Clofarabin and GO in refractory AML

Title A Phase II study of clofarabine (Clo, Evoltra®) gemtuzumab ozogamicin (GO, Mylotarg®) in children with relapsed/refractory acute myeloid leukemia
Disease Children with relapsed/refractory acute myeloid leukemia
Type Prospective, non-blinded, open label, phase I/II trial
Problem / Objectives

Primary objective:
To establish the recommended dose of Clofarabine in combination with Gemtuzumab ozogamicin in children with either a 2nd relapse of AML or who are refractory to the 1st block of regular re-induction therapy in 1st relapse.

Secondary objectives:
To determine the safety and tolerability of this combination
To determine (preliminary) the hematological remission rate in these patients
To describe the durability of response, including the number of patients that undergo stem-cell transplant after re-induction with this regimen
To determine the plasma pharmacokinetic parameters of clofarabine and GO to exclude interaction between these 2 compounds
To preliminary assess the CSF blast disappearance, and the CSF-levels of Clofarabine

Inclusion Criteria

General conditions:
• AML in 2nd relapse or refractory 1st relapse defined as ≥ 20% blasts in the bone marrow after the 1st course of re-induction therapy according to the European relapsed AML protocol
• 1 year to ≤ 18 years old at initial diagnosis
• Lansky play score > 60; or Karnofsky performance status > 60
• Life expectancy >= 6 weeks
• Normal renal function defined as less than or equal to NCI-CTG grade 1 (max 1.5 x ULN)
• Normal liver function defined as less than or equal to NCI-CTG grade 1 (max 2.0 x ULN for transaminases and bilirubin)
• In case of a WBC >30.000x106/l, a pre-treatment with cytarabine is needed to lower the WBC to 30.000 or less, after which the patient can be included.

Initial work-up:

• Complete initial work-up within 7 days prior to first treatment, including bone-marrow aspiration, lumbar puncture, and assessment of organ toxicity


• Able to comply with scheduled follow-up and with management of toxicity.
• For patients with childbearing potential, a negative test for pregnancy is to be considered before entry on study
• Written informed consent from patients or from parents or legal guardians for minor patients, according to local law and regulations

Exclusion Criteria

General conditions:
• Isolated extramedullary relapse
• Symptomatic CNS leukemia in case of combined relapse
• Relapsed/refractory acute promyelocytic leukemia ( APL)
• Relapsed/refractory myeloid leukemia of Down Syndrome (ML DS)

Prior or current history:
• Other serious illnesses or medical conditions
• Current uncontrolled infection
• Evidence of cardiac toxicity (shortening fraction below 30%)
• History of veno-occlusive disease (VOD)
• Hypersensitivity to gemtuzumab ozogamicin or clofarabine

Concomitant treatments:
• Concomitant (or within 1 week prior to start with study medication) administration of any other experimental drug under investigation or concurrent treatment with any other anti-cancer therapy is not allowed.
• Prophylactic use of defibrotide to prevent VOD is not allowed. However, therapeutic use in case of symptomatic VOD may be considered

Intrathecal therapy
• In case of asymptomatic CNS-involvement, intrathecal therapy is allowed according to investigator's discretion. However, this should be delayed to day +6 of treatment to assess CSF-levels of clofarabine and early response in the CSF. It is not allowed to give intrathecal therapy prior to treatment with clofarabine as we do not know if this can be done safe. In case of neurotoxicity on clofarabine the intrathecal may need to be delayed.

• Patients who cannot be regularly followed up for psychological, social, familial or geographic reasons,
• Patient with expected non compliance to toxicity management guidelines.

Recruitment 40
Principal Investigator CM Zwaan, MD, PhD, Dirk Reinhardt, MD, PhD

Principal Investigator: Overall PIs:

CM Zwaan, MD, PhD
Erasmus MC – Sophia Children’s Hospital,
POB 2060, 3000 CB Rotterdam, Netherlands
Phone : +31-10-463.6691/6363
Fax : +31-10-364.1134

Dirk Reinhardt, MD, PhD
Medizinische Hochschule Hannover

Participants Hannover, Rotterdam, Berlin, Munster, Frankfurt, Düsseldorf, Munich