Trial record 2 of 146 for:    Open Studies | "Anemia, Sickle Cell"

Hematopoietic Stem Cell Transplant for Sickle Cell Disease

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified February 2014 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: February 18, 2014
Last verified: February 2014
  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: March 2014
Estimated Primary Completion Date: November 2016 (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 Names:
  • Fludarabine monophosphate
  • Fludarabine
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.

Detailed Description:

Primary Objective

1. To evaluate the safety and feasibility of hematopoietic stem cell transplant (HSCT) after treatment with fludarabine in adult patients with Sickle Cell Disease (SCD).

Secondary Objective(s), in HSCT for SCD

  1. To evaluate the rates of disease-free and overall survival in both MSD and alternate graft donor (MUD, haploidentical, or cord blood-derived) recipients
  2. To evaluate fertility in matched sibling and alternate-donor graft recipients
  3. To evaluate GVHD rates in MSD and Alternate Graft Donor recipients in SCD.
  4. To evaluate cerebral, pulmonary, renal, and generalized vasculopathy before and after HSCT in SCD.
  5. To evaluate hematopoiesis and erythropoiesis before and before HSCT in SCD.
  6. Modulation of SCD Phenotype by Allogeneic Transplantation We will perform rigorous clinical follow-up, per routine care, to evaluate those consequences of SCD that will be modified by allogeneic transplantation in the short-term (4-12 weeks), in the medium-term (12-24 weeks) and in the long-term (>24 weeks). Short-term changes would include disappearance of stress hematopoiesis and erythropoiesis; medium- and long-term changes would include effects on pain, fertility (TSH, LH), cognition (routine cognitive assessments), and end-organ damage (including urine albumin-to-creatinine ratios and tricuspid regurgitant jet velocities, as indicated).

Procedures:

The study will start with at least 10 and up to 25 patients. They will be given the lowest starting dose of fludarabine. This is done to make sure it is safe. Researchers will watch the patients during what is called the dose-limiting toxicity (DLT) period. Their safety will be monitored by a Safety Monitoring Committee, which is made up of people who run research studies. The study will not take new patients until the DLT period is done.

If at least 3 of the 10 patients enrolled do not benefit, the maximum tolerated dose (MTD) will be considered exceeded. After the DLT period is complete, patients will receive a stem cell transplant from a genetically matched donor. Patients will be continued to be monitored for a year after the transplant.

To prepare for the transplant patients will have to undergo the following treatments:

  • an exchange transfusion
  • a stem cell graft infusion from either a:

    • perfectly matched sibling donor (called MSD),
    • perfectly matched but unrelated donor (called MUD),
    • a half-matched related donor (called Haploidentical), or
    • a cord blood donor
  • rabbit antithymocyte globulin (ATG)
  • cytoxan (a type of chemotherapy)
  • Fludarabine (you get this medicine a few weeks before transplant and again, as part of the routine chemotherapy treatment). This is the main drug being studies in this research
  • total body irradiation (also called TBI)
  • tacrolimus, mycophenolate (MMF) and/or methotrexate (MTX). These drugs will weaken your immune system. They are given to lower your chances of getting GVHD and rejecting the donor cells.

Patients will be in the study for approximately 14 months.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

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

    1. Hemoglobin SS
    2. Hemoglobin SC
    3. Hemoglobin S-Beta-zero-Thalassemia or
    4. Hemoglobin S-Beta-plus Thalassemia
  • Disease Morbidity
  • For matched sibling donor grafts (low-risk e.g., matched sibling donor), patients must have evidence for morbid disease that has failed conventional therapy:

    1. 2 or more painful episode/year (requiring Emergency Department or inpatient care) x 3 years or
    2. 2 or more diagnoses of Acute Chest Syndrome within 5 years, or
    3. 2-year mortality 5-10%
  • Baseline LDH>600 IU or
  • history of sepsis, with or without a WBC>13.5, or
  • on chronic transfusions
  • For alternate donor grafts (moderate risk e.g., haploidentical or matched unrelated donor), patients must have history of high-level vasculopathy:

    1. Urine Albumin to Creatinine Ratio of >300mg/g or eGFR 50-90 ml/min x 2 evaluations within 3 months or
    2. history of overt clinical stroke, or progressive cerebral vasculopathy radiographically or
    3. 2 or more diagnoses of Acute Chest Syndrome within 5 years, or
    4. *excessively morbid disease. These patients can be considered for moderate-risk alternate donor transplants. The palliative nature of the transplant will be explicit in the consent.
    5. 2-year mortality >10-15%

    i. Baseline WBC>13.5 and on chronic transfusions or baseline LDH>600 or age >35 yo, or ii. Baseline TRV ≥3 m/s, or iii. Chronic transfusion therapy and age >35 yo or male gender, or iv. Baseline LDH>600 and age >35 yo or history of sepsis or v. history of sepsis and age >35 yo or male gender.

  • For alternate donor grafts (high risk or untested, e.g. umbilical cord blood), patients must have a >15% risk of 2-year mortality:

    1. baseline TRV ≥3 m/s and baseline WBC >13.5 or on chronic transfusions or history of sepsis or age >35 yo, or
    2. baseline WBC>13.5 and chronic transfusions or baseline LDH>600 or age >35 yo or
    3. Age >35 yo and chronic transfusions or
    4. Chronic transfusions and male gender.
  • Available suitable donor

    1. 6/6 HLA-matched sibling donor (HLA A, B, and DRB1), bone marrow only
    2. 8/8 HLA-matched unrelated donor (HLA A, B, C, DRB1), bone marrow only
    3. 4/8, 5/8, 6/8, 7/8 Haploidentical donor, bone marrow only or
    4. Cord Blood, availability of 2 units with 6/8, 7/8, or 8/8 match (HLA-A, B, & C)
  • Patients must have adequate hematologic, hepatic, and renal function as defined below:
  • Direct bilirubin within 1.5 X normal institutional limits
  • ALT (SGPT) < 2.5 X institutional upper limit of normal
  • Creatinine clearance >50 mL/min/1.73 m2 for patients with creatinine levels above institutional normal, using 4-value Cockcroft-Gault.
  • 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.
  • Subjects must have the ability to understand and the willingness to sign a written informed consent document.

Should a woman become pregnant or suspect that she is pregnant while she or her partner is participating in this study, she should inform the treating physician immediately.

Exclusion Criteria:

  • eGFR <50 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.
  • Subjects must not have evidence for impaired liver function due to iron overload, +/- hepatitis. Patients will be evaluated by hepatology if ferritin >1500, if history of hepatitis, or ALT/ALP are >1.5 X ULN.
  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
Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center Not yet recruiting
Cleveland, Ohio, United States, 44106
Sponsors and Collaborators
Case Comprehensive Cancer Center
Investigators
Principal Investigator: Jane Little, MD Case Comprehensive Cancer Center
  More Information

No publications provided

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: February 18, 2014
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
Hematologic Diseases
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Hemoglobinopathies
Genetic Diseases, Inborn
Fludarabine
Fludarabine monophosphate
Vidarabine
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antiviral Agents
Anti-Infective Agents

ClinicalTrials.gov processed this record on July 28, 2014