Safety and Efficacy of Pentostatin and Low Dose TBI With Allogenic Peripheral Blood Stem Cell Transplant

• Sponsor: University of Nebraska (Other)
• Overall Status: Completed
• CT.gov ID: NCT00571662
• Collaborator: Astex Pharmaceuticals, Inc. (Industry)
• Enrollment: 76
• Location: 1
• Arm: 1
• Duration (Months): 96
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

This is a continuation of a pilot study which is now regarded as a phase II trial with a plan to enroll an additional 40 patients (20 related and 20 unrelated donor transplants) with hematological malignancy assessing the safety and efficacy of a minimally myelosuppressive regimen with pentostatin and low-dose total body irradiation (TBI) followed by allogeneic peripheral blood stem cell transplantation (alloPSCT).

Condition or Disease	Intervention/Treatment	Phase
Acute Myelogenous Leukemia; Acute Lymphocytic Leukemia; Chronic Myelogenous Leukemia; Chronic Lymphocytic Leukemia; Myelodysplastic Syndromes; Multiple Myeloma; Non-Hodgkins Lymphoma; Hodgkins Disease; Peripheral T-cell Lymphoma	Drug: Pentostatin; Radiation: Total-body irradiation (TBI); Drug: Cyclosporine A (CsA); Drug: Mycophenolate Mofetil (MMF); Drug: G-CSF	Phase 2

Detailed Description

This is a pilot study which began with a plan to enroll 50 patients (20 related and 30 unrelated donor transplants) with hematological malignancy assessing the safety and efficacy of a minimally myelosuppressive regimen with Pentostatin and low-dose total body irradiation (TBI) followed by allogeneic peripheral blood stem cell transplantation (alloPSCT). Patients with persistent or progressive malignancy after transplantation will be treated with GM-CSF (cytokine therapy) to assess its toxicity and potential therapeutic efficacy. Patients with persistent or progressive disease who fail or do not qualify for the cytokine therapy portion of the study will become candidates for donor leukocyte infusions.

The purpose of this protocol remains a pilot study which is now regarded as a phase II trial with a plan to enroll 40 ADDITIONAL patients (20 related and 20 unrelated donor transplants) with hematological malignancy assessing the safety and efficacy of a modified version of the original preparative regimen of Pentostatin and low-dose total body irradiation (TBI) followed by allogeneic peripheral blood stem cell transplantation (alloPSCT). Patients who fail will become candidates for donor-leukocyte infusion (DLI).

Primary Objectives

1. To determine the safety of treating hematological malignancies by establishing donor hematopoietic chimerism using pentostatin and low-dose total body irradiation followed by allogeneic peripheral blood stem cell transplantation.

2. To determine the immunomodulatory effects of pentostatin as part of the conditioning regimen for allogeneic peripheral blood stem cell transplantation.

Secondary Objectives

1. To determine the incidence of infections after using a minimally myelosuppressive conditioning regimen.

2. To determine the kinetics of hematological and immunological reconstitution after allotransplantation with a minimally myelosuppressive conditioning regimen.

3. To determine the incidence of chronic GVHD after using allogeneic peripheral blood stem cell transplantation with a minimally myelosuppressive preparative regimen.

4. To evaluate the role of the preparative regimen and donor source (related versus unrelated) on inflammatory cytokine profiles.

5. To evaluate blood and where possible, biopsy specimens for a recently identified nuclear protein (molecular weight 44/46) in mononuclear cells obtained from study subjects.

Interventions, evaluation, and follow up will include:

Pentostatin 4 mg/m^2/d intravenously once a day x 3 days will be administered with 1000 cc NS hydration before and after pentostatin ten days prior to stem cell infusion (days -10, -9, and -8). Total-body irradiation (TBI): TBI 2.0 Gy will be given on day -1. Antiemetics will be given as needed. Patients will receive one liter normal saline over 2 hours pre TBI. A bone marrow biopsy and aspiration with cytogenetics and flow cytometry will be performed on Day +28, Day +70 and 6, 12, 18 and 24 months following the transplant to monitor hematologic recovery. DNA fingerprinting will also be conducted at the same time at 3, 4, 5, 6, 12, 18, and 24 months to determine chimerism.

