Allo Non-myeloablative SCT Utilizing Matched Family Member Stem Cells Purged Using Campath

• Sponsor: David Rizzieri, MD (Other)
• Overall Status: Completed
• CT.gov ID: NCT00578942
• Collaborator: Miltenyi Biomedicine GmbH (Industry)
• Enrollment: 48
• Location: 1
• Arm: 1
• Duration (Months): 95
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

Allogeneic transplantation is used to treat many malignant and non-malignant diseases, though the potential toxicities of the procedure remain high. We and others have shown that a less toxic preparative regimen allows reliable allogeneic engraftment for allogeneic transplantation.

The primary purpose of this treatment trial is to follow subjects undergoing allogeneic transplantation for long term outcomes. The regimen used has been tested in our prior phase I / II trial which has completed accrual. The issues of engraftment and rate of graft versus host disease have been answered and our success has led to this regimen being a standard approach for less toxic allogeneic therapy.

Condition or Disease	Intervention/Treatment	Phase
Lymphoma; Myeloma; Leukemia; Myelodysplasia; Solid Tumors	Drug: Campath Purged Non-myeloablative ASCT	Phase 2

Detailed Description

Allogeneic bone marrow transplantation may cure or ameliorate illnesses of many types; however the toxicity of the procedure limits its broad applicability. Hematologic malignancies of all types have shown responses. Those with marrow failure, such as aplasia, and hemoglobinopathies have further shown responses in multiple trials as well. Even patients with certain solid tumors, such as breast, renal cell, and melanoma have shown partial or complete responses to allogeneic therapy. The limiting effect of the historical methods of aggressive induction for allogeneic therapy were extremely toxic, requiring limiting those offered allogeneic therapy to the healthiest of the ill patients. Work over the last decade has shown that less toxic agents targeting the immune system effectively allowed engraftment with less effects on the patient's liver, lungs, and other vital organs. We and others have completed multiple trials showing the effective use of these less toxic, non-myeloablative, regimens for allogeneic therapy. Trials with fludarabine and cyclophosphamide at standard doses (patients are not ablated and recover blood counts in 2 weeks) allow for 80% of patients to engraft donor cells. Some groups have added low doses of radiation to this combination, with 80-100% allogeneic engraftment. The lessened toxicity of this approach has been confirmed in multiple studies, including our own data with the specific schema in this treatment plan reviewed below. Phase I results with this combination: Our group has combined the above combination of fludarabine and cyclophosphamide with the antibody CAMPATH 1H. This antibody is given to the patient to purge the immune system and prevent rejection. It also purges the T cells in the donated stem cells to minimize graft versus host disease (GVHD). This approach has been proven successful in multiple trials using standard more toxic ablative procedures. Our approach over the last 3 years has been very successful using this antibody with the less toxic non-myeloablative procedure and our trials have completed. We have presented our preliminary results, with data on long term follow up for outcomes being collected. We have shown that 100% of patients with a malignancy or marrow failure treated with this regimen in our early phase trial engrafted donor cells. There was only an 8% severe GVHD risk, though the risk for infection remains high with a risk of fungal and viral infection about 5% each. Despite working with older, more infirmed patients, only 3/40 patients died within the first 100 days from therapy. Similar approaches on matched unrelated donors have been reported by other groups as well. As the phase I feasibility trial is complete and the outcomes encouraging, this protocol will follow the same general treatment plan and allow further information to be gained for long term follow up of subjects treated with this approach.

Study Design

• Study Type: Interventional
• Actual Enrollment: 48 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Allogeneic Non-myeloablative Stem Cell Transplantation Utilizing Matched Family Member Stem Cells Purged Using Campath-1H
• Study Start Date: May 1, 2005
• Actual Primary Completion Date: Apr 1, 2013
• Actual Study Completion Date: Apr 1, 2013

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Campath Purged Non-myeloablative ASCT Campath Purged Non-myeloablative Allo Stem Cell Transplant (ASCT) in lymphoma, myeloma, or marrow failure: leukemia or myelodysplasia; and solid tumors

Drug: Campath Purged Non-myeloablative ASCT; Preparative regimen: Begins on day -5 and consist of 4 days of daily fludarabine at 30 mg/m2/d infused over 30 minutes, cyclophosphamide 500 mg/m2/d infused over 1 hour, 5 days of Campath-1H at 20 mg/d in 250 ml of D5 normal saline or normal saline infused over 3 hours. Subject Evaluation will occur 2-3 times per week by physical exam for toxicity through day 45.; Other Names: Allogeneic Stem Cell Transplant (ASCT)

