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

Acute Lymphoblastic Leukemia Clinical Trial

— LAL1610  

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"

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01462253
• Other study ID #: LAL1610
• Status: Completed
• Phase: Phase 2
• Start date: October 2012
• Est. completion date: March 11, 2017

Study information

• Verified date: August 2018
• Source: Gruppo Italiano Malattie EMatologiche dell'Adulto
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 35
• Est. completion date: March 11, 2017
• Est. primary completion date: March 11, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

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.

Related Conditions & MeSH terms

• Acute Lymphoblastic Leukemia
• Leukemia
• Leukemia, Lymphoid
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

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

Locations

Country	Name	City	State
Italy	Unità Operativa Ematologia 1 - Università degli Studi di Bari	Bari
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
Italy	Azienda ASL di Cagliari	Cagliari
Italy	Ospedale Santa Croce Divisione di Ematologia Cuneo	Cuneo
Italy	Policlinico di Careggi, Università delgi studi di Firenze	Firenze
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	Milano
Italy	UO Centro Trapianti di Midollo - IRCCS Ospedale Maggiore Policlinico	Milano
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"	Napoli
Italy	Azienda Ospedaliera Universitaria - Università degli Studi di Napoli "Federico II" - Facoltà di Medicina e Chirurgia	Napoli
Italy	Ospedale Cervello	Palermo
Italy	U.O. Ematologia Clinica - Azienda USL di Pescara	Pescara
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	Complesso Ospedaliero S. Giovanni Addolorata	Roma
Italy	Umberto I di Roma - Dipartimento di Biotecnologie Cellulari ed Ematologia	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

Sponsors (1)

Lead Sponsor	Collaborator
Gruppo Italiano Malattie EMatologiche dell'Adulto

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	At day +28 from start of chemotherapy cycle 1 and after cycle 2 in pts with PR
Secondary	Number of Participants With Toxicity of Grade 2 or Greater	Referring to CTCAE (Common Toxicity Criteria Events), version 4.0	At 13 months from study entry
Secondary	Number of Participants With Minimal Residual Disease (MRD) Response in Remission.		At week 10, 16 and 22 from start of treatment and the, every three months till study completion
Secondary	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	At one year from completion of chemotherapy
Secondary	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.	At one year from therapy completion.
Secondary	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.	At one year from therapy completion.

External Links

•   GIMEMA Foundation Website