Cladribine, Cytarabine and Sorafenib Alternating with Decitabine and Sorafenib for the Treatment of Pediatric Patients with Relapsed and Refractory Acute Leukemias

Inclusion Criteria

• Age ≥ 1 year to 21 years
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
• Relapsed/refractory: Acute myeloid leukemia (AML) or mixed phenotype acute leukemia (MPAL) patients /acute leukemia of ambiguous lineage (ALAL) with * ≥ 1% leukemic blasts in the bone marrow * As detected by minimal residual disease (MRD) testing ≥ 25% or MRD is ≥ 5% with 1 additional sensitive diagnostic test demonstrating ≥ 1% blasts (next generation sequencing [NGS]-MRD [clonoSeq] or fluorescence in situ hybridization [FISH] or cytogenetics or reverse transcriptase-polymerase chain reaction [RT-PCR] of leukemic specific marker or M2/M3 morphology); or MRD is ≥ 1% with 2 additional sensitive diagnostic tests demonstrating ≥ 1% blasts ** If the MRD is ≥ 1% but without the required confirmatory tests, then a relapse can still be defined if a consecutive marrow evaluation separated by ≥ 1 week demonstrates, ≥ 1% using 2 sensitive diagnostic tests ** If MRD testing is unavailable, then a single marrow is sufficient to define relapse if M3 morphology or M2 morphology with 1 additional sensitive diagnostic test demonstrating ≥ 1% blasts (FISH or cytogenetics or RT-PCR of leukemic specific marker) or M1 morphology with 2 additional sensitive diagnostic tests demonstrating, ≥ 1% blasts is present ** If the morphology is M2 with no confirmatory tests, then a relapse can still be defined if a consecutive marrow evaluation separated by ≥ 1 week demonstrates M2 morphology * Marrow definitions: M2 marrow ≥ 5 to < 25% blasts; M3 marrow ≥ 25% blasts
• White blood cell (WBC) must be below 25,000/ uL at time of enrollment. Patients may receive cytoreduction prior to enrollment
• Baseline ejection fraction must be > 40%
• Direct bilirubin < 1.5 x upper limit of normal (ULN) unless increase is due to Gilbert’s disease or leukemic involvement, in which case direct bilirubin < 5 x ULN will be considered eligible
• Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) < 5 x ULN unless considered due to leukemic involvement, in which case AST and/or ALT < 5 x ULN will be considered eligible
• Creatinine clearance ≥ 30 mL/min unless related to disease
• In the absence of rapidly proliferative disease, the interval from prior treatment to time of initiation will be at least 14 days for cytotoxic or non-cytotoxic (immunotherapy agent[s]), or an interval of 5 half-lives of the prior therapy. Oral hydroxyurea and/or cytarabine (up to 2 g/m^2) for patients with rapidly proliferative disease is allowed before the start of study therapy, as needed, for clinical benefit and after discussion with the principal investigator (PI). Concurrent therapy for central nervous system (CNS) prophylaxis or continuation of therapy for controlled CNS disease is permitted
• Unless surgically or biologically sterile: Women of childbearing potential must agree to adequate methods of contraception during the study and at least 3 months for males, and 6 months for females, after the last treatment

Exclusion Criteria

• Patients who weigh less than 10kg
• Patients with any concurrent uncontrolled medical condition, laboratory abnormality, or psychiatric illness which could place the patient at unacceptable risk of study treatment
• The use of other chemotherapeutic agents or anti-leukemic agents is not permitted during study with the following exceptions (1) intrathecal chemotherapy for prophylactic use or for controlled CNS leukemia (2) use of hydroxyurea for patients with rapidly proliferative disease or for control of counts during differentiation syndrome (3) use of steroids for treatment of differentiation syndrome
• Patients with any severe gastrointestinal or metabolic condition which could interfere with the absorption of oral study medications
• Patients with a concurrent active malignancy under treatment
• Known active hepatitis B (hepatitis B virus [HBV]) or hepatitis C (hepatitis C virus [HCV]) infection or known HIV infection
• Female subjects who are pregnant or breast-feeding
• Patient has an active uncontrolled infection
• History of or any concurrent condition, therapy, or laboratory abnormality that in the investigator’s opinion might confound the results of the study, interfere with the patient’s participation for the full duration of the study, or is not in the best interest of the patient to participate
• Clinically active central nervous system (CNS) leukemia