Outcome Measures

Primary Outcome Measures

1. Toxicity [1 year]

   Acute graft versus host disease (GVHD) was graded according to the consensus criteria and NCI common terminology criteria for adverse events (CTCAE) v2.0 or 3.0 was used for all other toxicities. Recognizing that acute GVHD pathology in the nonablative and donor lymphocyte infusion (DLI) setting may occur late, we tabulated skin, gut and liver toxicity consistent with acute GVHD (aGVHD) at anytime in the year following the infusion as aGVHD. Toxicities were formally recorded for all patients twice weekly for the first 100 days, at each follow up visit, and as needed intercurrently.

2. Overall Survival (OS) [Up to 12 years; participants were followed for the duration of the study, an average of 8 years]

   Estimate overall survival rates in subjects treated with a non-myeloablative preparative regimen followed by matched related allogeneic stem cells for allogeneic transplantation.

Secondary Outcome Measures

1. Response [1 year]

   Response Assessment included physical exam and evaluation of peripheral blood and bone marrow. There's no widely accepted criteria for response other than complete response (CR). CR for malignant hematologic diseases is met if all the following are met for >/= 1 month: absence of pathologic lymphadenopathy by physical and radiographic exam absence of constitutional symptoms due to disease Polymorphonuclear leukocyte count > 1,500/uL; platelet count >50,000/uL; and hemoglobin >10.0 g/dL bone marrow aspirate/biopsy done after (a) through (c) have been met, >/= 30% cellularity and an absence of abnormal lymphoid nodules or cells by flow cytometry, cytogenetics, etc. molecular markers of disease must be negative by polymerase chain reaction, Fluorescence in situ hybridization, cytogenetics etc. CR for solid tumors requires complete resolution of disease on physical exam and radiographs. CR for marrow failure is normal white cell, platelet and hematocrit values.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 17 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Subjects must have their pathology reviewed and the diagnosis confirmed.

• Performance status must be Cancer and Leukemia Group B (CALGB) performance score 0, 1, or 2

• Subjects must have a 6/6 Human leukocyte antigen (HLA)-matched related donor who is evaluated and deemed able to provide peripheral blood progenitor cells (PBPC) and/or marrow by the transplant team.

• HIV antibody negative.

• Subjects must test negative serum beta-human chorionic gonadotropin (HCG) and must agree to use some form of adequate birth control during the periods they receive chemotherapy and any post-chemotherapy medications related to the transplant.

• Subjects must be >/=17 years of age

• Subjects must also have a resting multigated acquisition (MUGA) and/or ECHO and pulmonary function test (PFT) with diffusion capacity of lung (DLCO) performed before transplant and found to be acceptable according to the treating institution's guidelines. The required minimum standards include MUGA and/or ECHO showing an ejection fraction (EF) of 40% and PFTs showing DLCO of 40%. Those with an EF 40-50%, undergo cardiac evaluation and consultation. Also, those with DLCO 40-50%, undergo pulmonary evaluation and consultation.

• Specific populations for each disease category:

1. Hematologic malignancies Those with high risk or relapsed hematologic malignancy (including myeloid and lymphoid leukemias and lymphomas, myeloma or myelomatous like diseases, myeloproliferative disease, myelodysplasia). Those with good risk disease (first remission acute myeloid leukemia (AML) with inv 16 M4 Eos, M3 AML with t(15;17); or t(8;21) in first remission are not eligible).

2. Bone marrow failure

1. Those specifically with idiopathic or secondary moderate, severe or very severe aplastic anemia (idiopathic or secondary) according to the accepted 'Camitta criteria' would be candidates.

2. Those with diseases known to lead to severe marrow failure are eligible as well. These include those with myelofibrosis or paroxysmal nocturnal hemoglobinuria (PNH).

1. Solid Tumors Subjects must have had a biopsy confirming disease recurrence (metastases) at some point in their history, unless the patient presented with metastatic disease, in which case the initial primary site biopsy is adequate.

1. Subjects with renal cell cancer, or melanoma will be eligible for this approach at this time. Subjects will have had documented metastatic disease at some time in the past. Subjects who are in remission or with residual disease after prior therapy for their metastatic disease are eligible, as there is no accepted cure for these patients with metastatic disease.

