A Phase III Randomized Trial Investigating Bortezomib on a Modified Augmented BFM Backbone in Newly Diagnosed T-Lymphoblastic Leukemia and T-Lymphoblastic Lymphoma

Primary Aims
1.1.1 To compare EFS in patients with newly diagnosed T-ALL and T-LLy who are randomized to a modified ABFM backbone versus bortezomib plus the modified ABFM backbone.
1.2 Secondary Aims
1.2.1 To determine the safety and feasibility of modifying standard therapy for T-ALL and T-LLy based on the results of UKALL 2003, which includes a dexamethasone-based Induction, additional doses of pegaspargase (PEG-ASP) during Induction and Delayed Intensification (DI), and dexamethasone pulses during Maintenance therapy
1.2.2 To determine if prophylactic (presymptomatic) cranial radiation therapy (CRT) can be safely and effectively eliminated in the 85-90% of T-ALL patients classified as
standard or intermediate risk.
1.2.3 To determine the proportion of EOC MRD ? 0.1% T-ALL patients who become MRD
negative (undetectable by flow cytometry) after intensification of chemotherapy, using three high risk (HR) BFM blocks, and to compare EFS between the patients who become MRD negative after the three HR BFM blocks and continue on chemotherapy with those who continue to have detectable MRD and are eligible for other treatment strategies, including hematopoietic stem cell transplant (HSCT).
Similarly, to compare the EFS between very high risk (Induction failure) T-LLy
patients treated with HR BFM intensification blocks who have partial or complete response (PR or CR) with those who do not respond (NR).
1.3 Correlative Aims
1.3.1 To investigate the prognostic significance of Day 29 BM MRD in T-LLy patients.
1.3.2 To determine if protein expression patterns can predict bortezomib response and drug resistance in T-ALL
1.3.3 To analyze and target relevant signaling pathways in T-ALL blasts, focusing on Early T cell Precursor (ETP) ALL

Study phase: III

Basic eligibility criteria:
Please contact the study coordinator for additional eligibility information.

a. Classification Study:
• T-ALL: T-ALL patients must be enrolled on AALL08B1 or Project: Every Child (APEC14B1) prior to treatment and enrollment on AALL1231.
• T-LLy: If Project: Every Child (APEC14B1) is available, T-LLy patients must be
enrolled on APEC14B1 prior to treatment and enrollment on AALL1231
b. Age at Diagnosis: All patients must be > 1 and < 31 years of age.
c. Diagnosis: Patients must have newly diagnosed T-Lymphoblastic Leukemia (T-ALL) or T-Lymphoblastic Lymphoma (T-LLy) Stages II-IV (see Appendix VIII).
Version Date: 12/09/2014 Page 34
Note: A diagnosis of T-ALL is established when leukemic blasts lack myeloperoxidase or evidence of B-lineage derivation (CD19/CD22/CD20), and express either surface or cytoplasmic CD3 or two or more of the antigens CD8, CD7, CD5, CD4, CD2 or CD1a,
and are present either in peripheral blood or >25% in the bone marrow. If surface CD3 is expressed on all leukemic cells, additional markers of immaturity, including TdT, CD34 or CD99 will be assessed for expression. Cases with uncertain expression will receive additional review within the appropriate COG reference laboratory.
For T-LLy patients with tissue available for flow cytometry, the criterion for diagnosis
should be analogous to T-ALL. For tissue processed by other means (i.e. paraffin blocks), the methodology and criteria for immunophenotypic analysis to establish the diagnosis of T-LLy defined by the submitting institution will be accepted. See pathologic diagnosis recommendation in Section 13.4.
d. Informed consent: All patients and/or their parents or legal guardians must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines
a. Prior Therapy: Patients must not have received any cytotoxic chemotherapy for either the current diagnosis of T-ALL, T-L-Ly or for any cancer diagnosis prior to the initiation of protocol therapy on AALL1231, with the exception of:
• Steroid pretreatment: Prednisone or methylprednisolone for ? 120 hours (5 days) in
the 7 days prior to initiating Induction chemotherapy or for ? 336 hours (14 days) in the 28 days prior to initiating Induction chemotherapy. Prior exposure to ANY steroids that occurred > 28 days before the initiation of protocol therapy does not affect eligibility. The dose of prednisone or methylprednisolone does not affect eligibility.
• Intrathecal cytarabine; or
• 600 cGy of chest irradiation, if medically necessary. Pre-treatment with dexamethasone in the 28 days prior to initiation of protocol therapy is
not allowed.
b. Peripheral neurotoxicity: Pre-existing ? grade 2 sensory or motor peripheral neurotoxicity.
c. Seizures disorder: Uncontrolled seizure disorder
d. Diagnosis of Down syndrome (Trisomy 21) e. Patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential.
f. Lactating females who plan to breastfeed.
Version Date: 12/09/2014 Page 35
g. Sexually active patients of reproductive potential who have not agreed to use an effective
contraceptive method for the duration of their study participation.
h Patient has hypersensitivity to bortezomib, boron, or mannitol.
i Serious medical or psychiatric illness likely to interfere with participation in this clinical study.
j Participation in clinical trials with other investigational agents not included in this trial,
within 14 days of the start of this trial and within 30 days of any dose of bortezomib.

Primary disease category: Cancer

Sponsor: Children's Oncology Group

Protocol number: AALL1231

Projected enrollment dates: May 2015 to April 2017

Official study title: A Phase III Randomized Trial Investigating Bortezomib on a Modified Augmented BFM Backbone in Newly Diagnosed T-Lymphoblastic Leukemia and T-Lymphoblastic Lymphoma