Study of Stem Cell Transplantation for Hematologic Malignancies Using Clofarabine and Busulfan Regimen

• Sponsor: University of Michigan Rogel Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00556452
• Collaborator: Genzyme, a Sanofi Company (Industry)
• Enrollment: 46
• Location: 1
• Arm: 1
• Duration (Months): 59
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

The goals of the study are (Phase I) to determine the appropriate dose for Clofarabine with Busulfan as a full-intensity conditioning (Clo/BU4 regimen) prior to transplant and then (Phase II) to investigate the safety and effectiveness of this regimen as a conditioning for stem cell transplant in the treatment of aggressive hematologic malignancies in subjects where more conventional approaches are failing.

Condition or Disease	Intervention/Treatment	Phase
Leukemia; Hodgkin Lymphoma; Non-Hodgkin Lymphoma; Multiple Myeloma; Myelodysplastic Syndrome	Drug: Clofarabine/Busulfan x 4; Procedure: Peripheral blood stem cell transplant; Radiation: Total Lymphoid Irradiation	Phase 1/Phase 2

Detailed Description

Transplants with stem cells collected from the blood of an unrelated donor (allo-HSCT) are being used more commonly for many blood cancers which are not curable with more conventional methods of chemotherapy. Although allo-HSCT has great potential, there are still high risks due to infections, graft-versus-host disease (GVHD), where the donor's cells attack the recipient's tissues as foreign, and due to toxic effects of the chemotherapy drugs given to prepare (or condition) the recipient's bone marrow for transplant.

As a reduced intensity conditioning, a combination of Fludarabine and a lower dose of Busulfan (Flu/BU2) is one of the most popular regimens. Among full-intensity regimens, a combination of Fludarabine and standard-dose Busulfan (Flu/BU4) has been investigated recently and shown to be very well tolerated.

Clofarabine, similar to Fludarabine, is known to have a stronger anti-tumor effect than Fludarabine and has shown promise in treating aggressive acute leukemias. In addition, evidence is that it is well-tolerated with manageable side effects especially in older subjects. Thus replacing Fludarabine with Clofarabine in a full-intensity transplant regimen, Clo/BU4 may provide a regimen with increased anti-tumor activity without adding significant risks of toxicity.

The goals of the study are (Phase I) to determine the appropriate dose for Clofarabine with Busulfan as a full-intensity regimen (Clo/BU4) and then (Phase II) to investigate the safety and effectiveness of this regimen as a conditioning for HSCT in the treatment for aggressive hematologic malignancies, in subjects where more conventional approaches are failing.

Study Design

• Study Type: Interventional
• Actual Enrollment: 46 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I/II Study of Myeloablative Allogeneic Stem Cell Transplantation for Aggressive Hematologic Malignancies Using Clofarabine and Busulfan x 4 (Clo/BU4) Regimen
• Study Start Date: Oct 1, 2007
• Actual Primary Completion Date: Jun 1, 2011
• Actual Study Completion Date: Sep 1, 2012

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Clo/BU4 Study will start at the 2nd dose level of three Clofarabine levels, in combination with Busulfan. The Clofarabine level that each subsequent patient is treated at is determined by a method using continual reassessment. After pre-conditioning, subjects will receive a peripheral blood stem cell transplant.

Drug: Clofarabine/Busulfan x 4; Clofarabine IV (dose levels) 1st dose level: 20 mg/m2/day x 5 days 2nd dose level: 30 mg/m2/day x 5 days 3rd dose level: 40 mg/m2/day x 5 days Busulfan IV 3.2 mg/kg daily x 4 days; Procedure: Peripheral blood stem cell transplant; Peripheral blood stem cell transplant, after pre-conditioning drug treatment; Radiation: Total Lymphoid Irradiation; Total Lymphoid Irradiation (TLI) of 4 Gy, if cord blood transplant

Outcome Measures

Primary Outcome Measures

1. Regimen Related Toxicities [two years]

   The incidence of non-hematological toxicities (Common Terminology Criteria for Adverse Events (CTCAE) 3.0) from initiation of conditioning to Day + 30 or toxicities after day +30, possibly, probably or definitely related to conditioning for all patients treated with Clofarabine (independent of dose level).

2. One-year Overall Survival Rate for AML [1 year]

   Percent Overall Survival (OS) for at one year for subjects with Acute Myeloid Leukemia (AML).

Secondary Outcome Measures

1. Two-year Overall Survival for All Cases. [2 years]

   Percent Overall Survival (OS) at two years for all patients.

