Clinical trial NCT01462253: Clofarabine-cyclophosphamide as Salvage Therapy for Refractory and Relapsed Acute Lymphoblastic Leukemia (ALL) Adults
Official title: "A Phase II Study With a Sequential Clofarabine-cyclophosphamide Combination Schedule as Salvage Therapy for Refractory and Relapsed Acute Lymphoblastic Leukemia (ALL) in Adult Patients"
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Acute Lymphoblastic Leukemia
Keywords: Adult patients
Refractory
Relapsed
clofarabine
cyclophosphamide
refractory and relapsed acute lymphoblastic leukemia
ALL
Lead sponsor: Gruppo Italiano Malattie EMatologiche dell'Adulto
Sponsor class: OTHER
First posted: 2011-10-31
Enrollment: 35
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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).

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.

Eligibility criteria: 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:

* 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.

Primary outcomes:
measure: The Primary End-point is the Number of Patients in CR After Induction Therapy.
timeFrame: At day +28 from start of chemotherapy cycle 1 and after cycle 2 in pts with PR
Secondary outcomes:
measure: Number of Participants With Toxicity of Grade 2 or Greater
timeFrame: At 13 months from study entry
measure: Number of Participants With Minimal Residual Disease (MRD) Response in Remission.
timeFrame: At week 10, 16 and 22 from start of treatment and the, every three months till study completion
measure: Disease-free Survival (DFS)
timeFrame: At one year from completion of chemotherapy
measure: Overall Survival (OS)
timeFrame: At one year from therapy completion.
measure: Cumulative Incidence of Relapse (CIR)
timeFrame: At one year from therapy completion.
Other outcomes:
Locations:
city: Bari
country: Italy
facility: Unità Operativa Ematologia 1 - Università degli Studi di Bari
city: Bergamo
country: Italy
facility: Divisione di Ematologia - Ospedali Riuniti
city: Bologna
country: Italy
facility: Istituto di Ematologia "Lorenzo e A. Seragnoli" - Università degli Studi di Bologna - Policlinico S. Orsola - Malpighi
city: Bolzano
country: Italy
facility: Azienda Sanitaria di Bolzano - Ospedale Centrale - Ematologia e Centro TMO
city: Brescia
country: Italy
facility: Sezione di Ematologia e Trapianti Spedali Civili
city: Cagliari
country: Italy
facility: Azienda ASL di Cagliari
city: Cuneo
country: Italy
facility: Ospedale Santa Croce Divisione di Ematologia Cuneo
city: Firenze
country: Italy
facility: Policlinico di Careggi, Università delgi studi di Firenze
city: Meldola
country: Italy
facility: Istituto Scientifico Romagnoli per lo Studio e la Cura dei Tumori- IRST
city: Mestre
country: Italy
facility: U.O. di Ematologia- Ospedale dell'Angelo - Mestre
city: Milano
country: Italy
facility: U.O. Ematologia e Trapianto di MIdollo - Ist.Scientifico Ospedale San Raffaele
city: Milano
country: Italy
facility: UO Centro Trapianti di Midollo - IRCCS Ospedale Maggiore Policlinico
city: Modena
country: Italy
facility: Centro Oncologico Modenese - Dipartimento di Oncoematologia
city: Monza
country: Italy
facility: N. Osp. divisione di Ematologia "S.Gerardo dei Tintori"
city: Napoli
country: Italy
facility: Azienda Ospedaliera di Rilievo Nazionale "A. Cardarelli"
city: Napoli
country: Italy
facility: Azienda Ospedaliera Universitaria - Università degli Studi di Napoli "Federico II" - Facoltà di Medicina e Chirurgia
city: Palermo
country: Italy
facility: Ospedale Cervello
city: Pescara
country: Italy
facility: U.O. Ematologia Clinica - Azienda USL di Pescara
city: Pisa
country: Italy
facility: Università di Pisa - Azienda Ospedaliera Pisana - Dipartimento di Oncologia, dei Trapianti e delle nuove Tecnologie in Medicina - Divisione di Ematologia
city: Ravenna
country: Italy
facility: Dipartimento Oncologico - Ospedale S.Maria delle Croci
city: Reggio Calabria
country: Italy
facility: Calabria Dipartimento Emato-Oncologia A.O."Bianchi-Melacrino-Morelli"
city: Roma
country: Italy
facility: Umberto I di Roma - Dipartimento di Biotecnologie Cellulari ed Ematologia
city: Roma
country: Italy
facility: Complesso Ospedaliero S. Giovanni Addolorata
city: Roma
country: Italy
facility: Università degli Studi "Sapienza" - Dip Biotecnologie Cellulari ed Ematologia - Divisione di Ematologia
city: Roma
country: Italy
facility: Università degli Studi - Policlinico di Tor Vergata
city: San Giovanni Rotondo
country: Italy
facility: Istituto di Ematologia - IRCCS Ospedale Casa Sollievo della Sofferenza
city: Torino
country: Italy
facility: SCDO Ematologia 2 AOU Giovanni Battista
Study officials:
affiliation: U.O. di Ematologia- Ospedale dell'Angelo - Mestre
name: Renato BASSAN, Pr.
role: PRINCIPAL_INVESTIGATOR
References: