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A phase II study of clofarabine in combination with cytarabine and daunoxome for children with acute myeloid leukemia withour other treatment options.


- candidate number6020
- NTR NumberNTR1880
- ISRCTNISRCTN wordt niet meer aangevraagd.
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR25-jun-2009
- Secondary IDsITCC020 I-BFM 2009/02
- Public TitleA phase II study of clofarabine in combination with cytarabine and daunoxome for children with acute myeloid leukemia withour other treatment options.
- Scientific TitleA Phase I/II study of clofarabine in combination with cytarabine and liposomal daunorubicin in children with relapsed/refractory pediatric AML.
- ACRONYMCLARA-DNX
- hypothesisThis is a dose-escalation study to determine the safe dose of clofarabine given in combination with cytarabine and liposomal daunorubicin.
- Healt Condition(s) or Problem(s) studiedAcute Myeloid Leukemia (AML), Children, Relapse
- Inclusion criteria1. 2nd relapse of AML;
2. Refractory AML in 1st relapse (defined as ≥ 20% blasts in the bone marrow after the 1st course of re-induction therapy according to the AML 2001/01 protocol);
3. 1st early relapse (relapse within one year from initial diagnosis) of AML (only when the Relapsed AML 2001/01 study is closed);
4. ≤ 18 years old at initial diagnosis;
5. Lansky play score > 60; or Karnofsky performance status > 60;
6. Life expectancy  6 weeks;
7. Calculated creatinine clearance ≥ 90 ml/min/1.73m2 as calculated by the Schwartz formula for estimated glomerular filtration rate (GFR) where GFR (ml/min/1.73 m2) = k*Height (cm)/serum creatinine (mg/dl). k is a proportionality constant which varies with age and is a function of urinary creatinine excretion per unit of body size; 0.45 up to 12 months of age; 0.55 children and adolescent girls; and 0.70 adolescent boys;
8. Liver function:
A. Serum bilirubin ≤1.5 × upper limit of normal (ULN);
B. Aspartate transaminase (AST)/alanine transaminase (ALT) <=2.5 × ULN;
C. Alkaline phosphatase <= 2.5 × ULN.
9. Able to comply with scheduled follow-up and with management of toxicity;
10. For female patients with childbearing potential, a negative test for pregnancy is to be considered before entry on study;
11. Male and female patients must use an effective contraceptive method during the study and for a minimum of 6 months after study treatment;
12. Written informed consent from patients or from parents or legal guardians for minor patients, according to local law and regulations.
- Exclusion criteria1. Isolated extramedullary relapse, including isolated CNS-relapse;
2. Symptomatic CNS leukemia in case of combined relapse;
3. Relapsed/refractory acute promyelocytic leukemia (APL);
4. Relapsed/refractory myeloid leukemia of Down Syndrome (ML DS);
5. Other serious illnesses or medical conditions;
6. Current uncontrolled infection;
7. Evidence of cardiac dysfunction (shortening fraction below 28%);
8. Pregnant or lactating patients;
9. Use of any anticancer therapy within 2 weeks before study entry. The patient must have recovered from all acute toxicities from any previous therapy (note: hematological toxicities do not need to be considered since the patient has overt leukemia);
10. History of prior veno-occlusive disease (VOD);
11. Hypersensitivity to cytarabine, clofarabine or liposomal daunorubicin;
12. Concomitant administration of any other experimental drug under investigation, or concurrent treatment with any other anti-cancer therapy other than specified in the protocol is not allowed;
13. GCSF will not be used for priming and no routine GCSF support is allowed during the 1st course, except for life-threatening infections;
14. In case of non-symptomatic CNS-involvement, intrathecal therapy is allowed according to investigator's discretion. It is not allowed to give intrathecal therapy prior to treatment with clofarabine, as we do not know if this can be done without safety concerns. Hence, this should be delayed to day +7 of treatment, which will allow us to assess the CSF penetration of clofarabine (clofarabine CSF levels and early response). In case of neurotoxicity experienced during the IV treatment, the intrathecal may need to be further delayed.
- mec approval receivedyes
- multicenter trialyes
- randomisedno
- group[default]
- TypeSingle arm
- Studytypeintervention
- planned startdate 1-aug-2009
- planned closingdate1-aug-2012
- Target number of participants28
- InterventionsPatients will be treated with a combination of clofarabine, liposomal daunorubicina nd cytarabine. Clofarabine is the IMP in this study.
- Primary outcomeTo establish the recommended dose of clofarabine in combination with cytarabine and liposomal daunorubicin (DaunoXome®) in children with relapsed/refractory AML, based on the FLAG regimen as used in the Relapsed AML 2001/01 study.
- Secondary outcome1. To determine the safety and tolerability of this combination;
2. To determine (preliminary) efficacy in terms of the hematological remission rate in these patients;
3. To describe the durability of response, including the number of patients that undergo stem-cell transplant after re-induction with this regimen;
4. To describe the pharmacokinetics of clofarabine in combination with cytarabine and liposomal daunorubicin;
5. To preliminary assess the CSF blast disappearance, and the CSF-levels of clofarabine.
- TimepointsCR rate after 1 course of treatment.
- Trial web siteN/A
- statusstopped: trial finished
- CONTACT FOR PUBLIC QUERIESMD, PhD C.M. Zwaan
- CONTACT for SCIENTIFIC QUERIES C.M. Zwaan
- Sponsor/Initiator Erasmus Medical Center
- Funding
(Source(s) of Monetary or Material Support)
Genzyme Corporation, Stichting Kinderen Kankervrij, Nederland
- PublicationsN/A
- Brief summaryAML is a rare disease, and accounts for approximately 20% of pediatric leukemias. Treatment with intensive chemotherapy results in approximately 60-70% survival in newly diagnosed patients.
Prognosis at relapse is worse, and is in the 30-40% range. A couple of years ago an international relapse study was opened asking a randomized question in relapsed/refractory AML (study relapsed AML 2001/01). This randomization concerned the superiority of the FLAG regimen in combination with DaunoXome® (liposomal daunorubicine) versus FLAG alone, and is still ongoing. Overall results show that poor response to the 1st course of therapy (>20% of blasts in the BM shortly before the 2nd course), was seen in 23% of patients, and more often in early relapses (31%) than in late relapses (15%). Early death occurred in 6% of patients. Complete remission (CR) was achieved in 63% of patients after 2 courses, and these patients have a probability of survival at 3 years of 47%, compared to 33% for the total group, and only 8% for patients not achieving CR. Compared to early relapses, patients with late relapse had higher CR rates (76 vs. 51%), and higher 3-yr probability of survival of 42% vs. 23%. Clearly, nor the induction nor the consolidation chemotherapy is effective enough - and we need new and better treatment options for these children.