Study Design

• Study Type: Interventional
• Actual Enrollment: 76 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Allogeneic Peripheral Blood Stem Cell Transplantation With Minimally Myelosuppressive Regimen of Pentostatin and Low-dose Total-body Irradiation
• Study Start Date: Dec 1, 2000
• Actual Primary Completion Date: Dec 1, 2008
• Actual Study Completion Date: Dec 1, 2008

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Cohort I Pentostatin to be administered intravenously on days - 10, -9, and -8 at a dose of 4mg/m2/day

Drug: Pentostatin; 4 mg/m^2 intravenous(IV)once a day(QD)x3days (days -10, -9, -8); Other Names: Nipent ; Radiation: Total-body irradiation (TBI); TBI will consist of 2.0 GY at 8-12cGy/min via 6MV photons delivered AP/PA fields, without lung blocks or via lateral fields with lucite compensator along the head and neck region. TLD (thermal luminescent dosimetry) will be used to verify dose uniformity. TBI will be given on day -1.; Drug: Cyclosporine A (CsA); CsA will be given at 2.0 mg/kg intravenous (IV) Q 12hrs on days -1,0,and+1 (total 6 doses) then converted to oral at 2 mg/kg by mouth (PO) twice a day (BID) until day+80, then tapered 10% per week over approximately 3 months if no GVHD for related donor transplants. For unrelated CsA will be given at same dose and schedule until day+100 then tapered by 10% per week if no GVHD; Other Names: Neoral ; Drug: Mycophenolate Mofetil (MMF); MMF 15 mg/kg by mouth twice a day (PO BID) will be given from day 0-27 then stopped without tapering for related donor transplants. For unrelated donor transplants MMF will be given at same dose until day+40 then tapered over 2months. in absence of GVHD. Doses will be rounded to nearest 250 mg.; Drug: G-CSF; 10 mcg/kg/day subcutaneously for at least 4 consecutive days.; Other Names: Leukine

Outcome Measures

Primary Outcome Measures

1. Percent of Participants With Chimerism: Full Donor Chimerism Defined as >95% Donor CD3+ Cell in Blood as Assessed by DNA Fingerprinting [days +28 and +70]

   the efficacy of the regimen as determined by engraftment rate and establishment of donor hematopoietic chimerism at day +28 and day +70.

2. Toxicity for the Combination of Pentostatin and Low Dose Total Body Irradiation (TBI) [Conditioning regimen to count recovery (D + 28 post transplant)]

Secondary Outcome Measures

1. Incidence of Acute and Chronic Graft-versus-host Disease [twice weekly until day 100 up to 1 year post transplant]

   Incidence of acute and chronic graft-versus-host disease. Acute GVHD usually occurs during the first three months following transplant. Chronic GVHD usually develops after the third month post-transplant.

2. Responses to Therapy [every 6 mo. up to 2 years]

   event-free and overall survival at 12 months

3. Kinetics of Immunologic Reconstitution After Allogeneic Transplantation [at day 100 post transplantation]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 19 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

Age 19-75 years

1. Patients who relapse after autologous stem cell transplantation.

2. Patients who are candidates for an autologous or conventional allogeneic stem cell transplantation from a disease standpoint but who do not qualify functionally (from the point of view of organ function, or performance status) for a myeloablative protocol.

3. Any patient, where in the opinion of the primary treating oncologist, nonmyleoablative therapy would be the treatment option in the best patients interest providing the patient fits all other eligibility criteria for this protocol.

Identification of a matched related or unrelated stem cell donor

Diseases:

Acute myelogenous leukemia first complete remission with high-risk cytogenetics>second complete remission minimal residual disease (<10% blasts*). Acute lymphocytic leukemia first complete remission with high-risk cytogenetics >second complete remission minimal residual disease (<10% blasts*). Chronic myelogenous leukemia first chronic phase, accelerated phase (<10% blasts*)blast phase with minimal residual disease (<10% blasts*)second chronic phase. Chronic lymphocytic leukemia recurrence after the front line regimen (related donor transplant), chemorefractory disease (unrelated donor transplant),T-CLL in partial remission or any minimal residual disease. Myelodysplastic syndromes refractory anemia with or without ringed sideroblasts,RAEB, RAEB-T, and CMML (< than 10% blasts*). *both in peripheral blood and bone marrow

Multiple myeloma - after receiving at least one regimen of prior chemotherapy

Non-Hodgkin's Lymphomas:

