Imatinib Mesylate and Combination Chemotherapy in Treating Patients With Newly Diagnosed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia
- Conditions
- B Acute Lymphoblastic LeukemiaAcute Lymphoblastic LeukemiaMixed Phenotype Acute LeukemiaT Acute Lymphoblastic Leukemia
- Interventions
- Procedure: Allogeneic Hematopoietic Stem Cell TransplantationOther: Laboratory Biomarker AnalysisOther: Questionnaire Administration
- Registration Number
- NCT03007147
- Lead Sponsor
- Children's Oncology Group
- Brief Summary
This randomized phase III trial studies how well imatinib mesylate works in combination with two different chemotherapy regimens in treating patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (ALL). Imatinib mesylate has been shown to improve outcomes in children and adolescents with Philadelphia chromosome positive (Ph+) ALL when given with strong chemotherapy, but the combination has many side effects. This trial is testing whether a different chemotherapy regimen may work as well as the stronger one but have fewer side effects when given with imatinib. The trial is also testing how well the combination of chemotherapy and imatinib works in another group of patients with a type of ALL that is similar to Ph+ ALL. This type of ALL is called "ABL-class fusion positive ALL", and because it is similar to Ph+ ALL, is thought it will respond well to the combination of agents used to treat Ph+ ALL.
- Detailed Description
PRIMARY OBJECTIVE:
I. To compare disease-free survival (DFS) of standard risk (SR) pediatric Philadelphia chromosome (Ph)+ acute lymphoblastic leukemia (ALL) treated with continuous imatinib mesylate (imatinib) combined with either a high-risk Children's Oncology Group (COG) ALL chemotherapy backbone or the more intensive European (Es)PhALL chemotherapy backbone.
SECONDARY OBJECTIVES:
I. To compare DFS of SR pediatric Ph+ and ABL-class fusion positive ALL patients treated with continuous imatinib combined with either a high-risk COG-ALL chemotherapy backbone or the more intensive EsPhALL chemotherapy backbone.
II. To determine the feasibility of administration of imatinib after allogeneic hematopoietic stem cell transplantation (HSCT) in high risk (HR) Ph+ ALL patients.
III. To determine event-free survival (EFS) of HR pediatric Ph+ ALL patients treated with EsPhALL chemotherapy, HSCT in first complete remission and post-HSCT imatinib.
IV. To compare rates of grade 3 or higher infections in standard risk (SR) Ph+ ALL patients between the two randomized arms.
V. To evaluate EFS and overall survival (OS) of all eligible Ph+ALL patients enrolled on the study.
VI. To evaluate OS in SR Ph+ ALL patients. VII. To evaluate OS in HR Ph+ ALL patients. VIII. To evaluate EFS and OS of all eligible ABL-class fusion positive ALL patients enrolled on the study.
EXPLORATORY OBJECTIVES:
I. To describe the toxicities associated with post-HSCT administration of imatinib in HR Ph+ALL patients.
II. To evaluate the long-term toxicities in SR Ph+ ALL patients treated with chemotherapy plus imatinib (no transplant), overall and between both randomized arms.
III. To determine prognostic significance of minimal residual disease (MRD) in Ph+ ALL at various time points during therapy.
IIIa. To evaluate MRD in HR patients just prior to HSCT and then at regular intervals post-HSCT and explore the association of these measurements with long-term outcome.
IIIb. To evaluate concordance of MRD assessments made by IGH-T cell receptor (TCR) polymerase chain reaction (PCR) assay and next generation sequencing (NGS) assays.
IV. To determine and validate if IKZF1 deletions alone (IKZF1del) or with other transcription factor deletions (ie, IKZF1 plus subtype \[IKZF1plus\]) or other identified genetic lesions predict poor outcomes in Ph+/ABL-class Ph-like ALL in patients treated on AALL1631.
V. To determine the frequency and prognostic significance of p190 and p210 BCR::ABL1 fusion variants in pediatric Ph+ ALL/ABL-class Ph-like ALL.
VI. To measure adherence to oral chemotherapeutic agents (imatinib, 6-mercaptopurine and methotrexate) during the maintenance phase in SR Ph+ ALL patients.
VIa. To identify factors associated with poor adherence. VIb. To determine association between relapse risk and adherence to each oral chemotherapeutic agent (separately and combined).
VII. To measure adherence to imatinib after allogeneic HSCT in HR Ph+ ALL patients and identify factors associated with poor adherence.
VIII. To compare DFS of SR ABL-class fusion positive ALL patients treated with continuous imatinib combined with either a high-risk COG-ALL chemotherapy backbone or the more intensive EsPhALL chemotherapy backbone.
IX. To determine the potential therapeutic impact of major secondary events via pharmacologic inhibitor screens in existing/engineered cell models of Ph+ and ABL-class Ph-like ALL harboring secondary events and to test the in vivo activity of the most compelling candidate compounds from pilot studies using patient-derived xenograft (PDX) models established from Ph+ and ABL-class Ph-like ALL samples collected from patients treated on AALL1631.
