Trial document




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  DRKS00000580

Trial Description

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Title

A multicenter Phase I/II trial investigating the safety and efficacy (CR rate and OS) of low dose AraC with Clofarabine in patients ≥60 years with AML not eligible for conventional
Chemotherapy

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Trial Acronym

Clofarabine

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URL of the Trial

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Brief Summary in Lay Language

This trial is performed in several trial centres in Germany with the target to assess the safety, feasibility and efficacy of a combination induction chemotherapy of Clofarabine and low-dose AraC in older patients with AML who are not eligible for conventional chemotherapy.
To investigate the feasibility of this induction therapy, three different dose levels are initiated subsequently.
To determine the efficacy of the combination therapy, the therapeutic achievements of each patient are followed.

Age has a strong impact on outcome in acute myeloid leukemia, with a gradual and consistent decline in survival with increasing age. Many older patients cannot be treated with curative intention because of comorbidities and/or increased toxicity of induction and consolidation chemotherapy. Older patients mostly do not tolerate chemotherapy as well as younger patients.
These observations indicate the poor outcome in elderly patients with AML and the need for more effective and less toxic treatment approaches.
Progress concerning rates of overall survival and complete remissions in curative treatment of elderly patients with AML can be obtained only using less toxic and more efficient drugs. Considering studies evaluating Clofarabine as single agent and the results of other trials, the treatment with Clofarabine in combination with AraC as described in this protocol seems promising concerning these objectives.

The trial treatment consists of a maximum of 4 induction cycles and up to 4 consolidation cycles. Every induction cycle comprises five days of Clofarabine and 14 days of AraC administration. Every consolidation cycle consists of three days of Clofarabine and seven days of AraC administration.
After the last administration of trial therapy there will be a follow up phase of 13 months.

Patients may participate in this trial if ALL of the following criteria are met:
1. Diagnosis of AML as defined by WHO
2. Primary or secondary AML
3. Age ≥60 years
4. Not eligible for standard/”curative” chemotherapy as defined in the trial protocol
5. Adequate renal and hepatic functions
6. Capable of understanding the investigational nature, potential risks and benefits of the study, and able to provide valid informed consent.
7. Written informed consent (ICF)

This trial is designed to assess safety and feasibility (tolerability) of the induction treatment with Clofarabine in combination with low dose AraC. This is reflected by the evaluation of this trial. The hypotheses are, that the treatment with Clofarabine in combination with low dose AraC is less toxic and that this treatment is effective for older patients who are not eligible for standard/curative chemotherapy.
Therefor the occurrence of adverse events will be documented and the response to the induction therapy is assessed.

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Brief Summary in Scientific Language

This is a prospective open-label Phase I / II multicentre trial to assess the safety and feasibility of Clfarabine in combination with low-dose AraC in patients not eligible for conventional chemotherapy.

The trial starts with a dose escalation phase with regard to the dose of Clofarabine. Three cohorts of 3-6 patients will be included in the dose escalation phase. All further patients will be treated at the dose level resulting from the dose escalation phase. Patient recruitment will continue until a total of 60 patients are included.

During the dose evaluation phase, the investigational treatment consists of a maximum of four (dose level 1), three (dose level 2) resp. two (dose level 3) induction and a maximum of four consolidation cycles of the combined therapy with Clofarabine and low-dose AraC.

The dose escalation algorithm is based on the incidence of adverse reactions with CTC Grade 4 (AR4) during the individually first induction cycle. Dose evaluation can be based only on informative patients with respect to AR4. That means that patients who die within 14 days of the individually first induction cycle from other than treatment-related causes,will not be counted for the dose evaluation.

The trial starts with the enrolment of 3 patients on dose level 1. Depending on the results of the first three informative patients, the further procedure is:

If in the first three informative patients there is no case of adverse reactions CTC grade 4 (AR4), the study will be continued with dose level 2.
If there is one case of AR4 in the first three informative patients on dose level 1, another three patients are treated on this dose level. If there are less than two cases of AR4 in the first six informative patients, the trial will be continued with dose level 2. If there are two or more cases of AR4 in the first six informative patients, the DMC will be informed and decides on the further course of the trial

If there are two or three cases of AR4 in the first three informative patients, the DMC will be informed and decides on the further course of the trial.

