A safe RP2D of Vyxeos®/CPX-351 in combination with clofarabine can be identified in this phase 1b study.
ID
Bron
Verkorte titel
Aandoening
relapsed/refractory AML (pediatric)
Ondersteuning
Onderzoeksproduct en/of interventie
Uitkomstmaten
Primaire uitkomstmaten
To establish the recommended phase 2 dose of Vyxeos®/CPX-351 in combination with clofarabine in children with relapsed/refractory AML
Achtergrond van het onderzoek
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 in Europe, 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. Preliminary 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 (80%), with 70% of patients reaching CR/CRi as best response after single agent-treatment with Vyxeos®/CPX-351. Preclinical data have also assessed an increased Ara-CTP accumulation and cytotoxicity in immortalized cell lines, and 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 we therefore evaluate Vyxeos®/CPX-351 in combination with clofarabine in a phase 1b study with the aim to establish the RP2D of this combination.
Doel van het onderzoek
A safe RP2D of Vyxeos®/CPX-351 in combination with clofarabine can be identified in this phase 1b study.
Onderzoeksopzet
C1D1, C2D1, 4 weeks after C2D28 (EOT)
Onderzoeksproduct en/of interventie
Combination treatment is allowed only for Course 1: An adapted regimen is used to combine Vyxeos®/CPX-351 given at day 1, 3, 5 with clofarabine given at day 2-6.
- Vyxeos®/CPX-351 will be infused on day 1, 3 and 5 only, 3 hours after the end of clofarabine (if on the same day).
- Clofarabine infusion will be given daily on day 2-6.
- CNS prophylaxis (recommended) on day +6.
Patients may repeat one course of Vyxeos®/CPX-351 as single agent in Course 2, in the absence of significant safety concerns or progressive disease:
- Vyxeos®/CPX-351 will be administered alone, at the same dose level and with the same infusion schedule of Course 1
- CNS prophylaxis IT therapy, is recommended and scheduled at day 1 of course 2.
Publiek
Miriam Stumpf
+31 650006609
m.k.stumpf@prinsesmaximacentrum.nl
Wetenschappelijk
Miriam Stumpf
+31 650006609
m.k.stumpf@prinsesmaximacentrum.nl
Belangrijkste voorwaarden om deel te mogen nemen (Inclusiecriteria)
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 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 protocol 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 conditions:
• Lansky play score ≥ 60; or Karnofsky performance status ≥ 60
• Life expectancy > 6 weeks
• The patient must have a radioisotope GFR ≥ 70mL/min/1.73 m2.
• Liver function: serum bilirubin ≤3 × upper limit of normal (ULN) and aspartate transaminase (AST)/alanine transaminase (ALT) ≤5×ULN
• Adequate cardiac function (defined as shortening fraction ≥28% or ejection fraction ≥50%)
• No evidence of a currently uncontrolled bacterial, viral or parasitic infection
• No evidence of a fungal infection, defined as either:
- Pulmonary infiltrates suggestive of a fungal infection at HR-CT (within 3 weeks prior to enrollment)
- Positive Aspergillus serum test (galactomannan), according to local laboratory
practice (within 3 weeks prior to enrollment)
• No evidence of isolated extramedullary relapse, including isolated CNS-relapse
• No evidence of CNS3 or symptomatic CNS leukemia
• No presence of Down Syndrome
• No evidence of relapsed/refractory acute promyelocytic leukemia (APL)
• No 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)
• No history of prior veno-occlusive disease (VOD)
• No known hypersensitivity to cytarabine, clofarabine or liposomal daunorubicin
Other:
• For female patients with childbearing potential, a negative test for pregnancy is to be performed before entry on study.
• Male and female patients must use a highly effective contraceptive method during the study and for a minimum of 6 months after study treatment.
• Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule is required; those conditions should be discussed with the patient before registration in the trial.
• Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations.
Concomitant treatments:
• 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.
• GCSF will not be used for priming and no routine GCSF support is allowed during the 1st course, except for life-threatening infections.
Additional criteria:
• At least 6 patients must be enrolled with an M3 or a WBC count >10x109/L with blasts
Belangrijkste redenen om niet deel te kunnen nemen (Exclusiecriteria)
see inclusion criteria
Opzet
Deelname
Voornemen beschikbaar stellen Individuele Patiënten Data (IPD)
Opgevolgd door onderstaande (mogelijk meer actuele) registratie
Geen registraties gevonden.
Andere (mogelijk minder actuele) registraties in dit register
Geen registraties gevonden.
In overige registers
Register | ID |
---|---|
NTR-new | NL8134 |
Ander register | METC Utrecht : not known yet |