EZN-3042 Administered With Re-induction Chemotherapy in Children With Relapsed Acute Lymphoblastic Leukemia (ALL)
Condition: Lymphoblastic Leukemia, Acute; Lymphoblastic Leukemia, Acute, Childhood; Leukemia, Lymphoblastic, Acute, T Cell; Leukemia, Lymphoblastic, Acute
MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Acute Disease
Intervention: EZN-3042; Cytarabine; Doxorubicin; Prednisone; Vincristine; PEG-asparaginase; Methotrexate; Hydrocortisone
Intervention description: Dose will be assigned at study entry. To be given as a 2 hour intravenous infusion on days -5, -2, 8, 15, 22 and 29. Dose levels: L0 (level zero): 1.5 mg/kg, L1: 2.5 mg/kg, L2: 5 mg/kg, L3: 6.5 mg/kg; Given intrathecally on day -6. Patients who may have received intrathecal chemotherapy within 7 days of day 0 as part of their prior maintenance chemotherapy (e.g. before the diagnosis of relapse) or as part of the diagnostic workup will not receive this dose of IT cytarabine. If given, dose is defined by age:
1-1.99 years: 30 mg 2-2.99 years: 50 mg
Greater than or equal to 3 years: 70 mg.
Cytarabine is also part of the triple intrathecal therapy given to CNS 3 patients on Days 8, 15, 22 and 29. Dose is defined by age:
- 1.99 years: 16 mg
- 2.99 years: 20 mg
- 8.99 years: 24 mg
Greater than or equal to 9 years: 30 mg; 60 mg/m2/day given intravenous infusion (IV) over 15 minutes on day 1.; 40 mg/m2/day divided BID or TID given orally on days 1 through 29. For patients who are unable to tolerate prednisone orally, substitute IV methylprednisolone at 80% of the oral prednisone dose.; 1.5 mg/m2/day (maximum dose 2 mg) given intravenous push over 1 minute or infusion via mini-bag as per institutional policy on days 1, 8, 15 and 22.; 2500 IU/m2 intramuscular injection on days 2, 9, 16, 23. If available, Erwinia L-asparaginase may be substituted for pegaspargase in patients with clinically significant prior allergies to pegaspargase.; Given intrathecally to patients with CNS1 or CNS2 disease at the dose defined by age below on days 15 and 36:
1-1.99 years: 8 mg 2-2.99 years: 10 mg 3-8.99 years: 12 mg
Greater than or equal to 9 years: 15 mg
Given as part of the Triple intrathecal therapy to patients with CNS 3 disease at the doses defined by age below on days 8, 15, 22 and 29:
- 1.99 years: 8 mg
- 2.99 years: 10 mg
- 8.99 years: 12 mg
Greater than or equal to 9 years: 15 mg; Given as part of the Triple intrathecal therapy to patients with CNS 3 disease at the doses defined by age below on days 8, 15, 22 and 29:
- 1.99 years: 8 mg
- 2.99 years: 10 mg
- 8.99 years: 12 mg
Greater than or equal to 9 years: 15 mg
Intervention MeSH terms: Cytarabine; Prednisone; Hydrocortisone; Hydrocortisone 17-butyrate 21-propionate; Hydrocortisone acetate; Hydrocortisone hemisuccinate; Cortisone; Doxorubicin; Methotrexate; Vincristine; Asparaginase; Pegaspargase
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 6.0
Sex: All
Minimum age: 1 Year
Maximum age: 21 Years
Healthy volunteers: No
Keywords: Relapse; T cell; Lymphoblastic; Leukemia; EZN3042; Refractory; Precursor B; Pre B cell; Survivin; Acute; Childhood; Pediatric

Summary:

      An experimental drug called EZN-3042 targets survivin, a protein expressed in leukemia cells
      at relapse that promotes the leukemia cells to grow. The main goal of this phase I study is
      to find out the dose of EZN-3042 that can be safely given without serious side effects both
      alone and in combination with standard chemotherapy drugs during re-induction.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients must be ≥1 and ≤ 21 years of age when originally diagnosed with acute
             lymphoblastic leukemia (ALL).

          -  Patients must have relapsed or refractory B-precursor acute lymphoblastic leukemia
             (ALL) with ≥25% blasts in the bone marrow (M3), with or without extramedullary
             disease.

