CompletedNCT01462253LAL1610Updated Jan 25, 2019Results posted

Clofarabine-cyclophosphamide as Salvage Therapy for Refractory and Relapsed Acute Lymphoblastic Leukemia (ALL) Adults

A Phase 2 interventional study of Clofarabine, Cyclophosphamide in Acute Lymphoblastic Leukemia, sponsored by Gruppo Italiano Malattie EMatologiche dell'Adulto. Completed at 27 sites in Italy. Open to participants aged 18 Years to 60 Years. Per ClinicalTrials.gov, last updated 2019-01-25.

Sponsored by Gruppo Italiano Malattie EMatologiche dell'Adulto · Phase 2, Interventional, and Treatment

Phase: Phase 2
Study type: Interventional
Enrollment: 35
Allocation: Not applicable
Ages: 18 Years to 60 Years
Sex: All

Study summary

This is a multicentric, prospective pilot trial testing a Clofarabine-Cyclophosphamide combination to treat refractory and first bone marrow relapse adult ALL, for the achievement of a complete remission (CR) and the concurrent evaluation of biological response in ALL cells (minimal residual disease, apoptosis and DNA cell damage, pharmacogenomics).

Read the detailed description

The proposed treatment schedule consists of a combination of Clofarabine plus Cyclophosphamide administered over 5 consecutive days (Treatment scheme). This is an open, nonrandomized prospective phase II trial aimed to evaluating (1) activity of this combination in terms of CR rate.

STEP 1. All eligible patients will be screened for the availability of an HLA-matched or partially mismatched compatible HSCT donor, of both family related - or unrelated type (early activation required), including cord blood and haploidentical siblings. Moreover, pre-treatment investigation will include collection and storage of patient ALL cells for specific biological studies relating to sensitivity and response to study chemotherapeutic combination.
STEP 2. Cycle 1 will be applied to all eligible patients once all enrollment criteria are confirmed.
STEP 3. After cycle 1, response will be evaluated.
STEP 4. After remission induction cycle 1, only responsive patients (CR or PR, see below for definitions) could be given cycle 2, according to the opinion of the responsible physician and with a minimum intercycle interval of 4 weeks from day 1 of cycle 1. All NR patients will be declared off study and will not be given a second course with study combination. The suggested treatment following cycle 2 (or cycle 1 if cycle 2 is omitted) is HSCT.

Conditions studied

Acute Lymphoblastic Leukemia

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Keywords

Adult patients
Refractory
Relapsed
clofarabine
cyclophosphamide
refractory and relapsed acute lymphoblastic leukemia
ALL

In context

Precursor Cell Lymphoblastic Leukemia-Lymphoma

2,121 studies on the registry are indexed under Precursor Cell Lymphoblastic Leukemia-Lymphoma; 492 are open to participants now.

This study's enrollment of 35 is below the median of 40 across 1,691 interventional studies indexed under Precursor Cell Lymphoblastic Leukemia-Lymphoma.

Browse Precursor Cell Lymphoblastic Leukemia-Lymphoma studies →

Lead sponsor

Gruppo Italiano Malattie EMatologiche dell'Adulto is the lead sponsor of 134 studies on the registry; 35 are open to participants now.

Browse Gruppo Italiano Malattie EMatologiche dell'Adulto studies →

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 18 Years to 60 Years
Sexes eligible: All
Accepts healthy volunteers: No

Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.

