Acute Lymphoblastic Leukemia
Conditions
Keywords
Adult patients, Refractory, Relapsed, clofarabine, cyclophosphamide, refractory and relapsed acute lymphoblastic leukemia, ALL
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.
Interventions
DRUGClofarabine, Cyclophosphamide
The proposed treatment schedule consists of a combination of Clofarabine plus Cyclophosphamide administered over 5 consecutive days (Treatment scheme).
Sponsors
Gruppo Italiano Malattie EMatologiche dell'Adulto
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Primary End-point is the Number of Patients in CR After Induction Therapy. | At day +28 from start of chemotherapy cycle 1 and after cycle 2 in pts with PR | 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
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Toxicity of Grade 2 or Greater | At 13 months from study entry | Referring to CTCAE (Common Toxicity Criteria Events), version 4.0 |
| 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 | — |
| Disease-free Survival (DFS) | At one year from completion of chemotherapy | 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) | At one year from therapy completion. | 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) | At one year from therapy completion. | 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. |
Countries
Italy
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Clofarabine + Cyclophosphamide Patients received a maximum of two consecutive cycles of Clofarabine-Cyclophosphamide, at an intercycle interval of 28 days or greater, according to tolerability and clinical status.
Cycle 2 was only administered to patients obtaining at least a partial response (PR) after cycle 1. | 27 |
| Total | 27 |
Baseline characteristics
| Characteristic | Clofarabine + Cyclophosphamide | — |
|---|---|---|
| Age, Continuous | 38.7 Years | — |
| Patient status - refractory | 2 participants | — |
| Patient status - relapsed | 25 participants | — |
| Platelets count | 105000.0 cells/microliter | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment Italy | 27 participants | — |
| Sex: Female, Male Female | 12 Participants | — |
| Sex: Female, Male Male | 15 Participants | — |
| White Blood Cells (WBC) | 5670.0 cells/microliter | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 4 / 27 |
| other Total, other adverse events | 12 / 27 |
| serious Total, serious adverse events | 7 / 27 |
Outcome results
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.
Time frame: At day +28 from start of chemotherapy cycle 1 and after cycle 2 in pts with PR
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Clofarabine + Cyclophosphamide | The Primary End-point is the Number of Patients in CR After Induction Therapy. | 9 Participants |
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.
Time frame: At one year from therapy completion.
Population: Cumulative incidence of relapse was estimated only in CR patients (n=16) from date of first CR to date of death, relapse or last follow-up; considering death in CR as a competing risk.~Median CIR not yet reached.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clofarabine + Cyclophosphamide | Cumulative Incidence of Relapse (CIR) | 31.25 Percentage of patients |
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
Time frame: At one year from completion of chemotherapy
Population: Disease-free survival was estimated in CR patients (n=16) from date of first CR to date of death, relapse or last follow-up.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clofarabine + Cyclophosphamide | Disease-free Survival (DFS) | 31.25 Percentage of patients |
Secondary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Clofarabine + Cyclophosphamide | Number of Participants With Minimal Residual Disease (MRD) Response in Remission. | 1 Participants |
Secondary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Clofarabine + Cyclophosphamide | Number of Participants With Toxicity of Grade 2 or Greater | 10 Participants |
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.
Time frame: At one year from therapy completion.
Population: Overall survival was estimated from date of informed consent to date of death or last follow-up.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clofarabine + Cyclophosphamide | Overall Survival (OS) | 28.6 Percentage of patients |