A Two-Step Approach to Bone Marrow Transplant Using Cells From A Partially-Matched Relative

• Sponsor: Sidney Kimmel Cancer Center at Thomas Jefferson University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00429143
• Collaborator: (none)
• Enrollment: 27
• Location: 1
• Arm: 1
• Duration (Months): 53
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

The purpose of this study is to develop a way of treating patients who do not have a completely matched family donor or a readily available unrelated donor with bone marrow transplant by using a partially-matched family donor. Patients receiving this type of transplant will receive chemotherapy and/or radiation to treat their disease. They will also receive their donor's cells in 2 parts. During the first part, the donor's lymphocytes will be exposed to one of the chemotherapy agents to help the patient become tolerant to the lymphocytes. In the second part of the transplant, the patient will receive their donor's stem cells to help recover their peripheral blood counts and establish long-term engraftment. The hypothesis of this study is that in partially-matched allogeneic transplant, there is a defined number of donor T-cells that can be treated and given to the recipient to avoid post-transplant infection without causing severe graft-versus-host disease.

Condition or Disease	Intervention/Treatment	Phase
Hematologic Malignancies	Radiation: Total Body Irradiation (TBI); Biological: Donor Lymphocyte Infusion (DLI); Drug: Cyclophosphamide (CY); Drug: Tacrolimus; Drug: Mycophenolate Mofetil (MMF); Biological: Hematopoietic Stem Cell Transplant (HSCT)	Phase 1/Phase 2

Detailed Description

Haploidentical hematopoietic stem cell transplant is a life-saving therapy for patients who are without well matched donors. This type of therapy has been associated with poor outcomes in the past due to complications such as infection. The Jefferson 2 Step approach was designed to allow the infusion of an exact dose of tolerized lymphocytes in haploidentical transplant in order to allow for immune reconstitution post transplant to avoid infectious complications while still having acceptable rates of GVHD. In this approach, patients with high-risk hematological malignancies undergo 8 fractions of TBI (12 Gy) followed by an exact dose of donor lymphocytes. The phase I portion of the study determined the optimal dose of lymphocytes. Two days after receiving the donor lymphocytes, the patients receive 2 daily doses of cyclophosphamide. One day after receiving cyclophosphamide, the patients receive stem cell from their donor. Tacrolimus and mycophenylate mofetil are used as GVHD prophylaxis.

Study Design

• Study Type: Interventional
• Actual Enrollment: 27 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Two Step Approach To Allogeneic Hematopoietic Stem Cell Transplantation for Hematologic Malignancies From HLA Partially-Matched Related Donors
• Study Start Date: Jan 1, 2006
• Actual Primary Completion Date: Aug 1, 2009
• Actual Study Completion Date: Jun 1, 2010

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Haploidentical Allogeneic Transplantation Patients undergoing hematopoietic stem cell transplant from a partially matched related donor

Radiation: Total Body Irradiation (TBI); TBI twice daily days 6-9 prior to transplant (HSCT); Other Names: TBI radiotherapy ; Biological: Donor Lymphocyte Infusion (DLI); DLI given 6 days prior to transplant (HSCT).; Other Names: DLI T cell infusion ; Drug: Cyclophosphamide (CY); Cyclophosphamide given once daily at 60 mg/kg on days 2 and 3 prior to transplant (HSCT).; Other Names: CY Endoxan Cytoxan Neosar Procytox Revimmune cytophosphane ; Drug: Tacrolimus; Tacrolimus given one day prior to transplant (HSCT).; Other Names: FK-506 fujimycin Prograf Advagraf Protopic ; Drug: Mycophenolate Mofetil (MMF); MMF given one day prior to transplant (HSCT).; Other Names: MMF CellCept Myfortic ; Biological: Hematopoietic Stem Cell Transplant (HSCT); CD34+ selected Hematopoietic Stem Cell Transplant (HSCT) is performed. This is the day of transplantation.; Other Names: HSCT stem cell transplant

Outcome Measures

Primary Outcome Measures

1. Overall Survival of Participants [6 months]

   To determine overall survival at 6 months post-transplant.

2. Optimal Dose of CD3+ Donor Lymphocytes (T-cells) for Consistent Engraftment Without GVHD [6 months]

   To determine the optimal dose of CD3+ donor lymphocytes required for consistent engraftment without the development of grade III/IV GVHD. Measured as CD3+ donor lymphocytes given as n x 10^8/kg. "n" was found to be 2 and was found to be the optimal dose and was the only dose given.

