LLC0405: Fludarabine and Alemtuzumab or Cyclophosphamide Followed by Peripheral Blood Stem Cell Transplant or Alemtuzumab in Treating Patients With Advanced or Progressive Chronic Lymphocytic Leukemia

• Sponsor: Gruppo Italiano Malattie EMatologiche dell'Adulto (Other)
• Overall Status: Completed
• CT.gov ID: NCT00462332
• Collaborator: (none)
• Enrollment: 86
• Locations: 23
• Arms: 2
• Duration (Months): 49
• Patients Per Site: 3.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy, such as fludarabine and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as alemtuzumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. A peripheral stem cell transplant using stem cells from the patient or a donor may replace the patient's immune cells that were destroyed by chemotherapy.

PURPOSE: This phase II trial is studying how well giving fludarabine together with alemtuzumab or cyclophosphamide followed by peripheral blood stem cell transplant or alemtuzumab works in treating patients with advanced or progressive chronic lymphocytic leukemia.

Condition or Disease	Intervention/Treatment	Phase
Leukemia	Drug: Fludarabine; Drug: Campath; Procedure: Transplant; Drug: Campath; Drug: Fludarabine; Drug: Campath; Drug: Campath	Phase 2

Detailed Description

OBJECTIVES:

Primary

• Determine the antitumor activity of induction therapy comprising fludarabine phosphate with either alemtuzumab or cyclophosphamide followed by peripheral blood stem cell transplantation or alemtuzumab in patients with advanced or progressive chronic lymphocytic leukemia.

Secondary

• Determine the toxicity of this regimen in these patients.

• Determine the length of survival, event-free survival, and disease-free survival of patients treated with this regimen.

• Evaluate the relationship between different clinical and biological disease characteristics, therapeutic response, and survival.

OUTLINE: This is a pilot, multicenter study. Patients are stratified according to biological risk profile (high vs low risk).

• Group 1 (high-risk patients):

• Induction therapy: Patients receive fludarabine phosphate IV and alemtuzumab IV on days 1-3. Treatment repeats for 4 courses.

Patients with no response (no good clinical partial response, steady disease, or progressive disease) after induction therapy are removed from the study. Other patients proceed to post-induction therapy based on response to induction therapy.

• Post-induction therapy:

• Complete clinical, cytometric, and molecular response: Patients undergo peripheral blood stem cell (PBSC) mobilization with cytarabine IV twice daily on days 1-3 and filgrastim (G-CSF) followed by no further therapy.

• Response to induction therapy and evidence of residual disease (complete clinical and cytometric response with molecular evidence of disease; complete clinical response only; or good clinical partial response): Patients without an HLA familial matched donor undergo PBSC mobilization with cytarabine IV twice daily on days 1-3 and G-CSF. Patients with sufficient harvested autologous PBSCs undergo autologous PBSC transplantation (with BEAM conditioning regimen [carmustine, etoposide, cytarabine, and melphalan]). Patients without sufficient harvested

• PBSCs receive alemtuzumab subcutaneously (SC) weekly for 6 weeks. Patients who do not achieve molecular remission after 6 weeks of alemtuzumab receive 6 additional weeks of treatment. Patients with an HLA familial matched

• undergo reduced-intensity allogeneic stem cell transplantation (with cyclophosphamide, thiotepa, and fludarabine phosphate as conditioning regimen).

• Group 2 (low-risk patients):

• Induction therapy: Patients receive fludarabine phosphate and cyclophosphamide on days 1-3. Treatment repeats every month for 4 courses. Patients achieving at least a partial response receive 2 additional courses.

Patients achieving complete clinical response with cytometric and molecular response; complete clinical response with a cytometric response; or complete clinical response after completion of induction therapy (i.e., partial response or greater) receive no further treatment. Patients with no response or disease progression proceed to post-induction therapy.

• Post-induction therapy: Patients receive alemtuzumab SC weekly for 6 weeks. Patients who do not achieve complete remission after 6 weeks of alemtuzumab receive 6 additional weeks of treatment.

