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

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ClinicalTrials.gov Identifier: NCT02512679
Recruitment Status : Terminated (Optimal dose obtained for engraftment and minimizing toxicity)
First Posted : July 31, 2015
Results First Posted : June 17, 2016
Last Update Posted : February 27, 2017
Sponsor:
Collaborator:
Lucile Packard Children's Hospital
Information provided by (Responsible Party):
Neena Kapoor, M.D., Children's Hospital Los Angeles

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Stem Cell Transplantation
Bone Marrow Transplantation
Peripheral Blood Stem Cell Transplantation
Allogeneic Transplantation
Genetic Diseases
Thalassemia
Pediatrics
Diamond-Blackfan Anemia
Combined Immune Deficiency
Wiskott-Aldrich Syndrome
Chronic Granulomatous Disease
X-linked Lymphoproliferative Disease
Metabolic Diseases
Interventions Drug: Cyclophosphamide Dose Level 1
Drug: Cyclophosphamide Dose Level 2
Drug: Cyclophosphamide Dose Level 3
Drug: Cyclophosphamide Dose Level 4
Enrollment 20
Recruitment Details Patients for bone marrow transplantation who met the eligibility criteria of diagnosis and clinical status and had histocompatible sibling donor. These patients were recruited at Children's Hospital Los Angeles and Lucille Packard Children's Hospital at Stanford University. Patients were recruited between 2006 and 2013.
Pre-assignment Details This is a sequential dose de-escalation of Cyclophosphamide with first at 105 mg/kg total dose compared to standard 200mg/kg total dose (Arm 1). Prior to enrollment patients had to meet all eligibility criteria for allogeneic transplantation. Study closed after 1st level because all patients engrafted and none had toxicity related to transplant.
Arm/Group Title Cyclophosphamide Dose Level 1 Cyclophosphamide Dose Level 2
Hide Arm/Group Description

Cyclophosphamide 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

Cyclophosphamide Dose Level 1: 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.

De-escalation of Cyclophosphamide given by Intravenous (IV) at a total dose of 70 mg/kg, to be divided into two doses of one 35 mg/kg dose per day, for 2 days

Drug to be given in combination of Busulfan, Campath and Fludarabine

Cyclophosphamide Dose Level 1: given by IV at a total dose of 75 mg/kg, to be divided into two doses of one 35 mg/kg dose per day, for 2 days. After ten patients the de-escalation will begin if the stopping rule is not met.

Period Title: Overall Study
Started 20 0
Completed 20 0
Not Completed 0 0
Arm/Group Title Cyclophosphamide Dose Level 1
Hide Arm/Group Description

Cyclophosphamide 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

Cyclophosphamide Dose Level 1: 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.

Overall Number of Baseline Participants 20
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 20 participants
<=18 years
19
  95.0%
Between 18 and 65 years
1
   5.0%
>=65 years
0
   0.0%
Age, Continuous   [1] 
Median (Full Range)
Unit of measure:  Years
Number Analyzed 20 participants
2.3
(.4 to 26)
[1]
Measure Description: Deviation from study protocol - enrollment of 26-year-old subject with pediatric disease. Subject's data included in outcome measurements/analysis.
Gender  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 20 participants
Female
13
  65.0%
Male
7
  35.0%
Region of Enrollment   [1] 
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 20 participants
20
[1]
Measure Description: Enrollment of participants was conducted in California.
1.Primary Outcome
Title Number of Participants With Neutrophil Engraftment (=/>500 Cells/uL) and Platelet Engraftment (>20K Cell/uL) at 30 Days
Hide Description 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
Time Frame 30 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Subject enrolled and received Dose Level 1 of Cyclophosphamide and engrafted with Absolute Neutrophil Count (ANC) =/>500;(recovery of white cell count - self sustain platelet above 20k - evaluation by Chimerism Study (STR or FISH) at day +30.
Arm/Group Title Cyclophosphamide Dose Level 1
Hide Arm/Group Description:

Cyclophosphamide 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

Cyclophosphamide Dose Level 1: 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.

Overall Number of Participants Analyzed 20
Measure Type: Number
Unit of Measure: participants
20
2.Primary Outcome
Title Number of Participants With Disease Recurrence at 1 Year Post-transplant
Hide Description assess rate of disease recurrence (“late relapse”) due to autologous recovery of recipient hematopoiesis at one year post-HSCT.
Time Frame 1 year
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All subjects who received dose level 1 of Cyclophosphamide did not experience re-occurrence of disease.
Arm/Group Title Cyclophosphamide Dose Level 1
Hide Arm/Group Description:

Cyclophosphamide 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

Cyclophosphamide Dose Level 1: 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.