2. Five Year Overall Survival for All Cases [five years]

   The number of patients alive at 5 years

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

Disease Criteria

• Acute leukemia or chronic myelogenous leukemia in blastic crisis or accelerated phase, not in remission at the time of transplant

• Myelodysplastic syndrome, with more than 5% blasts in bone marrow at the time of transplant

• Hodgkin and Non-Hodgkin Lymphomas: Not in CR in PET scan or CT scan before transplant, or relapsed within 1 year from previous remission

• CLL not in remission

• Multiple Myeloma, not in remission

• Suitable donor available (related or unrelated)

Age, Organ Function Criteria

• Age: ≤ 70 years

• Cardiac: LV Ejection Fraction ≥ 40% by MUGA or Echocardiogram

• Pulmonary: FEV1 and FVC ≥ 40% predicted, and DLCO (corrected for hemoglobin) ≥ 40% of predicted

• Renal: Adult population: serum creatinine ≤ 1.0 mg/dL (if serum creatinine > 1.0 mg/dL, then the estimated glomerular filtration rate (GFR) must be > 60 mL/min/1.73 m2 as calculated by the Modification of Diet in Renal Disease equation)

• Renal: Pediatric population: serum creatinine clearance ≥ 90 ml/min/1.73 m2 as calculated by the Schwartz formula for estimated GFR

• Hepatic: serum total bilirubin ≤ 2.0 mg/dl and AST / ALT ≤ ULN x 4

• Performance status: Karnofsky ≥ 70%

Exclusion Criteria:

• Other active life-threatening cancer requiring treatment other than allo-HSCT

• HIV1 or HIV2 positive

• Uncontrolled medical or psychiatric disorder

• Uncontrolled viral or fungal infection

• Active CNS leukemia

• Non-compliant to medications

• No appropriate caregivers identified

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Michigan, Department of Internal Medicine, Blood and Marrow Transplant Program	Ann Arbor	Michigan	United States	48170

Sponsors and Collaborators

• University of Michigan Rogel Cancer Center
• Genzyme, a Sanofi Company

Investigators

• Principal Investigator: John Magenau, M.D., University of Michigan, Department of Internal Medicine, Blood and Marrow Transplant Program

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of Michigan Rogel Cancer Center
• ClinicalTrials.gov Identifier: NCT00556452
• Other Study ID Numbers: UMCC 2007.055
• First Posted: Nov 12, 2007
• Last Update Posted: Dec 5, 2017
• Last Verified: Oct 1, 2017

• Additional relevant MeSH terms: Lymphoma; Multiple Myeloma; Hematologic Neoplasms; Myelodysplastic Syndromes; Busulfan; Clofarabine

Study Results

Participant Flow

Recruitment Details	Patients with relapsed or refractory hematologic malignancies not in remission received unmanipulated HSCT with CloBu4 conditioning from October 2007 to November 2009 at the University of Michigan. Patients received a clofarabine dose of 20mg/m^2, 30 mg/m^2 or 40 mg/m^2.

