## Protocol Section
### Identification Module
**NCT ID:** NCT02512679

**Brief Title:** Related Hematopoietic Stem Cell Transplantation (HSCT) for Genetic Diseases of Blood Cells

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

#### Organization Study ID Info
**ID:** CCI-06-00177
#### Organization
**Class:** OTHER
**Full Name:** Children's Hospital Los Angeles
### Status Module
#### Completion Date
**Date:** 2014-02

**Type:** ACTUAL

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2017-02-27

**Type:** ACTUAL

**Last Update Submit Date:** 2017-01-12

**Overall Status:** TERMINATED

#### Primary Completion Date
**Date:** 2013-09

**Type:** ACTUAL

#### Results First Post Date
**Date:** 2016-06-17

**Type:** ESTIMATED

**Results First Submit Date:** 2016-01-29

**Results First Submit QC Date:** 2016-05-11

#### Start Date
**Date:** 2007-02

**Status Verified Date:** 2017-01

#### Study First Post Date
**Date:** 2015-07-31
**Type:** ESTIMATED
**Study First Submit Date:** 2015-05-21
**Study First Submit QC Date:** 2015-07-29
**Why Stopped:** Optimal dose obtained for engraftment and minimizing toxicity
### Sponsor Collaborators Module

#### Collaborators

**Class:** OTHER

**Name:** Lucile Packard Children's Hospital

#### Lead Sponsor

**Class:** OTHER

**Name:** Children's Hospital Los Angeles

#### Responsible Party

**Investigator Affiliation:** Children's Hospital Los Angeles

**Investigator Full Name:** Neena Kapoor, M.D.

**Investigator Title:** Principal Investigator

**Type:** PRINCIPAL_INVESTIGATOR

### Oversight Module

**Oversight Has DMC:** True

### Description Module

**Brief 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 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).

**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.

### Conditions Module

**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

**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

### Design Module

#### Design Info

**Allocation:** NON_RANDOMIZED

**Intervention Model:** SINGLE_GROUP

##### Masking Info

**Masking:** NONE

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 20

**Type:** ACTUAL

**Phases:**

- PHASE2

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**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

**Intervention Names:**

- Drug: Cyclophosphamide Dose Level 1

**Label:** Cyclophosphamide Dose Level 1

**Type:** OTHER

#### Arm Group 2

**Description:** Cyclophosphamide 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.

**Intervention Names:**

- Drug: Cyclophosphamide Dose Level 2

**Label:** Cyclophosphamide Dose Level 2

**Type:** OTHER

#### Arm Group 3

**Description:** Cyclophosphamide given by intravenous (IV) at total does of 35 mg/kg as a one time dose in combination with Busulfan, Fludarabine and Campath

**Intervention Names:**

- Drug: Cyclophosphamide Dose Level 3

**Label:** Cyclophosphamide Dose Level 3

**Type:** OTHER

#### Arm Group 4

**Description:** No cyclophosphamide given with Busulfan, Fludarabine and Campath

**Intervention Names:**

- Drug: Cyclophosphamide Dose Level 4

**Label:** Cyclophosphamide Dose Level 4

**Type:** OTHER

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Cyclophosphamide Dose Level 1