Overall Number of Participants Analyzed 20
Measure Type: Number
Unit of Measure: participants
0
3.Primary Outcome
Title 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
Hide Description 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.
Time Frame 1 year
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Subjects who received dose level 1 of Cyclophosphamide did not experience veno-occlusive disease, organ failure or severe mucositis.
Arm/Group Title Cyclophosphamide Dose Level 1
Hide Arm/Group Description:

Cyclophosphamide 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

Cyclophosphamide Dose Level 1: 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.

Overall Number of Participants Analyzed 20
Measure Type: Number
Unit of Measure: participants
Veno-Occlusive Disease 0
Viral Infection 8
Toxicity of Kidney, Liver, or Gastrointestinal 0
Severe Mucositis 0
4.Secondary Outcome
Title Number of Participants Who Developed Graft-Versus-Host-Disease (GVHD) as Determined by the Glucksberg Scale
Hide Description 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.
Time Frame 1 yr
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Subjects who received dose level 1 of Cyclophosphamide were revaluated for graft-versus-host disease (GVHD) post transplantation.
Arm/Group Title Cyclophosphamide Dose Level 1
Hide Arm/Group Description:

Cyclophosphamide 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

Cyclophosphamide Dose Level 1: 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.

Overall Number of Participants Analyzed 20
Measure Type: Number
Unit of Measure: participants
Acute GVHD (Grade 1-2) 10
Acute GVHD (Grade 3-4) 0
Chronic GVHD 0
5.Secondary Outcome
Title Number of Participants Who Were Disease Progression-Free and Death-Free at 1 Year Post-transplant
Hide Description 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.
Time Frame 1 yr
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Subjects receiving dose level 1 of Cyclophosphamide event free survival post transplant at 100 days was 95% and 90% 1 year.
Arm/Group Title Cyclophosphamide Dose Level 1
Hide Arm/Group Description:

Cyclophosphamide 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

Cyclophosphamide Dose Level 1: 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.

Overall Number of Participants Analyzed 20
Measure Type: Number
Unit of Measure: participants
100 Day Event Free Survival Post Transplant 19
One Year Event Free Survival Post Transplant 18
Disease Progression-Free 20
Time Frame Adverse event data was collected throughout the course of the study up to 2 years post transplantation. Subjects were evaluated for post transplant complications related to conditioning, such as VOD, GVHD, infections and engraftment failure.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Cyclophosphamide Dose Level 1
Hide Arm/Group Description

Cyclophosphamide 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

Cyclophosphamide Dose Level 1: 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.

All-Cause Mortality
Cyclophosphamide Dose Level 1
Affected / at Risk (%)
Total   --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Cyclophosphamide Dose Level 1
Affected / at Risk (%) # Events
Total   2/20 (10.00%)    
Respiratory, thoracic and mediastinal disorders   
Death due to pre-exisiting mucormycosis  1 [1]  1/20 (5.00%)  1
Death due to interstitial pneumonia  2 [2]  1/20 (5.00%)  1
Indicates events were collected by systematic assessment
1
Term from vocabulary, Fungal infection
2
Term from vocabulary, Pneumonia
[1]
Subject had pretransplant history of mucormycosis infection. Patient was received anti-fungal medications.
[2]
Subject developed interstitial pneumonia on Day +187 post transplant. Onset thought to be community acquired pneumonia.
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Cyclophosphamide Dose Level 1
Affected / at Risk (%) # Events
Total   7/20 (35.00%)    
Blood and lymphatic system disorders   
Cytomegalovirus (CMV) infection  1 [1]  5/20 (25.00%)  5
Epstein-Barr Virus (EBV)  2 [2]  1/20 (5.00%)  1
Adenovirus  3 [3]  1/20 (5.00%)  1
Indicates events were collected by systematic assessment
1
Term from vocabulary, Viral Infection
2
Term from vocabulary, Viremia, Epstein-Bar
3
Term from vocabulary, Adenovirus
[1]
Re-activation of cytomegalovirus (CMV) in 5/20 enrolled subjects documented by blood CMV Polymerase Chain Reaction (PCR) test.
[2]
Epstein-Barr Virus (EBV) was documented to be positive in 1/20 subjects enrolled in the study; confirmed by Polymerase Chain Reaction (PCR).
[3]
Adenovirus was detected in one (1) enrolled subject by blood PCR.
De-escalation was not ensued. All enrolled subjects engrafted without toxicity for dose level one.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Neena Kapoor, M.D.
Organization: Children's Hospital Los Angeles
Phone: 343-361-2434
Responsible Party: Neena Kapoor, M.D., Children's Hospital Los Angeles
ClinicalTrials.gov Identifier: NCT02512679     History of Changes
Other Study ID Numbers: CCI-06-00177
First Submitted: May 21, 2015
First Posted: July 31, 2015
Results First Submitted: January 29, 2016
Results First Posted: June 17, 2016
Last Update Posted: February 27, 2017