Dose Escalation of Clofarabine in Combination With Cytarabine and Idarubicin as Induction Therapy in High Risk AML (CIARA)

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2012 by Hannover Medical School
Sponsor:
Collaborators:
Hannover Clinical Trial Center GmbH
Genzyme, a Sanofi Company
Information provided by (Responsible Party):
Prof. Dr. Juergen Krauter, Hannover Medical School
ClinicalTrials.gov Identifier:
NCT01534702
First received: February 14, 2012
Last updated: February 17, 2012
Last verified: February 2012
  Purpose

With current chemotherapy protocols, in 60-80% of patients with acute myeloid leukemia (AML) the leukemic blasts in the bone marrow can be reduced to < 5%. This is called "complete remission (CR)" and is the prerequisite for cure of the disease. During the last years, several genetic and biologic risk factors for the achievement of CR have been defined, and the remission rates vary considerably between patient groups with different risk profiles. On one hand, patients with certain chromosomal or molecular aberrations have very high CR rates of approximately 90%. Moreover, in some of these patients, molecularly targeted therapies for specific genetic aberrations are currently evaluated in clinical trials. However, these genetic aberrations account for only 50-60% of the overall patient population in AML. The remaining patients have a significantly inferior CR rate of only 50-60% with 30% resistant disease after two cycles of standard induction chemotherapy. In conclusion, there is need for improved induction regimens in a large number of adult patients with AML. An improved CR rate in this patient population will increase the number of patients eligible for intensive consolidation such as an allogeneic stem cell transplantation and might thereby be the basis for a better overall outcome. However, there is no clear evidence that this goal can be achieved with the currently available chemotherapy protocols. Clofarabine (2-chloro-2-fluoro-deoxy-9-D-arabinofuranosyladenine) is a nucleoside analogon which combines properties of fludarabine and cladribine. Due to the lack of neurological side effects, clofarabine could be explored in higher doses than other nucleoside analogues and has shown considerable antileukemic activity in patients with relapsed or refractory acute leukemias and elderly AML patients alone or in combination with cytarabine. In addition, the combination of clofarabine, cytarabine and idarubicin has produced promising results with acceptable toxicity in patients with relapsed or refractory AML. Based on these initial studies, there is need for a further optimization of the clofarabine dose in this combination. The aim of the AMLSG 17-10 study is therefore to evaluate the tolerability and safety of increasing doses of clofarabine in combination with idarubicin/cytarabine in patients with high risk AML defined by the genetic and molecular risk profile.


Condition Intervention Phase
Acute Myeloid Leukemia
Drug: clofarabine, cytarabine, idarubicin
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I/II Study on Cytarabine and Idarubicin Combined With Escalating Doses of Clofarabine as Induction Therapy in Patients With Acute Myeloid Leukemia and High Risk for Induction Failure (AMLSG 17-10)

Resource links provided by NLM:


Further study details as provided by Hannover Medical School:

Primary Outcome Measures:
  • maximal tolerated dose of clofarabine in combination with cytarabine and idarubicin [ Time Frame: six weeks ] [ Designated as safety issue: Yes ]
    maximal tolerated dose of clofarabine in combination with cytarabine and idarubicin in the therapy of previously untreated AML and high risk for induction failure


Secondary Outcome Measures:
  • complete remission rate [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    complete remission rate after two cycles of induction therapy

  • relapse-free, event-free and overall survival [ Time Frame: 4 years ] [ Designated as safety issue: No ]
  • blast reduction in the bone marrow after the first induction cycle [ Time Frame: 15 days ] [ Designated as safety issue: No ]
  • duration of aplasia [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
  • therapy-associated morbidity and mortality [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
  • course of molecular and cytogenetic markers during chemotherapy [ Time Frame: four years ] [ Designated as safety issue: No ]
    molecular and cytogenetic markers will be evaluated by cytognetic analysis and molecular techniuques (e.g. RT-PCR)

  • fraction of patients who receive an allogeneic stem cell transplantation in first complete remission [ Time Frame: four years ] [ Designated as safety issue: No ]

Estimated Enrollment: 60
Study Start Date: January 2012
Estimated Study Completion Date: September 2015
Estimated Primary Completion Date: April 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment Drug: clofarabine, cytarabine, idarubicin

Treatment is stratified according to patients age (< 60 years vs. ≥ 60 years).

