed if possible): All donor types are eligible. Must have high risk disease and a >15% risk of 2-year mortality as defined by at least one of the criteria below.

    • a. Baseline TRV ≥3 m/s and baseline WBC >13.5 or on chronic transfusions or history of sepsis or age >35 years old, or
    • b. Baseline WBC>13.5 and chronic transfusions or baseline LDH>600 or age >35 years old or
    • c. Age >35 years old and chronic transfusions
  • Available suitable donor

    • a. 6/6 HLA-matched sibling donor (HLA A, B, and DRB1), bone marrow only
    • b. 8/8 HLA-matched unrelated donor (HLA A, B, C, DRB1), bone marrow only
    • c. 4/8, 5/8, 6/8, 7/8 Haploidentical donor, bone marrow only or
    • d. Cord Blood, availability of 2 units with 6/8, 7/8, or 8/8 match (HLA-A, B, & C). Overall: class I A, B and Class II DRBII match. Class I A, B can be low or intermediate resolution (serology and/or molecular) and class II must be molecular high resolution.
  • Patients must have adequate hematologic, hepatic, and renal function as defined below:

    • Direct bilirubin within 2.5 X normal institutional limits
    • ALT (SGPT) < 2.5 X institutional upper limit of normal
    • Creatinine clearance >21 mL/min/1.73 m2 for subjects with creatinine clearance values below 50 mL/min/1.73 m2, the principal investigator may use discretion for appropriate fludarabine dose adjustment as noted.
  • Contraception/Child Bearing The effects of Fludarabine, cytoxan, ATG, tacrolimus/sirolimus and MTX are cumulatively known to be deleterious to the health of the developing human fetus. For this reason, and because of teratogenic potential, all women of child-bearing potential and men must agree to use adequate contraception (double barrier method of birth control or abstinence) for the duration of study participation and for 12 months after completing treatment.
  • Performance Status: Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2
  • Subjects must have the ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

  • Red cell alloimmunization to a degree that precludes extended transfusion
  • Patients with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Subjects must not have evidence of impaired liver function due to iron overload, +/- hepatitis. Patients will be evaluated by liver consult if ferritin >1500, history of hepatitis,or ALTis ≥3 X Upper limit of normal (ULN). Recommended evaluations could include liver biopsy if there is evidence for significant hepatic iron deposition or fibrosis/cirrhosis on T2* MRI of the liver.
  • eGFR <21 ml/min
  • ≥2.0 liter-per-minute pm home oxygen requirement
  • An estimated Left Ventricular Ejection Fraction ≤40% (echo or MUGA)
  • Hepatic cirrhosis (Biopsy Proven)
  • HIV positive, ineligible because of the increased risk of lethal infections when treated with marrow suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated
  • Red cell alloimmunization to a degree that precludes extended transfusion
  • Patients with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnant or breastfeeding women are excluded from this study because the immunomodulatory treatment, preparative regimen, and anti-GVH therapy contain agents with the potential for teratogenic or abortifacient effects. Further, this treatment, if indicated, is for a chronic condition, and can be delayed until the pregnancy has been successfully concluded. Because there is an unknown, but potential risk for adverse events in nursing infants secondary to treatment of the mother with, breastfeeding should be discontinued if the mother is treated with these agents. These potential risks may also apply to other agents used in this study.
  • Evidence of uncontrolled bacterial, viral, or fungal infections (currently taking medication and progression of clinical symptoms) within 1 month prior to starting the conditioning regimen. Patients with fever or suspected minor infection should await resolution of symptoms before starting the conditioning regimen.
  • Prior allogeneic marrow or stem cell transplantation.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02065596

Contacts
Contact: Jane Little, MD 216-844-1272 jane.little@uhhospitals.org

Locations
United States, Ohio
University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center Recruiting
Cleveland, Ohio, United States, 44106
Contact: Jane Little, MD    216-844-1272    jane.little@uhhospitals.org   
Principal Investigator: Jane Little, MD         
Sponsors and Collaborators
Case Comprehensive Cancer Center
Investigators
Principal Investigator: Jane Little, MD Case Comprehensive Cancer Center
  More Information

Responsible Party: Case Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT02065596     History of Changes
Other Study ID Numbers: CASE12Z13 
Study First Received: February 14, 2014
Last Updated: December 5, 2016
Health Authority: United States: Food and Drug Administration

Keywords provided by Case Comprehensive Cancer Center:
Sickle Cell Disease
Sickle Cell Anemia
GvHD
fludarabine

Additional relevant MeSH terms:
Anemia, Sickle Cell
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn
Fludarabine
Fludarabine phosphate
Vidarabine
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antiviral Agents
Anti-Infective Agents

ClinicalTrials.gov processed this record on December 07, 2016