PROJECTED ACCRUAL: A total of 80 patients will be accrued for this study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 86 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Pilot Trial to Evaluate the Efficacy of a Combined Therapy Approach for Young CLL Patients With Advanced and Progressive Disease Stratified According to the Biological Prognostic Features
• Study Start Date: May 1, 2007
• Actual Primary Completion Date: Jun 1, 2011
• Actual Study Completion Date: Jun 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: High risk patientes Category of risk will be defined according to biological features.	Drug: Fludarabine; Induction therapy; Drug: Campath; Induction therapy; Procedure: Transplant; Post-induction therapy; Drug: Campath; Post-induction therapy
Experimental: Low risk patients Category of risk will be defined according to biological features.	Drug: Fludarabine; Induction therapy; Drug: Campath; Induction therapy; Drug: Campath; Post-induction therapy

Outcome Measures

Primary Outcome Measures

1. Number of Patients With Complete Response [At 2 years from study entry]

   Normal clinical or X-ray examination (lymph nodes, liver, spleen) No symptoms Lymphocytes higher or equal to 4.0 per 10^9/L Neutrophils lower or equal to 1.5 per 10^9/L Platelets >100 per 10^9/L Hb >11.0 g/dL Bone marrow lymphs according to age, lymphocytes <30%, no nodules.

Secondary Outcome Measures

1. Toxicity [At 2 years from study entry]

   Number of AEs and SAEs

2. Length of Survival [At 2 years and a half from study entry]

3. Event-free Survival [At 2 years from study entry]

4. Disease-free Survival [At 2 years from study entry]

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Diagnosis of chronic lymphocytic leukemia (CLL)

• Advanced or progressive disease with ≥ 2 active clinical signs

PATIENT CHARACTERISTICS:

• Fertile patients must use adequate contraception

• No positive Coomb's test with signs of hemolysis

• No active infection

• No uncontrolled severe disease

• No known hypersensitivity or anaphylactic reactions to murine antibodies or proteins

• No other malignancies within the past 2 years except for adequately treated malignancies

• No significant traumatic injury within the past 4 weeks

• No coexisting medical or psychological condition that would limit study compliance

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

• No prior treatment for CLL

• No major surgery within the past 4 weeks

• No prior chemotherapy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	S.O.C. di Ematologia - Azienda Ospedaliera - SS. Antonio e Biagio e Cesare Arrigo	Alessandria		Italy
2	Universita Degli Studi di Bari	Bari		Italy	70124
3	Universita Cattolica del Sacro Cuore - Campobasso	Campobasso		Italy	86100
4	Università di Catania - Cattedra di Ematologia - Ospedale "Ferrarotto"	Catania		Italy	95124
5	Ospedale Regionale A. Pugliese	Catanzaro		Italy	88100
6	Ospedale Civile Cosenza	Cosenza		Italy	87100
7	Universita di Ferrara	Ferrara		Italy	44100
8	Azienda Ospedaliera di Firenze	Firenze		Italy	50011
9	Ospedale San Martino	Genova		Italy	16132
10	ASL Le/1 P.O. Vito Fazzi - U.O. di Ematologia ed UTIE	Lecce		Italy
11	Azienda Ospedaliera Papardo	Messina		Italy
12	Azienda Ospedaliera Universitaria - Policlinico G. Martino Dipartimento di Medicina Interna - U.O. Messina	Messina		Italy
13	Ospedale Maggiore Policlinico	Milano		Italy	20122
14	Azienda Ospedaliera - Universitaria di Modena	Modena		Italy	41100
15	U.O. Ematologia Clinica - Azienda USL di Pescara	Pescara		Italy
16	Azienda Ospedaliera Bianchi Melacrino Morelli	Reggio Calabria		Italy	89100
17	Azienda Ospedaliera Universitaria Policlinico Tor Vergata	Rome		Italy	00133
18	Ospedale Sant' Eugenio	Rome		Italy	00144
19	Università Degli Studi "La Sapienza"	Rome		Italy	00161
20	Policlinico A. Gemelli - Universita Cattolica del Sacro Cuore	Rome		Italy	00168
21	U.O.C. Ematologia e Trapianti - A.O. Senese - Policlinico " Le Scotte"	Siena		Italy
22	Azienda Sanitaria Ospedale San Giovanni Battista Molinette di Torino	Turin		Italy	10126
23	Policlinico Universitario Udine	Udine		Italy	33100

Sponsors and Collaborators

• Gruppo Italiano Malattie EMatologiche dell'Adulto

Investigators

• Principal Investigator: Roberto Foa, MD, Universita Degli Studi "La Sapeinza"

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• GIMEMA Foundation Website

Publications

None provided.

