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

17 februari 2012 bijgewerkt door: Prof. Dr. Juergen Krauter, Hannover Medical School

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)

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.

Studie Overzicht

Toestand

Onbekend

Conditie

Interventie / Behandeling

Studietype

Ingrijpend

Inschrijving (Verwacht)

60

Fase

  • Fase 2
  • Fase 1

Contacten en locaties

In dit gedeelte vindt u de contactgegevens van degenen die het onderzoek uitvoeren en informatie over waar dit onderzoek wordt uitgevoerd.

Studie Locaties

  • Duitsland
      • Düsseldorf, Duitsland, 40225
      • Essen, Duitsland, 45239
      • Freiburg, Duitsland, D-79106
      • Hamburg, Duitsland, 20246
        • Nog niet aan het werven
        • Universitätsklinikum Hamburg-Eppendorf
        • Contact:
        • Hoofdonderzoeker:
          • Walter Fiedler, MD
      • Hannover, Duitsland, D-30625
        • Werving
        • Hannover Medical School
        • Contact:
        • Hoofdonderzoeker:
          • Juergen Krauter, MD
      • Muenchen, Duitsland, 81675
        • Nog niet aan het werven
        • Klinikum rechts der Isar
        • Contact:
        • Hoofdonderzoeker:
          • Justus Duyster, MD
      • Ulm, Duitsland, 89081

Deelname Criteria

Onderzoekers zoeken naar mensen die aan een bepaalde beschrijving voldoen, de zogenaamde geschiktheidscriteria. Enkele voorbeelden van deze criteria zijn iemands algemene gezondheidstoestand of eerdere behandelingen.

Geschiktheidscriteria

Leeftijden die in aanmerking komen voor studie

18 jaar en ouder (Volwassen, Oudere volwassene)

Accepteert gezonde vrijwilligers

Nee

Geslachten die in aanmerking komen voor studie

Allemaal

Beschrijving

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

Studie plan

Dit gedeelte bevat details van het studieplan, inclusief hoe de studie is opgezet en wat de studie meet.

Hoe is de studie opgezet?

Ontwerpdetails

  • Primair doel: Behandeling
  • Toewijzing: NVT
  • Interventioneel model: Opdracht voor een enkele groep
  • Masker: Geen (open label)

Wapens en interventies

Deelnemersgroep / Arm
Interventie / Behandeling
Experimenteel: Behandeling
Geneesmiddel: 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.

Wat meet het onderzoek?

Primaire uitkomstmaten

Uitkomstmaat
Maatregel Beschrijving
Tijdsspanne
maximal tolerated dose of clofarabine in combination with cytarabine and idarubicin
Tijdsspanne: six weeks
maximal tolerated dose of clofarabine in combination with cytarabine and idarubicin in the therapy of previously untreated AML and high risk for induction failure
six weeks

Secundaire uitkomstmaten

Uitkomstmaat
Maatregel Beschrijving
Tijdsspanne
complete remission rate
Tijdsspanne: 12 weeks
complete remission rate after two cycles of induction therapy
12 weeks
relapse-free, event-free and overall survival
Tijdsspanne: 4 years
4 years
blast reduction in the bone marrow after the first induction cycle
Tijdsspanne: 15 days
15 days
duration of aplasia
Tijdsspanne: 12 weeks
12 weeks
therapy-associated morbidity and mortality
Tijdsspanne: 12 weeks
12 weeks
course of molecular and cytogenetic markers during chemotherapy
Tijdsspanne: four years
molecular and cytogenetic markers will be evaluated by cytognetic analysis and molecular techniuques (e.g. RT-PCR)
four years
fraction of patients who receive an allogeneic stem cell transplantation in first complete remission
Tijdsspanne: four years
four years

Medewerkers en onderzoekers

Hier vindt u mensen en organisaties die betrokken zijn bij dit onderzoek.

Sponsor

Hannover Medical School

Medewerkers

Genzyme, a Sanofi Company

Onderzoekers

  • Hoofdonderzoeker: Juergen Krauter, MD, Hannover Medical School

Studie record data

Deze datums volgen de voortgang van het onderzoeksdossier en de samenvatting van de ingediende resultaten bij ClinicalTrials.gov. Studieverslagen en gerapporteerde resultaten worden beoordeeld door de National Library of Medicine (NLM) om er zeker van te zijn dat ze voldoen aan specifieke kwaliteitscontrolenormen voordat ze op de openbare website worden geplaatst.

Bestudeer belangrijke data

Studie start

1 januari 2012

Primaire voltooiing (Verwacht)

1 april 2013

Studie voltooiing (Verwacht)

1 september 2015

Studieregistratiedata

Eerst ingediend

14 februari 2012

Eerst ingediend dat voldeed aan de QC-criteria

16 februari 2012

Eerst geplaatst (Schatting)

17 februari 2012

Updates van studierecords

Laatste update geplaatst (Schatting)

20 februari 2012

Laatste update ingediend die voldeed aan QC-criteria

17 februari 2012

Laatst geverifieerd

1 februari 2012

Meer informatie

Termen gerelateerd aan deze studie

Trefwoorden

Aanvullende relevante MeSH-voorwaarden

Andere studie-ID-nummers

  • KS-2009-003
  • 2010-021719-18 (EudraCT-nummer)

Deze informatie is zonder wijzigingen rechtstreeks van de website clinicaltrials.gov gehaald. Als u verzoeken heeft om uw onderzoeksgegevens te wijzigen, te verwijderen of bij te werken, neem dan contact op met register@clinicaltrials.gov. Zodra er een wijziging wordt doorgevoerd op clinicaltrials.gov, wordt deze ook automatisch bijgewerkt op onze website .

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