Arm/Group Title	Clo/BU4 20mg/m^2	Clo/BU4 30mg/m^2	Clo/BU4 40mg/m^2
Arm/Group Description	Clofarabine/Busulfan x 4 : Clofarabine IV 20 mg/m^2/day x 5 days Busulfan IV 3.2 mg/kg daily x 4 days Peripheral blood stem cell transplant : Peripheral blood stem cell transplant, after pre-conditioning drug treatment.	Clofarabine/Busulfan x 4 : Clofarabine IV 30 mg/m^2/day x 5 days Busulfan IV 3.2 mg/kg daily x 4 days Peripheral blood stem cell transplant : Peripheral blood stem cell transplant, after pre-conditioning drug treatment.	Clofarabine/Busulfan x 4 : Clofarabine IV 40 mg/m^2/day x 5 days Busulfan IV 3.2 mg/kg daily x 4 days Peripheral blood stem cell transplant : Peripheral blood stem cell transplant, after pre-conditioning drug treatment.
Period Title: Overall Study
STARTED	6	21	19
COMPLETED	6	21	19
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Clo/BU4 20mg/m^2	Clo/BU4 30mg/m^2	Clo/BU4 40mg/m^2	Total
Arm/Group Description	Clofarabine/Busulfan x 4 : Clofarabine IV 20 mg/m^2/day x 5 days Busulfan IV 3.2 mg/kg daily x 4 days Peripheral blood stem cell transplant : Peripheral blood stem cell transplant, after pre-conditioning drug treatment.	Clofarabine/Busulfan x 4 : Clofarabine IV 30 mg/m^2/day x 5 days Busulfan IV 3.2 mg/kg daily x 4 days Peripheral blood stem cell transplant : Peripheral blood stem cell transplant, after pre-conditioning drug treatment.	Clofarabine/Busulfan x 4 : Clofarabine IV 40 mg/m^2/day x 5 days Busulfan IV 3.2 mg/kg daily x 4 days Peripheral blood stem cell transplant : Peripheral blood stem cell transplant, after pre-conditioning drug treatment.	Total of all reporting groups
Overall Participants	6	21	19	46
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	48.5	54	51	53
Sex: Female, Male (Count of Participants)
Female	2 33.3%	9 42.9%	11 57.9%	22 47.8%
Male	4 66.7%	12 57.1%	8 42.1%	24 52.2%
Region of Enrollment (participants) [Number]
United States	6 100%	21 100%	19 100%	46 100%
Disease (participants) [Number]
Acute Myeloid Leukemia (AML)	4 66.7%	13 61.9%	14 73.7%	31 67.4%
Chronic Myeloid Leukemia (CML)	1 16.7%	1 4.8%	0 0%	2 4.3%
Acute Lymphoblastic Leukemia (ALL)	1 16.7%	1 4.8%	2 10.5%	4 8.7%
Chronic Lymphocytic Leukemia (CLL)	0 0%	3 14.3%	1 5.3%	4 8.7%
Non-Hodgkin Lymphoma (NHL)	0 0%	2 9.5%	1 5.3%	3 6.5%
Myelodysplastic Syndromes (MDS)	0 0%	0 0%	1 5.3%	1 2.2%
Multiple Myeloma (MM)	0 0%	1 4.8%	0 0%	1 2.2%

Outcome Measures

1. Primary Outcome

Title	Regimen Related Toxicities
Description	The incidence of non-hematological toxicities (Common Terminology Criteria for Adverse Events (CTCAE) 3.0) from initiation of conditioning to Day + 30 or toxicities after day +30, possibly, probably or definitely related to conditioning for all patients treated with Clofarabine (independent of dose level).
Time Frame	two years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Clo/Bu4
Arm/Group Description	Experimental: Clo/BU4
Measure Participants	46
Liver	56
Gastrointestinal	70
Genito-Urinary	4
Cardiopulmonary	10
Neurologic	8
Skin	11
Other	3

2. Primary Outcome

Title	One-year Overall Survival Rate for AML
Description	Percent Overall Survival (OS) for at one year for subjects with Acute Myeloid Leukemia (AML).
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

Patients with Acute Myeloid Leukemia (AML)

Arm/Group Title	Clo/BU4
Arm/Group Description	Study will start at the 2nd dose level of three Clofarabine levels, in combination with Busulfan. The Clofarabine level that each subsequent patient is treated at is determined by a method using continual reassessment. After pre-conditioning, subjects will receive a peripheral blood stem cell transplant. Total Lymphoid Irradiation : Total Lymphoid Irradiation (TLI) of 4 Gy, if cord blood transplant Clofarabine/Busulfan x 4 : Clofarabine IV (dose levels) 1st dose level: 20 mg/m2/day x 5 days 2nd dose level: 30 mg/m2/day x 5 days 3rd dose level: 40 mg/m2/day x 5 days Busulfan IV 3.2 mg/kg daily x 4 days Peripheral blood stem cell transplant : Peripheral blood stem cell transplant, after pre-conditioning drug treatment
Measure Participants	31
Number (95% Confidence Interval) [percent overall survival]	48

3. Secondary Outcome

Title	Two-year Overall Survival for All Cases.
Description	Percent Overall Survival (OS) at two years for all patients.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Clo/BU4
Arm/Group Description	Study will start at the 2nd dose level of three Clofarabine levels, in combination with Busulfan. The Clofarabine level that each subsequent patient is treated at is determined by a method using continual reassessment. After pre-conditioning, subjects will receive a peripheral blood stem cell transplant. Total Lymphoid Irradiation : Total Lymphoid Irradiation (TLI) of 4 Gy, if cord blood transplant Clofarabine/Busulfan x 4 : Clofarabine IV (dose levels) 1st dose level: 20 mg/m2/day x 5 days 2nd dose level: 30 mg/m2/day x 5 days 3rd dose level: 40 mg/m2/day x 5 days Busulfan IV 3.2 mg/kg daily x 4 days Peripheral blood stem cell transplant : Peripheral blood stem cell transplant, after pre-conditioning drug treatment
Measure Participants	46
Number (95% Confidence Interval) [percent overall survival]	28

