EZN-3042 Administered With Re-induction Chemotherapy in Children With Relapsed Acute Lymphoblastic Leukemia (ALL)

This is a phase I multi-site study of the new investigational agent EZN-3042, which is highly effective at blocking survivin and inhibiting survivin protein expression. Survivin plays pivotal roles in tumor formation by inhibiting cell death and regulating cell cycle progression. The primary objective is to study EZN-3042 in children with relapsed acute lymphoblastic leukemia (ALL). Patients will receive 2 doses of EZN-3042 (and intrathecal cytarabine, conditionally) prior to initiating systemic therapy with vincristine, doxorubicin, prednisone and PEG-asparaginase. Patients with CNS 1 or 2 will also receive intrathecal methotrexate, and patients with CNS 3 will also receive triple intrathecal therapy (methotrexate, hydrocortisone, and cytarabine). Blood and bone marrow specimens will be drawn to measure minimal residual disease (MRD), pharmacokinetic levels of EZN-3042 and survivin expression. The study will follow a standard 3+3 dose escalation design. We hypothesize that EZN-3042 will be safe, tolerable and biologically active, when given both alone and in combination with standard re-induction chemotherapy.

• EZN-3042 (Drug), also known as SPC 3042: 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
• Cytarabine (Drug), also known as ARA-C, cytosine arabinoside, Cytosar, Cytosar-U®, Arabinosylcytosine: 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. \- 1.99 years: 16 mg 2. \- 2.99 years: 20 mg 3. \- 8.99 years: 24 mg Greater than or equal to 9 years: 30 mg
• Doxorubicin (Drug), also known as Adriamycin, Rubex: 60 mg/m2/day given intravenous infusion (IV) over 15 minutes on day 1.
• Prednisone (Drug), also known as Prednisone Intensol®, Sterapred®, Sterapred® DS, Predone®, Deltasone®: 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.
• Vincristine (Drug), also known as Oncovin®, vincristine sulfate, Vincasar Pfs®, VCR, LCR: 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.
• PEG-asparaginase (Drug), also known as Oncaspar®, PEG-L-asparaginase: 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.
• Methotrexate (Drug), also known as Rheumatrex, Trexall, Amethopterin, Methotrexate Sodium, MTX: 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. \- 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
• Hydrocortisone (Drug), also known as Ala-Cort ®, Hydrocortone Phosphate, Solu-Cortef®, Hydrocort Acetate®, Lanacort®, Cortef®, Westcort®, Cortisone, Hydrocortisone Sodium Succinate, Hydrocortisone Sodium Phosphate: 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. \- 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

Primary outcomes

• Maximum Tolerated Dose of EZN-3042 [2 months]: To determine the recommended dose of EZN-3042 administered weekly in combination with re-induction chemotherapy. Based on disease response at Day 36 and toxicity profile assessed until 30 days after discontinuation of study drug.

Secondary outcomes

• Number of Participants Who Showed a Decrease From Day -6 in Survivin Transcript Expression After EZN-3042 Administration [Day -6 to Day 0]: To evaluate primary target engagement of EZN-3042 we will examine survivin transcript and protein expression before (Day -6) and after EZN-3042 administration (Day 0) in enriched bone marrow blasts in children with relapsed B-precursor leukemia.

Sex: All, ages: 1 Year to 21 Years

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.

Participant flow

Outcome results

• Maximum Tolerated Dose of EZN-3042 (Primary), Count of participants, Participants: EZN Dose Level 1 4; EZN Dose Level 0 0
• Number of Participants Who Showed a Decrease From Day -6 in Survivin Transcript Expression After EZN-3042 Administration (Secondary), Count of participants, Participants: EZN Dose Level 1 2

Adverse events

Time frame: 11 months

Serious adverse events by term

Other adverse events by term

10 more terms not shown.

Limitations and caveats: The study was terminated early because Enzon Pharmaceuticals decided to halt development of EZN-3042.

• Results publication: Raetz EA, Morrison D, Romanos-Sirakis E, Gaynon P, Sposto R, Bhojwani D, Bostrom BC, Brown P, Eckroth E, Cassar J, Malvar J, Buchbinder A, Carroll WL. A phase I study of EZN-3042, a novel survivin messenger ribonucleic acid (mRNA) antagonist, administered in combination with chemotherapy in children with relapsed acute lymphoblastic leukemia (ALL): a report from the therapeutic advances in childhood leukemia and lymphoma (TACL) consortium. J Pediatr Hematol Oncol. 2014 Aug;36(6):458-63. doi: 10.1097/MPH.0b013e3182a8f58f. PMID 24276047

• Elizabeth Raetz, MD, Study chair, NYU Langone Health
• William Carroll, MD, Study chair, NYU Langone Health