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Clofarabine-cyclophosphamide as Salvage Therapy for Refractory and Relapsed Acute Lymphoblastic Leukemia (ALL) Adults (LAL1610)

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Gruppo Italiano Malattie EMatologiche dell'Adulto
ClinicalTrials.gov Identifier:
NCT01462253
First received: October 21, 2011
Last updated: September 13, 2016
Last verified: September 2016
  Purpose
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).

Condition Intervention Phase
Acute Lymphoblastic Leukemia
Drug: Clofarabine, Cyclophosphamide
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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"

Resource links provided by NLM:


Further study details as provided by Gruppo Italiano Malattie EMatologiche dell'Adulto:

Primary Outcome Measures:
  • The primary end-point is the rate of patients in CR after induction therapy. [ Time Frame: At day +28 from start of chemotherapy cycle 1 and after cycle 2 in pts with PR ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Number of participants with toxicity of grade 2 or greater (CTCAE version 4.0) events [ Time Frame: At 13 months from study entry ] [ Designated as safety issue: Yes ]
  • Rate of ALL blast cells in apoptosis and DNA damage per patient induced by Clofarabine when used in combination with Cyclophosphamide. [ Time Frame: At 13 months from study entry ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • Disease-free survival (DFS) [ Time Frame: At one year from completion of chemotherapy ] [ Designated as safety issue: No ]
    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

  • Overall Survival (OS). [ Time Frame: At one year from therapy completion. ] [ Designated as safety issue: No ]
    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.

  • Cumulative incidence of relapse (CIR). [ Time Frame: At one year from therapy completion. ] [ Designated as safety issue: No ]
    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.

  • Rate of Disease free survival (DFS) in very high risk and high risk patients [ Time Frame: At one year from therapy completion. ] [ Designated as safety issue: No ]
    DFS in two different risk groups: VHR (very high risk) includes 1st relapse within 6 months from date of 1st CR; HR (high risk) includes relapse after 6 months from date of 1st CR.

  • Rate of Overall Survival (OS) in very high risk and high risk patients [ Time Frame: At one year from therapy completion. ] [ Designated as safety issue: No ]
    OS in two different risk groups: VHR (very high risk) includes 1st relapse within 6 months from date of 1st CR; HR (high risk) includes relapse after 6 months from date of 1st CR.

  • Rate of Cumulative Incidence of Relapse (CIR) in very high risk and high risk patients [ Time Frame: At one year from therapy completion. ] [ Designated as safety issue: No ]
    CIR in two different risk groups: VHR (very high risk) includes 1st relapse within 6 months from date of 1st CR; HR (high risk) includes relapse after 6 months from date of 1st CR.


Enrollment: 35
Study Start Date: October 2012
Estimated Study Completion Date: December 2016
Estimated Primary Completion Date: December 2016 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Clofarabine, Cyclophosphamide

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

    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.

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

Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01462253

Locations
Italy
Unità Operativa Ematologia 1 - Università degli Studi di Bari
Bari, Italy, 70010
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, 21125
Azienda ASL di Cagliari
Cagliari, Italy, 9121
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, Venezia, 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, 90146
U.O. Ematologia Clinica - Azienda USL di Pescara
Pescara, Italy, 65100
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, Italy, 00161
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
Sponsors and Collaborators
Gruppo Italiano Malattie EMatologiche dell'Adulto
Investigators
Principal Investigator: Renato BASSAN, Pr. U.O. di Ematologia- Ospedale dell'Angelo - Mestre
  More Information

Additional Information:
Responsible Party: Gruppo Italiano Malattie EMatologiche dell'Adulto
ClinicalTrials.gov Identifier: NCT01462253     History of Changes
Other Study ID Numbers: LAL1610 
Study First Received: October 21, 2011
Last Updated: September 13, 2016
Health Authority: Italy: Ethics Committee

Keywords provided by Gruppo Italiano Malattie EMatologiche dell'Adulto:
Adult patients
Refractory
Relapsed
clofarabine
cyclophosphamide
refractory and relapsed acute lymphoblastic leukemia
ALL

Additional relevant MeSH terms:
Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Cyclophosphamide
Clofarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antimetabolites

ClinicalTrials.gov processed this record on September 28, 2016