Medication:

Patients < 60 years:

  • idarubicin 7.5 mg/m2 iv, days 1 + 3
  • cytarabine 750 mg/m2 iv, days 1 to 5

Patients ≥ 60 years:

  • idarubicine 6 mg/m2 iv, days 1 + 3
  • cytarabine 750 mg/m2 iv, days 1 to 5

Clofarabine will be given in escalating doses to cohorts of at least three patients:

Clofarabine:

  • level -1: 15 mg/m2 iv, days 1 to 5
  • level 1: 20 mg/m2 iv, days 1 to 5
  • level 2: 25 mg/m2 iv, days 1 to 5
  • level 3: 30 mg/m2 iv, days 1 to 5
  • level 4: 35 mg/m2 iv, days 1 to 5

Patients will be recruited according to a 3+3 design. New cohorts will be initiated depending on toxicity of the previous cohort during the first induction cycle. Enrollment will begin with dose level 1.


  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patients with newly diagnosed AML according to WHO classification and aged ≥ 18 years eligible for an intensive induction chemotherapy with with the following characteristics:

    • absence of a t(15;17), t(8;21), inv(16)/t(16;16) and the respective fusion transcripts PML-RARA, RUNX1-RUNX1T1 and CBFB-MYH11
    • absence of an activating FLT3-mutation (FLT3-ITD or TKD-mutation)
    • absence of an NPM1 exon12 mutation
  2. Written informed consent
  3. No previous cytotoxic chemotherapy for the treatment of AML (exception: oral hydroxyurea for up to 5 days during screening/baseline to control hyperleukocytosis)
  4. Adequate renal and hepatic functions as indicated by the following laboratory values:

    • Serum creatinine > upper limit of normal (ULN) or glomerular filtration rate (GFR) > 60 mL/min/1.73 m2, respectively
    • Serum bilirubin < 1.5 x ULN
    • Aspartate aminotransferase (AST/SGOT)/ alanine aminotransferase (ALT/SGPT) < 2.5 x ULN
    • Alkaline phosphatase (ALP) < 2.5 x ULN
  5. Capable of understanding the investigational nature, potential risks and benefits of the study
  6. Women of childbearing potential must have a negative serum pregnancy test with a sensitivity of at least 25 MIU/ml within 72 hours prior to start of IMP treatment
  7. Female patients must meet one of the following criteria:

    • For female patients > 50 years of age at the day of inclusion: Menopause since at least 1 year
    • Female patients < 50 years of age at the day of inclusion who meet all of the following criteria:

      • menopause since at least 1 year
      • serum FSH levels > 40 MIU/mL
      • serum estrogen levels < 30 pg/ml or negative estrogen test
    • 6 weeks after surgical sterilization by bilateral tubal ligation or bilateral ovariectomy with or without hysterectomy
    • Correct use of two reliable contraception methods from the time of screening/baseline and during the study for a minimum of 90 days after the last administration of study medication. This includes every combination of a hormonal contraceptive (such as oral, injection, transdermal patch, implant, cervical ring) or of an intrauterine device (IUD) with a barrier method (diaphragm, cervical cap, Lea contraceptive, femidom or condom) or with a spermicide. In case the patient takes hormone preparations for suppression of menstruation during the period of aplasia, a suitable and effective method of contraception has to be discussed with the investigator and used by the patient
    • General sexual abstinence from the time of screening/baseline, during the study until a minimum of 90 days after the last administration of study medication
    • Having only female sexual partners
    • Monogamous relationship with sterile male partner
  8. Male patients must meet one of the following criteria:

    • 6 weeks after surgical sterilization by vasectomy
    • Correct use of two reliable contraception methods from the time of screening/baseline and during the study for a minimum of 90 days after the last administration of study medication. This includes every combination of a hormonal contraceptive (such as oral, injection, transdermal patch, implant, cervical ring) or of an IUD with a barrier method (diaphragm, cervical cap, Lea contraceptive, femidom or condom) or with a spermicide.
    • General sexual abstinence from the time of screening/baseline, during the study until a minimum of 90 days after the last administration of study medication
    • Having only male sexual partners
    • Monogamous relationship with sterile female partner

