Transplantation of Umbilical Cord Blood Following Chemotherapy for Blood Cancers

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00539656
• Collaborator: Children's Cancer Foundation (Other)
• Enrollment: 3
• Location: 1
• Arm: 1
• Actual Duration (Months): 22
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This study is to evaluate the safety of transplantation of two cord blood products, including toxicities in patients following high-dose, myeloablative chemotherapy for blood malignancies. It is also to determine if the use of two cord products results in an improvement in neutrophil engraftment.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia; Leukemia, Lymphoblastic, Acute; Leukemia, Bilineage, Acute; Leukemia, Myeloid, Chronic	Biological: Ex vivo expansion of cord blood	Phase 1/Phase 2

Detailed Description

The success of BMT as a curative option for patients with malignancies is frequently limited by the inability to identify an appropriate donor in time for transplantation.

Transplantations utilizing umbilical cord blood stem cells are increasingly successful. Data suggest that there are fewer and less developed T-cells in cord products when compared to bone marrow and so are likely to produce less graft-vs.-host disease (GVHD) even in the mismatched setting. In addition, the grafts are easily available second to the ease of collection as compared with other sources such as bone marrow and peripheral blood stem cells (PBSCs). The ability to build cord blood repositories containing samples with HLA types from minorities has and will continue to increase the likelihood of finding suitable products for under represented minorities such as African-Americans, Hispanic populations and mixed ethnic populations.

Unfortunately, limitations remain, secondary to the time to engraftment when the cell dose is less than optimal, resulting in delayed or failed engraftment. In addition, increased cell dose appears to be associated with disease free survival. Therefore, this modality of transplant is generally limited to smaller patients. This protocol evaluates the infusion and engraftment of two cord blood products - one that has been expanded ex vivo and one that has not been expanded following myeloablative chemotherapy for the treatment of hematological malignancies.

Primary Objective:

-To evaluate the safety of transplantation of two cord products including an expanded unit including infusional toxicities and potential immunologic competition.

Secondary Objective:

-To determine if the use of two cord products results in an improvement in neutrophil engraftment (ANC>500) in subjects as demonstrated by engraftment <=21 days.

Tertiary Objectives:

Patients will be compared with patients participating in other trials at our institution and to those who receive therapy as per standard of care.

• To evaluate the rate, extent, and durability of hematopoietic reconstitution and in particular to determine the relative contribution of each cord unit in early engraftment and long-term engraftment

• To estimate the rate and severity of graft-vs-host disease

• To estimate the rates of infectious complications

• To obtain preliminary data regarding disease-free and overall survival

• To collect samples for future studies of immune reconstitution and for future studies in the laboratory regarding disease and the immune system

We will be able to track the fate of both the unmanipulated and expanded CB progenitors by evaluating differences in the cord products and the recipient by evaluation of sex mismatch, HLA type and/or restriction length polymorphisms (RFLPs). If the expanded CB cells are detected in the patients long-term, this will give us confidence to use expanded CB as the sole hematopoietic progenitor cell support, in future studies.

The major risk is non-engraftment of either one or both of the cord blood units. Non-engraftment of one of the units may lead to prolonged cytopenia and a marked increased risk for infection. Failure of either unit to engraft as defined as failure to detect cells from either cord blood product at Day +60 is likely to result in the death of the subject. There is the possibility of failure of long-term engraftment from both cords. This would be fatal unless an alternative donor option was identified or the unlikely event of autologous reconstitution of bone marrow. There is a possibility of an immune competition of both cord blood products . This could result in the loss of the cord product that would have been responsible for long term engraftment. There is a possibility of the expanded cord product to fail release testing. In this event, only the unexpanded cord would be infused and would likely result in delayed engraftment.

As with all cellular products there are risks associated with the infusion including but not limited to anaphylaxis, transfusion reaction, hemolysis, side-effects of the DMSO that the product is stored in (bradycardia, hypothermia, neurologic changes). The expanded product will be washed however there remains a small chance that a small amount of growth factor remains. The risk associated with these will be allergic.

Busulfan toxicity

1. Nausea and vomiting

2. Myeloablation

3. Pulmonary complications

4. Seizures

5. Other toxic effects which may be produced by Busulfan erythematous skin rash, hyperpigmentation, hepatic dysfunction, amenorrhea, testicular atrophy, gynecomastia, myasthenia symptoms, cataract and atrophic bronchitis associated with cytologic dysplasia.

Cyclophosphamide Toxicity

1. Leukopenia, anemia

2. Alopecia

3. Nausea, vomiting, increased AST, ALT, mucositis, diarrhea

4. Headache, dizziness

5. Cardiac necrosis rarely with high dose cyclophosphamide

6. Hemorrhagic cystitis, SIADH

7. Teratogenic, may cause secondary neoplasms, anaphylaxis (rare)

8. Fluid retention.

9. Cardiomyopathy.

10. Hemorrhagic Cystitis.

At the doses used for uroprotection mesna is virtually non-toxic. However, adverse effects which may be attributable to mesna include nausea and vomiting, diarrhea, abdominal pain, altered taste, rash, urticaria, headache, joint or limb pain, hypotension and fatigue.

