Pentostatin and Alemtuzumab as a Preparative Regimen for Allogeneic Peripheral Blood Stem Cell Transplantation

• Sponsor: University of Arizona (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00698685
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 14
• Locations: 2
• Arm: 1
• Actual Duration (Months): 63
• Patients Per Site: 7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This study tests the hypothesis that a purely immunosuppressive preparative regimen allows engraftment of related or unrelated allogeneic hematopoietic stem cells in subjects with high-risk malignancies, without causing the post-transplant myelosuppression (e.g., neutropenia, thrombocytopenia) that occurs with currently used reduced-intensity (nonmyeloablative) preparative regimens. This study incorporates both safety and efficacy endpoints and evaluates a novel preparative regimen of alemtuzumab plus continuous-infusion pentostatin, two immunosuppressive agents with different mechanisms of action, in recipients of related or unrelated allogeneic hematopoietic stem cell transplantation.

Condition or Disease	Intervention/Treatment	Phase
Leukemia; Lymphoma; Hodgkin's Disease; Hematologic Neoplasms; Multiple Myeloma; Carcinoma, Renal Cell	Drug: Pentostatin; Biological: Alemtuzumab; Procedure: Allogeneic hematopoietic stem cell transplantation	Phase 2

Detailed Description

Primary Objectives of the study:

• To determine the efficacy of a preparative regimen of pentostatin and alemtuzumab plus related or unrelated allogeneic peripheral blood stem cell transplantation (PBSCT) in inducing durable donor lymphohematopoietic cell chimerism (defined as at least 50% donor cells in the peripheral blood) by 100 days after PBSCT (day +100) in subjects with high-risk malignancies who are at high risk for morbidity and mortality with conventional intensive pre-transplant conditioning regimens.

• To determine the safety of a preparative regimen of pentostatin and alemtuzumab plus related or unrelated allogeneic PBSCT, as measured by the non-relapse mortality at day +100 in the study subject population.

Study Design

• Study Type: Interventional
• Actual Enrollment: 14 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Related or Unrelated Allogeneic Hematopoietic Cell Transplantation for High-Risk Malignancies, Using a Preparative Regimen of Pentostatin (Nipent®) and Alemtuzumab (Campath®)
• Actual Study Start Date: Jan 23, 2006
• Actual Primary Completion Date: Apr 13, 2009
• Actual Study Completion Date: Apr 26, 2011

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Preparative Regimen Days - 8 through -6: pentostatin 4 mg/m2/24 hr as a continuous intravenous infusion (CIVI) (total cumulative dose, 12 mg/m2 over 3 days) Days - 5 through - 1: alemtuzumab 20 mg per dose intravenously over 8 hours daily for 5 doses (total cumulative dose, 100 mg) Followed by Allogeneic hematopoietic stem cell transplantation, related or unrelated donor, on day 0. Patients also receive cyclosporine intravenous (IV) continuously beginning on day -2, continuing (IV or orally) until day 100, followed by a taper.

Drug: Pentostatin; Days - 8 through -6: pentostatin 4 mg/m2/24 hr as a continuous intravenous infusion (CIVI) (total cumulative dose, 12 mg/m2 over 3 days); Other Names: Nipent ; Biological: Alemtuzumab; Days - 5 through - 1: alemtuzumab 20 mg per dose intravenously over 8 hours daily for 5 doses (total cumulative dose, 100 mg); Other Names: Campath ; Procedure: Allogeneic hematopoietic stem cell transplantation; Infusion of related or unrelated donor peripheral blood progenitor cells on day 0.; Other Names: HSCT

Outcome Measures

Primary Outcome Measures

1. Actuarial Probability of Donor Hematopoietic Engraftment (Defined as at Least 50% Donor DNA in Bone Marrow at Day 100). [Day 100 after transplant.]

   The number of participants with donor hematopoietic engraftment at day 100 is reported in the data table, and the actuarial probability is calculated using the Kaplan-Meier product-limit estimate statistic, as reported in the statistical analysis section below.

