Protocol Version Date: April13, 2021 DF/HCC Protocol

1 DFCI Protocol 16-001PI: Lewis Silverman, MDVersion: April 13, 20211 Protocol Version Date: April13, 2021DF/HCC Protocol #: 16-001 IND Status: Not applicable TITLE: Treatment of Newly Diagnosed Acute Lymphoblastic Leukemia in Children and AdolescentsCoordinating Center: Dana-Farber/Boston Children s Cancer and Blood Disorders Center Principal Investigator (PI): Lewis Silverman, MD, Dana-Farber Cancer Institute DFCI/BCH Collaborating Investigators Kira Bona, MD (Dana-Farber/Boston Children s Hospital) Melissa Burns, MD (Dana-Farber/Boston Children s Hospital) Kimberly Davies, MD (Dana-Farber/Boston Children s Hospital) Barbara Degar, MD (Dana-Farber/Boston Children s Hospital) Alejandro Gutierrez, MD (Dana-Farber/Children s Hospital) Marian Harris, MD, PhD (Boston Children s Hospital) Jennifer Kesselheim, MD (Dana-Farber/Boston Children s Hospital) Birgit Knoechel, MD, PhD (Dana-Farber/Boston Children s Hospital) Yana Pikman, MD (Dana-Farber/Boston Children s Hospital) Andrew Place, MD, PhD (Dana-Farber/Boston Children s Hospital) Jessica Pollard, MD (Dana-Farber/Boston Children s Hospital) Stephen E.

2 Sallan, MD (Dana-Farber/Boston Children s Hospital) Kimberly Stegmaier, MD (Dana-Farber/Boston Children s Hospital) Lynda Vrooman, MD (Dana-Farber/Boston Children s Hospital) Olga Weinberg, MD (Boston Children s Hospital)Participating SitesUSA Columbia University Medical Center, Morgan Stanley Children's Hospital of New York-Presbyterian, New York, NY (Site PI: Justine Kahn, MD) Hasbro Children s Hospital, Providence, RI (Site PI: Jennifer Welch, MD) Montefiore Medical Center, New York, New York (Site PI: Lisa Gennarini, MD) Roswell Park Cancer Institute, Buffalo, New York (Site PI: Kara Kelly, MD) Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey (Site PI: Peter Cole, MD)Canada CHU de Quebec, Centre Hospitalier de l'Universite Laval, Quebec City, Quebec (PI : Bruno Michon, MD) CHU Sainte-Justine, Montreal, Quebec (PI: Thai-Hoa Tran, MD)DFCI Protocol 16-001PI: Lewis Silverman, MDVersion: April 13, 20212 Statistician: Kristen Stevenson, MS, Dana-Farber Cancer InstituteYael Flamand, Dana-Farber Cancer InstituteDonna Neuberg, ScD, Dana-Farber Cancer InstituteStudy Coordinators: Victoria Koch, Dana-Farber Cancer Institute450 Brookline Ave, SW461 Boston, MA 02215 Phone: 617-632-4878 Fax: 617-632-3977 Email: Kaitlin Schroeder, Dana-Farber Cancer Institute450 Brookline Ave, SW461 Boston, MA 02215 Phone: 617-632-3662 Fax: 617-632-3977 Email.

3 Barros, Dana-Farber Cancer Institute450 Brookline Ave, SW461 Boston, MA 02215 Phone: 857-215-1227 Fax: 617-632-3977 Email: Crossman-Sexton450 Brookline Ave, SW461 Boston, MA 02215 Phone: 617-632-6841 Fax: 617-632-3977 Email: Nurses: Olivia Caradonio, RN, BSN, Dana-Farber Cancer Institute 450 Brookline Ave, SW463 Boston, MA 02215 Phone: 617-582-9709 Fax: 617-632-3977 Email: Braun, RN, BSN, Dana-Farber Cancer Institute 450 Brookline Ave, SW463 Boston, MA 02215 Phone: 617-632-6367 Fax: 617-632-3977 Email: Protocol 16-001PI: Lewis Silverman, MDVersion: April 13, 20213 Meghan Dens, RN, BSN, Dana-Farber Cancer Institute450 Brookline Ave, SW463 Boston, MA 02215 Fax: 617-632-6977 Email: Investigators (outside sites) Justine Kahn, MD, Columbia University Medical Center Maja Krajinovic, MD, CHU Sainte-Justine Stephen Sands, PsyD Memorial Sloan Kettering Cancer Center Daniel Sinnett, PhD, CHU Sainte-Justine Yves Theoret, PhD, CHU Sainte-JustineDFCI Protocol 16-001PI: Lewis Silverman, MDVersion: April 13, 20214 DFCI Protocol 16-001PI: Lewis Silverman, MDVersion: April 13, 20215 DFCI Protocol 16-001PI: Lewis Silverman, MDVersion: April 13, 20216 TABLE OF CONTENTS1.

4 Objective .. Objectives .. Objectives .. Group Randomization .. Outcome .. to Oral Material Protocol ELIGIBILITY .. Criteria .. Criteria .. of Women, Minorities and Other Underrepresented PROCEDURES .. Process for Dana-Farber Cancer Process for Other Investigative GROUP CLASSIFICATION .. Risk Group .. Risk Group .. to HR/VHR group .. for Randomization .. Procedure .. Randomization Treatment Assignments .. PLAN .. Prophase (All patients) .. IA Phase ..56 DFCI Protocol 16-001PI: Lewis Silverman, MDVersion: April 13, IB Phase (All patients, regardless of risk group).. I Phase .. II Phase .. Phase (All Risk Groups) .. for VHR B-ALL Patients with HIGH TP3 MRD .. CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES.

