EZN-2285 or Pegaspargase and Combination Chemotherapy in Treating Younger Patients With Newly Diagnosed High-Risk Acute Lymphoblastic Leukemia

• Pharmacodynamics of EZN-2285 compared to pegaspargase during induction and consolidation therapy [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  Pharmacodynamics of EZN-2285 and of Oncaspar® during Induction and during Consolidation will be assessed.
• Response rate [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  End of Induction therapy Day 29 MRD results as well as the response rates of the EZN-2285 containing regimen and the Oncaspar® containing regimen also be assessed.
• Event-free survival [ Time Frame: from the date of diagnosis to the date of the first documented progression/relapse event, (including Induction failure), diagnosis of a second malignant neoplasm, or death from any cause ] [ Designated as safety issue: No ]
  Estimates of median EFS and the corresponding 95% CI will be calculated after minimum follow-up of 3 years

• Pharmacodynamics of EZN-2285 compared to pegaspargase during induction and consolidation therapy [ Designated as safety issue: No ]
• Response rate [ Designated as safety issue: No ]
• Event-free survival [ Designated as safety issue: No ]
• Minimal residual disease at day 29 of induction therapy [ Designated as safety issue: No ]
• Complete remission rates [ Designated as safety issue: No ]
• Immunogenicity of EZN-2285 compared to pegaspargase [ Designated as safety issue: No ]
• Toxicities [ Designated as safety issue: Yes ]

RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells.

PURPOSE: This randomized clinical trial is studying giving EZN-2285 together with combination chemotherapy to see how well it works compared with giving pegaspargase together with combination chemotherapy in treating younger patients with newly diagnosed high-risk acute lymphoblastic leukemia.

OBJECTIVES:

Primary

• Determine the pharmacokinetic (PK) comparability of SC-PEG E. coli L-asparaginase (EZN-2285)[As of 12/22/2010, patients no longer receive EZN-2285][As of amendment #6, patients receive EZN-2285 again.] to pegaspargase given intravenously during induction and consolidation in patients with high-risk acute lymphoblastic leukemia (ALL) receiving augmented Berlin-Frankfurt-Munster (BFM) therapy.

Secondary

• Describe the pharmacodynamics of EZN-2285 compared to pegaspargase in these patients.
• Determine, at end of induction therapy by day 29, minimal residual disease for patients randomized to the EZN-2285-containing regimen compared to the pegaspargase-containing regimen.
• Determine the complete remission rates for patients receiving EZN-2285, by day 29 of induction, compared to pegaspargase.
• Assess event-free survival associated with the administration of EZN-2285 compared to pegaspargase given during augmented post-induction intensification therapy in patients with high-risk ALL.
• Determine the proportion of patients with an asparaginase level of at least 0.1 IU/mL and the proportion of patients with that of at least 0.4 IU/mL on days 4, 15, 22, and 29 of induction in both arms.
• Determine the plasma and cerebrospinal fluid concentrations of asparagine after administration of EZN-2285 compared to pegaspargase.
• Assess the immunogenicity of EZN-2285, including the detection of binding and neutralizing antibodies, compared to pegaspargase.
• Assess the tolerability and toxicities associated with the administration of EZN-2285 compared to pegaspargase given during augmented post induction intensification therapy in patients with high-risk ALL .
• Explore the relationship between the terminal PKs of EZN-2285 and the presence of antibodies.

OUTLINE: This is a multicenter study. Patients are stratified according to response to induction therapy (slow early responders [SER] vs rapid early responders [RER]. Patients are randomized to 1 of 2 treatment arms in 2:1 ratio (arm I:arm II) (patients randomized to arm I receive study drug SC-PEG E. coli L-asparaginase [EZN-2285]*; patients randomized to arm II receive study drug pegaspargase).

NOTE: *As of 12/22/2010, all patients randomized to receive EZN-2285 will receive pegaspargase instead.NOTE: *As of amendment #6, patients receive EZN-2285 again.

• Induction therapy** (all patients): Patients receive cytarabine intrathecally (IT) on day 1; vincristine IV and daunorubicin hydrochloride IV over 15 minutes on days 1, 8, 15, and 22; prednisone*** orally or IV twice a day on days 1-28; study drug IV over 1 hour on day 4; and methotrexate IT on days 8, 15*, 22*, and 29.