**Description:** 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.

**Name:** Cyclophosphamide Dose Level 1

**Other Names:**

- Cytoxan

**Type:** DRUG

#### Intervention 2

**Arm Group Labels:**

- Cyclophosphamide Dose Level 2

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

**Name:** Cyclophosphamide Dose Level 2

**Other Names:**

- Cytoxan

**Type:** DRUG

#### Intervention 3

**Arm Group Labels:**

- Cyclophosphamide Dose Level 3

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

**Name:** Cyclophosphamide Dose Level 3

**Other Names:**

- Cytoxan

**Type:** DRUG

#### Intervention 4

**Arm Group Labels:**

- Cyclophosphamide Dose Level 4

**Description:** Level 4 will be no cytoxan.

**Name:** Cyclophosphamide Dose Level 4

**Other Names:**

- Cytoxan

**Type:** DRUG

### Outcomes Module

#### Primary Outcomes

**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

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

**Time Frame:** 30 days

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

**Measure:** Number of Participants With Disease Recurrence at 1 Year Post-transplant

**Time Frame:** 1 year

**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.

**Measure:** 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

**Time Frame:** 1 year

#### Secondary Outcomes

**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.

**Measure:** Number of Participants Who Developed Graft-Versus-Host-Disease (GVHD) as Determined by the Glucksberg Scale

**Time Frame:** 1 yr

**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.

**Measure:** Number of Participants Who Were Disease Progression-Free and Death-Free at 1 Year Post-transplant

**Time Frame:** 1 yr

### Eligibility Module

**Eligibility Criteria:** Inclusion Criteria:

* 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.

Exclusion Criteria:

* 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.

**Minimum Age:** 3 Months

**Sex:** ALL

**Standard Ages:**

- CHILD

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Overall Officials

**Official 1:**

**Affiliation:** Children's Hospital Los Angeles

**Name:** Neena Kapoor, M.D.

**Role:** PRINCIPAL_INVESTIGATOR

### IPD Sharing Statement Module

**Description:** Tranplant data is reported to CIBMTR and is available to the other investigators

**IPD Sharing:** YES

### References Module

#### References

**Citation:** 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.

**PMID:** 25459642

#### See Also Links

**Label:** Reduced-toxicity regimen for related HSCT transplants

**URL:** http://www.ncbi.nlm.nih.gov/pubmed?term=%22Biology+of+blood+and+marrow+transplantation+%3A+journal+of+the+American+Society+for+Blood+and+Marrow+Transplantation%22%5BJour%5D+AND+21%5Bvolume%5D+AND+Mahadeo%5Bauthor%5D&cmd=detailssearch