5 Medications .. Care at Diagnosis and during Steroid Prophase/Induction Prophylaxis and Management of Fever During Steroid Prophase and Induction Supportive Care During Post-Induction IA Therapy ..12010. DURATION OF THERAPY .. Duration of Follow Up .. Suggested Assessment Schedule after Completion of Treatment .. Criteria for Removal from Study ..12311. CLINICAL RESPONSE DEFINITIONS .. Definition of Marrow Status .. Definition of CNS Definition of Complete Remission .. Failure to Achieve Remission (Induction Failure) .. High Minimal Residual Disease (High MRD).. Criteria for DOSE MODIFICATIONS AND TOXICITY MANAGEMENT .. Allowable Variations in Dosing (All Phases).. Allowable Deviations Due to Significant Illness.

6 Induction IA: Dose Modifications .. Induction IB: Dose Modifications .. Consolidation I (including Consolidation IA, IB, and IC): Dose Modifications .. CNS Treatment Phase: Dose Consolidation II and Continuation Therapy: Dose Blinatumomab: Dose ANTICIPATED TOXICITIES .. Adverse event list for Pegaspargase (Oncaspar ) .. Adverse Event List for Erwinia L-Asparaginase (Erwinaze ) and for Adverse event list for blinatumomab ..157 DFCI Protocol 16-001PI: Lewis Silverman, MDVersion: April 13, Adverse Event List for Cyclophosphamide (Cytoxan ).. Adverse Event List for Cytarabine (Cytosine Arabinoside, Ara-C, Cytosar ).. Adverse Event List for Adverse Event List for Dexamethasone, (Decadron , Hexadrol , Dexone , Dexameth ).

7 Adverse Event List for Dexrazoxane (Zinecard ) .. Adverse Event List for Doxorubicin (Adriamycin ) .. Adverse Event List for Etoposide (VePesid , Etopophos , VP-16) .. Adverse Event List for Triple Intrathecal Chemotherapy (IT Methotrexate/Cytarabine/Hydrocortisone) . Adverse Event List for Leucovorin Calcium (Wellcovorin , Citrovorum Factor, Folinic Acid) .. Adverse Event List for Mercaptopurine (6-MP, Purinethol , PurixanTM, 6-Mercaptopurine).. Adverse Event List for Methotrexate (Amethopterine, Trexall ) .. Adverse Event List for Nelarabine .. Adverse Event List for Prednisone, Prednisolone, Methylprednisolone .. Adverse Event List for Vincristine (Oncovin )..16814. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS .. Adverse Event Characteristics.

8 Routine Adverse Event Serious Adverse Protocol Specific Serious Adverse Event Reporting Exclusions .. Reporting to Regulatory Reporting to Servier, .. Expedited Reporting to Hospital Management ..17315. DATA AND SAFETY MONITORING .. Data Reporting .. Safety Monitoring ..17516. PHARMACEUTICAL INFORMATION .. Asparaginase: Pegaspargase (PEG-asparaginase, , Oncaspar ,) NSC # Asparaginase: Erwinia NSC #106977 (Erwinaze , Erwinia chrysanthemi, Erwinase , Crisantaspase) . L-ASPARAGINASE (KIDROLASE ) NSC # BLINATUMOMAB (BLINCYTO) NSC # Cyclophosphamide (Cytoxan) NSC #26271 .. Cytarabine (cytosine arabinoside, Ara-C, Cytosar ) NSC # 63878 .. Dasatinib (Sprycel) NSC #732517 .. Dexamethasone (Decadron , Hexadrol , Dexone , Dexameth ) NSC #34521.

9 183 DFCI Protocol 16-001PI: Lewis Silverman, MDVersion: April 13, Dexrazoxane (Zinecard ), NSC# Doxorubicin (Adriamycin ) NSC #123127) .. Etoposide (VePesid , Etopophos , VP-16) NSC # Hydrocortisone .. Leucovorin Calcium (LCV, Wellcovorin , citrovorum factor, folinic acid), NSC #003590 .. Mercaptopurine (6-MP, Purinethol , 6-mercaptopurine, Purixan ) NSC #000755 .. Methotrexate (MTX, amethopterin, Trexall ) NSC #000740 .. Nelarabine (Arranon) NSC # Prednisone (Deltasone, Meticorten, Orasone , Liquid Pred, Pediapred , Sterapred ) NSC # Vincristine (Oncovin , VCR, LCR) NSC #67574 ..19317. STUDY CALENDAR: .. Study Assessments: Study Entry and Induction Phase .. Study Assessments: Post Induction Treatment Phases .. Bone Marrow Assessments.

10 19918. CORRELATIVE BIOLOGY/SPECIAL STUDIES .. Asparaginase Pharmacokinetic Samples .. IKZF1 SCREENING .. MRD to Adaptive .. COG Fusion Screening (NCI HR B-ALL Patients only-Required) .. BCH Archer Fusion Testing .. Biology Research Samples (Optional).. CSF Research Samples (Optional) .. Serial Neurocognitive Screening/ Cogstate Testing (Optional) .. Adherence Studies (Surveys/MEMS Caps/6-MP Metabolites) (Optional) .. Household Material Hardship (HMH) Survey Procedures (optional)..21419. LABORATORY STUDIES AND THERAPY AT OUTSIDE AFFILIATE SITES .. Laboratory Studies .. STATISTICAL CONSIDERATIONS .. New Risk Group Asparaginase Randomization .. Toxicity Monitoring .. Pilot intensified regimen for very high risk patients.