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

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Brief Title

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"

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.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

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

Secondary Outcome

 Number of Participants With Toxicity of Grade 2 or Greater

Condition

Acute Lymphoblastic Leukemia

Intervention

Clofarabine, Cyclophosphamide

Study Arms / Comparison Groups

 Clofarabine, Cyclophosphamide
Description:  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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

35

Start Date

October 2012

Completion Date

March 11, 2017

Primary Completion Date

March 11, 2017

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.
      

Gender

All

Ages

18 Years - 60 Years

Accepts Healthy Volunteers

No

Contacts

Renato BASSAN, Pr., , 

Location Countries

Italy

Location Countries

Italy

Administrative Informations


NCT ID

NCT01462253

Organization ID

LAL1610


Responsible Party

Sponsor

Study Sponsor

Gruppo Italiano Malattie EMatologiche dell'Adulto


Study Sponsor

Renato BASSAN, Pr., Principal Investigator, U.O. di Ematologia- Ospedale dell'Angelo - Mestre


Verification Date

August 2018