Inclusion criteria

Signed written informed consent according to IGH/EU/GCP and national local laws.
Age 18-60 years.
ALL with B-/T-precursor phenotype refractory to first line therapy.
ALL with B-/T-precursor phenotype 1st isolated bone marrow relapse, occurring \< 24 months from the achievement of first CR, after chemotherapy or hematopoietic stem-cell transplantation (HSCT) defined as follows:
* ≥ 5% leukemic blasts in the bone marrow not attributable to another cause (e.g. marrow regeneration); if there are no circulating blasts and the bone marrow contain 5-20% leukemic blasts, a repeat bone marrow performed at least a week later is necessary to confirm relapse.
ECOG performance status 0-2 or reversible ECOG 3 score following intensive care of complications.
Adequate hepatic and renal function, unless considered due to organ leukemic involvement:
- Serum creatinine \<1.5 mg/dl; if serum creatinine >1.5 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 where Predicted GFR (ml/min/1.73 m2) = 186 x (Serum Creatinine)-1.154 x (age in years)-0.023 x (0.742 if patient is female), x (1.212) if patient is black.
- Serum bilirubin ≤ 1.5 x upper limit of normal (ULN).
- Aspartate transaminase (AST)/alanine transaminase (ALT) ≤ 2.5 x ULN.
- Alkaline phosphatase ≤ 2.5 x ULN.

Exclusion criteria

Exclusion Criteria:

Prior exposure to Clofarabine or, in primary refractory patients only, to Cyclophosphamide during induction courses.
Patients relapsed > 24 months from first CR. - Philadelphia chromosome-positive (Ph+) ALL.
Diagnosis of Burkitt-type/B-ALL, or B-/T-lymphoblastic lymphoma with \< 25% bone marrow involvement.
Concurrent or isolated central nervous system (CNS) relapse.
Pre-existing, uncontrolled pathology such as cardiac disease (congestive/ischemic, acute myocardial infarction within the past 3 months, untreatable arrythmias, NYHA classes III and IV).
Severe neurological or psychiatric disorder that impairs the patient's ability to understand and sign the informed consent, or to cope with the intended treatment plan.
Active uncontrolled systemic fungal, bacterial, viral, or other infection (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment).
HIV positive serology or active hepatitis infection. - Concurrent diagnosis of active cancer requiring concurrent chemotherapy and/or radiotherapy, and/or with life expectancy \< 1 year.
Patients who are pregnant or adults of reproductive potential not employing an effective method of birth control (women of childbearing potential must have a negative serum pregnancy test within 48 hrs prior to administration of Clofarabine-Cyclophosphamide). Post menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. Male and female patients must agree to employ an effective barrier method of birth control throughout the study and for up to 3 months following discontinuation of study drugs.

Study design

Phase: Phase 2
Primary purpose: Treatment
Allocation: Not applicable
Intervention model: Single group
Masking: None (open label)
Enrollment: 35 participants (actual)

Study arms

Experimental
Clofarabine, Cyclophosphamide
Clofarabine concentrate for solution for infusion should be filtered using a 0.2 micron filter and diluted to a final concentration between 0.15 mg/mL and 0.4 mg/mL with 0.9% sodium chloride injection USP or European Pharmacopeia (EP) normal saline (NS), or 5% dextrose injection (D5W) USP or EP prior to infusion. Cyclophosphamide should be prepared for parenteral use by adding 0.9% sterile sodium chloride solution. Solutions of cyclophosphamide may be injected intravenously without further dilution or may be infused following further dilution: Dextrose Injection, USP (5% dextrose), Dextrose and Sodium Chloride Injection, USP (5% dextrose and 0.9% sterile sodium chloride), 5% Dextrose and Ringer's Injection.
Drug: Clofarabine, Cyclophosphamide

Interventions

DrugClofarabine, Cyclophosphamide
Drug pages: Clofarabine · Cyclophosphamide
The proposed treatment schedule consists of a combination of Clofarabine plus Cyclophosphamide administered over 5 consecutive days (Treatment scheme).