Secondary Outcome Measures

1. Engraftment Rates [6 months]

   To assess hematopoietic engraftment rates.

2. Lymphoid Recovery [6 months]

   To assess the pace of lymphoid recovery in this patient population.

3. Incidence of Grades III-IV GVHD [6 months]

   To determine the incidence and severity of GVHD in these patients using a combination of cyclophosphamide, tacrolimus and mycophenolate mofetil (MMF) as GVHD prophylaxis.' Severity was graded using CTCAE 3.0 (1=mild, 2=moderate, 3=severe, 4=life threatening/disabling, 5=death)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Any patient with a hematologic or oncologic diagnosis in which allogeneic HSCT is thought to be beneficial, and in whom front-line therapy has already been applied.

2. Patients must have a related donor who is either a one, two or three out of six antigen mismatch at the HLA-A;B;DR loci.

3. Patients without a well-matched unrelated donor or those who have a disease status that precludes a wait for an identified unrelated donor.

4. Patients must adequate organ function:

• LVEF of >45%

• FVC or FEV1 >45% of predicted

• Adequate liver function as defined by a serum bilirubin <1.8, AST or ALT < 2.5X upper limit of normal

• Serum creatinine < 2.0 mg/dl or creatinine clearance of > 40 ml/min

1. Performance status > 60% (Karnofsky)

2. Patients must be willing to use contraception if they have childbearing potential

3. Able to give informed consent

Exclusion Criteria:

1. An eligible HLA-identical sibling donor.

2. Performance status < 60% (Karnosfsky)

3. HIV positive

4. Active involvement of the central nervous system with malignancy

5. Psychiatric disorder that would preclude patients from signing an informed consent

6. Pregnancy

7. Patients with life expectancy of < 6 months for reasons other than their underlying hematologic/oncologic disorder.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Thomas Jefferson University	Philadelphia	Pennsylvania	United States	19107

Sponsors and Collaborators

• Sidney Kimmel Cancer Center at Thomas Jefferson University

Investigators

• Principal Investigator: Neal Flomenberg, MD, Thomas Jefferson University

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Kimmel Cancer Center at Thomas Jefferson University, an NCI-Designated Cancer Center
• Thomas Jefferson University Hospitals

Publications

None provided.

• Responsible Party: Sidney Kimmel Cancer Center at Thomas Jefferson University
• ClinicalTrials.gov Identifier: NCT00429143
• Other Study ID Numbers: 06U.20; 2005-84
• First Posted: Jan 31, 2007
• Last Update Posted: Nov 29, 2016
• Last Verified: Oct 1, 2016

• Keywords provided by Sidney Kimmel Cancer Center at Thomas Jefferson University: Hematologic Malignancies; Two Step Approach; Haploidentical Transplant
• Additional relevant MeSH terms: Neoplasms; Hematologic Neoplasms; Mycophenolic Acid; Cyclophosphamide; Tacrolimus

Study Results

Participant Flow

Recruitment Details	Patients presenting to Thomas Jefferson University with hematological malignancies requiring hematopoeitic stem cell transplantation without matched related donors. Opened January, 2006 through August, 2009

Arm/Group Title	Haploidentical Allogeneic Transplantation
Arm/Group Description	Patients undergoing hematopoietic stem cell transplant from a partially matched related donor
Period Title: Overall Study
STARTED	27
COMPLETED	27
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Haploidentical Allogeneic Transplantation
Arm/Group Description	Patients undergoing hematopoietic stem cell transplant from a partially matched related donor
Overall Participants	27
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	24 88.9%
>=65 years	3 11.1%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	50 (12.9)
Sex: Female, Male (Count of Participants)
Female	16 59.3%
Male	11 40.7%
Region of Enrollment (participants) [Number]
United States	27 100%

Outcome Measures

1. Primary Outcome

Title	Overall Survival of Participants
Description	To determine overall survival at 6 months post-transplant.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

27 Patients undergoing haploidentical transplant at Thomas Jefferson University

Arm/Group Title	Haploidentical Allogeneic Transplantation
Arm/Group Description	Patients undergoing hematopoietic stem cell transplant from a partially matched related donor
Measure Participants	27
Number [participants]	13 48.1%

2. Primary Outcome

Title	Optimal Dose of CD3+ Donor Lymphocytes (T-cells) for Consistent Engraftment Without GVHD
Description	To determine the optimal dose of CD3+ donor lymphocytes required for consistent engraftment without the development of grade III/IV GVHD. Measured as CD3+ donor lymphocytes given as n x 10^8/kg. "n" was found to be 2 and was found to be the optimal dose and was the only dose given.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Two patients died prior to expected day of engraftment

Arm/Group Title	Haploidentical Allogeneic Transplantation
Arm/Group Description	Patients undergoing hematopoietic stem cell transplant from a partially matched related donor
Measure Participants	25
Number [lymphocytes x 10^8/kg]	2

3. Secondary Outcome

Title	Engraftment Rates
Description	To assess hematopoietic engraftment rates.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Two patients died prior to expected engraftment day

Arm/Group Title	Haploidentical Allogeneic Transplantation
Arm/Group Description	Patients undergoing hematopoietic stem cell transplant from a partially matched related donor
Measure Participants	25
Number [participants]	23 85.2%

4. Secondary Outcome

Title	Lymphoid Recovery
Description	To assess the pace of lymphoid recovery in this patient population.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Two patients did not engraft, two patients died prior to expected day of engraftment

Arm/Group Title	Haploidentical Allogeneic Transplantation
Arm/Group Description	Patients undergoing hematopoietic stem cell transplant from a partially matched related donor
Measure Participants	23
Number [participants]	23 85.2%

5. Secondary Outcome

Title	Incidence of Grades III-IV GVHD
Description	To determine the incidence and severity of GVHD in these patients using a combination of cyclophosphamide, tacrolimus and mycophenolate mofetil (MMF) as GVHD prophylaxis.' Severity was graded using CTCAE 3.0 (1=mild, 2=moderate, 3=severe, 4=life threatening/disabling, 5=death)
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Two patients died prior to expected engraftment. Two patients who rejected were retransplanted and were evaluable for GVHD.

Arm/Group Title	Haploidentical Allogeneic Transplantation
Arm/Group Description	Patients undergoing hematopoietic stem cell transplant from a partially matched related donor
Measure Participants	25
Number [participants]	2 7.4%

Adverse Events

Time Frame	6 Months
Arm/Group Title	Haploidentical Allogeneic Transplantation
Arm/Group Description	Patients undergoing hematopoietic stem cell transplant from a partially matched related donor
All Cause Mortality
	Haploidentical Allogeneic Transplantation
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Haploidentical Allogeneic Transplantation
	Affected / at Risk (%)	# Events
Total	23/27 (85.2%)
Gastrointestinal disorders
Diarrhea	2/27 (7.4%)	2
Nausea	1/27 (3.7%)	1
General disorders
Death - Disease progression NOS	5/27 (18.5%)	5
Death - Multi-organ failure	3/27 (11.1%)	3
Constitutional Symptoms - Other	1/27 (3.7%)	1
Death - Death NOS	2/27 (7.4%)	2
Hepatobiliary disorders
Liver dysfunction/failure	1/27 (3.7%)	1
Immune system disorders
Cytokine release syndrome/acute infusion reaction	1/27 (3.7%)	1
Infections and infestations
Opportunistic infection associated with >=Grade 2 Lymphopenia	8/27 (29.6%)	9
Infection - Other	4/27 (14.8%)	4
Infection with normal ANC or Grade 1 or 2 neutrophils	2/27 (7.4%)	2
Renal and urinary disorders
Renal/Genitourinary - Other	1/27 (3.7%)	1
Respiratory, thoracic and mediastinal disorders
Pneumonitis/pulmonary infiltrates	1/27 (3.7%)	1
Hypoxia	1/27 (3.7%)	1
Vascular disorders
Thrombosis/embolism	1/27 (3.7%)	1
Other (Not Including Serious) Adverse Events
	Haploidentical Allogeneic Transplantation
	Affected / at Risk (%)	# Events
Total	27/27 (100%)
Gastrointestinal disorders
Mucositis/stomatitis	23/27 (85.2%)	23
Metabolism and nutrition disorders
Bilirubin	3/27 (11.1%)	3
Renal and urinary disorders
Renal/Genitourinary - Other	2/27 (7.4%)	2

Limitations/Caveats

Limitations of the trial include small sample size and single institution

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.