Small Lympho(plasma)cytic Lymphoma (B-SLL, B-LPL): recurrence after a front line regimen (related donor transplant), or chemorefractory disease (related or unrelated donor transplant). Follicular Low-Grade Lymphoma, Marginal Zone Lymphomas (splenic, nodal, or extranodal/MALT type): chemorefractory disease or > 2 prior regimens. Mantle Cell Lymphoma: first complete or partial remission, refractory disease, or failed prior ASCT. Diffuse Large B-cell Lymphoma, Follicular Large cell Lymphoma, Peripheral T-cell Lymphoma, Anaplastic Large Cell Lymphoma: refractory disease, or failed prior ASCT. Burkitt or Acute Lymphoblastic Lymphomas: high-risk disease in remission, chemosensitive persistent or recurrent disease. Cutaneous T-cell Lymphomas: (Mycosis Fungoides, Sezary Syndrome): chemorefractory disease of > 2 prior regimens

Hodgkins Disease: refractory or persistent disease and not candidate for ASCT, or failed prior ASCT.

Peripheral T-cell Lymphoma

Exclusion Criteria:

• Age > 75 years and < 19 years

• progressive disease within 8 weeks of prior therapy or within 12 weeks after prior autologous stem cell transplantation

• Active CNS malignancy (patients with known positive CSF cytology or parenchymal lesions visible by CT or MRI)

• Fertile men or women unwilling to use appropriate contraceptive techniques during and for 12 months following treatment

• Females who are pregnant

• Patients who are HIV seropositive

• Active uncontrolled infection or immediate life-threatening condition at the time of enrollment

• Significant Organ dysfunction:

1. Calculated Creatinine Clearance <55ml/min

2. cardiac ejection fraction <40%, NYHA class II or greater cardiac disease.

3. DLCO < 40% , FEV1/FVC ratio <50% predicted, or receiving supplementary continuous oxygen

4. total bilirubin > 2x upper limit of normal (unless due to Gilberts disease or malignancy), ALT and AST 4x the upper limit of normal

• Karnofsky score <60%

• Patients with uncontrolled medical illnesses (e.g., uncontrolled systemic hypertension, diabetes)

Donor Inclusion Criteria:

• HLA genotypically matched relative

• siblings or first-degree relatives matched at HLA-A, B, or DR loci (6 antigen match) are acceptable donors

• HLA matched unrelated volunteer donor

• unrelated donor matched at HLA-A, B, or DR loci (6 antigen match) are acceptable donors

• One antigen mismatch related or unrelated donor will also be acceptable, molecular typing needs to be used at each H LA-A, B, or DR loci in case of mismatched unrelated donor.

Donor Exclusion Criteria:

• Identical twin

• Pregnancy

• HIV positive

• Serious Allergy to G-CSF

• Current serious systemic illness

• Failure to meet the UNMC or NMDP criteria for donors

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Nebraska Medical Center, Section of Oncology/Hematology	Omaha	Nebraska	United States	68198

Sponsors and Collaborators

• University of Nebraska
• Astex Pharmaceuticals, Inc.

Investigators

• Principal Investigator: Gregory Bociek, M.D., University of Nebraska

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: R. Gregory Bociek, MD, Principal Investigator, University of Nebraska
• ClinicalTrials.gov Identifier: NCT00571662
• Other Study ID Numbers: 389-00; IRB389-00
• First Posted: Dec 12, 2007
• Last Update Posted: Nov 20, 2018
• Last Verified: Nov 1, 2018

• Additional relevant MeSH terms: Lymphoma; Leukemia; Multiple Myeloma; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Lymphoma, T-Cell, Peripheral; Leukemia, Myeloid, Acute; Hodgkin Disease; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Myelodysplastic Syndromes; Cyclosporine; Mycophenolic Acid; Pentostatin; Cyclosporins

Study Results

Participant Flow

Recruitment Details	Between November 2001 and February 2007 sixty eight patients were treated on this protocol and have been included in the analysis

Arm/Group Title	Cohort I
Arm/Group Description	Pentostatin to be administered intravenously on days -10, -9, and -8 at a dose of 4mg/m2/day
Period Title: Overall Study
STARTED	76
COMPLETED	68
NOT COMPLETED	8