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000000745

- Term: Anemia, Hemolytic, Congenital

- ID: D000000743

- Term: Anemia, Hemolytic

- ID: D000000740

- Term: Anemia

- ID: D000006402

- Term: Hematologic Diseases

- ID: D000006453

- Term: Hemoglobinopathies

- ID: D000007154

- Term: Immune System Diseases

- ID: D000008206

- Term: Lymphatic Diseases

- ID: D000010335

- Term: Pathologic Processes

- ID: D000010585

- Term: Phagocyte Bactericidal Dysfunction

- ID: D000007960

- Term: Leukocyte Disorders

- ID: D000040181

- Term: Genetic Diseases, X-Linked

- ID: D000002908

- Term: Chronic Disease

- ID: D000020969

- Term: Disease Attributes

- ID: D000007160

- Term: Immunoproliferative Disorders

- ID: D000029502

- Term: Anemia, Hypoplastic, Congenital

- ID: D000000741

- Term: Anemia, Aplastic

- ID: D000012010

- Term: Red-Cell Aplasia, Pure

- ID: D000080984

- Term: Congenital Bone Marrow Failure Syndromes

- ID: D000080983

- Term: Bone Marrow Failure Disorders

- ID: D000001855

- Term: Bone Marrow Diseases

- ID: D000025861

- Term: Blood Coagulation Disorders, Inherited

- ID: D000001778

- Term: Blood Coagulation Disorders

- ID: D000008231

- Term: Lymphopenia

- ID: D000007970

- Term: Leukopenia

- ID: D000095542

- Term: Cytopenia

- ID: D000006474

- Term: Hemorrhagic Disorders

- ID: D000081207

- Term: Primary Immunodeficiency Diseases

### Condition Browse Module - Browse Branches

- Abbrev: BC23

- Name: Symptoms and General Pathology

- Abbrev: All

- Name: All Conditions

- Abbrev: BC15

- Name: Blood and Lymph Conditions

- Abbrev: BC18

- Name: Nutritional and Metabolic Diseases

- Abbrev: BC20

- Name: Immune System Diseases

- Abbrev: BC16

- Name: Diseases and Abnormalities at or Before Birth

- Abbrev: BC14

- Name: Heart and Blood Diseases

- Abbrev: Rare

- Name: Rare Diseases

### Condition Browse Module - Browse Leaves

- ID: M16355

- Name: Syndrome

- Relevance: LOW

- As Found: Unknown

- ID: M4070

- Name: Anemia

- Relevance: LOW

- As Found: Unknown

- ID: M11639

- Name: Metabolic Diseases

- Relevance: HIGH

- As Found: Metabolic Diseases

- ID: M11225

- Name: Lymphoproliferative Disorders

- Relevance: HIGH

- As Found: X-linked Lymphoproliferative Disease

- ID: M16557

- Name: Thalassemia

- Relevance: HIGH

- As Found: Thalassemia

- ID: M10199

- Name: Immunologic Deficiency Syndromes

- Relevance: HIGH

- As Found: Immune Deficiency

- ID: M9208

- Name: Granulomatous Disease, Chronic

- Relevance: HIGH

- As Found: Chronic Granulomatous Disease

- ID: M23456

- Name: Anemia, Diamond-Blackfan

- Relevance: HIGH

- As Found: Diamond Blackfan Anemia

- ID: M17662

- Name: Wiskott-Aldrich Syndrome

- Relevance: HIGH

- As Found: Wiskott-Aldrich Syndrome

- ID: M23686

- Name: Genetic Diseases, Inborn

- Relevance: HIGH

- As Found: Genetic Diseases

- ID: M9547

- Name: Hemolysis

- Relevance: LOW

- As Found: Unknown

- ID: M4073

- Name: Anemia, Hemolytic

- Relevance: LOW

- As Found: Unknown

- ID: M4075

- Name: Anemia, Hemolytic, Congenital

- Relevance: LOW

- As Found: Unknown

- ID: M9490

- Name: Hematologic Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M9539

- Name: Hemoglobinopathies

- Relevance: LOW

- As Found: Unknown

- ID: M10200

- Name: Immune System Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M11203

