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Stem Cell TransplantationPhase 2NCT02512679

Related Hematopoietic Stem Cell Transplantation (HSCT) for Genetic Diseases of Blood Cells

A Phase 2 study testing Cyclophosphamide Dose Level 1, Cyclophosphamide Dose Level 2 and Cyclophosphamide Dose Level 3 in people with Stem Cell Transplantation and Bone Marrow Transplantation, run by Children's Hospital Los Angeles.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

Many genetic diseases of lymphohematopoietic cells (such as sickle cell anemia, thalassemia, Diamond-Blackfan anemia, Combined Immune Deficiency (CID), Wiskott-Aldrich syndrome, chronic granulomatous disease, X-linked lymphoproliferative disease, and metabolic diseases affecting hematopoiesis) are sublethal diseases… Read more about this study

Who is it for?
Ages 3 months and older
What is being tested?
Cyclophosphamide Dose Level 1, Cyclophosphamide Dose Level 2 and Cyclophosphamide Dose Level 3
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
20 participants
Where
No sites listed yet
Study dates
Feb 2007to Feb 2014
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 3 months and older
  • All sexes
  • No healthy volunteers
  • Child, Adult, Older adult

Who may be able to join

  • All patients with lethal or sublethal genetic lymphohematological disease (such as Hemaphagocytic lymphohistiocytosis (HLH) / Familial Erythrophagocytic Lymphohistiocytosis (FEL), Hurler's Syndrome, Hunter's Syndrome, Kostmann's Syndrome, Blackfan-Diamond Anemia, Chronic granulomatous Disease (CGD), Red Cell Aplasia, CID, Sickle Cell Anemia, Thalassemia, Adreno-leukodystrophy, metachromatic leukodystrophy, Wiskott-Aldrich Syndrome, X-Linked Lymphoproliferative Disease (XLD), Metabolic diseases affecting hematopoiesis, but not limited to), who are candidates for allogeneic transplantation for their disease and have a histocompatible sibling or related donor, ages 0 to 21 years, will be candidates for this study protocol. The suitable related donor is a 10/10 or 9/10 allele Human Leukocyte Antigen (HLA) match with the patient. All patients who have previously had serious life- threatening events due to disease process may be included in the study. Patients must have adequate physical function and vital organ function to tolerate transplant procedure, as measured by:
  • Cardiac: Shortening fraction >26% or left ventricular ejection fraction at rest must be > 40%.
  • Hepatic: Bilirubin, Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) < 3x upper limit of normal (as per local laboratory) for age (with the exception of isolated hyperbilirubinemia due to Gilbert's syndrome).
  • Renal: Serum creatinine < 2x upper limit of normal for age or if serum creatinine elevated beyond normal range patient must have creatinine Clearance or Glomerular filtration rate (GFR) >50% lower limit of normal for age.
  • Pulmonary: Forced expiratory volume (FEV)1, Forced Vital Capacity (FVC), and Diffusing Lung Capacity for Carbon Monoxide (DLCO) (corrected for Hgb) > 50% predicted. For patients where pulse oximetry is performed, O2 saturation > 92%
  • Evaluation of iron status in patients who have received more than 12 red cell transfusions. Measurements of serum ferritin levels and MRI of the liver and heart tissue will evaluate the iron stores. If high iron load is identified in these organs further evaluation will be done to determine the suitability as transplant recipient. Should these studies indicate that chelation is necessary the following should apply: That the treating hematologist will provide the specific chelation type and timing. Evaluation of organ iron load will be part of the HSCT work-up and if high iron load is identified then the BMT team will work with the hematologist attending in developing a plan for the patient.

Who cannot join

  • Karnofsky performance status < 70%, or Lansky < 40% for patients < 16 years old.
  • Uncontrolled bacterial, viral, or fungal infections (currently taking medication yet clinical symptoms progress).
  • Seropositivity for the human immunodeficiency virus (HIV).
  • Acute active hepatitis.
  • Diagnosis of end-organ dysfunction that precludes the ability to tolerate the transplant procedure.
  • Patients with a diagnosis of Fanconi Anemia are excluded.

About this study

Official title: Protocol for Related Donor Hematopoietic Stem Cell Transplantation (HSCT) for Treatment of Symptomatic Genetic Lymphohematological Diseases

Many genetic diseases of lymphohematopoietic cells (such as sickle cell anemia, thalassemia, Diamond-Blackfan anemia, Combined Immune Deficiency (CID), Wiskott-Aldrich syndrome, chronic granulomatous disease, X-linked lymphoproliferative disease, and metabolic diseases affecting hematopoiesis) are sublethal diseases caused by mutations that adversely affect the development or function of different types of blood cells. Although pathophysiologically diverse, these genetic diseases share a similar clinical course of significant progressive morbidity, overall poor quality of life, and ultimate death from complications of the disease or its palliative treatment. Supportive care for these diseases includes chronic transfusion, iron chelation, and surgery (splenectomy or cholecystectomy) for the hemoglobinopathies; prophylactic antibiotics, intravenous immunoglobulin, and immunomodulator therapies for the immune deficiencies; and enzyme replacement injections and dietary restriction for some of the metabolic diseases. The suboptimal results of such supportive care measures have led to efforts to implement more aggressive therapeutic interventions to cure these lymphohematopoietic diseases. The most logical strategies for cure of these diseases have been either replacement of the patient's own hematopoietic stem cells (HSC) with those derived from a normal donor allogeneic bone marrow transplant (BMT) or hematopoietic stem cell transplant (HSCT), or to genetically modify the patient's own stem cells to replace the defective gene (gene therapy).