What researchers measure

Primary outcomes

The Primary End-point is the Number of Patients in CR After Induction Therapy.
Disappearance of any clinical and laboratoristic sign of ALL. The patient must be transfusion-free with neutrophils \>1.0 x109/L and platelets \>100 x109/L. BM examination must show absence or reduction of blast cell content (\< 5%, none of which obviously leukemic), with cellularity in the normal or slightly hypocellular range and with evidence of trilineage hemopoiesis. BM is examined on day 28 from start of chemotherapy cycle 1, or later as clinically indicated in ill/cytopenic patients, and after cycle 2 in patients with PR proceeding to this treatment.
Time frame: At day +28 from start of chemotherapy cycle 1 and after cycle 2 in pts with PR

Secondary outcomes

Number of Participants With Toxicity of Grade 2 or Greater
Referring to CTCAE (Common Toxicity Criteria Events), version 4.0
Time frame: At 13 months from study entry
Number of Participants With Minimal Residual Disease (MRD) Response in Remission.
Time frame: At week 10, 16 and 22 from start of treatment and the, every three months till study completion
Disease-free Survival (DFS)
Disease-free survival (DFS) at 1 year, defined as the time interval between the evaluation of CR and relapse of the disease or death in first CR; patients still alive, in first CR, will be censored at the time of the last follow-up. In this case, the DFS curve will be truncated at 1 year
Time frame: At one year from completion of chemotherapy
Overall Survival (OS)
Overall Survival (OS) at 1 year; defined as the time interval between inclusion and death for any cause; patients still alive will be censored at the time of the last follow-up. In this case, the OS curve will be truncated at 1 year.
Time frame: At one year from therapy completion.
Cumulative Incidence of Relapse (CIR)
Cumulative incidence of relapse (CIR) at 1 year, it will be calculated from the date of achievement of the first CR, using the cumulative incidence method, considering death in CR as a competing risk. Patients still alive, without a date of relapse, will be censored at the time of the last follow-up. In this case, the CIR curve will be truncated at 1 year.
Time frame: At one year from therapy completion.

Results

Posted Jan 25, 2019

Participant flow

Participant flow — Overall Study
Milestone	Clofarabine + Cyclophosphamide
Started	35
Completed	27
Not completed	8

Outcome measures

PrimaryThe Primary End-point is the Number of Patients in CR After Induction Therapy.

Disappearance of any clinical and laboratoristic sign of ALL. The patient must be transfusion-free with neutrophils \>1.0 x109/L and platelets \>100 x109/L. BM examination must show absence or reduction of blast cell content (\< 5%, none of which obviously leukemic), with cellularity in the normal or slightly hypocellular range and with evidence of trilineage hemopoiesis. BM is examined on day 28 from start of chemotherapy cycle 1, or later as clinically indicated in ill/cytopenic patients, and after cycle 2 in patients with PR proceeding to this treatment.

Time frame:: At day +28 from start of chemotherapy cycle 1 and after cycle 2 in pts with PR
Reported as:: Count of participants · Participants

The Primary End-point is the Number of Patients in CR After Induction Therapy.
Participants	Clofarabine + Cyclophosphamide
The Primary End-point is the Number of Patients in CR After Induction Therapy.	9

SecondaryNumber of Participants With Toxicity of Grade 2 or Greater

Referring to CTCAE (Common Toxicity Criteria Events), version 4.0

Time frame:: At 13 months from study entry
Reported as:: Count of participants · Participants

Number of Participants With Toxicity of Grade 2 or Greater
Participants	Clofarabine + Cyclophosphamide
Number of Participants With Toxicity of Grade 2 or Greater	10

SecondaryNumber of Participants With Minimal Residual Disease (MRD) Response in Remission.

Time frame:: At week 10, 16 and 22 from start of treatment and the, every three months till study completion
Reported as:: Count of participants · Participants

Number of Participants With Minimal Residual Disease (MRD) Response in Remission.
Participants	Clofarabine + Cyclophosphamide
Number of Participants With Minimal Residual Disease (MRD) Response in Remission.	1

SecondaryDisease-free Survival (DFS)

Disease-free survival (DFS) at 1 year, defined as the time interval between the evaluation of CR and relapse of the disease or death in first CR; patients still alive, in first CR, will be censored at the time of the last follow-up. In this case, the DFS curve will be truncated at 1 year

Time frame:: At one year from completion of chemotherapy
Reported as:: Number · Percentage of patients

Disease-free Survival (DFS)
Percentage of patients	Clofarabine + Cyclophosphamide
Disease-free Survival (DFS)	31.25 (17.3 to 69.7)

SecondaryOverall Survival (OS)

Overall Survival (OS) at 1 year; defined as the time interval between inclusion and death for any cause; patients still alive will be censored at the time of the last follow-up. In this case, the OS curve will be truncated at 1 year.