Total Body Irradiation Toxicity:

1. Nausea and Vomiting

2. Alopecia

3. Parotitis and Pancreatitis

4. Diarrhea

5. Fever

6. Erythema

7. Hyperpigmentation

8. Mucositis

9. Late Effects - cataract formation, growth retardation, carcinogenesis and the probability of sterilization.

Study Design

• Study Type: Interventional
• Actual Enrollment: 3 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Transplantation of Expanded and Unexpanded Umbilical Cord Blood Units Following Myeloablative Chemotherapy for Hematologic Malignancies
• Actual Study Start Date: Dec 20, 2007
• Actual Primary Completion Date: Oct 20, 2009
• Actual Study Completion Date: Oct 20, 2009

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Receive two cord blood units One cord blood unit will be thawed on day -14 before transplantation and selected using the CliniMACS for primitive cells that express CD133. These cells will be expanded ex vivo for a total of 14 days, using a two-stage procedure. On Day 0 the expanded cells will be harvested, washed three times with CliniMACS buffer (Miltenyi) plus 1% HSA per standard laboratory and clinical practice and the expanded cell product will be infused to a patient who has been prepared with a standard, myeloablative preparative regimen. A second, unexpanded, cord blood product will be infused on Day +1 for safety.

Biological: Ex vivo expansion of cord blood; Day 0: the expanded cell product will be infused to patient; Day +1: A second, unexpanded, cord blood product will be infused; Other Names: Miltenyi CliniMACS CD133

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Toxicities Related to Infusion of Expanded Cord Blood Products [7 days]

2. Neutrophil Engraftment Within 21 Days [21 days]

   Number of participants who reached 3 consecutive days with ANC > 500

Secondary Outcome Measures

1. Non-relapse Mortality [100 days]

   Number of participants who died without relapse in less than 100 days.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Months to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patient must have two cord units available. Units must be minimally matched to the subject at 4/6 antigens (HLA Class I (A or B) and Class II (DRB1) - units must have at lease one HLA DRB1 matched allele) and at least one unit must contain a minimum of 1.0 x 107 Total Nucleated Cells /Kg but neither unit may have > 5 x 107Total Nucleated Cells /Kg. (The feasibility of using particular units will be discussed with the Principal Investigators)

• Disease status precludes waiting to identify a suitably HLA matched unrelated donor

• Patients must have a diagnosis of one of the following:

• AML

• refractory AML

• Secondary AML

• ALL in CR2 with high-risk features such as short CR1 and/or high-risk cytogenetics

• ALL in CR1 following initial induction failure

• Acute mixed lineage leukemia

• CML beyond chronic phase 1.

• Lymphoma (Hodgkins or Non-Hodgkins) ineligible for Autologous-BMT

• Myelodysplastic Syndrome

• Able to provide informed consent or parent/guardian able to provide informed consent.

Exclusion Criteria:

• Consenting 5/6 or 6/6 HLA matched related donor available

• Single cord blood product with cell count >5 x10E7 Total Nucleated Cells/kg

• Poor Performance Status: ECOG performance status >= 2 (Karnofsky or Lansky Play performance<70).

• Poor Cardiac Function (obtained within 3 weeks of the start of transplant): Left ventricular ejection fraction <= 45% as determined by MUGA or ECHO. For pediatric patients LVEF < 45 % or a Shortening Fraction below normal limits for age.

• Poor Pulmonary Function (obtained within 3 weeks of the start of transplant):

• FEV1 and FVC <50% of predicted for patients who have not received thoracic or mantle irradiation.

• For patients who have received thoracic or mantle irradiation, FEV1 and FVC <= 75% of predicted or DLCO <= 50% of predicted

• For children unable to perform PFTs second to developmental stage, Pulse oximetry <= 85% on RA

• Poor Liver Function (obtained within 1 week of the start of transplant): Bilirubin >= 2.0 mg/dl. (with the exception of patients whose hyperbilirubinemia is the result of Gilbert's disease)

• Poor Renal Function (obtained within 3 weeks of the start of transplant): Corrected CrCl < 60 mg/min. CrCl will be estimated by the Schwartz formula. A measured CrCl or a GFR may be substituted to determine the subject's CrCl

• HIV Infection: Patients who are HIV positive. (The role of allogenic transplant in HIV+ individuals has not been studied)

• Pregnancy: Patients who are pregnant. (The chemotherapeutic agents used in bone marrow transplant are teratogenic)

• Uncontrolled viral, bacterial or fungal infections

• Patients with symptoms consistent with RSV, influenza A, B or parainfluenza at the time of enrollment on this study will be assayed for the above viruses and if positive are not eligible for the trial until are no longer symptomatic (patients may have continued assay positivity for a period of time post resolution of symptoms second to the nature of the assay)

• Presence of concomitant medication or incident condition that would create an unreasonable risk for the subject to participate in this study as determined by the investigators (Primary or co-investigators).