Patients are assessed for response on day 8 and/or day 15 and day 29. Patients who achieve M1 marrow on day 8 or 15 and negative minimum residual disease (MRD) (i.e., < 0.1%) on day 29 are considered RER. Patients who achieve M2 or M3 marrow on day 15 OR MRD ≥ 0.1% but < 1% on day 29 are considered SER. Patients with M3 bone marrow are removed from the study. Patients with Very High Risk (VHR) disease are removed from the study. RER and SER proceed to consolidation therapy. Patients with M2 marrow or M1 marrow with ≥ 1% MRD receive extended induction therapy.

NOTE: *For patients with CNS3 disease only.

NOTE: ***As of Amendment #6, patients aged less than 10 years receive dexamethasone twice daily on days 1-14 while patients at least 10 years old receive prednisone twice daily on days 1-28.

• Extended induction therapy**: Patients receive vincristine IV on days 1 and 8; prednisone orally or IV twice a day on days 1-14; daunorubicin hydrochloride IV over 15 minutes on day 1; and study drug IV over 1 hour on day 4.

NOTE: **As of Amendment #6, patients aged less than 10 years receive dexamethasone twice daily on days 1-14 while patients at least 10 years old receive prednisone twice daily on days 1-28.

Patients are assessed for response on day 43. Patients who achieve M1 and MRD < 1% are treated as SER (proceed to consolidation therapy). All other patients are removed from study.

• Consolidation therapy** (all patients): Beginning on day 36 (after completion of induction therapy) or after completion of extended induction therapy, patients (RER and SER) receive cyclophosphamide IV over 30 minutes on days 1 and 29; cytarabine IV over 15-30 minutes or SC on days 1-4, 8-11, 29-32, and 36-39; oral mercaptopurine on days 1-14 and 29-42; vincristine IV on days 15, 22, 43, and 50; study drug IV over 1 hour on days 15 and 43; and methotrexate IT on days 1, 8, 15*, and 22*. NOTE: As per amendment #6, CNS3 patients no longer receive cranial radiotherapy as Consolidation therapy. Patients then proceed to interim maintenance I therapy.

NOTE: *Omit doses for patients with CNS3 disease.

• Interim maintenance I**(all patients): Patients receive vincristine IV and high-dose methotrexate** IV on days 1, 15, 29, 31, and 43; study drug IV over 1 hour on days 2 and 22; and methotrexate IT on days 1 and 29. Patients then proceed to delayed intensification I therapy.
• Delayed intensification I** (all patients^): Patients receive vincristine IV on days 1, 8, 15, 43, and 50; dexamethasone orally or IV twice a day on days 1-21 for patients age 1-9, or on days 1-7 and 15-21 for patients age ≥ 10; doxorubicin hydrochloride IV over 15 minutes on days 1, 8, and 15; study drug IV over 1 hour on days 4 and 43; cyclophosphamide IV over 30 minutes on day 29; cytarabine IV or subcutaneously (SC) on days 29-32 and 36-39; oral thioguanine on days 29-42; and methotrexate IT on days 1, 29, and 36.

Patients treated as RER proceed to maintenance therapy. Patients treated as SER (i.e., patients with CNS3 disease at diagnosis, or pre-treated with steroids, or who are RERs with mixed lineage leukemia [MLL] gene rearrangements) proceed to interim maintenance II followed by delayed intensification II.

As per amendment #6, an augmented BFM backbone is used with a single delayed intensification for RERs and a double delayed intensification for SERs. All patients receive discontinuous dexamethasone (one week on, one week off, one week on) during the Delayed Intensification phases.

• Interim maintenance II** (SER only): Patients receive vincristine IV, high-dose methotrexate IV, study drug IV, and methotrexate IT as in interim maintenance I. Patients who were initially diagnosed with CNS3 disease receive cranial radiotherapy on days 1-5 and 8-12.
• Delayed intensification II** (SER only): Beginning on day 29, patients (except patients enrolled prior to Amendment #6) receive 8 daily fractions of cranial radiotherapy(CRT) (CNS3 patients enrolled after Amendment #6 undergo 10 daily fractions of CRT). All patients then receive vincristine IV, dexamethasone orally or IV, doxorubicin hydrochloride IV, study drug IV, cyclophosphamide IV, cytarabine IV or SC, oral thioguanine, and methotrexate IT as in delayed intensification I. Patients then proceed to maintenance therapy. As per amendment #6, patients who were initially diagnosed with CNS3 disease receive cranial radiotherapy on days 1-5 and 8-12. All patients receive discontinuous dexamethasone (one week on, one week off, one week on) during the Delayed Intensification phases.
• Maintenance therapy** (all patients): Patients receive vincristine IV on days 1, 29, and 57; oral dexamethasone on days 1-5, 29-33, and 57-61; oral mercaptopurine on days 1-84; methotrexate IT on day 29; and oral methotrexate on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. Treatment repeats every 12 weeks for up to 2 years (for female patients) or up to 3 years (for male patients) from the start of interim maintenance I.