2. Non-relapse Mortality at or Before Day 100 [Day 100 after transplant]

   The primary safety outcome is indicated by the number of participants who died at or before Day 100 after transplant for any reason other than relapse of disease (Leukemia, Lymphoma, Hodgkin's disease, Hematologic Neoplasms, Multiple Myeloma, Renal Cell Carcinoma).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

One of these diagnoses:

• Acute myeloid leukemia in complete or partial remission

• Acute lymphocytic leukemia in complete or partial remission

• Chronic myeloid leukemia in first or subsequent chronic phase or accelerated phase

• Chronic lymphocytic leukemia that has recurred or failed after at least one course of front-line therapy

• Hodgkin's disease or non-Hodgkin's lymphoma that has failed front-line therapy, is in second or subsequent remission, or is in chemosensitive relapse

• Multiple myeloma that is in complete or partial remission or in chemosensitive relapse

• Myelodysplastic Syndrome classified as intermediate-2 or high risk according to International Prognostic Scoring System

• Metastatic renal cell carcinoma that has failed at least one previous front-line chemotherapy and/or biological therapy regimen and that is radiographically detectable and evaluable

• Treatment with at least one previous course of chemotherapy or biological therapy for the malignancy for which allogeneic PBPCT is being considered (i.e., a subject cannot be enrolled on this study for initial treatment of a malignancy).

AND at least one of the following:

• Age 50 years or older.

• Previous transplant with autologous or allogeneic hematopoietic cells (peripheral blood, bone marrow, or placental blood).

• High-risk status of hematologic malignancy, i.e., not in first complete remission or first chronic phase.

• Presence of other medical condition that could place subject at unacceptably high risk of regimen-related mortality such as documented chronic bronchitis or emphysema; decreased cardiac ejection fraction (but with ejection fraction at least 30%), or history of coronary artery disease; renal insufficiency (but with creatinine clearance at least 30 mL/min); hepatic cirrhosis (but with normal hepatic synthetic function); or documented or presumed invasive fungal infection requiring treatment with intravenous antifungal agent(s).

Exclusion Criteria:

• Eligibility for another clinical therapeutic protocol or standard-of-care treatment that offers higher probability of cure or long-term control of subject's malignancy.

• Progressive Hodgkin's disease, non-Hodgkin's lymphoma, Hodgkin disease or multiple myeloma that is refractory to salvage chemotherapy.

• Acute leukemia (AML or ALL) in relapse, CML in blast phase/blast crisis, or MDS with greater than 30% marrow involvement (MDS-AML). Subjects with these disease characteristics may be considered for this study if complete or partial remissions (CRs or PRs) occur after salvage chemotherapy.

• Severe organ dysfunction, such as: cardiac ejection fraction below 30% or symptomatic ischemic cardiac disease; creatinine clearance below 30 mL/min; carbon monoxide diffusing capacity (DLCO) below 35% and/or need for supplemental oxygen; severe hepatic cirrhosis with ascites and/or varices; hepatic dysfunction associated with abnormal synthetic function (e.g., coagulopathy) and/or bilirubin greater than two times upper limit of normal and/or transaminases (AST or ALT) above four times upper limit of normal.

• Untreated or progressive central nervous system involvement by malignancy

• Subject is pregnant or breast-feeding.

• Karnofsky score below 50

• Seropositivity for human immunodeficiency virus (HIV).

• Life expectancy less than 12 weeks with conventional treatments.

• For subjects who are fertile, refusal to practice contraception upon entering this study and for at least 12 months after PBPCT or after cessation of immunosuppressive treatments (e.g., cyclosporine), whichever occurs later.

• Failure to obtain at least 5.0 x 106 allogeneic donor CD34+ cells per kg of recipient weight in PBPC product.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Arizona Cancer Center at UMC North/University Medical Center	Tucson	Arizona	United States	85724
2	Arizona Cancer Center at UMC North	Tucson	Arizona	United States	85724

Sponsors and Collaborators

• University of Arizona
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Andrew M Yeager, MD, University of Arizona

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of Arizona
• ClinicalTrials.gov Identifier: NCT00698685
• Other Study ID Numbers: 05-0624-04; R21CA106177; 05110; UARIZ-05-0624-01; UARIZ-SRC17920; NCT00543283
• First Posted: Jun 17, 2008
• Last Update Posted: Mar 31, 2017
• Last Verified: Mar 1, 2017

• Keywords provided by University of Arizona: Allogeneic Hematopoietic Cell Transplantation; Preparative Regimen; Pentostatin; Alemtuzumab; Hodgkin Disease and Lymphoma, non-Hodgkin; leukemia, myeloid, acute; leukemia, lymphocytic, acute; leukemia, myeloid, chronic; leukemia, lymphocytic, chronic; Multiple Myeloma; Myelodysplastic Syndromes; Carcinoma, Renal Cell
• Additional relevant MeSH terms: Leukemia; Multiple Myeloma; Hodgkin Disease; Carcinoma, Renal Cell; Hematologic Neoplasms; Alemtuzumab; Pentostatin

Study Results

Participant Flow

Recruitment Details	Following University of Arizona IRB review and approval, the study opened to accrual on November 2005 at the Arizona Cancer Center clinic and University Medical Center sites [Tucson, Arizona].
Pre-assignment Detail	Following consent process, subjects who consented to participate were screened per the selection criteria in the study.