Exclusion Criteria:

  1. Current concomitant chemotherapy, radiation therapy or immunotherapy not defined in the study protocol
  2. Use of investigational agents within 30 days or any anticancer therapy within 2 weeks before study entry with the exception of oral hydroxyurea. The patient must have recovered from all non-hematological acute toxicities from any previous therapy
  3. Participation in a clinical trial within 30 days before inclusion in this study or concurrent to this study.
  4. Bleeding disorder independent of AML
  5. Patients with uncontrolled systemic fungal, bacterial, viral or other infection (defined as persistent disease signs/symptoms without improvement despite appropriate antibiotics or other treatment)
  6. HIV Infection
  7. Pregnant or lactating women
  8. Any significant concurrent disease, illness, psychiatric disorder or history of serious organ dysfunction that would compromise patient safety or compliance, interfere with consent, study participation, follow up, or interpretation of study results
  9. Diagnosis of another malignancy, unless the patient is disease-free for at least 3 years following the completion of curative intent therapy, with the following exceptions:

    • Myelodysplastic syndrome (MDS) in patients with AML after MDS according to the WHO classification
    • 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.
  10. Known hypersensitivity to any of the investigational medical products
  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: NCT01534702

Locations
Germany
Universitätsklinikum Düsseldorf Not yet recruiting
Düsseldorf, Germany, 40225
Contact: Andrea Kuendgen, MD       andrea.kuendgen@med.uni-duesseldorf.de   
Principal Investigator: Andrea Kuendgen, MD         
Klinikum Essen-Werden Recruiting
Essen, Germany, 45239
Contact: Mohammad Wattad, MD       m.wattad@kliniken-essen-sued.de   
Principal Investigator: Mohammad Wattad, MD         
Universitätsklinikum Freiburg Recruiting
Freiburg, Germany, D-79106
Contact: Michael Luebbert, MD       luebbert@mm11.ukl.uni-freiburg.de   
Principal Investigator: Michael Luebbert, MD         
Universitätsklinikum Hamburg-Eppendorf Not yet recruiting
Hamburg, Germany, 20246
Contact: Walter Fiedler, MD       fiedler@uke.uni-hamburg.de   
Principal Investigator: Walter Fiedler, MD         
Hannover Medical School Recruiting
Hannover, Germany, D-30625
Contact: Juergen Krauter, MD    +49-511-532-3720    Krauter.Juergen@MH-Hannover.de   
Principal Investigator: Juergen Krauter, MD         
Klinikum Rechts der Isar Not yet recruiting
Muenchen, Germany, 81675
Contact: Justus Duyster       justus.duyster@lrz.tum.de   
Principal Investigator: Justus Duyster, MD         
Universitätsklinikum Ulm Not yet recruiting
Ulm, Germany, 89081
Contact: Richard Schlenk, MD       Richard.Schlenk@uniklinik-ulm.de   
Principal Investigator: Richard Schlenk, MD         
Sponsors and Collaborators
Hannover Medical School
Hannover Clinical Trial Center GmbH
Genzyme, a Sanofi Company
Investigators
Principal Investigator: Juergen Krauter, MD Hannover Medical School
  More Information

No publications provided

Responsible Party: Prof. Dr. Juergen Krauter, Professor of Medicine, Hannover Medical School
ClinicalTrials.gov Identifier: NCT01534702     History of Changes
Other Study ID Numbers: KS-2009-003, 2010-021719-18
Study First Received: February 14, 2012
Last Updated: February 17, 2012
Health Authority: Germany: Federal Institute for Drugs and Medical Devices

Keywords provided by Hannover Medical School:
Acute Myeloid Leukemia
chemotherapy
clofarabine

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Neoplasms by Histologic Type
Neoplasms
Cytarabine
Clofarabine
Idarubicin
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antibiotics, Antineoplastic

ClinicalTrials.gov processed this record on July 23, 2014