NCT07156435 Vyxeos® With Clofarabine for Pediatric AML

Trial Parameters

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Brief Summary

Treatment with intensive chemotherapy in AML results in approximately 70% survival in newly diagnosed patients. Prognosis at relapse is worse and is in the 30-40% range. Relapse treatment generally consists of one course of fludarabine, cytarabine and liposomal daunorubicin (FLAG-DNX), followed by a fludarabine and cytarabine course, and subsequent stem-cell transplantation. Cytarabine has been used in combination with fludarabine and cladribine, with the aim to induce synergism by increasing Ara-CTP (active cytotoxic metabolite from ara-C) accumulation, which can be seen as a surrogate marker for cytarabine induced cell-kill. 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. The phase IB trial ITCC020/I-BFM 2009-02 recently reported that clofarabine, replacing fludarabine in the standardly used fludarabine, cytarabine and liposomal daunorubicin (FLAG-DNX) combination regimen, showed high response rates (Overall Response Rate - ORR 68% and 80% at the recommended phase 2 dose - RP2D) in patients with refractory/relapsed AML, and was generally tolerable, with infectious complications as the main side-effect due to the immunosuppressive properties of clofarabine. Currently DNX is unavailable, which urges the need to develop other treatment blocks. The liposomal formulation of Vyxeos®/CPX-351 may be a suitable replacement for DNX, considering the long-term side effect of cardiotoxicity due to anthracyclines which is of primary importance in younger heavily pre-treated patients. The hypothesis is that due to the liposomal formulation there is less penetrance in the cardiac muscle and hence less cardiac damage. The results in pediatric and young adult patients with relapsed/refractory AML in a COG study using Vyxeos®/CPX-351 at a RP2D of 135 U/m2 (AAML1421) showed encouraging ORR, with 70% of patients reaching CR/CRi as best response after single agent-treatment with Vyxeos®/CPX-351. Preclinical data have also demonstrated an increased Ara-CTP accumulation and cytotoxicity in cell lines, and were confirmed by tests in ex-vivo blasts from a cohort of AML patients (n=5), when cells were exposed to Vyxeos®/CPX-351 after 4 hours of incubation with fludarabine. In this study Vyxeos®/CPX-351 was evaluated in combination with clofarabine with the aim to establish the RP2D of this combination.

Eligibility Criteria

We will include pediatric patients ≥1 year and ≤21 years with: * Any ≥ 2nd relapse of AML * Refractory AML (defined as ≥ 20% blasts in the bone marrow after standard (re-) induction therapy) * Early 1st relapse (defined as relapse within one year from initial diagnosis) of AML * Any relapse of AML after prior allogenic HSCT * Any relapse of AML with high risk cytogenetic characteristics (as defined in Appendix V) In order to be eligible to participate in this study, a subject must meet all of the following criteria: Initial work-up: • Complete initial work-up within 7 days prior to study entry, including bone-marrow aspiration, lumbar puncture (without intrathecal therapy) General condition: * Lansky play score ≥ 60 for patients \<16 years of age; or Karnofsky performance status ≥ 60 for patients ≥ 16 years of age (see Appendix I for Performance scales). * Life expectancy \> 6 weeks * The patient must have a calculated GFR ≥ 70mL/min/1.73 m2. * Liver function: total serum bilirubin ≤ 3

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