- Name: Lymphatic Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M13493

- Name: Phagocyte Bactericidal Dysfunction

- Relevance: LOW

- As Found: Unknown

- ID: M10963

- Name: Leukocyte Disorders

- Relevance: LOW

- As Found: Unknown

- ID: M24877

- Name: Genetic Diseases, X-Linked

- Relevance: LOW

- As Found: Unknown

- ID: M6147

- Name: Chronic Disease

- Relevance: LOW

- As Found: Unknown

- ID: M22700

- Name: Disease Attributes

- Relevance: LOW

- As Found: Unknown

- ID: M10206

- Name: Immunoproliferative Disorders

- Relevance: LOW

- As Found: Unknown

- ID: M23455

- Name: Anemia, Hypoplastic, Congenital

- Relevance: LOW

- As Found: Unknown

- ID: M4071

- Name: Anemia, Aplastic

- Relevance: LOW

- As Found: Unknown

- ID: M14852

- Name: Red-Cell Aplasia, Pure

- Relevance: LOW

- As Found: Unknown

- ID: M2241

- Name: Bone Marrow Failure Disorders

- Relevance: LOW

- As Found: Unknown

- ID: M13118

- Name: Pancytopenia

- Relevance: LOW

- As Found: Unknown

- ID: M2242

- Name: Congenital Bone Marrow Failure Syndromes

- Relevance: LOW

- As Found: Unknown

- ID: M5134

- Name: Bone Marrow Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M21977

- Name: Hemostatic Disorders

- Relevance: LOW

- As Found: Unknown

- ID: M5059

- Name: Blood Coagulation Disorders

- Relevance: LOW

- As Found: Unknown

- ID: M23095

- Name: Blood Coagulation Disorders, Inherited

- Relevance: LOW

- As Found: Unknown

- ID: M11224

- Name: Lymphopenia

- Relevance: LOW

- As Found: Unknown

- ID: M10973

- Name: Leukopenia

- Relevance: LOW

- As Found: Unknown

- ID: M3170

- Name: Cytopenia

- Relevance: LOW

- As Found: Unknown

- ID: M9560

- Name: Hemorrhagic Disorders

- Relevance: LOW

- As Found: Unknown

- ID: M2285

- Name: Primary Immunodeficiency Diseases

- Relevance: LOW

- As Found: Unknown

- ID: T1303

- Name: Chronic Graft Versus Host Disease

- Relevance: LOW

- As Found: Unknown

- ID: T5622

- Name: Thalassemia

- Relevance: HIGH

- As Found: Thalassemia

- ID: T1304

- Name: Chronic Granulomatous Disease

- Relevance: HIGH

- As Found: Chronic Granulomatous Disease

- ID: T5990

- Name: X-linked Lymphoproliferative Syndrome

- Relevance: HIGH

- As Found: X-linked Lymphoproliferative Disease

- ID: T1837

- Name: Diamond-Blackfan Anemia

- Relevance: HIGH

- As Found: Diamond Blackfan Anemia

- ID: T5939

- Name: Wiskott Aldrich Syndrome

- Relevance: HIGH

- As Found: Wiskott-Aldrich Syndrome

- ID: T4833

- Name: Pure Red Cell Aplasia

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000013789

- Term: Thalassemia

- ID: D000006105

- Term: Granulomatous Disease, Chronic

- ID: D000008232

- Term: Lymphoproliferative Disorders

- ID: D000029503

- Term: Anemia, Diamond-Blackfan

- ID: D000014923

- Term: Wiskott-Aldrich Syndrome

- ID: D000030342

- Term: Genetic Diseases, Inborn

- ID: D000008659

- Term: Metabolic Diseases

- ID: D000007153

- Term: Immunologic Deficiency Syndromes

### Intervention Browse Module - Ancestors

- ID: D000007166

- Term: Immunosuppressive Agents

- ID: D000007155

- Term: Immunologic Factors

- ID: D000045505

- Term: Physiological Effects of Drugs

- ID: D000018501

- Term: Antirheumatic Agents

- ID: D000018906

- Term: Antineoplastic Agents, Alkylating

- ID: D000000477

- Term: Alkylating Agents

- ID: D000045504

- Term: Molecular Mechanisms of Pharmacological Action