NOTE: ** As per amendment #4, most patients receive high-dose methotrexate instead of Capizzi methotrexate at most stages of therapy. CNS3 patients and SER patients who have received cranial irradiation receive planned therapy with no modifications.NOTE: As per amendment #4, the maximum number of intrathecal treatments is limited by RER/SER/CNS3 status and gender.

Blood and cerebrospinal fluid samples are collected periodically for correlative studies, including immunogenicity, pharmacokinetic, and pharmacodynamic studies.

After completion of study therapy, patients are followed every 2 months for 2 years, every 3 months for 1 year, and then every 6-12 months for 2 years.

• Drug: calaspargase pegol
  Given IV
  Other Names:

  • CALASPARGASE PEGOL
  • EZN-2285
  • SC-PEG E. coli L-asparaginase
  • IND# 100594
• Drug: cyclophosphamide
  All drugs are given IV
• Drug: cytarabine
  Given IV, intrathecally, and subcutaneously
• Drug: daunorubicin hydrochloride
  All drugs are given IV
• Drug: dexamethasone
  Both are given IV or orally
• Drug: doxorubicin hydrochloride
  All drugs are given IV
• Drug: methotrexate
  Given IV, intrathecally, and orally
• Drug: pegaspargase
  Given IV
• Drug: prednisone
  Both are given IV or orally
• Drug: vincristine sulfate
  All drugs are given IV
• Radiation: radiation therapy
  Some patients undergo cranial radiotherapy

• Experimental: Arm I
  Patients receive SC-PEG E. coli L-asparaginase (EZN-2285) together with combination chemotherapy. Patients receive chemotherapy by mouth, infusion, injection, and intrathecally. Some patients also undergo radiation therapy to the head. Treatment may continue for up to 4 years. (As of 12/22/2010, patients do not receive EZN-2285. They receive pegaspargase as in arm II.) (As of amendment #6, patients receive EZN-2285 again.)
  Interventions:

  • Drug: calaspargase pegol
  • Drug: cyclophosphamide
  • Drug: cytarabine
  • Drug: daunorubicin hydrochloride
  • Drug: dexamethasone
  • Drug: doxorubicin hydrochloride
  • Drug: methotrexate
  • Drug: prednisone
  • Drug: vincristine sulfate
  • Radiation: radiation therapy
• Active Comparator: Arm II
  Patients receive pegaspargase together with combination chemotherapy. Patients receive chemotherapy by mouth, infusion, injection, and intrathecally. Some patients also undergo radiation therapy to the head. Treatment may continue for up to 4 years.
  Interventions:

  • Drug: cyclophosphamide
  • Drug: cytarabine
  • Drug: daunorubicin hydrochloride
  • Drug: dexamethasone
  • Drug: doxorubicin hydrochloride
  • Drug: methotrexate
  • Drug: pegaspargase
  • Drug: prednisone
  • Drug: vincristine sulfate
  • Radiation: radiation therapy

DISEASE CHARACTERISTICS:

• Newly diagnosed high-risk B lymphoblastic leukemia (WHO 2008 classification) (also termed B-precursor acute lymphoblastic leukemia
• No Down syndrome
• No testicular leukemia
• Enrolled on COG-AALL08B1 study or the successor classification study
• Enrolled on COG-AALL07P4 study before systemic treatment begins

PATIENT CHARACTERISTICS:

• WBC ≥ 50,000/μL for patients age 1-9 OR any WBC count for patients age 10-30 or for patients treated with prior steroids
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

• No prior cytotoxic chemotherapy except for steroid therapy or intrathecal cytarabine

• National Cancer Institute (NCI)
• Sigma Tau Pharmaceuticals, Inc.