X. To decipher the molecular and cellular heterogeneity of chronic myelogenous leukemia (CML)-like versus typical Ph+ ALL via single-cell genomics and functional assays and investigate CML-like phenotypes via single-cell ribonucleic acid (RNA) and deoxyribonucleic acid (DNA) sequencing to identify distinct transcriptomic and mutational profiles that will provide novel opportunities for diagnostic and therapeutic interventions.
OUTLINE:
INDUCTION IA PART 1: Patients receive induction IA according to standard of care on days 1-14.
INDUCTION IA PART 2: Patients receive imatinib mesylate orally (PO) once daily (QD) or twice daily (BID) on days 15-33, prednisolone PO twice daily (BID) or methylprednisolone intravenously (IV) on days 15-28, vincristine sulfate IV over 1 minute on days 15 and 22, daunorubicin hydrochloride IV over 1-15 minutes on days 15 and 22, and methotrexate intrathecally (IT) on day 29.
INDUCTION IB: Patients receive imatinib mesylate PO QD or BID on days 1-35, cyclophosphamide IV over 30-60 minutes on days 1 and 28, mercaptopurine PO on days 1-28, cytarabine IV or subcutaneously (SC) on days 3-6, 10-13, 17-20, and 24-27, and methotrexate IT on days 10 and 24.
POST-INDUCTION THERAPY: Patients classified as standard risk are randomized to 1 of 2 arms. Patients with high risk are assigned to Arm C.
ARM A:
CONSOLIDATION BLOCK 1: Patients receive imatinib mesylate PO QD or BID on days 1-21, methotrexate IT, cytarabine IT, and therapeutic hydrocortisone IT on day 1, high dose methotrexate IV over 24 hours on day 1, vincristine sulfate IV over 1 minute on days 1 and 6, dexamethasone PO BID or IV on days 1-5, cyclophosphamide IV over 30-60 minutes on days 2-4, leucovorin calcium or levoleucovorin PO or IV on days 3 and 4, high dose cytarabine IV over 3 hours and pegaspargase or calaspargase pegol IV over 1-2 hours on day 5, and filgrastim SC or IV on days 7-11 in the absence of disease progression or unexpected toxicity.
CONSOLIDATION BLOCK 2: Patients receive imatinib mesylate PO QD or BID on days 1-21, methotrexate IT, cytarabine IT, and therapeutic hydrocortisone IT on day 1, high dose methotrexate IV over 24 hours on day 1, dexamethasone PO BID or IV on days 1-5, vincristine sulfate IV over 1 minute on days 1 and 6, ifosfamide IV over 1 hour on days 2-4, leucovorin calcium or levoleucovorin PO or IV on days 3 and 4, dexrazoxane hydrochloride IV over 15 minutes and daunorubicin hydrochloride IV over 1-15 minutes on day 5, pegaspargase or calaspargase pegol IV over 1-2 hours on day 6, and filgrastim SC or IV on days 7-11 in the absence of disease progression or unexpected toxicity.
CONSOLIDATION BLOCK 3: Patients receive imatinib mesylate PO QD or BID on days 1-21, high dose cytarabine IV over 3 hours on days 1-3, dexamethasone PO BID or IV on days 1-5, etoposide IV over 1-2 hours on days 3-5, methotrexate IT, cytarabine IT, and therapeutic hydrocortisone IT on day 5, pegaspargase or calaspargase pegol IV over 1-2 hours on day 6, and filgrastim SC or IV on days 7-11 in the absence of disease progression or unexpected toxicity.
DELAYED INTENSIFICATION 1 PART 1: Patients receive imatinib mesylate PO QD or BID on days 1-35, methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine sulfate IV over 1 minute, dexrazoxane hydrochloride IV over 15 minutes, and doxorubicin IV over 3-15 minutes on days 8, 15, 22, and 29, and pegaspargase or calaspargase pegol IV over 1-2 hours on day 8 in the absence of disease progression or unexpected toxicity.
DELAYED INTENSIFICATION 1 PART 2: Patients receive imatinib mesylate PO QD on days 36-63, cyclophosphamide IV over 30-60 minutes on day 36, thioguanine PO on days 36-49, cytarabine IV over 1-30 minutes or SC on days 38-41 and 45-48, and methotrexate IT on days 38 and 45in the absence of disease progression or unexpected toxicity.
INTERIM MAINTENANCE: Patients receive imatinib mesylate PO QD or BID on days 1-28, methotrexate PO on days 1, 8, 15, and 22, and mercaptopurine PO on days 1-28 in the absence of disease progression or unexpected toxicity.
DELAYED INTENSIFICATION 2 PART 1: Patients receive imatinib mesylate PO QD or BID on days 1-35, methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine sulfate IV over 1 minute, dexrazoxane hydrochloride IV over 15 minutes, and doxorubicin IV over 3-15 minutes on days 8, 15, 22, and 29, and pegaspargase or calaspargase pegol IV over 1-2 hours on day 8 in the absence of disease progression or unexpected toxicity.