2. Breast Cancer- Subjects will have had documented metastatic disease at some time in the past. Subjects who are in remission or with residual disease after prior therapy for their metastatic disease are eligible. Subjects must have failed at least one chemotherapy regimen for their metastatic disease and 1 hormonal agent if they are receptor positive.

Exclusion Criteria:

1. pregnant or lactating women,

2. patients with other major medical or psychiatric illnesses which the treating physician feels could seriously compromise tolerance to this protocol, and

3. Leukemia patients in first remission with good risk cytogenetics for leukemia [t(15;17); t(8,22)]

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Duke University Health Systems	Durham	North Carolina	United States	27710

Sponsors and Collaborators

• David Rizzieri, MD
• Miltenyi Biomedicine GmbH

Investigators

• Principal Investigator: David Rizzieri, MD, Duke Health

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: David Rizzieri, MD, Professor of Medicine, Duke University
• ClinicalTrials.gov Identifier: NCT00578942
• Other Study ID Numbers: Pro00008380
• First Posted: Dec 21, 2007
• Last Update Posted: Jun 24, 2016
• Last Verified: May 1, 2016

• Keywords provided by David Rizzieri, MD, Professor of Medicine, Duke University: Allogeneic Stem Cell Transplantation, Campath, HLA-Matched
• Additional relevant MeSH terms: Preleukemia; Myelodysplastic Syndromes; Alemtuzumab

Study Results

Participant Flow

Recruitment Details	This study was opened and first consent obtained on 9/11/2002 and was closed to accrual on 2/18/2008 as enrollment goal was met. Recruitment took place at Duke hospital in the Bone Marrow Transplant clinic during time of clinical appointments in a private location. Follow up for survival was discontinued in April 2013.
Pre-assignment Detail	Prior to selecting a donor: donor and subjects had history and physical exam, labs and chest x-ray performed per program and FACT requirements. Female donors should have a negative pregnancy test. Subjects also had bone marrow aspirate/biopsy. Subjects were premedicated with Benadryl and acetaminophen.

Arm/Group Title	Campath Purged Non-myeloablative ASCT
Arm/Group Description	Campath Purged Non-myeloablative Allo Stem Cell Transplant (ASCT) in lymphoma, myeloma, or marrow failure: leukemia or myelodysplasia; and solid tumors Preparative regimen: Begins on day -5 and consist of 4 days of daily fludarabine at 30 mg/m2/d infused over 30 minutes, cyclophosphamide 500 mg/m2/d infused over 1 hour, 5 days of Campath-1H at 20 mg/d in 250 ml of D5 normal saline or normal saline infused over 3 hours. Subject Evaluation will occur 2-3 times per week by physical exam for toxicity through day 45.
Period Title: Overall Study
STARTED	48
COMPLETED	47
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Campath Purged Non-myeloablative ASCT
Arm/Group Description	Campath Purged Non-myeloablative Allo Stem Cell Transplant (ASCT) in lymphoma, myeloma, or marrow failure: leukemia or myelodysplasia; and solid tumors Preparative regimen: Begins on day -5 and consist of 4 days of daily fludarabine at 30 mg/m2/d infused over 30 minutes, cyclophosphamide 500 mg/m2/d infused over 1 hour, 5 days of Campath-1H at 20 mg/d in 250 ml of D5 normal saline or normal saline infused over 3 hours. Patient Evaluation will occur 2-3 times per week by physical exam for toxicity through day 45.
Overall Participants	48
Age (Count of Participants)
<=18 years	1 2.1%
Between 18 and 65 years	41 85.4%
>=65 years	6 12.5%
Sex: Female, Male (Count of Participants)
Female	17 35.4%
Male	31 64.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	6 12.5%
White	42 87.5%
More than one race	0 0%
Unknown or Not Reported	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 2.1%
Not Hispanic or Latino	47 97.9%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	48 100%

Outcome Measures

1. Primary Outcome

Title	Toxicity
Description	Acute graft versus host disease (GVHD) was graded according to the consensus criteria and NCI common terminology criteria for adverse events (CTCAE) v2.0 or 3.0 was used for all other toxicities. Recognizing that acute GVHD pathology in the nonablative and donor lymphocyte infusion (DLI) setting may occur late, we tabulated skin, gut and liver toxicity consistent with acute GVHD (aGVHD) at anytime in the year following the infusion as aGVHD. Toxicities were formally recorded for all patients twice weekly for the first 100 days, at each follow up visit, and as needed intercurrently.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

Cohort of subjects who received >/=1 donor lymphocyte infusion (DLI). DLI doses thus ranged from 1×104 CD3+ cells/kg to 3.27 ×108 CD3+ cells/kg.Subjects were grouped into 4 categories within the range of cell doses delivered and were considered evaluable from the day of first donor lymphocyte (DLI) infusion. Results are not exclusive.