Time frame:: At one year from therapy completion.
Reported as:: Number · Percentage of patients

Overall Survival (OS)
Percentage of patients	Clofarabine + Cyclophosphamide
Overall Survival (OS)	28.6 (15.3 to 53.3)

SecondaryCumulative Incidence of Relapse (CIR)

Cumulative incidence of relapse (CIR) at 1 year, it will be calculated from the date of achievement of the first CR, using the cumulative incidence method, considering death in CR as a competing risk. Patients still alive, without a date of relapse, will be censored at the time of the last follow-up. In this case, the CIR curve will be truncated at 1 year.

Time frame:: At one year from therapy completion.
Reported as:: Number · Percentage of patients

Cumulative Incidence of Relapse (CIR)
Percentage of patients	Clofarabine + Cyclophosphamide
Cumulative Incidence of Relapse (CIR)	31.25 (10.774 to 54.485)

Adverse events

Collected over 54 months from study entry. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
Clofarabine + Cyclophosphamide	4/27 (14.8%)	7/27 (25.9%)	12/27 (44.4%)

Most frequent serious events

Most frequent serious events
Event	Clofarabine + Cyclophosphamide
Septic shockInfections and infestations	2/27
BradycardiaCardiac disorders	1/27
Atrial fibrilationCardiac disorders	1/27
PneumonitisInfections and infestations	1/27
Cytomegalovirus infectionInfections and infestations	1/27
Klebsiella sepsisInfections and infestations	1/27
Acute renal failureRenal and urinary disorders	1/27
Depressed level of consciousnessNervous system disorders	1/27
Hepatitis acuteHepatobiliary disorders	1/27
Subdural haemorrhageInjury, poisoning and procedural complications	1/27

Most frequent other events

Showing 10 of 22

Most frequent other events
Event	Clofarabine + Cyclophosphamide
PyrexiaGeneral disorders	3/27
Bacterial sepsisInfections and infestations	3/27
BronchopneumoniaInfections and infestations	2/27
Vena cava thromboisVascular disorders	1/27
Staphylococcal infectionInfections and infestations	1/27
Alanine aminotransferase increasedInvestigations	1/27
Aspartate aminotransferase increasedInvestigations	1/27
Blood bilirubin increasedInvestigations	1/27
Weight decreasedInvestigations	1/27
DyspnoeaRespiratory, thoracic and mediastinal disorders	1/27

Baseline characteristics

Age, Continuous
Age, Continuous(Years)	Clofarabine + Cyclophosphamide
Median	38.7 (20.5 to 59.6)

Sex: Female, Male
Sex: Female, Male(Participants)	Clofarabine + Cyclophosphamide
Female	12
Male	15

Race and Ethnicity Not Collected
Race and Ethnicity Not Collected(Participants)	Clofarabine + Cyclophosphamide

Region of Enrollment
Region of Enrollment(participants)	Clofarabine + Cyclophosphamide
Italy	27

Patient status - relapsed
Patient status - relapsed(participants)	Clofarabine + Cyclophosphamide
Number	25

Patient status - refractory
Patient status - refractory(participants)	Clofarabine + Cyclophosphamide
Number	2

White Blood Cells (WBC)
White Blood Cells (WBC)(cells/microliter)	Clofarabine + Cyclophosphamide
Median	5670.0 (104.9 to 55000.0)

Platelets count
Platelets count(cells/microliter)	Clofarabine + Cyclophosphamide
Median	105000.0 (14000.0 to 270000.0)