DELAYED INTENSIFICATION 2 PART 2: Patients receive imatinib mesylate PO QD on days 36-49, cyclophosphamide IV over 30-60 minutes on day 36, thioguanine PO on days 36-49, cytarabine IV over 1-30 minutes or SC on days 36-39 and 43-46, and methotrexate IT on days 36 and 43 in the absence of disease progression or unexpected toxicity.
MAINTENANCE: Patients receive imatinib mesylate PO QD or BID on days 1-84, methotrexate PO once weekly (QW) and IT on days 1 and 43 of cycles 1, 2, and 3, and mercaptopurine PO on days 1-84. Cycles with imatinib mesylate and mercaptopurine repeat every 84 days for up to 104 weeks from the start of Induction IA in the absence of disease progression or unexpected toxicity.
ARM B:
INTERIM MAINTENANCE: Patients receive imatinib mesylate PO QD or BID on days 1-63, vincristine sulfate IV over 1 minute and high dose methotrexate IV over 24 hours on days 1, 15, 29, and 43, leucovorin calcium or levoleucovorin PO or IV on days 3-4, 17-18, 31-32, and 45-46, mercaptopurine PO on days 1-56, and methotrexate IT on days 1 and 29 in the absence of disease progression or unexpected toxicity.
DELAYED INTENSIFICATION PART 1: Patients receive imatinib mesylate PO QD or BID on days 1-28, methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine sulfate IV over 1 minute, dexrazoxane hydrochloride IV over 15 minutes, and doxorubicin IV over 3-15 minutes on days 1, 8, and 15, and pegaspargase or calaspargase pegol IV over 1-2 hours or IM on day 4 in the absence of disease progression or unexpected toxicity.
DELAYED INTENSIFICATION PART 2: Patients receive imatinib mesylate PO QD on days 29-56, cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO on days 29-42, cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39, methotrexate IT on days 29 and 36, vincristine sulfate IV over 1 minute on days 43 and 50, and pegaspargase or calaspargase pegol IV over 1-2 hours on day 43 in the absence of disease progression or unexpected toxicity.
INTERIM MAINTENANCE WITH CAPIZZI METHOTREXATE: Patients receive imatinib mesylate PO QD or BID on days 1-56, vincristine sulfate IV over 1 minute and methotrexate IV over 2-15 minutes on days 1, 11, 21, 31, and 41, methotrexate IT on days 1 and 31, and pegaspargase or calaspargase pegol IV over 1-2 hours on days 2 and 23 in the absence of disease progression or unexpected toxicity.
MAINTENANCE: Patients receive imatinib mesylate PO QD or BID on days 1-84, vincristine sulfate IV over 1 minute on days 1, 29, and 57, prednisolone PO BID (or methylprednisolone IV for cycle 1 and 2) on days 1-5, 29-33, and 57-61, mercaptopurine PO on days 1-84, methotrexate PO QW, and methotrexate IT on day 1 (and day 29 for cycle 1 and 2). Cycles repeat every 84 days for up to 104 weeks from the start of Induction IA in the absence of disease progression or unexpected toxicity.
ARM C:
CONSOLIDATION BLOCK 1: Patients receive imatinib mesylate, methotrexate, cytarabine, therapeutic hydrocortisone, high dose methotrexate, vincristine sulfate, dexamethasone, leucovorin calcium or levoleucovorin, high dose cytarabine, and pegaspargase or calaspargase pegol as in Arm A Consolidation Block 1, and filgrastim SC or IV on day 7 in the absence of disease progression or unexpected toxicity.
CONSOLIDATION BLOCK 2: Patients receive imatinib mesylate, methotrexate, cytarabine, therapeutic hydrocortisone, high dose methotrexate, dexamethasone, vincristine sulfate, ifosfamide, leucovorin calcium or levoleucovorin, dexrazoxane hydrochloride, daunorubicin hydrochloride, pegaspargase or calaspargase pegol, and filgrastim as Arm A Consolidation Block 2 in the absence of disease progression or unexpected toxicity.
CONSOLIDATION BLOCK 3: Patients receive imatinib mesylate, dexamethasone, etoposide, methotrexate, cytarabine, therapeutic hydrocortisone, pegaspargase or calaspargase pegol, and filgrastim as in Arm A Consolidation Block 3, and high dose cytarabine IV over 3 hours on days 1-2 in the absence of disease progression or unexpected toxicity.
HSCT: Patients undergo HSCT on day 0. Patients who do not proceed to HSCT receive Delayed Intensification 1, Interim Maintenance, Delayed Intensification 2, and Maintenance as in Arm A.
POST-HSCT: Patients receive imatinib mesylate PO QD or BID starting on days 56-365 in the in the absence of disease progression or unexpected toxicity.