Cytarabine (Ara-C) and the anthracyclines are the back-bone of pediatric AML treatment. Cytarabine can be given in various different schedules, including higher-dose regimens such as 1-3 gr/m2 IV every 12 hours for 3 consecutive days, but also as a lower dose continuous IV schedule (0.5 gr/m2 CI over 24 hours x 4 days). Cytarabine has been used in combination with fludarabine and cladribine, with the aim to induce synergism by increasing Ara-CTP accumulation, which can be seen as a surrogate marker for cytarabine induced cell-kill. In the current European relapsed AML study, the FLAG (fludarabine 30 mg/m2/day x5 days, Ara-C 2 gr/m2 bolus IV in 3 hours, 4 hours following fludarabine, for 5 days; plus GCSF) regimen is used as standard re-induction therapy. Synergy with cytarabine can also be achieved with clofarabine, which is a potent inhibitor of ribonucleotide reductase, leading to a depletion of normal deoxynucleotides and subsequently to increased Ara-CTP levels. In the experimental arm of the European relapsed AML protocol liposomal daunorubicin is added. This drug was chosen for its favorable toxicity profile, in particular the expected lack of long-term cardiac toxicity, which is of serious concern for those who survive relapsed AML given the cumulative anthracycline dose these patients may have received during their treatment. The current dose we use is 60 mg/m2 on days 1, 3 and 5 of the FLAG-regimen.
Clofarabine has been tested in phase I/II studies in children with AML. For clofarabine, the DLT was hepatic toxicity and rash, and the MTD for children was defined as 52 mg/m2/day x 5 days per block. Clofarabine is myelo-suppressive, and minimal neurotoxicity has also been reported. The response rate to clofarabine as a single agent in children with AML was relatively low, but this is probably related to the very heavy pre-treatment status of these children, and patients were transplanted in aplasia before proper response determination could take place. Adult AML data do show that the drug is active in AML, even at dosages from 15-20 mg/m2 onwards. Clofarabine has also been studied in combination with cytarabine in adults.