Dose level 2 starts with the enrolment of another 3 patients. The further procedure is:

If in the first three informative patients on dose level 2 there is no case of adverse re-actions CTC grade 4 (AR4), the study will be continued with dose level 3.
If there is maximally one case of AR4 in these three informative patients on dose level 2, another three patients are treated on this dose level. If there are less than two cases of AR4 in the first six informative patients, the trial will be continued with dose level 3. If there are two or more than two cases of AR4 the first six informative patients, the final dose level is dose level 1. If there are two or three cases of AR4 in these three informative patients, the final dose level is dose level 1

Dose level 3 starts with the enrolment of another 3 patients. The further procedure is: If there is maximally one case of AR4 in three informative patients on dose level 3, another three patients are treated on this dose level. If there are less than two cases of AR4 in the first six informative patients, the final dose level is dose level 3. If there are two or more cases of AR4 in the first six informative patients, the final dose level is dose level 2. If there are two or more cases of AR4 in these three patients, the final dose level is dose level 2.
The final dose level will be maintained until a total of 60 patients have been enrolled into the trial.

Every induction cycle comprises five days of Clofarabine where the dosage depends on the dose level the patient is allocated to and 14 days of AraC administration. Every consolidation cycle consists of three days of Clofarabine (15 mg/m2/day) and seven days of AraC administration. AraC will be given in all induction and all consolidation cycles at a dose of 20 mg/m2 per day.

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Organizational Data

  •   DRKS00000580
  •   2010/10/07
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  •   yes
  •   Approved
  •   180-10-12072010-ff, Ethikkommission an der Medizinischen Fakultät der Universität Leipzig
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Secondary IDs

  •   2009-017347-33 
  •   4036362 
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Health Condition or Problem studied

  •   10000886, akute myeloische Leukämie, acute myeloid leukemia
  •   C92.0 -  Acute myeloid leukaemia
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Interventions/Observational Groups

  •   Dosis evaluation phase:

    Dose level 1:
    1. cycle: Clofarabine 10mg/m2, i.v., days 1-5, Ara-C 20mg/m2, s.c., days 1-14.

    2. cycle: Clofarabine 15mg/m2, i.v., days 1-5, Ara-C 20mg/m2, s.c., days 1-14.

    3. cycle: Clofarabine 20mg/m2, i.v., days 1-5, Ara-C 20mg/m2, s.c., days 1-14.

    4. cycle: Clofarabine 30mg/m2, i.v., days 1-5, Ara-C 20mg/m2, s.c., days 1-14.


    Dose level 2:
    1. cycle: Clofarabine 15mg/m2, i.v., days 1-5, Ara-C 20mg/m2, s.c., days 1-14.

    2. cycle: Clofarabine 20mg/m2, i.v., days 1-5, Ara-C 20mg/m2, s.c., days 1-14.

    3. cycle: Clofarabine 30mg/m2, i.v., days 1-5, Ara-C 20mg/m2, s.c., days 1-14.


    Dose level 3 and target dose for induction therapy with Clofarabine and low dose AraC:

    1. cycle: Clofarabine 20mg/m2, i.v., days 1-5, Ara-C 20mg/m2, s.c., days 1-14.

    2. cycle: Clofarabine 30mg/m2, i.v., days 1-5, Ara-C 20mg/m2, s.c., days 1-14.


    Consolidation therapy with Clofarabine and low dosw AraC:

    1 to 4 cycles: Clofarabine 15mg/m2, i.v., days 1-3, Ara-C 20mg/m2, s.c., days 1-7.
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Characteristics

  •   Interventional
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  •   Single arm study
  •   Open (masking not used)
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  •   Uncontrolled/Single arm
  •   Treatment
  •   Single (group)
  •   I-II
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Primary Outcome

Adverse and serious adverse events during induction therapy, Adverse and serious adverse reactions during induction therapy, Adverse Reactions CTC grade 4 (AR4)

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Secondary Outcome

Response after induction therapy: assessed at d21 of the last cycle of induction therapy of the patient, with the following response categories: complete remission (CR), complete remission with incomplete recovery (CRi), partial response (PR), resistant disease (RD), death during induction therapy.

Overall survival (OS): defined as time from the date of enrollment to the day of death from any cause.

Event-free survival (EFS): defined as time from the date of enrolment to the day of induction failure treatment, or relapse after CR or death from any cause. Patients not known to have experienced any of these events will be censored on the day they were last examined.

Relapse-free survival (RFS): defined as time from the date of achievement of a complete remission to the day of relapse or death from any cause. Patients not known to have experienced any of these events will be censored on the day they were last examined. RFS is defined only for patients achieving CR.