After completion of study treatment, patients are followed up every year for 3 years.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 475
-
For patients enrolled on APEC14B1 prior to enrollment on AALL1631, the required diagnostic bone marrow sample has been fulfilled
- For patients who have not previously enrolled on APEC14B1 prior to enrollment on AALL1631, a baseline diagnostic sample (or peripheral blood sample with blasts if marrow sample unavailable) must be available to develop an MRD probe
- In addition, laboratory reports detailing evidence of BCR::ABL1 fusion or ABL-class fusion must be submitted for rapid central review within 72 hours of study enrollment
-
>= 1 year (365 days) and =< 21 years at ALL diagnosis
-
Ph+ (BCR::ABL1 fusion): newly diagnosed de novo ALL (B-ALL or T-ALL) or mixed phenotypic acute leukemia (MPAL meeting 2016 World Health Organization [WHO] definition) with definitive evidence of BCR::ABL1 fusion by karyotype, fluorescence in situ hybridization (FISH) and/or molecular methodologies
-
ABL-class fusion: newly diagnosed B-ALL with definitive evidence of ABL-class fusions. ABL-class fusions are defined as those involving the following genes: ABL1, ABL2, CSF1R, PDGFRB, PDGFRA. Methods of detection include fluorescence in-situ hybridization ([FISH], e.g. using break-apart or colocalization signals probes), multiplex or singleplex reverse-transcription polymerase chain reaction (RT-PCR), whole transcriptome or panel-based RNA-sequencing (e.g. TruSight RNA Pan-Cancer Panel; Illumina, San Diego, California [CA], United States of America [USA] or similar)
-
Ph+ patients must have previously started Induction therapy, which includes vincristine, a corticosteroid, pegaspargase, with or without anthracycline, and/or other standard cytotoxic chemotherapy
-
Ph+ patients have not received more than 14 days of multiagent Induction therapy beginning with the first dose of vinCRIStine
-
Ph+ patients may have started imatinib prior to study entry but have not received more than 14 days of imatinib
-
ABL-class fusion patients must have previously completed the 4 or 5 weeks of multiagent Induction chemotherapy (Induction IA phase)
-
ABL-class fusion patients may have started imatinib during Induction IA, at the same time of or after the first vinCRIStine dose
-
Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1, or 2
-
Direct bilirubin =< 2.0 mg/dL
-
Shortening fraction of >= 27% by echocardiogram
-
Ejection fraction of >= 50% by radionuclide angiogram or echocardiogram
-
Corrected QT interval, QTc < 480 msec
- Note: Repeat echocardiogram and electrocardiogram are not required if they were performed at or after initial ALL diagnosis, before study enrollment
-
Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or serum creatinine within normal limits based on age/gender, as follows:
- 1 to < 2 years: maximum serum creatinine 0.6 mg/dL (both male and female)
- 2 to < 6 years: maximum serum creatinine 0.8 mg/dL (both male and female)
- 6 to < 10 years: maximum serum creatinine 1 mg/dL (both male and female)
- 10 to < 13 years: maximum serum creatinine 1.2 mg/dL (both male and female)
- 13 to < 16 years: maximum serum creatinine 1.5 mg/dL (male), 1.4 mg/dL (female)
- >= 16 years: maximum serum creatinine 1.7 mg/dL (male), 1.4 mg/dL (female)
-
Known history of chronic myelogenous leukemia (CML)
-
ALL developing after a previous cancer treated with cytotoxic chemotherapy
-
Active, uncontrolled infection, or active systemic illness that requires ongoing vasopressor support or mechanical ventilation
-
Down syndrome
-
Pregnancy and breast feeding
- Female 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
- Lactating females who plan to breastfeed their infants
- Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of treatment according to protocol
-
Patients with congenital long QT syndrome, history of ventricular arrhythmias or heart block
-
Prior treatment with dasatinib, or any TKI other than imatinib
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm A (imatinib mesylate, EsPhALL chemotherapy) Calaspargase Pegol See Detailed Description Arm A (imatinib mesylate, EsPhALL chemotherapy) Cyclophosphamide See Detailed Description Arm A (imatinib mesylate, EsPhALL chemotherapy) Cytarabine See Detailed Description Arm A (imatinib mesylate, EsPhALL chemotherapy) Daunorubicin Hydrochloride See Detailed Description Arm A (imatinib mesylate, EsPhALL chemotherapy) Dexamethasone See Detailed Description Arm A (imatinib mesylate, EsPhALL chemotherapy) Dexrazoxane Hydrochloride See Detailed Description Arm A (imatinib mesylate, EsPhALL chemotherapy) Doxorubicin See Detailed Description Arm A (imatinib mesylate, EsPhALL chemotherapy) Etoposide See Detailed Description Arm A (imatinib mesylate, EsPhALL chemotherapy) Filgrastim See Detailed Description Arm A (imatinib mesylate, EsPhALL chemotherapy) Ifosfamide See Detailed Description Arm A (imatinib mesylate, EsPhALL chemotherapy) Imatinib Mesylate See Detailed Description Arm A (imatinib mesylate, EsPhALL chemotherapy) Laboratory Biomarker Analysis See Detailed Description Arm A (imatinib mesylate, EsPhALL chemotherapy) Leucovorin Calcium See Detailed Description Arm A (imatinib mesylate, EsPhALL chemotherapy) Levoleucovorin See Detailed Description Arm A (imatinib mesylate, EsPhALL chemotherapy) Mercaptopurine See Detailed Description Arm A (imatinib mesylate, EsPhALL chemotherapy) Methotrexate See Detailed Description Arm A (imatinib mesylate, EsPhALL chemotherapy) Methylprednisolone See Detailed Description Arm A (imatinib mesylate, EsPhALL chemotherapy) Pegaspargase See