- ID: D000000970

- Term: Antineoplastic Agents

- ID: D000019653

- Term: Myeloablative Agonists

### Intervention Browse Module - Browse Branches

- Abbrev: All

- Name: All Drugs and Chemicals

- Abbrev: ANeo

- Name: Antineoplastic Agents

- Abbrev: ARhu

- Name: Antirheumatic Agents

### Intervention Browse Module - Browse Leaves

- ID: M16759

- Name: Tin Fluorides

- Relevance: LOW

- As Found: Unknown

- ID: M6727

- Name: Cyclophosphamide

- Relevance: HIGH

- As Found: Cycle

- ID: M283230

- Name: Fludarabine

- Relevance: LOW

- As Found: Unknown

- ID: M5336

- Name: Busulfan

- Relevance: LOW

- As Found: Unknown

- ID: M225513

- Name: Fludarabine phosphate

- Relevance: LOW

- As Found: Unknown

- ID: M1347

- Name: Alemtuzumab

- Relevance: LOW

- As Found: Unknown

- ID: M10212

- Name: Immunosuppressive Agents

- Relevance: LOW

- As Found: Unknown

- ID: M10201

- Name: Immunologic Factors

- Relevance: LOW

- As Found: Unknown

- ID: M20604

- Name: Antirheumatic Agents

- Relevance: LOW

- As Found: Unknown

- ID: M20942

- Name: Antineoplastic Agents, Alkylating

- Relevance: LOW

- As Found: Unknown

- ID: M3820

- Name: Alkylating Agents

- Relevance: LOW

- As Found: Unknown

### Intervention Browse Module - Meshes

- ID: D000003520

- Term: Cyclophosphamide

### Misc Info Module

- Version Holder: 2024-05-24

## Results Section

### Adverse Events Module

#### Event Groups

**Group ID:** EG000

**Title:** Cyclophosphamide Dose Level 1

**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.

**ID:** EG000

**Other Num Affected:** 7

**Other Num at Risk:** 20

**Serious Number Affected:** 2

**Serious Number At Risk:** 20

**Title:** Cyclophosphamide Dose Level 1

**Frequency Threshold:** 0

#### Other Events

**Term:** Cytomegalovirus (CMV) infection

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Notes:** Re-activation of cytomegalovirus (CMV) in 5/20 enrolled subjects documented by blood CMV Polymerase Chain Reaction (PCR) test.

**Organ System:** Blood and lymphatic system disorders

**Source Vocabulary:** Viral Infection

**Term:** Epstein-Barr Virus (EBV)

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Notes:** Epstein-Barr Virus (EBV) was documented to be positive in 1/20 subjects enrolled in the study; confirmed by Polymerase Chain Reaction (PCR).

**Organ System:** Blood and lymphatic system disorders

**Source Vocabulary:** Viremia, Epstein-Bar

**Term:** Adenovirus

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Notes:** Adenovirus was detected in one (1) enrolled subject by blood PCR.

**Organ System:** Blood and lymphatic system disorders

**Source Vocabulary:** Adenovirus

#### Serious Events

**Term:** Death due to pre-exisiting mucormycosis

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Notes:** Subject had pretransplant history of mucormycosis infection. Patient was received anti-fungal medications.

**Organ System:** Respiratory, thoracic and mediastinal disorders

**Source Vocabulary:** Fungal infection

##### Stats

**Group ID:** EG000

**Num Affected:** 1

**Num At Risk:** 20

**Num Events:** 1

**Term:** Death due to interstitial pneumonia

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Notes:** Subject developed interstitial pneumonia on Day +187 post transplant. Onset thought to be community acquired pneumonia.