          -  Patients may have central nervous system 1, 2 or 3 disease.

          -  Karnofsky Performance Level ≥ 50 for patients > 10 years of age and Lansky ≥ 50 for
             patients ≤ 10 years of age.

          -  Patients must have had 2 or more prior therapeutic attempts defined as:

               -  Relapse after going into remission from re-induction for the first or subsequent
                  relapse (ie: 2nd , 3rd, 4th…relapse), or

               -  Refractory disease after first or greater relapse and a single re-induction
                  attempt. *Please note, Enrollment will be restricted to at most one refractory
                  patient in each cohort of 3 patients per dose level.

               -  Patients with ALL who are refractory to frontline induction therapy are not
                  eligible.

          -  Patients who relapse while receiving standard ALL maintenance chemotherapy will not be
             required to have a waiting period before entry onto this study.

          -  Patients who relapse when they are not receiving standard ALL maintenance therapy must
             have fully recovered from grade 3 or 4 toxic effects of all prior chemotherapy,
             immunotherapy, or radiotherapy prior to entering this study.

          -  Cytotoxic Therapy: It must be at least 14 days since the completion of cytotoxic
             therapy (excluding hydroxyurea) at the time of study enrollment.

          -  Hematopoietic Stem Cell Transplant (HSCT): Patients who have experienced their relapse
             after a HSCT are eligible, provided they have no evidence of active Graft-versus-Host
             Disease (GVHD) and are at least 120 days post-transplant at the time of enrollment.

          -  Prior anthracycline exposure: Patients must have ≤ 400 mg/m2 lifetime exposure of
             anthracycline chemotherapy.

          -  Biologic (anti-neoplastic) therapy: It must be at least 7 days since the completion of
             therapy with a biologic agent at the time of study enrollment. For agents that have
             known adverse events occurring 7 days after administration, this period must be
             extended beyond the time during which adverse events are known to occur.

          -  Patients must have a calculated creatinine clearance or radioisotope GRF ≥
             70mL/min/1.73m2 OR a normal serum creatinine based on the institutional normal values
             according to age.

          -  Patient's ALT must be < 5 x institutional upper limit of norm (ULN), unless the
             elevation is suspected to be disease-related.

          -  Patient's total bilirubin must be ≤ 1.5 x ULN.

          -  Patient's serum albumin must be ≥ 2 g/dL.

          -  Patient must have prothrombin time (PT), partial thromboplastin time (PTT) and
             international normalized ratio (INR) ≤ 1.5 times the ULN.

          -  Patient must have a shortening fraction ≥ 27% by echocardiogram or an ejection
             fraction ≥ 45% by gated nucleotide study.

          -  Female patients of childbearing potential must have a negative urine or serum
             pregnancy test confirmed prior to enrollment.

          -  Female patients with infants must agree not to breastfeed their infants while on this
             study.

          -  Male and female patients of child-bearing potential must agree to use an effective
             method of contraception approved by the investigator during the study.

        Exclusion Criteria:

          -  Patients with Down syndrome are excluded.

          -  Patients with B-cell ALL (L3 morphology or evidence of myc translocation by molecular
             or cytogenetic technique) are not eligible

          -  Patients who cannot receive asparaginase on this study due to prior pancreatitis,
             stroke or other toxicity are not eligible.

               -  Patients with clinically significant prior allergies to PEG asparaginase are
                  eligible if Erwinia L-asparaginase can be substituted. The study will not supply
                  Erwinia.

               -  Patients who initially receive asparaginase, but must discontinue due to
                  toxicity, remain eligible.

          -  Patients with documented active and uncontrolled infection at the time of study entry
             are not eligible.

          -  Patient will be excluded if they are currently receiving other investigational drugs.

          -  Patients will be excluded if they are taking strong CYP3A4 inducers or inhibitors.

          -  Patients will be excluded if there is a plan to administer non-protocol chemotherapy,
             radiation therapy, or immunotherapy during the study period.

          -  Patients will be excluded if they have significant concurrent disease, illness,
             psychiatric disorder or social issue that would compromise patient safety or
             compliance, interfere with consent, study participation, follow up, or interpretation
             of study results.