Study locations

27 sites

Unità Operativa Ematologia 1 - Università degli Studi di Bari
Bari, 70010, Italy
Divisione di Ematologia - Ospedali Riuniti
Bergamo, Italy
Istituto di Ematologia "Lorenzo e A. Seragnoli" - Università degli Studi di Bologna - Policlinico S. Orsola - Malpighi
Bologna, Italy
Azienda Sanitaria di Bolzano - Ospedale Centrale - Ematologia e Centro TMO
Bolzano, Italy
Sezione di Ematologia e Trapianti Spedali Civili
Brescia, 21125, Italy
Azienda ASL di Cagliari
Cagliari, 9121, Italy
Ospedale Santa Croce Divisione di Ematologia Cuneo
Cuneo, Italy
Policlinico di Careggi, Università delgi studi di Firenze
Florence, Italy
Istituto Scientifico Romagnoli per lo Studio e la Cura dei Tumori- IRST
Meldola, Italy
U.O. di Ematologia- Ospedale dell'Angelo - Mestre
Mestre, Italy
U.O. Ematologia e Trapianto di MIdollo - Ist.Scientifico Ospedale San Raffaele
Milan, Italy
UO Centro Trapianti di Midollo - IRCCS Ospedale Maggiore Policlinico
Milan, Italy
Centro Oncologico Modenese - Dipartimento di Oncoematologia
Modena, Italy
N. Osp. divisione di Ematologia "S.Gerardo dei Tintori"
Monza, Italy
Azienda Ospedaliera di Rilievo Nazionale "A. Cardarelli"
Naples, Italy
Azienda Ospedaliera Universitaria - Università degli Studi di Napoli "Federico II" - Facoltà di Medicina e Chirurgia
Naples, Italy
Ospedale Cervello
Palermo, 90146, Italy
U.O. Ematologia Clinica - Azienda USL di Pescara
Pescara, 65100, Italy
Università di Pisa - Azienda Ospedaliera Pisana - Dipartimento di Oncologia, dei Trapianti e delle nuove Tecnologie in Medicina - Divisione di Ematologia
Pisa, Italy
Dipartimento Oncologico - Ospedale S.Maria delle Croci
Ravenna, Italy
Calabria Dipartimento Emato-Oncologia A.O."Bianchi-Melacrino-Morelli"
Reggio Calabria, Italy
Umberto I di Roma - Dipartimento di Biotecnologie Cellulari ed Ematologia
Roma, 00161, Italy
Complesso Ospedaliero S. Giovanni Addolorata
Roma, Italy
Università degli Studi "Sapienza" - Dip Biotecnologie Cellulari ed Ematologia - Divisione di Ematologia
Roma, Italy
Università degli Studi - Policlinico di Tor Vergata
Roma, Italy
Istituto di Ematologia - IRCCS Ospedale Casa Sollievo della Sofferenza
San Giovanni Rotondo, Italy
SCDO Ematologia 2 AOU Giovanni Battista
Torino, Italy

References and documents

Study documents

Statistical analysis plan · Jan 17, 2012
Study protocol · Jan 17, 2012

Documents are hosted by the registry — open the source record to download them.

Updates

Tracking since Sep 25, 2026

No changes since tracking began. The registry record was last updated on Jan 25, 2019, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT01462253
Lead sponsor: Gruppo Italiano Malattie EMatologiche dell'Adulto
Responsible party: Sponsor
First posted: Oct 31, 2011
Start date: Oct 2012
Primary completion: Mar 11, 2017
Completion: Mar 11, 2017
Results posted: Jan 25, 2019
Last update: Jan 25, 2019

Study contacts

Renato BASSAN, Pr.

principal investigator · U.O. di Ematologia- Ospedale dell'Angelo - Mestre

Oversight

Data monitoring committee: No

View the source record on ClinicalTrials.gov ↗

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Studies of the drugs tested here: Clofarabine · Cyclophosphamide

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