Detailed Description Arm A (imatinib mesylate, EsPhALL chemotherapy) Prednisolone See Detailed Description Arm A (imatinib mesylate, EsPhALL chemotherapy) Questionnaire Administration See Detailed Description Arm A (imatinib mesylate, EsPhALL chemotherapy) Therapeutic Hydrocortisone See Detailed Description Arm A (imatinib mesylate, EsPhALL chemotherapy) Thioguanine See Detailed Description Arm A (imatinib mesylate, EsPhALL chemotherapy) Vincristine Sulfate See Detailed Description Arm B (imatinib mesylate, COG/BFM chemotherapy) Calaspargase Pegol See Detailed Description. Arm B (imatinib mesylate, COG/BFM chemotherapy) Cyclophosphamide See Detailed Description. Arm B (imatinib mesylate, COG/BFM chemotherapy) Cytarabine See Detailed Description. Arm B (imatinib mesylate, COG/BFM chemotherapy) Dexamethasone See Detailed Description. Arm B (imatinib mesylate, COG/BFM chemotherapy) Dexrazoxane Hydrochloride See Detailed Description. Arm B (imatinib mesylate, COG/BFM chemotherapy) Doxorubicin See Detailed Description. Arm B (imatinib mesylate, COG/BFM chemotherapy) Imatinib Mesylate See Detailed Description. Arm B (imatinib mesylate, COG/BFM chemotherapy) Laboratory Biomarker Analysis See Detailed Description. Arm B (imatinib mesylate, COG/BFM chemotherapy) Leucovorin Calcium See Detailed Description. Arm B (imatinib mesylate, COG/BFM chemotherapy) Levoleucovorin See Detailed Description. Arm B (imatinib mesylate, COG/BFM chemotherapy) Mercaptopurine See Detailed Description. Arm B (imatinib mesylate, COG/BFM chemotherapy) Methotrexate See Detailed Description. Arm B (imatinib mesylate, COG/BFM chemotherapy) Methylprednisolone See Detailed Description. Arm B (imatinib mesylate, COG/BFM chemotherapy) Pegaspargase See Detailed Description. Arm B (imatinib mesylate, COG/BFM chemotherapy) Prednisolone See Detailed Description. Arm B (imatinib mesylate, COG/BFM chemotherapy) Questionnaire Administration See Detailed Description. Arm B (imatinib mesylate, COG/BFM chemotherapy) Thioguanine See Detailed Description. Arm B (imatinib mesylate, COG/BFM chemotherapy) Vincristine Sulfate See Detailed Description. Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT) Allogeneic Hematopoietic Stem Cell Transplantation See Detailed Description Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT) Calaspargase Pegol See Detailed Description Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT) Cyclophosphamide See Detailed Description Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT) Cytarabine See Detailed Description Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT) Daunorubicin Hydrochloride See Detailed Description Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT) Dexamethasone See Detailed Description Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT) Dexrazoxane Hydrochloride See Detailed Description Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT) Doxorubicin See Detailed Description Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT) Etoposide See Detailed Description Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT) Filgrastim See Detailed Description Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT) Ifosfamide See Detailed Description Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT) Imatinib Mesylate See Detailed Description Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT) Laboratory Biomarker Analysis See Detailed Description Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT) Leucovorin Calcium See Detailed Description Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT) Levoleucovorin See Detailed Description Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT) Mercaptopurine See Detailed Description Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT) Methotrexate See Detailed Description Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT) Methylprednisolone See Detailed Description Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT) Pegaspargase See Detailed Description Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT) Prednisolone See Detailed Description Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT) Questionnaire Administration See Detailed Description Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT) Therapeutic Hydrocortisone See Detailed Description Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT) Thioguanine See Detailed Description Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT) Vincristine Sulfate See Detailed Description
- Primary Outcome Measures
Name Time Method Disease free survival (DFS) of Randomized Arms (standard risk [SR] Philadelphia chromosome [Ph+] acute lymphoblastic leukemia [ALL] patients) Up to 3 years Three-year DFS and 95% confidence intervals (CI) of SR Ph+ ALL patients treated continuous imatinib mesylate with high risk Children's Oncology Group (COG)-ALL chemotherapy backbone or more intensive European (Es)PhALL chemotherapy backbone.
- Secondary Outcome Measures
Name Time Method DFS on Randomized Arms (SR Ph+ ALL and ABL-class fusion positive patients) Up to 3 years Three-year DFS (time from randomization to relapse, second malignancy, or death in complete remission) and 95% CI of SR pediatric Ph+ and ABL-class fusion positive patients treated with continuous imatinib combined with either a high-risk COG-ALL chemotherapy backbone or the more intensive EsPhALL chemotherapy backbone.
Feasibility of post hematopoietic stem cell transplantation (HSCT) imatinib mesylate administration after allogenic HSCT in high risk Ph+ ALL patients Up to 2 years The proportion of patients who receive at least 75% of intended doses.