Arm/Group Title	Preparative Regimen of Pentostatin and Alemtuzumab
Arm/Group Description	Pentostatin and Alemtuzumab as a Preparative Regimen for Allogeneic [related or unrelated] Hematopoietic SCT. Pentostatin: 4 mg/m2/24 hour IV continuously over 72 hours on days -8 to -6. Alemtuzumab: 20 mg per dose IV over 8 hours on days -5 to -1. Patients then received infusion of related or unrelated donor peripheral blood progenitor cells on day 0. Patients also receive cyclosporine IV continuously beginning on day -2, continuing (IV or orally) until day 100, followed by a taper.
Period Title: Overall Study
STARTED	14
COMPLETED	12
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Preparative Regimen of Pentostatin and Alemtuzumab
Arm/Group Description	Pentostatin and Alemtuzumab as a Preparative Regimen for Allogeneic [related or unrelated] Hematopoietic SCT. Pentostatin: 4 mg/m2/24 hour IV continuously over 72 hours on days -8 to -6. Alemtuzumab: 20 mg per dose IV over 8 hours on days -5 to -1. Patients then received infusion of related or unrelated donor peripheral blood progenitor cells on day 0. Patients also receive cyclosporine IV continuously beginning on day -2, continuing (IV or orally) until day 100, followed by a taper.
Overall Participants	14
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	11 78.6%
>=65 years	3 21.4%
Sex: Female, Male (Count of Participants)
Female	5 35.7%
Male	9 64.3%
Region of Enrollment (participants) [Number]
United States	14 100%

Outcome Measures

1. Primary Outcome

Title	Actuarial Probability of Donor Hematopoietic Engraftment (Defined as at Least 50% Donor DNA in Bone Marrow at Day 100).
Description	The number of participants with donor hematopoietic engraftment at day 100 is reported in the data table, and the actuarial probability is calculated using the Kaplan-Meier product-limit estimate statistic, as reported in the statistical analysis section below.
Time Frame	Day 100 after transplant.

Outcome Measure Data

Analysis Population Description

All participants who completed treatment and underwent allogeneic transplant.

Arm/Group Title	Preparative Regimen of Pentostatin and Alemtuzumab
Arm/Group Description	Pentostatin and Alemtuzumab as a Preparative Regimen for Allogeneic [related or unrelated] Hematopoietic SCT. Pentostatin: 4 mg/m2/24 hour IV continuously over 72 hours on days -8 to -6. Alemtuzumab: 20 mg per dose IV over 8 hours on days -5 to -1. Patients then received infusion of related or unrelated donor peripheral blood progenitor cells on day 0. Patients also receive cyclosporine IV continuously beginning on day -2, continuing (IV or orally) until day 100, followed by a taper.
Measure Participants	12
Number [participants]	4 28.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Preparative Regimen of Pentostatin and Alemtuzumab
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	actuarial probability of engraftment
	Estimated Value	70
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	Actuarial probability of engraftment at day +100 is calculated according to the product-limit estimate method.

2. Primary Outcome

Title	Non-relapse Mortality at or Before Day 100
Description	The primary safety outcome is indicated by the number of participants who died at or before Day 100 after transplant for any reason other than relapse of disease (Leukemia, Lymphoma, Hodgkin's disease, Hematologic Neoplasms, Multiple Myeloma, Renal Cell Carcinoma).
Time Frame	Day 100 after transplant

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 day of treatment.

Arm/Group Title	Preparative Regimen of Pentostatin and Alemtuzumab
Arm/Group Description	Pentostatin and Alemtuzumab as a Preparative Regimen for Allogeneic [related or unrelated] Hematopoietic SCT. Pentostatin: 4 mg/m2/24 hour IV continuously over 72 hours on days -8 to -6. Alemtuzumab: 20 mg per dose IV over 8 hours on days -5 to -1. Patients then received infusion of related or unrelated donor peripheral blood progenitor cells on day 0. Patients also receive cyclosporine IV continuously beginning on day -2, continuing (IV or orally) until day 100, followed by a taper.
Measure Participants	13
Number [Participants]	3 21.4%