Baseline Characteristics

Arm/Group Title	Cohort I
Arm/Group Description	Pentostatin to be administered intravenously on days -10, -9, and -8 at a dose of 4mg/m2/day
Overall Participants	76
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	71 93.4%
>=65 years	5 6.6%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	56
Sex: Female, Male (Count of Participants)
Female	29 38.2%
Male	47 61.8%
Region of Enrollment (participants) [Number]
United States	76 100%

Outcome Measures

1. Primary Outcome

Title	Percent of Participants With Chimerism: Full Donor Chimerism Defined as >95% Donor CD3+ Cell in Blood as Assessed by DNA Fingerprinting
Description	the efficacy of the regimen as determined by engraftment rate and establishment of donor hematopoietic chimerism at day +28 and day +70.
Time Frame	days +28 and +70

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort I
Arm/Group Description	Pentostatin to be administered intravenously on days -10, -9, and -8 at a dose of 4mg/m2/day
Measure Participants	68
Day 28	85 111.8%
Day 70	90 118.4%

2. Primary Outcome

Title	Toxicity for the Combination of Pentostatin and Low Dose Total Body Irradiation (TBI)
Time Frame	Conditioning regimen to count recovery (D + 28 post transplant)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort I
Arm/Group Description	Pentostatin to be administered intravenously on days -10, -9, and -8 at a dose of 4mg/m2/day
Measure Participants	68
Absolute neutrophil count < 500/mm^3	40 52.6%
platelet count < 20,000/mm^3	29 38.2%
Grade 3 or 4 Fever	2 2.6%
Grade 3 or 4 hypokalemia	1 1.3%
Grade 3 or 4 bacteremia	2 2.6%
Grade 3 or 4 infection	6 7.9%
Grade 3 or 4 renal toxicity	1 1.3%
Grade 3 or 4 thromboembolism	1 1.3%

3. Secondary Outcome

Title	Incidence of Acute and Chronic Graft-versus-host Disease
Description	Incidence of acute and chronic graft-versus-host disease. Acute GVHD usually occurs during the first three months following transplant. Chronic GVHD usually develops after the third month post-transplant.
Time Frame	twice weekly until day 100 up to 1 year post transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort I
Arm/Group Description	Pentostatin to be administered intravenously on days -10, -9, and -8 at a dose of 4mg/m2/day
Measure Participants	68
Acute GVHD	31
Chronic GVHD	33

4. Secondary Outcome

Title	Responses to Therapy
Description	event-free and overall survival at 12 months
Time Frame	every 6 mo. up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort I
Arm/Group Description	Pentostatin to be administered intravenously on days -10, -9, and -8 at a dose of 4mg/m2/day
Measure Participants	68
Event free survival	52 68.4%
Overall survival	59 77.6%

5. Secondary Outcome

Title	Kinetics of Immunologic Reconstitution After Allogeneic Transplantation
Time Frame	at day 100 post transplantation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Study Baseline	Day + 28 Post Transplant
Arm/Group Description
Measure Participants	68	68
CD3 cells	13	7
CD4	5	3.5
CD8	5	1.7

Adverse Events

Arm/Group Title	Cohort I
Arm/Group Description	Pentostatin to be administered intravenously on days -10, -9, and -8 at a dose of 4mg/m2/day
All Cause Mortality
	Cohort I
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Cohort I
	Affected / at Risk (%)	# Events
Total	26/76 (34.2%)
Blood and lymphatic system disorders
decreased WBC	9/76 (11.8%)	9
decreased ANC	7/76 (9.2%)	7
decreased hgb	1/76 (1.3%)	1
decreased platelets	3/76 (3.9%)	3
decreased leukocyte	1/76 (1.3%)	1
pulmonary embolism	1/76 (1.3%)	1
Cardiac disorders
klebsiella	1/76 (1.3%)	1
Gastrointestinal disorders
hypokalemia	1/76 (1.3%)	1
General disorders
fever	3/76 (3.9%)	3
Hepatobiliary disorders
increased LDH	1/76 (1.3%)	1
Immune system disorders
herpes simplex	1/76 (1.3%)	1
Infections and infestations
reddened catheter site	1/76 (1.3%)	1
Renal and urinary disorders
Yeast infection	1/76 (1.3%)	1
azotemia	1/76 (1.3%)	1
atubular necrosis	1/76 (1.3%)	1
Other (Not Including Serious) Adverse Events
	Cohort I
	Affected / at Risk (%)	# Events
Total	0/76 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.