Event free survival (EFS) of high risk pediatric Ph+ ALL patients treated with EsPhALL chemotherapy, HSCT in first complete remission, and post-HSCT imatinib mesylate Up to 3 years Three-year EFS and 95% CI for high risk pediatric Ph+ ALL patients treated with EsPhALL chemotherapy, HSCT in first complete remission, and post-HSCT imatinib mesylate. EFS is defined as the time from the date of bone marrow for minimal residual disease (MRD) assessment at end-IB to first event (resistant disease \[MRD \>= 10-2 or morphologic residual disease at end of consolidation block 3\], relapse, progressive disease \[i.e., MRD \>= 10-2 at two post-HSCT time points separated by at least 2 weeks\], second malignancy, or death in complete remission), or time to last follow-up for patients without events.
Incidence of grade 3 or higher infections in standard risk Ph+ ALL patients in the two randomized arms Up to 3 years Evaluated according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The rate of infections during the post IB/pre-maintenance phases of treatment will be described for each randomization group.
EFS of all Ph+ patients Up to 3 years Three-year EFS and 95% CI for Ph+ ALL patients. EFS here is defined as the time from enrollment until resistant disease, relapse, progressive disease post-HSCT, second malignant, or death, whichever occurs first.
Overall survival (OS) of all Ph+ patients Up to 3 years Three-year OS and 95% CI for Ph+ ALL patients. OS is defined as the time from study enrollment to death from any cause.
OS of SR Ph+ patients Up to 3 years Three-year OS (time from randomization to death from any cause) and 95% CI of SR pediatric Ph+ patients
OS of SR Ph+ patients by randomization group Up to 3 years Three-year OS (time from randomization to death from any cause) and 95% CI of SR pediatric Ph+ patients by randomization group: treated with continuous imatinib combined with either a high-risk COG-ALL chemotherapy backbone or the more intensive EsPhALL chemotherapy backbone.
OS of high risk Ph+ patients Up to 3 years Three-year OS (time from the date of MRD assessment at end-IB to death from any cause) and 95% CI of HR pediatric Ph+ patients.
EFS of all eligibility ABL-class fusion positive ALL patients Up to 3 years Three-year EFS (time from enrollment until resistant disease, relapse, progressive disease post-HSCT, second malignancy, or death, whichever occurs first) and 95% CI of ABL-class fusion positive patients.
OS of all eligibility ABL-class fusion positive ALL patients Up to 3 years Three-year OS (the time from study enrollment to death from any cause) and 95% CI of ABL-class fusion positive patients.
Trial Locations
- Locations (227)
Children's Hospital of Alabama
🇺🇸Birmingham, Alabama, United States
USA Health Strada Patient Care Center
🇺🇸Mobile, Alabama, United States
Providence Alaska Medical Center
🇺🇸Anchorage, Alaska, United States
Banner Children's at Desert
🇺🇸Mesa, Arizona, United States
Phoenix Childrens Hospital
🇺🇸Phoenix, Arizona, United States
Banner University Medical Center - Tucson
🇺🇸Tucson, Arizona, United States
Arkansas Children's Hospital
🇺🇸Little Rock, Arkansas, United States
Kaiser Permanente Downey Medical Center
🇺🇸Downey, California, United States
City of Hope Comprehensive Cancer Center
🇺🇸Duarte, California, United States
Loma Linda University Medical Center
🇺🇸Loma Linda, California, United States
Miller Children's and Women's Hospital Long Beach
🇺🇸Long Beach, California, United States
Children's Hospital Los Angeles
🇺🇸Los Angeles, California, United States
Cedars Sinai Medical Center
🇺🇸Los Angeles, California, United States
Valley Children's Hospital
🇺🇸Madera, California, United States
UCSF Benioff Children's Hospital Oakland
🇺🇸Oakland, California, United States
Kaiser Permanente-Oakland
🇺🇸Oakland, California, United States
Children's Hospital of Orange County
🇺🇸Orange, California, United States
Lucile Packard Children's Hospital Stanford University
🇺🇸Palo Alto, California, United States
University of California Davis Comprehensive Cancer Center
🇺🇸Sacramento, California, United States
Rady Children's Hospital - San Diego
🇺🇸San Diego, California, United States
UCSF Medical Center-Mission Bay
🇺🇸San Francisco, California, United States
Children's Hospital Colorado
🇺🇸Aurora, Colorado, United States
Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center
🇺🇸Denver, Colorado, United States
Connecticut Children's Medical Center
🇺🇸Hartford, Connecticut, United States
Yale University
🇺🇸New Haven, Connecticut, United States
Alfred I duPont Hospital for Children
🇺🇸Wilmington, Delaware, United States
MedStar Georgetown University Hospital