Adverse Events

Time Frame	Adverse event data for this study was collected from January 23, 2006 to April 13, 2009.
Adverse Event Reporting Description	Adverse event data was collected and entered into the AZCC database which is password protected. The safety population is defined to be all participants who completed at least 1 day of treatment.
Arm/Group Title	Preparative Regimen of Pentostatin and Alemtuzumab
Arm/Group Description	Pentostatin and Alemtuzumab as a Preparative Regimen for Allogeneic [related or unrelated] Hematopoietic SCT. Pentostatin: 4 mg/m2/24 hour IV continuously over 72 hours on days -8 to -6. Alemtuzumab: 20 mg per dose IV over 8 hours on days -5 to -1. Patients then received infusion of related or unrelated donor peripheral blood progenitor cells on day 0. Patients also receive cyclosporine IV continuously beginning on day -2, continuing (IV or orally) until day 100, followed by a taper.
All Cause Mortality
	Preparative Regimen of Pentostatin and Alemtuzumab
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Preparative Regimen of Pentostatin and Alemtuzumab
	Affected / at Risk (%)	# Events
Total	8/13 (61.5%)
Blood and lymphatic system disorders
metabolic/laboratory: elevated AST and ALT	1/13 (7.7%)	1
hyperbilirubinemia	1/13 (7.7%)	1
Cardiac disorders
Death on study, post BMT	1/13 (7.7%)	1
Infections and infestations
altered mental status and progressive obtundation [disseminated toxoplasmosis]	1/13 (7.7%)	1
disseminated toxoplasmosis	1/13 (7.7%)	1
Renal and urinary disorders
hemorrhagic cystitis associated with BK virus	1/13 (7.7%)	1
thrombotic microangiopathy	1/13 (7.7%)	1
Respiratory, thoracic and mediastinal disorders
hypoxia and dyspnea which was a result of pulmonary hemorrhage	1/13 (7.7%)	1
Other (Not Including Serious) Adverse Events
	Preparative Regimen of Pentostatin and Alemtuzumab
	Affected / at Risk (%)	# Events
Total	13/13 (100%)
Blood and lymphatic system disorders
Blood/Bone Marrow	5/13 (38.5%)	63
DIC (disseminated intravascular coagulation)	1/13 (7.7%)	1
Edema: limb	4/13 (30.8%)	9
Edema: viscera	1/13 (7.7%)	1
Fibrinogen	1/13 (7.7%)	1
Hemoglobin	8/13 (61.5%)	36
Leukocytes (total WBC)	4/13 (30.8%)	8
Lymphatics	8/13 (61.5%)	17
Lymphopenia	1/13 (7.7%)	1
Neutrophils/granulocytes (ANC/AGC)	1/13 (7.7%)	1
Platelets	7/13 (53.8%)	35
PTT (Partial Thromboplastin Time)	2/13 (15.4%)	2
Cardiac disorders
Cardiac General	6/13 (46.2%)	10
Cardiac Arrhythmia	1/13 (7.7%)	1
Cardiac troponin T (cTnT)	1/13 (7.7%)	2
Hypertension	5/13 (38.5%)	7
Hypotension	4/13 (30.8%)	5
Pericardial effusion (non-malignant)	1/13 (7.7%)	1
Supraventricular and nodal arrhythmia	2/13 (15.4%)	4
Ventricular arrhythmia	1/13 (7.7%)	1
Eye disorders
Death not associated with CTCAE term	1/13 (7.7%)	1
Ocular/Visual	3/13 (23.1%)	4
Vision-photophobia	1/13 (7.7%)	1
Gastrointestinal disorders
Anorexia	3/13 (23.1%)	7
Constipation	4/13 (30.8%)	9
Dehydration	2/13 (15.4%)	2
Diarrhea	2/13 (15.4%)	3
Flatulence	1/13 (7.7%)	2
Gastritis (including bile reflux gastritis)	1/13 (7.7%)	1
Gastrointestinal	6/13 (46.2%)	33
Heartburn/dyspepsia	1/13 (7.7%)	1
Nausea	6/13 (46.2%)	22
Vomiting	5/13 (38.5%)	12
General disorders
Constitutional Symptoms	7/13 (53.8%)	33
Fatigue (asthenia, lethargy, malaise)	4/13 (30.8%)	5