Several pediatric studies are ongoing in the US, evaluating clofarabine in combination with 1) cyclophosphamide; 2) cyclophosphamide and etoposide and 3) cytarabine 1 gram/m2 x 5 days, either in ALL or AML. The combination studies with cyclophosphamide have caused some toxicity concerns, especially hepatotoxicity.
We aim at developing a combination of clofarabine, cytarabine and DaunoXome®, based on the FLAG regimen, which is a combination that may be taken forward in the new European relapsed AML protocol, or in other studies.
In the adult studies the combination of cytarabine and clofarabine has been safe, using cytarabine 1 gr/m2 for 5 consecutive days on day 1-5, and clofarabine at 40 mg/m2 for 5 days on day 2-6. This is the same schedule as the COG is currently testing in children. No data on combination studies with anthracyclines are available as yet, but there is extensive experience with the FLAG regimen in combination with anthracyclines such as idarubicin or DaunoXome®.
We propose to use the cytarabine dose as administered in the FLAG regimen (2 gram/m2 bolus IV) – which will also allow a fair comparison with the FLAG regimen in later studies. This regimen is currently being tested in a trial in the USA in adults with relapsed/refractory AML by Agura et al., with a dosing regimen of cytarabine 2 gr/m2/day IV over 3 hours with clofarabine 40 mg/m2/day over 2 hours, daily, for 5 consecutive days. Considering GCSF priming, there are only data available in adults, with various results. As we expect that priming will in the future be done with CXCR4 inhibitors, and given the lack of hard evidence that GCSF priming works, we decided against using GCSF priming in this study.

Participating countries:
1. Austria (Vienna);
2. Czech Republic (Prague);
3. France (Lyon, Paris (Trousseau and St Louis));
4. Germany (Berlin, Frankfurt, Freiburg, Hannover, Munich, Munster);
5. Italy (Monza, Pavia).
- Main changes (audit trail)14-10-2013:
Inclusion criteria: Dose level 5
Newly diagnosed 1st relapse of AML: only patients with early relapses occurring within 1 year of initial diagnosis are eligible; Inclusion criteria 4-12: is Dose level 1-4

exclusion criteria: Dose level 5: -See Exclusion criteria 1-15 dose level 1-4; -prior stem-cell transplant in CR1

- PLANNED CLOSINGDATE 31-Jul-2014
- TARGET NUMBER OF PARTICIPANTS 39

Participating countries: 1. Austria (Vienna); 2. Czech Republic (Prague); 3. France (Lyon, Paris (Trousseau and Robert Debré)); 4. Germany (Berlin, Frankfurt, Freiburg, Hannover, Munster); 5, Netherlands (Rotterdam, Amsterdam, Groiningen)

Approved amendmend 1: implementation of additional screenings procedures for pulmonary aspergillosis; introduction of new dose level: dose level 5 for early relapsed AML patients occurring within 1 year of initial diagnosis
- RECORD25-jun-2009 - 23-dec-2015


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