Read the detailed description

The present study is to evaluate de-escalation of the cyclophosphamide (CY) dose in an innovative conditioning regimen with fludarabine and alemtuzumab as additional agents to achieve immunoablation, in combination with Busulfan (BU) to achieve myeloablation. Replacement of at least part of the cyclophosphamide dose by fludarabine in the conditioning regimen would be expected to maintain immunosuppression (and, therefore, engraftment) while reducing transplant-related complications (mucositis, hepatotoxicity, cardiotoxicity, pulmonary toxicity, hemorrhagic cystitis, mucositis, and possibly GVHD), thereby improving disease-free survival rates. Similarly, the potential benefits of alemtuzumab in the proposed conditioning regimen are increased rates of hematopoietic engraftment with less toxicity than that observed with cyclophosphamide, ultimately resulting in improved immune function and enhanced quality of life (12,13). A fludarabine/alemtuzumab-based, less intensive conditioning regimen with adequate immunosuppressive activity could conceivably allow more successful engraftment of stem cells from related donors in patients with genetic lymphohematological diseases, as well as lower rates of transplant-related mortality.

Regimen-related toxicity is also believed to be a major contributing factor to GVHD (14). Therefore, conditioning regimens that cause less tissue injury may also lead to reduced GVHD. In the present study, the use of alemtuzumab in the conditioning regimen may be an added benefit, as this antibody causes T-cell depletion, thus, the risk of GVHD may also be reduced (15). The overall goal of the study is to improve the therapeutic index of HSCT by decreasing and, if possible, eliminating cyclophosphamide as a component of the pre-transplant conditioning for patients with genetic diseases of lymphohematopoiesis. The investigation will explore the risks and benefits of the proposed novel-conditioning regimen using a decreased dose of cyclophosphamide and additional immunosuppression with fludarabine and alemtuzumab to prevent graft rejection and recurrence of disease. The investigators will evaluate this regimen's impact on conditioning-related morbidity and mortality, and measure the success of the transplant procedure by engraftment and disease-free survival. If this regimen is able to successfully permit engraftment and reduce regimen-related toxicity, the next phase of treatment will test a further dose de-escalation for cyclophosphamide. It is anticipated that there will be four dose levels of cyclophosphamide in the overall study: 1) 105 mg/kg; 2) 70 mg/kg; 3) 35 mg/kg; and then finally, 4) 0 mg/kg. This study design was chosen to minimize study risks possibly associated with substitution of fludarabine and alemtuzumab for CY as immunoablation. The present protocol represents Level 1 in the study design; an amended protocol will be prepared prior to further de-escalation of the cyclophosphamide dose.

Being tested
Cyclophosphamide Dose Level 1, Cyclophosphamide Dose Level 2, Cyclophosphamide Dose Level 3, Cyclophosphamide Dose Level 4
Keywords
Hematopoietic Stem Cell Transplantation Pediatrics,, stem cell transplantation, bone marrow transplantation, Peripheral Blood Stem Cell Transplantation, Allogeneic Transplantation, pediatrics, Combined Immune Deficiency, Chronic Granulomatous disease
Medical subject headings
Genetic Diseases, Inborn, Thalassemia, Anemia, Diamond-Blackfan, Wiskott-Aldrich Syndrome, Granulomatous Disease, Chronic, Lymphoproliferative Disorders, Metabolic Diseases

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Cyclophosphamide Dose Level 1Drug

    Also called Cytoxan

    given by IV at a total dose of 105 mg/kg, to be divided into three doses of one 35 mg/kg dose per day, for 3 days on the first level. After ten patients the de-escalation will begin if the stopping rule is not met.

  • Cyclophosphamide Dose Level 2Drug

    Also called Cytoxan

    Level 2 will be 70mg/kg in 2 divided given once a day for 2 days;

  • Cyclophosphamide Dose Level 3Drug

    Also called Cytoxan

    Level 3 will be 35mg/kg as a one-time dose.

  • Cyclophosphamide Dose Level 4Drug

    Also called Cytoxan

    Level 4 will be no cytoxan.