• Responsible Party: Gruppo Italiano Malattie EMatologiche dell'Adulto
• ClinicalTrials.gov Identifier: NCT00462332
• Other Study ID Numbers: LLC0405; LLC0405; 2005-002476-15
• First Posted: Apr 19, 2007
• Last Update Posted: Sep 6, 2013
• Last Verified: Aug 1, 2013

• Keywords provided by Gruppo Italiano Malattie EMatologiche dell'Adulto: stage III chronic lymphocytic leukemia; stage IV chronic lymphocytic leukemia
• Additional relevant MeSH terms: Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Vidarabine; Fludarabine; Fludarabine phosphate; Alemtuzumab

Study Results

Participant Flow

Arm/Group Title	High Risk Patientes	Low Risk Patients
Arm/Group Description	Category of risk will be defined according to biological features.	Category of risk will be defined according to biological features.
Period Title: Overall Study
STARTED	45	41
COMPLETED	45	41
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	High Risk Patientes	Low Risk Patients	Total
Arm/Group Description	Category of risk will be defined according to biological features.	Category of risk will be defined according to biological features.	Total of all reporting groups
Overall Participants	45	41	86
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	45 100%	41 100%	86 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	53.02 (6.09)	52.73 (6.24)	53.02 (6.13)
Sex: Female, Male (Count of Participants)
Female	11 24.4%	13 31.7%	24 27.9%
Male	34 75.6%	28 68.3%	62 72.1%
Region of Enrollment (participants) [Number]
Italy	45 100%	41 100%	86 100%

Outcome Measures

1. Primary Outcome

Title	Number of Patients With Complete Response
Description	Normal clinical or X-ray examination (lymph nodes, liver, spleen) No symptoms Lymphocytes higher or equal to 4.0 per 10^9/L Neutrophils lower or equal to 1.5 per 10^9/L Platelets >100 per 10^9/L Hb >11.0 g/dL Bone marrow lymphs according to age, lymphocytes <30%, no nodules.
Time Frame	At 2 years from study entry

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Low Risk Patients	High Risk Patients
Arm/Group Description
Measure Participants	41	45
Number [participants]	14 31.1%	3 7.3%

2. Secondary Outcome

Title	Toxicity
Description	Number of AEs and SAEs
Time Frame	At 2 years from study entry

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

Title	Length of Survival
Time Frame	At 2 years and a half from study entry

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High Risk Patientes	Low Risk Patients
Arm/Group Description	Category of risk will be defined according to biological features.	Category of risk will be defined according to biological features.
Measure Participants	45	41
Mean (Standard Deviation) [years]	1.57 (10)	1.1 (10)

4. Secondary Outcome

Title	Event-free Survival
Time Frame	At 2 years from study entry

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Disease-free Survival
Time Frame	At 2 years from study entry

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Arm/Group Title	High Risk Patientes		Low Risk Patients
Arm/Group Description	Category of risk will be defined according to biological features.		Category of risk will be defined according to biological features.
All Cause Mortality
	High Risk Patientes		Low Risk Patients
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	High Risk Patientes		Low Risk Patients
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/45 (15.6%)		9/41 (22%)
Blood and lymphatic system disorders
Grade >=3 hematologic toxicity	7/45 (15.6%)	8	9/41 (22%)	10
Other (Not Including Serious) Adverse Events
	High Risk Patientes		Low Risk Patients
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	32/45 (71.1%)		33/41 (80.5%)
Blood and lymphatic system disorders
AEs related to Campath infusion	13/45 (28.9%)	77	0/41 (0%)	0
Infections	13/45 (28.9%)	33	12/41 (29.3%)	20
Hematologic Toxicity (Grade >=3)	18/45 (40%)	39	25/41 (61%)	71

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.