**Organ System:** Respiratory, thoracic and mediastinal disorders

**Source Vocabulary:** Pneumonia

##### Stats

**Group ID:** EG000

**Num Affected:** 1

**Num At Risk:** 20

**Num Events:** 1

**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.

## Results Section - Baseline Characteristics Module

### Denomination Counts

**Group ID:** BG000

**Value:** 20

**Units:** Participants

### Group

**ID:** BG000

**Title:** Cyclophosphamide Dose Level 1

**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.

### Measure

#### Measurement

**Group ID:** BG000

**Value:** 19

**Category Title:** <=18 years

#### Measurement

**Group ID:** BG000

**Value:** 1

**Category Title:** Between 18 and 65 years

#### Measurement

**Group ID:** BG000

**Value:** 0

**Category Title:** >=65 years

**Class Title:** 

### Measure

#### Measurement

**Group ID:** BG000

**Lower Limit:** .4

**Upper Limit:** 26

**Value:** 2.3

**Class Title:** 

### Measure

#### Measurement

**Group ID:** BG000

**Value:** 13

**Category Title:** Female

#### Measurement

**Group ID:** BG000

**Value:** 7

**Category Title:** Male

**Class Title:** 

### Measure

#### Measurement

**Group ID:** BG000

**Value:** 20

**Class Title:** United States

**Denomination Units Selected:** 

## Results Section - Baseline Characteristics Module

### Measure 1
**Parameter Type:** COUNT_OF_PARTICIPANTS
**Title:** Age, Categorical
**Unit of Measure:** Participants
### Measure 2
**Description:** Deviation from study protocol - enrollment of 26-year-old subject with pediatric disease. Subject's data included in outcome measurements/analysis.
**Dispersion Type:** FULL_RANGE
**Parameter Type:** MEDIAN
**Title:** Age, Continuous
**Unit of Measure:** years
### Measure 3
**Parameter Type:** COUNT_OF_PARTICIPANTS
**Title:** Gender
**Unit of Measure:** Participants
### Measure 4
**Description:** Enrollment of participants was conducted in California.
**Parameter Type:** NUMBER
**Title:** Region of Enrollment
**Unit of Measure:** participants
## Results Section - More Information Module
### Certain Agreement
### Limitations and Caveats
**Description:** De-escalation was not ensued. All enrolled subjects engrafted without toxicity for dose level one.
### Point of Contact
**Email:** nkapoor@chla.usc.edu
**Organization:** Children's Hospital Los Angeles
**Phone:** 343-361-2434
**Title:** Neena Kapoor, M.D.
## Results Section - Outcome Measures Module
### Outcome Measure 1
### Outcome Measure 2
### Outcome Measure 3
### Outcome Measure 4
### Outcome Measure 5
## Results Section
### Outcome Measures Module
#### Outcome Measure 1
**Class:**
##### Category
**Measurements:**
- **Comment:** 
- **Group ID:** OG000
- **Lower Limit:** 
- **Spread:** 
- **Upper Limit:** 
- **Value:** 20
**Title:** 
#### Outcome Measure 2
**Class:**
##### Category
**Measurements:**
- **Comment:** 
- **Group ID:** OG000
- **Lower Limit:** 
- **Spread:** 
- **Upper Limit:** 
- **Value:** 0
**Title:** 
#### Outcome Measure 3
**Class:**
##### Category
**Measurements:**
- **Comment:** 
- **Group ID:** OG000
- **Lower Limit:** 
- **Spread:** 
- **Upper Limit:** 
- **Value:** 0
**Title:** 
**Class:**
##### Category
**Measurements:**
- **Comment:** 
- **Group ID:** OG000
- **Lower Limit:** 
- **Spread:** 
- **Upper Limit:** 
- **Value:** 8
**Title:** 
**Class:**
##### Category
**Measurements:**
- **Comment:** 
- **Group ID:** OG000
- **Lower Limit:** 
- **Spread:** 
- **Upper Limit:** 
- **Value:** 0
**Title:** 
**Class:**
##### Category
**Measurements:**
- **Comment:** 
- **Group ID:** OG000
- **Lower Limit:** 
- **Spread:** 
- **Upper Limit:** 
- **Value:** 0
**Title:** 
#### Outcome Measure 4
**Class:**
##### Category
**Measurements:**
- **Comment:** 
- **Group ID:** OG000
- **Lower Limit:** 
- **Spread:** 
- **Upper Limit:** 
- **Value:** 10
**Title:** 
**Class:**
##### Category
**Measurements:**
- **Comment:** 
- **Group ID:** OG000
- **Lower Limit:** 
- **Spread:** 
- **Upper Limit:** 
- **Value:** 0
**Title:** 
**Class:**
##### Category
**Measurements:**
- **Comment:** 
- **Group ID:** OG000
- **Lower Limit:** 
- **Spread:** 
- **Upper Limit:** 
- **Value:** 0
**Title:** 
#### Outcome Measure 5
**Class:**
##### Category
**Measurements:**
- **Comment:** 
- **Group ID:** OG000
- **Lower Limit:** 