• Patients with known intolerance to or contraindication for any agent that will be used in the subject's proposed myeloablative or required supportive care regimen.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Johns Hopkins Hospital	Baltimore	Maryland	United States	21287

Sponsors and Collaborators

• Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Children's Cancer Foundation

Investigators

• Principal Investigator: Allen R. Chen, MD,PhD. MHS, Johns Hopkins University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• ClinicalTrials.gov Identifier: NCT00539656
• Other Study ID Numbers: J0606; NA_00001903; M052663
• First Posted: Oct 4, 2007
• Last Update Posted: Feb 18, 2020
• Last Verified: Feb 1, 2020

• Keywords provided by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins: Cord blood stem cell transplantation; Ex vivo expansion; Alternative donor
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Study Results

Participant Flow

Arm/Group Title	Single Arm
Arm/Group Description	Patients with a hematologic malignancy who are candidates for myeloablative allogeneic BMT but lack an available matched sibling or unrelated marrow donor are eligible for this study if they have two suitably matched cord blood products with an adequate (1 x 10e7 TNC/kg IBW) but suboptimal (<5 x 10e7 TNC/kg IBW) cell dose. Eligible diagnoses include AML, MDS, ALL after failure of at least one regimen, mixed lineage leukemia, CML beyond first chronic phase, and lymphoma ineligible for autologous transplantation.
Period Title: Overall Study
STARTED	3
COMPLETED	3
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Single Arm
Arm/Group Description	Patients with a hematologic malignancy who are candidates for myeloablative allogeneic BMT but lack an available matched sibling or unrelated marrow donor are eligible for this study if they have two suitably matched cord blood products with an adequate (1 x 10e7 TNC/kg IBW) but suboptimal (<5 x 10e7 TNC/kg IBW) cell dose. One cord blood unit is expanded beginning 14 days before graft infusion (6 or 7 days before the start of the preparative regimen). Patients receive a standard myeloablative preparative regimen. The expanded cord blood unit is infused on day 0 and the unmanipulated cord blood unit is expanded on day 1.
Overall Participants	3
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	3 100%
>=65 years	0 0%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	37
Sex: Female, Male (Count of Participants)
Female	2 66.7%
Male	1 33.3%
Region of Enrollment (Count of Participants)
United States	3 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Toxicities Related to Infusion of Expanded Cord Blood Products
Time Frame	7 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Receive Two Cord Blood Units
Arm/Group Description	Ex vivo expansion of cord blood: Day 0: the expanded cell product will be infused to patient; Day +1: A second, unexpanded, cord blood product will be infused
Measure Participants	3
Count of Participants [Participants]	0 0%

2. Primary Outcome

Title	Neutrophil Engraftment Within 21 Days
Description	Number of participants who reached 3 consecutive days with ANC > 500
Time Frame	21 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Receive Two Cord Blood Units
Arm/Group Description	Ex vivo expansion of cord blood: Day 0: the expanded cell product will be infused to patient; Day +1: A second, unexpanded, cord blood product will be infused
Measure Participants	3
Engrafted by day 21	1 33.3%
Not engrafted by day 21	2 66.7%

3. Secondary Outcome

Title	Non-relapse Mortality
Description	Number of participants who died without relapse in less than 100 days.
Time Frame	100 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Receive Two Cord Blood Units
Arm/Group Description	Ex vivo expansion of cord blood: Day 0: the expanded cell product will be infused to patient; Day +1: A second, unexpanded, cord blood product will be infused
Measure Participants	3
Count of Participants [Participants]	1 33.3%

Adverse Events

Time Frame	up to 100 days
Adverse Event Reporting Description	Neutrophil count was followed based on regular lab assessments
Arm/Group Title	Single Arm
Arm/Group Description	Patients with a hematologic malignancy who are candidates for myeloablative allogeneic BMT but lack an available matched sibling or unrelated marrow donor are eligible for this study if they have two suitably matched cord blood products with an adequate (1 x 10e7 TNC/kg IBW) but suboptimal (<5 x 10e7 TNC/kg IBW) cell dose. One cord blood unit is expanded beginning 14 days before graft infusion (6 or 7 days before the start of the preparative regimen). Patients receive a standard myeloablative preparative regimen. The expanded cord blood unit is infused on day 0 and the unmanipulated cord blood unit is expanded on day 1.
All Cause Mortality
	Single Arm
	Affected / at Risk (%)	# Events
Total	1/3 (33.3%)
Serious Adverse Events
	Single Arm
	Affected / at Risk (%)	# Events
Total	1/3 (33.3%)
Respiratory, thoracic and mediastinal disorders
ARDS	1/3 (33.3%)	1
Other (Not Including Serious) Adverse Events
	Single Arm
	Affected / at Risk (%)	# Events
Total	3/3 (100%)
Blood and lymphatic system disorders
Neutropenia	3/3 (100%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.