Arm/Group Title	Campath Purged Non-myeloablative ASCT
Arm/Group Description	Campath Purged Non-myeloablative Allo Stem Cell Transplant (ASCT) in lymphoma, myeloma, or marrow failure: leukemia or myelodysplasia; and solid tumors Donor will receive Granulocyte colony-stimulating factor (G-CSF) 8 mcg/kg/d subcutaneously twice daily (dose will be rounded to the nearest whole vial size), Granulocyte-macrophage colony-stimulating factor (GM-CSF) 15 mcg/kg/d subcutaneous or similar growth factor for donor mobilization. Donors will receive at least 3-6 doses of daily growth factor until adequate cells are mobilized. Preparative regimen: Begins on day -5 and consist of 4 days of daily fludarabine at 30 mg/m2/d infused over 30 minutes, cyclophosphamide 500 mg/m2/d infused over 1 hour, 5 days of Campath-1H at 20 mg/d in 250 ml of D5 normal saline or normal saline infused over 3 hours. Subject Evaluation will occur 2-3 times per week by physical exam for toxicity through day 45.
Measure Participants	48
acute Graft versus Host Disease	21 43.8%
Death	25 52.1%

2. Primary Outcome

Title	Overall Survival (OS)
Description	Estimate overall survival rates in subjects treated with a non-myeloablative preparative regimen followed by matched related allogeneic stem cells for allogeneic transplantation.
Time Frame	Up to 12 years; participants were followed for the duration of the study, an average of 8 years

Outcome Measure Data

Analysis Population Description

Subjects who completed CAMPATH regimen + 45 days, until disease progression, or death. One participant who was lost to follow-up after 14 months was not included. Participants were followed for the duration of the study, an average of 8 years.

Arm/Group Title	Campath Purged Non-myeloablative ASCT
Arm/Group Description	Campath Purged Non-myeloablative Allo Stem Cell Transplant (ASCT) in lymphoma, myeloma, or marrow failure: leukemia or myelodysplasia; and solid tumors Donor will receive Granulocyte colony-stimulating factor (G-CSF) 8 mcg/kg/d subcutaneously twice daily (dose will be rounded to the nearest whole vial size), Granulocyte-macrophage colony-stimulating factor (GM-CSF) 15 mcg/kg/d subcutaneous or similar growth factor for donor mobilization. Donors will receive at least 3-6 doses of daily growth factor until adequate cells are mobilized. Preparative regimen: Begins on day -5 and consist of 4 days of daily fludarabine at 30 mg/m2/d infused over 30 minutes, cyclophosphamide 500 mg/m2/d infused over 1 hour, 5 days of Campath-1H at 20 mg/d in 250 ml of D5 normal saline or normal saline infused over 3 hours. Subject Evaluation will occur 2-3 times per week by physical exam for toxicity through day 45.
Measure Participants	47
Mean (Full Range) [months alive post-infusion]	32

3. Secondary Outcome

Title	Response
Description	Response Assessment included physical exam and evaluation of peripheral blood and bone marrow. There's no widely accepted criteria for response other than complete response (CR). CR for malignant hematologic diseases is met if all the following are met for >/= 1 month: absence of pathologic lymphadenopathy by physical and radiographic exam absence of constitutional symptoms due to disease Polymorphonuclear leukocyte count > 1,500/uL; platelet count >50,000/uL; and hemoglobin >10.0 g/dL bone marrow aspirate/biopsy done after (a) through (c) have been met, >/= 30% cellularity and an absence of abnormal lymphoid nodules or cells by flow cytometry, cytogenetics, etc. molecular markers of disease must be negative by polymerase chain reaction, Fluorescence in situ hybridization, cytogenetics etc. CR for solid tumors requires complete resolution of disease on physical exam and radiographs. CR for marrow failure is normal white cell, platelet and hematocrit values.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

Cohort of subjects on the study who actually received >/=1 donor lymphocyte infusion (DLI). DLI doses ranged from 1×104 CD3+ cells/kg to 3.27 ×108 CD3+ cells/kg. Subjects were considered for a second and third DLI 8 weeks apart if they did not have >grade 2 toxicity from the initial DLI, donor availability, and insurance approved the infusion.