🇺🇸Washington, District of Columbia, United States
Children's National Medical Center
🇺🇸Washington, District of Columbia, United States
Broward Health Medical Center
🇺🇸Fort Lauderdale, Florida, United States
Golisano Children's Hospital of Southwest Florida
🇺🇸Fort Myers, Florida, United States
University of Florida Health Science Center - Gainesville
🇺🇸Gainesville, Florida, United States
Memorial Regional Hospital/Joe DiMaggio Children's Hospital
🇺🇸Hollywood, Florida, United States
Nemours Children's Clinic-Jacksonville
🇺🇸Jacksonville, Florida, United States
Palms West Radiation Therapy
🇺🇸Loxahatchee Groves, Florida, United States
University of Miami Miller School of Medicine-Sylvester Cancer Center
🇺🇸Miami, Florida, United States
Nicklaus Children's Hospital
🇺🇸Miami, Florida, United States
Miami Cancer Institute
🇺🇸Miami, Florida, United States
AdventHealth Orlando
🇺🇸Orlando, Florida, United States
Arnold Palmer Hospital for Children
🇺🇸Orlando, Florida, United States
Nemours Children's Hospital
🇺🇸Orlando, Florida, United States
Sacred Heart Hospital
🇺🇸Pensacola, Florida, United States
Johns Hopkins All Children's Hospital
🇺🇸Saint Petersburg, Florida, United States
Tampa General Hospital
🇺🇸Tampa, Florida, United States
Saint Joseph's Hospital/Children's Hospital-Tampa
🇺🇸Tampa, Florida, United States
Saint Mary's Medical Center
🇺🇸West Palm Beach, Florida, United States
Children's Healthcare of Atlanta - Arthur M Blank Hospital
🇺🇸Atlanta, Georgia, United States
Augusta University Medical Center
🇺🇸Augusta, Georgia, United States
Atrium Health Navicent
🇺🇸Macon, Georgia, United States
Memorial Health University Medical Center
🇺🇸Savannah, Georgia, United States
Kapiolani Medical Center for Women and Children
🇺🇸Honolulu, Hawaii, United States
Saint Luke's Cancer Institute - Boise
🇺🇸Boise, Idaho, United States
Lurie Children's Hospital-Chicago
🇺🇸Chicago, Illinois, United States
University of Illinois
🇺🇸Chicago, Illinois, United States
University of Chicago Comprehensive Cancer Center
🇺🇸Chicago, Illinois, United States
Advocate Children's Hospital-Oak Lawn
🇺🇸Oak Lawn, Illinois, United States
Advocate Children's Hospital-Park Ridge
🇺🇸Park Ridge, Illinois, United States
Saint Jude Midwest Affiliate
🇺🇸Peoria, Illinois, United States
Southern Illinois University School of Medicine
🇺🇸Springfield, Illinois, United States
Riley Hospital for Children
🇺🇸Indianapolis, Indiana, United States
Ascension Saint Vincent Indianapolis Hospital
🇺🇸Indianapolis, Indiana, United States
Blank Children's Hospital
🇺🇸Des Moines, Iowa, United States
University of Iowa/Holden Comprehensive Cancer Center
🇺🇸Iowa City, Iowa, United States
University of Kentucky/Markey Cancer Center
🇺🇸Lexington, Kentucky, United States
Norton Children's Hospital
🇺🇸Louisville, Kentucky, United States
Ochsner Medical Center Jefferson
🇺🇸New Orleans, Louisiana, United States
Eastern Maine Medical Center
🇺🇸Bangor, Maine, United States
Maine Children's Cancer Program
🇺🇸Scarborough, Maine, United States
Sinai Hospital of Baltimore
🇺🇸Baltimore, Maryland, United States
Johns Hopkins University/Sidney Kimmel Cancer Center
🇺🇸Baltimore, Maryland, United States
Walter Reed National Military Medical Center
🇺🇸Bethesda, Maryland, United States
Tufts Children's Hospital
🇺🇸Boston, Massachusetts, United States
Massachusetts General Hospital Cancer Center
🇺🇸Boston, Massachusetts, United States
Dana-Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
UMass Memorial Medical Center - University Campus
🇺🇸Worcester, Massachusetts, United States
C S Mott Children's Hospital
🇺🇸Ann Arbor, Michigan, United States
Children's Hospital of Michigan
🇺🇸Detroit, Michigan, United States
Henry Ford Health Saint John Hospital
🇺🇸Detroit, Michigan, United States
Michigan State University Clinical Center
🇺🇸East Lansing, Michigan, United States
Corewell Health Grand Rapids Hospitals - Helen DeVos Children's Hospital
🇺🇸Grand Rapids, Michigan, United States
Bronson Methodist Hospital
🇺🇸Kalamazoo, Michigan, United States
Corewell Health Children's
🇺🇸Royal Oak, Michigan, United States
Children's Hospitals and Clinics of Minnesota - Minneapolis
🇺🇸Minneapolis, Minnesota, United States
University of Minnesota/Masonic Cancer Center
🇺🇸Minneapolis, Minnesota, United States
University of Mississippi Medical Center
🇺🇸Jackson, Mississippi, United States
University of Missouri Children's Hospital
🇺🇸Columbia, Missouri, United States
Children's Mercy Hospitals and Clinics
🇺🇸Kansas City, Missouri, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
Mercy Hospital Saint Louis
🇺🇸Saint Louis, Missouri, United States
Children's Hospital and Medical Center of Omaha
🇺🇸Omaha, Nebraska, United States
