Vyxeos® and Clofarabine in children with a specific type of blood cancer (AML) that has returned or is persistent

Phase 1

Conditions: Relapsed or refractory pediatric acute myeloid leukemia
MedDRA version: 21.0Level: LLTClassification code 10060558Term: Acute myeloid leukemia recurrentSystem Organ Class: 100000004864
MedDRA version: 21.1Level: LLTClassification code 10081514Term: Acute myeloid leukemia refractorySystem Organ Class: 100000004864
Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]

Registration Number: EUCTR2020-000142-34-NL

Lead Sponsor: Princess Máxima Center for pediatric oncology

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 25

Inclusion Criteria

• Age =1 year and <21 years
• 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

• Complete initial work-up within 7 days prior to study entry, including bone-marrow aspiration, lumbar puncture (without intrathecal therapy)
• 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 mg/dl or 50 µmol/L and aspartate transaminase (AST) and alanine transaminase (ALT) =200 U/L
• Adequate cardiac function (defined as shortening fraction =28% or ejection fraction =50%)

• 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.
• Female patients may not breastfeed during the study and for a minimum of 3 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, 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
Are the trial subjects under 18? yes
Number of subjects for this age range: 25
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 3
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion Criteria

• Evidence of a currently uncontrolled bacterial, viral or parasitic infection
• 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)
• Evidence of isolated extramedullary relapse, including isolated CNS-relapse
• Evidence of CNS3 or symptomatic CNS leukemia
• Down Syndrome
• Evidence of relapsed/refractory acute promyelocytic leukemia (APL)
• 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)
• History of prior veno-occlusive disease (VOD)
• Known hypersensitivity to cytarabine, clofarabine or liposomal daunorubicin
• Known copper metabolism deficiency, such as Wilson's disease

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To establish the recommended phase 2 dose of Vyxeos®/CPX-351 in combination with clofarabine in children with relapsed/refractory AML ;Secondary Objective: • To determine the safety and tolerability of this combination.<br>• To determine the (preliminary) efficacy in terms of the hematological remission rate in these patients as determined by morphology with flow cytometric confirmation.<br>• To describe the durability of response, including the number of patients that undergo stem- cell transplant after re-induction with this regimen<br>;Primary end point(s): Dose-limiting toxicities (DLTs) during the first course of therapy.<br><br><br>;Timepoint(s) of evaluation of this end point: DLT evaluation after course 1<br>

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): • safety and tolerability of combination clofarabine with Vyxeos/CPX-351<br>• hematological remission rate<br>• overall response rate (ORR)<br>• number of patients that undergo HSCT<br><br>Exploratory endpoints:<br>• serum and intracellular pharmacokinetics parameters of Vyxeos/CPX-351<br>• relationship ORR and intracellular Ara-CTP accumulation<br>• correlation duration of response and MRD;Timepoint(s) of evaluation of this end point: • After course 1, after each subsequent course of therapy, and at 4wks, 10wks, 3months, 6 months and 9 months, 12 months, 18 months and 24 months of FUP<br>• end of study (EOS)