Fever (in the absence of neutropenia, where neutropenia is defined as ANC >1.0 x="" 10e9=""/L)	6/13 (46.2%)	13
Insomnia	4/13 (30.8%)	10
Pain	12/13 (92.3%)	98
Rigors/chills	5/13 (38.5%)	7
Immune system disorders
Allergic reaction/hypersensitivity (including drug fever)	2/13 (15.4%)	2
Allergic rhinitis (including sneezing, nasal stuffiness, postnasal drip)	2/13 (15.4%)	2
Allergy/Immunology	3/13 (23.1%)	6
Autoimmune reaction	1/13 (7.7%)	2
Infections and infestations
Colitis, infectious (e.g., Clostridium difficile)	2/13 (15.4%)	2
Infection	8/13 (61.5%)	20
Infection with normal ANC or Grade 1 or 2 neutrophils	1/13 (7.7%)	1
Metabolism and nutrition disorders
Acidosis (metabolic or respiratory)	1/13 (7.7%)	2
Albumin, serum-low (hypoalbuminemia)	3/13 (23.1%)	12
Alkaline phosphatase, increased	1/13 (7.7%)	1
ALT, SGPT (serum glutamic pyruvic transaminase), increased	6/13 (46.2%)	8
AST, SGOT(serum glutamic oxaloacetic transaminase), increased	6/13 (46.2%)	7
Bicarbonate, serum-low	2/13 (15.4%)	10
Bilirubin (hyperbilirubinemia)	2/13 (15.4%)	2
Calcium, serum-low (hypocalcemia)	2/13 (15.4%)	4
Creatinine, increased	6/13 (46.2%)	18
Glucose, serum-high (hyperglycemia)	4/13 (30.8%)	36
Magnesium, serum-low (hypomagnesemia)	7/13 (53.8%)	40
Metabolic/Laboratory	10/13 (76.9%)	84
Phosphate, serum-low (hypophosphatemia)	2/13 (15.4%)	3
Potassium, serum-high (hyperkalemia)	1/13 (7.7%)	1
Potassium, serum-low (hypokalemia)	7/13 (53.8%)	19
Sodium, serum-high (hypernatremia)	1/13 (7.7%)	1
Sodium, serum-low (hyponatremia)	3/13 (23.1%)	5
Uric acid, serum-high (hyperuricemia)	1/13 (7.7%)	1
Musculoskeletal and connective tissue disorders
Musculoskeletal/Soft Tissue	2/13 (15.4%)	2
Nervous system disorders
Confusion	2/13 (15.4%)	3
Dizziness	1/13 (7.7%)	1
Extrapyramidal/involuntary movement/restlessness	1/13 (7.7%)	1
Mood alteration	4/13 (30.8%)	10
Neurology	6/13 (46.2%)	14
Neuropathy: sensory	1/13 (7.7%)	1
Speech impairment (e.g., dysphasia or aphasia)	1/13 (7.7%)	1
Tremor	1/13 (7.7%)	1
Renal and urinary disorders
Bladder spasms	1/13 (7.7%)	1
Cystitis	1/13 (7.7%)	1
Renal failure	4/13 (30.8%)	7
Renal/Genitourinary	5/13 (38.5%)	7
Urinary frequency/urgency	1/13 (7.7%)	1
Urinary retention (including neurogenic bladder)	1/13 (7.7%)	1
Respiratory, thoracic and mediastinal disorders
Cough	2/13 (15.4%)	2
Dyspnea (shortness of breath)	2/13 (15.4%)	7
Hemorrhage, pulmonary/upper respiratory	1/13 (7.7%)	1
Hemorrhage/Bleeding	1/13 (7.7%)	1
Hypoxia	1/13 (7.7%)	3
Pleural effusion (non-malignant)	1/13 (7.7%)	2
Pulmonary/Upper Respiratory	7/13 (53.8%)	28
Skin and subcutaneous tissue disorders
Cytokine release syndrome/acute infusion reaction	1/13 (7.7%)	1
Dermatology/Skin	8/13 (61.5%)	18
Flushing	1/13 (7.7%)	1
Pruritus/itching	2/13 (15.4%)	2
Rash/desquamation	1/13 (7.7%)	1
Rash: erythema multiforme (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis)	1/13 (7.7%)	1
Surgical and medical procedures
Hemorrhage/Bleeding	2/13 (15.4%)	3
Vascular disorders
Thrombosis/embolism (vascular access-related)	1/13 (7.7%)	2
Vascular	4/13 (30.8%)	5

Limitations/Caveats

We did not meet criteria to stop the study because of nonrelapse mortality (safety endpoint). However, we stopped accrual to the study because of failure to meet minimal criteria for engraftment (efficacy endpoint).

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.