- **Spread:** 
- **Upper Limit:** 
- **Value:** 19
**Title:** 
**Class:**
##### Category
**Measurements:**
- **Comment:** 
- **Group ID:** OG000
- **Lower Limit:** 
- **Spread:** 
- **Upper Limit:** 
- **Value:** 18
**Title:** 
**Class:**
##### Category
**Measurements:**
- **Comment:** 
- **Group ID:** OG000
- **Lower Limit:** 
- **Spread:** 
- **Upper Limit:** 
- **Value:** 20
**Title:** 
## Results Section
### Outcome Measures Module
#### Outcome Measure 1
**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
**Parameter Type:** NUMBER
**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.
**Reporting Status:** POSTED
**Time Frame:** 30 days
**Title:** Number of Participants With Neutrophil Engraftment (=/>500 Cells/uL) and Platelet Engraftment (>20K Cell/uL) at 30 Days
**Type:** PRIMARY
**Unit of Measure:** participants
##### 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.
**ID:** OG000
**Title:** Cyclophosphamide Dose Level 1
#### Outcome Measure 2
**Description:** assess rate of disease recurrence ("late relapse") due to autologous recovery of recipient hematopoiesis at one year post-HSCT.
**Parameter Type:** NUMBER
**Population Description:** All subjects who received dose level 1 of Cyclophosphamide did not experience re-occurrence of disease.
**Reporting Status:** POSTED
**Time Frame:** 1 year
**Title:** Number of Participants With Disease Recurrence at 1 Year Post-transplant
**Type:** PRIMARY
**Unit of Measure:** participants
##### 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.
**ID:** OG000
**Title:** Cyclophosphamide Dose Level 1
#### Outcome Measure 3
**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.
**Parameter Type:** NUMBER
**Population Description:** Subjects who received dose level 1 of Cyclophosphamide did not experience veno-occlusive disease, organ failure or severe mucositis.
**Reporting Status:** POSTED
**Time Frame:** 1 year
**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
**Type:** PRIMARY
**Unit of Measure:** participants
##### 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.
**ID:** OG000
**Title:** Cyclophosphamide Dose Level 1
#### Outcome Measure 4
**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.
**Parameter Type:** NUMBER
**Population Description:** Subjects who received dose level 1 of Cyclophosphamide were revaluated for graft-versus-host disease (GVHD) post transplantation.
**Reporting Status:** POSTED
**Time Frame:** 1 yr
**Title:** Number of Participants Who Developed Graft-Versus-Host-Disease (GVHD) as Determined by the Glucksberg Scale
**Type:** SECONDARY
**Unit of Measure:** participants
##### 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.
**ID:** OG000
**Title:** Cyclophosphamide Dose Level 1
#### Outcome Measure 5
**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.
**Parameter Type:** NUMBER
**Population Description:** Subjects receiving dose level 1 of Cyclophosphamide event free survival post transplant at 100 days was 95% and 90% 1 year.
**Reporting Status:** POSTED
**Time Frame:** 1 yr
**Title:** Number of Participants Who Were Disease Progression-Free and Death-Free at 1 Year Post-transplant
**Type:** SECONDARY
**Unit of Measure:** participants
##### 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.
**ID:** OG000
**Title:** Cyclophosphamide Dose Level 1
### Participant Flow Module
#### 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.
**ID:** FG000
**Title:** Cyclophosphamide Dose Level 1
#### Group
**Description:** 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.
**ID:** FG001
**Title:** Cyclophosphamide Dose Level 2
#### Period
**Title:** Overall Study
##### Milestone
**Type:** STARTED
###### Achievement
**Group ID:** FG000
**Number of Subjects:** 20
###### Achievement
**Group ID:** FG001
**Number of Subjects:** 0
##### Milestone
**Type:** COMPLETED
###### Achievement
**Group ID:** FG000
**Number of Subjects:** 20
###### Achievement
**Group ID:** FG001
**Number of Subjects:** 0
##### Milestone
**Type:** NOT COMPLETED
###### Achievement
**Group ID:** FG000
**Number of Subjects:** 0
###### Achievement
**Group ID:** FG001
**Number of Subjects:** 0
**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.
**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.
**Has Results:** True