Study groups in NCT02512679
Study groupRoleWhat they receive
Cyclophosphamide Dose Level 1OtherCyclophosphamide given by Intravenous (IV) at a total dose of 105 mg/kg, to be divided into three doses of one 35 mg/kg dose per day, for 3 days on the first level. Drug to be given in combination of Busulfan, Campath and Fludarabine
Receives: Drug: Cyclophosphamide Dose Level 1
Cyclophosphamide Dose Level 2OtherCyclophosphamide given by intravenous (IV) at a total dose of 70 mg/kg (divided in two doses) given once a day for two days in combination with Busulfan, Campath and Fludarabine.
Receives: Drug: Cyclophosphamide Dose Level 2
Cyclophosphamide Dose Level 3OtherCyclophosphamide given by intravenous (IV) at total does of 35 mg/kg as a one time dose in combination with Busulfan, Fludarabine and Campath
Receives: Drug: Cyclophosphamide Dose Level 3
Cyclophosphamide Dose Level 4OtherNo cyclophosphamide given with Busulfan, Fludarabine and Campath
Receives: Drug: Cyclophosphamide Dose Level 4

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Number of Participants With Neutrophil Engraftment (=/>500 Cells/uL) and Platelet Engraftment (>20K Cell/uL) at 30 Days

    Absolute Neutrophil Count (ANC) =/>500;(recovery of white cell count - self sustain platelet above 20,000 per cubic milimeter (20K) - evaluation by Chimerism Study (STR or FISH) at day +30

    Measured: 30 days

  2. Number of Participants With Disease Recurrence at 1 Year Post-transplant

    assess rate of disease recurrence ("late relapse") due to autologous recovery of recipient hematopoiesis at one year post-HSCT.

    Measured: 1 year

  3. Number of Participants Who Developed Severe Mucositis, Veno-occlusive Disease (VOD), Toxicity of the Kidney, Liver, or Gastrointestinal (GI) Tract up to 1 Year Post-transplant

    Assessment of conditioning regimen related toxicity was evaluated and documented with daily assessment during hospitalization and post-transplant follow-up up to one year. None of the subjects developed VOD necessitating any therapeutic intervention, severe mucositis, or toxicity of the Kidney, Liver or Gastrointestinal.

    Measured: 1 year

Secondary outcomes (2)

  1. Number of Participants Who Developed Graft-Versus-Host-Disease (GVHD) as Determined by the Glucksberg Scale

    Clinical evaluation on a daily basis during hospitalization and at each post transplant clinical visit, up to one year, to determine incidence of acute and chronic graft-versus-host disease using Glucksberg grading scale. Acute graft-versus-host disease (aGVHD) develops within the first three months after transplantation and appears as a skin rash, often accompanied by hyperbilirubenemia, abnormal liver enzymes and gastrointestinal symptoms, as diarrhea, nausea and vomiting. Level of aGVHD is graded from 1-4. Chronic GVHD, typically a late complication of Blood and Marrow Transplantation (BMT) characterized by skin changes, sometimes sclerotic changes, with joint contractures, liver function abnormality, gastrointestinal symptoms and sometime other organ involvement such as eyes, lungs, and obliterative bronchiolitis (OB). Chronic GVHD is graded as absent, limited, or extensive.

    Measured: 1 yr

  2. Number of Participants Who Were Disease Progression-Free and Death-Free at 1 Year Post-transplant

    Evaluation for engraftment, correction of the disease, transplant related complications and event-free survival and overall survival of the subjects post-transplant was undertaken by standard measures and evaluation of disease with disease-specific testing.

    Measured: 1 yr

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted31 Jul 2015 (estimated)
  2. Study startFeb 2007
  3. Primary completionSep 2013
  4. Study completionFeb 2014

Why it stopped: Optimal dose obtained for engraftment and minimizing toxicity

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Single group
Masking
None (open label)
Enrolment
20 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02512679
Sponsor's protocol ID
CCI-06-00177
Status last verified
Jan 2017
First submitted
21 May 2015
Last updated
27 Feb 2017
Data monitoring committee
Yes
Individual data sharing
Yes: Tranplant data is reported to CIBMTR and is available to the other investigators

Publications

  • Mahadeo KM, Weinberg KI, Abdel-Azim H, Miklos DB, Killen R, Kohn D, Crooks GM, Shah AJ, Kharbanda S, Agarwal R, Kapoor N. A reduced-toxicity regimen is associated with durable engraftment and clinical cure of nonmalignant genetic diseases among children undergoing blood and marrow transplantation with an HLA-matched related donor. Biol Blood Marrow Transplant. 2015 Mar;21(3):440-4. doi: 10.1016/j.bbmt.2014.11.005. Epub 2014 Nov 13.

    PubMed 25459642

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Cyclophosphamide Dose Level 1, Cyclophosphamide Dose Level 2 and Cyclophosphamide Dose Level 3 in people with Stem Cell Transplantation and Bone Marrow Transplantation, run by Children's Hospital Los Angeles.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 6 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 27 Feb 2017. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 17 Jun 2016). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Participants With Neutrophil Engraftment (=/>500 Cells/uL) and Platelet Engraftment (>20K Cell/uL) at 30 Days (time frame: 30 days). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02512679, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Feb 2017.

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