Allogeneic hematopoietic cell transplantation performed after reaching CR at the end of induction therapy (yes/no).

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

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Recruitment

  •   Actual
  •   2011/03/03
  •   60
  •   Multicenter trial
  •   National
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Inclusion Criteria

  •   Both, male and female
  •   60   Years
  •   no maximum age
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Additional Inclusion Criteria

1. Diagnosis of AML as defined by WHO
2. Primary or secondary AML
3. Age ≥60 years
4. Not eligible for standard/”curative” chemotherapy as described at the end of this section in refer-ence tables in section 4.3.
5. Adequate renal and hepatic functions as indicated by ALL of the following laboratory values:
a. Serum creatinine <=1.0 mg/dL (<=88,4 µmol/l) or
if serum creatinine >1.0 mg/dL (>88,4 µmol/l), 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)
b. Serum bilirubin ≤1.5 mg/dL (17,1 µmol/l) × upper limit of normal (ULN)
c. Aspartate transaminase (AST)/ alanine transaminase (ALT) <=2.5 × ULN
d. Alkaline phosphatase <=2.5 × ULN
6. Capable of understanding the investigational nature, potential risks and benefits of the study, and able to provide valid informed consent.
7. Written informed consent (ICF)

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Exclusion Criteria

1.Diagnosis of AML M3
2.Current concomitant chemotherapy, radiation therapy, or immunotherapy other than described in the trial protocol.
3.Use of investigational agents within 30 days or any anticancer therapy within 2 weeks before study entry. The patient must have recovered from all acute toxicities from any previous therapy.
4.Have any other severe concurrent disease, or have a history of serious organ dysfunction or disease involving the heart, kidney, liver, or other organ system that may place the patient at undue risk to undergo treatment.
5.Patients with a systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment).
6.Hypersensitivity to Clofarabine, AraC or one of their components.
7.Pregnant or nursing women.
8.Any significant concurrent disease, illness, or psychiatric disorder that would compromise patient safety or compliance, interfere with consent, study participation, follow up, or interpretation of study results.
9.Have had a diagnosis of another malignancy, unless the patient has been disease-free for at least 3 years following the completion of curative intent therapy, with the following exceptions:
9a.Patients with treated non-melanoma skin cancer, in situ carcinoma, or cervical intraepithelial neoplasia, regardless of the disease-free duration, are eligible for this study if definitive treatment for the condition has been completed.
9b.Patients with organ-confined prostate cancer with no evidence of recurrent or progressive disease based on prostate-specific antigen (PSA) values are also eligible for this study if hormonal therapy has been initiated or a radical prostatectomy has been performed.
10.Psychiatric illness that would prevent granting of informed consent.
11.Active viral infection with known human immunodeficiency virus (HIV) or viral hepatitis type B or C.
12.Ongoing drug abuse.
13.Women with child bearing potency without effective contraception (i. e. implants, injectables, combined oral contraceptives, some IUDs or vasectomised partner) during the conduct of the trial. Patients using hormonal methods of contraception must be informed about possible influences of the study drug on contraception.
14.Concomitant participation in other clinical trials:
During the verification of the in- and exclusion criteria the trial physician checks, if the patient is participating in any other interventional clinical trials following the AMG at the same time. Should this be the case, the patient will not be included. Simultaneously the patient declares not to take part in any parallel interventional clinical trials following the AMG by signing the informed consent sheet.

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Addresses

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    • Universität Leipzig
    • Ritterstr. 26
    • 04109  Leipzig
    • Germany
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    • Universität Leipzig Department für Innere Medizin Selbstständige Abteilung für Hämatologie, Internistische Onkologie und Hämostaseologie
    • Mr.  Prof. Dr. med. Dr. h.c.  Dietger  Niederwieser 
    • Johannisallee 32a
    • 04103  Leipzig
    • Germany
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    • Universität Leipzig Department für Innere Medizin Selbstständige Abteilung für Hämatologie, Internistische Onkologie und Hämostaseologie
    • Mr.  Prof. Dr. med. Dr. h.c.  Dietger  Niederwieser 
    • Johannisallee 32a
    • 04103  Leipzig
    • Germany
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Sources of Monetary or Material Support

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    • Genzyme Europe B.V.
    • Gooimeer 10
    • 1411 DD  Naarden
    • Netherlands
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Status

  •   Recruiting stopped after recruiting started
  •   2013/08/25
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Trial Publications, Results and other Documents

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* This entry means the parameter is not applicable or has not been set.