4. Secondary Outcome

Title	Five Year Overall Survival for All Cases
Description	The number of patients alive at 5 years
Time Frame	five years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Clo/BU4
Arm/Group Description	Study will start at the 2nd dose level of three Clofarabine levels, in combination with Busulfan. The Clofarabine level that each subsequent patient is treated at is determined by a method using continual reassessment. After pre-conditioning, subjects will receive a peripheral blood stem cell transplant. Total Lymphoid Irradiation : Total Lymphoid Irradiation (TLI) of 4 Gy, if cord blood transplant Clofarabine/Busulfan x 4 : Clofarabine IV (dose levels) 1st dose level: 20 mg/m2/day x 5 days 2nd dose level: 30 mg/m2/day x 5 days 3rd dose level: 40 mg/m2/day x 5 days Busulfan IV 3.2 mg/kg daily x 4 days Peripheral blood stem cell transplant : Peripheral blood stem cell transplant, after pre-conditioning drug treatment
Measure Participants	46
Count of Participants [Participants]	6 100%

Adverse Events

Time Frame	Adverse events occurring following study registration, but prior to beginning transplant therapy will not be reported. Post transplant, adverse events will be reported through day 100.
Adverse Event Reporting Description	Adverse events were analyzed for all patients that received Clofarabine, and not by Clofarabine dose received. All patients received the same study drug, Clofarabine.
Arm/Group Title	Clo/Bu4
Arm/Group Description
All Cause Mortality
	Clo/Bu4
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Clo/Bu4
	Affected / at Risk (%)	# Events
Total	23/46 (50%)
Blood and lymphatic system disorders
Blood Disorder	1/46 (2.2%)
Cardiac disorders
Atrial Fibrilation	1/46 (2.2%)
Gastrointestinal disorders
Ascites	2/46 (4.3%)
Diarrhea	2/46 (4.3%)
Esophagitis	1/46 (2.2%)
General disorders
Fever	1/46 (2.2%)
Death	1/46 (2.2%)
Immune system disorders
Graft Versus Host Disease	2/46 (4.3%)
Infections and infestations
Infection	7/46 (15.2%)
Sepsis	1/46 (2.2%)
Investigations
Disease Progression	1/46 (2.2%)
Musculoskeletal and connective tissue disorders
Bone Pain	1/46 (2.2%)
Back Pain	1/46 (2.2%)
Muscle Weakness	1/46 (2.2%)
Nervous system disorders
Dizziness	2/46 (4.3%)
Respiratory, thoracic and mediastinal disorders
Hypoxia/Dyspnea	3/46 (6.5%)
Vascular disorders
Vascular Access Complication	1/46 (2.2%)
Bladder Hemmorhage	1/46 (2.2%)
Portal Hypertension	1/46 (2.2%)
Other (Not Including Serious) Adverse Events
	Clo/Bu4
	Affected / at Risk (%)	# Events
Total	46/46 (100%)
Blood and lymphatic system disorders
Febrile Neutropenia	21/46 (45.7%)
Cardiac disorders
Hypertension	3/46 (6.5%)
Arrythmia	1/46 (2.2%)
Gastrointestinal disorders
Mucositis	31/46 (67.4%)
Nausea/Vomiting	25/46 (54.3%)
Diarrhea	10/46 (21.7%)
Abdominal Pain	5/46 (10.9%)
Ascites	3/46 (6.5%)
General disorders
Hypotention	2/46 (4.3%)
Hypersensitivity	1/46 (2.2%)
Hepatobiliary disorders
Transaminitis*	43/46 (93.5%)
Hyperbilirubiniemia	8/46 (17.4%)
Cholycytitis	1/46 (2.2%)
Cirrhosis	1/46 (2.2%)
Musculoskeletal and connective tissue disorders
Musculoskeletal Pain	2/46 (4.3%)
Fracture	1/46 (2.2%)
Nervous system disorders
Headache	4/46 (8.7%)
Confusion	1/46 (2.2%)
Syncope	2/46 (4.3%)
Siezure	1/46 (2.2%)
Renal and urinary disorders
Creatinine elevation	3/46 (6.5%)
Hemorragic Cystitis	1/46 (2.2%)
Respiratory, thoracic and mediastinal disorders
Hypoxia	6/46 (13%)
Skin and subcutaneous tissue disorders
Hand-foot syndrome	9/46 (19.6%)
Rash	2/46 (4.3%)
Vascular disorders
Veno-Occlusive Disease	2/46 (4.3%)
Deep Vein Thrombosis	2/46 (4.3%)

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.