Arm/Group Title	Campath Purged Non-myeloablative ASCT
Arm/Group Description	Campath Purged Non-myeloablative Allo Stem Cell Transplant (ASCT) in lymphoma, myeloma, or marrow failure: leukemia or myelodysplasia; and solid tumors Donor will receive Granulocyte colony-stimulating factor (G-CSF) 8 mcg/kg/d subcutaneously twice daily (dose will be rounded to the nearest whole vial size), Granulocyte-macrophage colony-stimulating factor (GM-CSF) 15 mcg/kg/d subcutaneous or similar growth factor for donor mobilization. Donors will receive at least 3-6 doses of daily growth factor until adequate cells are mobilized. Preparative regimen: Begins on day -5 and consist of 4 days of daily fludarabine at 30 mg/m2/d infused over 30 minutes, cyclophosphamide 500 mg/m2/d infused over 1 hour, 5 days of Campath-1H at 20 mg/d in 250 ml of D5 normal saline or normal saline infused over 3 hours. Subject Evaluation will occur 2-3 times per week by physical exam for toxicity through day 45.
Measure Participants	48
Number [participants]	18 37.5%

Adverse Events

Time Frame	Toxicities were formally recorded for all patients twice weekly for the first 100 days, at each follow up visit, and as needed intercurrently, up to 10 years
Adverse Event Reporting Description	NCI Common Terminology Criteria for Adverse Events version 3 was used to grade toxicities. The drug manufacturer, Berlex, required the reporting of all Serious Adverse Events associated with the study to Berlex Global Medical Safety Surveillance Group.
Arm/Group Title	Campath Purged Non-myeloablative ASCT
Arm/Group Description	Campath Purged Non-myeloablative Allo Stem Cell Transplant (ASCT) in lymphoma, myeloma, or marrow failure: leukemia or myelodysplasia; and solid tumors Preparative regimen: Begins on day -5 and consist of 4 days of daily fludarabine at 30 mg/m2/d infused over 30 minutes, cyclophosphamide 500 mg/m2/d infused over 1 hour, 5 days of Campath-1H at 20 mg/d in 250 ml of D5 normal saline or normal saline infused over 3 hours. Subject Evaluation will occur 2-3 times per week by physical exam for toxicity through day 45.
All Cause Mortality
	Campath Purged Non-myeloablative ASCT
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Campath Purged Non-myeloablative ASCT
	Affected / at Risk (%)	# Events
Total	36/48 (75%)
Blood and lymphatic system disorders
Thrombotic microangiopathy	1/48 (2.1%)	1
General disorders
Death	36/48 (75%)	36
Vascular disorders
Hemorrhage	5/48 (10.4%)	6
Other (Not Including Serious) Adverse Events
	Campath Purged Non-myeloablative ASCT
	Affected / at Risk (%)	# Events
Total	48/48 (100%)
Blood and lymphatic system disorders
Febrile neutropenia	16/48 (33.3%)	21
Cardiac disorders
Ventricular arrhythmia	2/48 (4.2%)	2
Cardiac Left Ventricular Function	2/48 (4.2%)	3
Gastrointestinal disorders
Diarrhea	8/48 (16.7%)	9
Vomiting	4/48 (8.3%)	4
Failure to engraft	1/48 (2.1%)	1
Immune system disorders
Allergic reaction / hypersensitivity	2/48 (4.2%)	2
Infections and infestations
Infection with Grade 3 or 4 neutrophils	12/48 (25%)	16
Infection with normal ANC or Grade 1/2 neutrophils	5/48 (10.4%)	6
Investigations
Creatinine	3/48 (6.3%)	4
Nervous system disorders
Neuropathy: motor	1/48 (2.1%)	2
Neuropathy: sensory	1/48 (2.1%)	1
Seizure	1/48 (2.1%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	2/48 (4.2%)	2
Hypoxia	5/48 (10.4%)	6
Pneumonitis	3/48 (6.3%)	4
Vascular disorders
Hypotension	4/48 (8.3%)	4

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.