University of Nebraska Medical Center
🇺🇸Omaha, Nebraska, United States
University Medical Center of Southern Nevada
🇺🇸Las Vegas, Nevada, United States
Sunrise Hospital and Medical Center
🇺🇸Las Vegas, Nevada, United States
Alliance for Childhood Diseases/Cure 4 the Kids Foundation
🇺🇸Las Vegas, Nevada, United States
Summerlin Hospital Medical Center
🇺🇸Las Vegas, Nevada, United States
Renown Regional Medical Center
🇺🇸Reno, Nevada, United States
Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center
🇺🇸Lebanon, New Hampshire, United States
Hackensack University Medical Center
🇺🇸Hackensack, New Jersey, United States
Morristown Medical Center
🇺🇸Morristown, New Jersey, United States
Jersey Shore Medical Center
🇺🇸Neptune, New Jersey, United States
Saint Peter's University Hospital
🇺🇸New Brunswick, New Jersey, United States
Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital
🇺🇸New Brunswick, New Jersey, United States
Newark Beth Israel Medical Center
🇺🇸Newark, New Jersey, United States
Saint Joseph's Regional Medical Center
🇺🇸Paterson, New Jersey, United States
Presbyterian Hospital
🇺🇸Albuquerque, New Mexico, United States
University of New Mexico Cancer Center
🇺🇸Albuquerque, New Mexico, United States
Albany Medical Center
🇺🇸Albany, New York, United States
Montefiore Medical Center - Moses Campus
🇺🇸Bronx, New York, United States
Maimonides Medical Center
🇺🇸Brooklyn, New York, United States
Roswell Park Cancer Institute
🇺🇸Buffalo, New York, United States
NYU Langone Hospital - Long Island
🇺🇸Mineola, New York, United States
The Steven and Alexandra Cohen Children's Medical Center of New York
🇺🇸New Hyde Park, New York, United States
Laura and Isaac Perlmutter Cancer Center at NYU Langone
🇺🇸New York, New York, United States
Mount Sinai Hospital
🇺🇸New York, New York, United States
NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
🇺🇸New York, New York, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
University of Rochester
🇺🇸Rochester, New York, United States
Stony Brook University Medical Center
🇺🇸Stony Brook, New York, United States
State University of New York Upstate Medical University
🇺🇸Syracuse, New York, United States
New York Medical College
🇺🇸Valhalla, New York, United States
Mission Hospital
🇺🇸Asheville, North Carolina, United States
UNC Lineberger Comprehensive Cancer Center
🇺🇸Chapel Hill, North Carolina, United States
Carolinas Medical Center/Levine Cancer Institute
🇺🇸Charlotte, North Carolina, United States
Novant Health Presbyterian Medical Center
🇺🇸Charlotte, North Carolina, United States
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
East Carolina University
🇺🇸Greenville, North Carolina, United States
Wake Forest University Health Sciences
🇺🇸Winston-Salem, North Carolina, United States
Sanford Broadway Medical Center
🇺🇸Fargo, North Dakota, United States
Children's Hospital Medical Center of Akron
🇺🇸Akron, Ohio, United States
Cincinnati Children's Hospital Medical Center
🇺🇸Cincinnati, Ohio, United States
Rainbow Babies and Childrens Hospital
🇺🇸Cleveland, Ohio, United States
Cleveland Clinic Foundation
🇺🇸Cleveland, Ohio, United States
Nationwide Children's Hospital
🇺🇸Columbus, Ohio, United States
Dayton Children's Hospital
🇺🇸Dayton, Ohio, United States
ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital
🇺🇸Toledo, Ohio, United States
University of Oklahoma Health Sciences Center
🇺🇸Oklahoma City, Oklahoma, United States
Legacy Emanuel Children's Hospital
🇺🇸Portland, Oregon, United States
Oregon Health and Science University
🇺🇸Portland, Oregon, United States
Lehigh Valley Hospital-Cedar Crest
🇺🇸Allentown, Pennsylvania, United States
Geisinger Medical Center
🇺🇸Danville, Pennsylvania, United States
Penn State Children's Hospital
🇺🇸Hershey, Pennsylvania, United States
Children's Hospital of Philadelphia
🇺🇸Philadelphia, Pennsylvania, United States
Saint Christopher's Hospital for Children
🇺🇸Philadelphia, Pennsylvania, United States
Children's Hospital of Pittsburgh of UPMC
🇺🇸Pittsburgh, Pennsylvania, United States
Rhode Island Hospital
🇺🇸Providence, Rhode Island, United States
Medical University of South Carolina
🇺🇸Charleston, South Carolina, United States
Prisma Health Richland Hospital
🇺🇸Columbia, South Carolina, United States
BI-LO Charities Children's Cancer Center
🇺🇸Greenville, South Carolina, United States
Sanford USD Medical Center - Sioux Falls
🇺🇸Sioux Falls, South Dakota, United States
T C Thompson Children's Hospital
🇺🇸Chattanooga, Tennessee, United States
East Tennessee Childrens Hospital
🇺🇸Knoxville, Tennessee, United States
The Children's Hospital at TriStar Centennial
🇺🇸Nashville, Tennessee, United States
Vanderbilt University/Ingram Cancer Center
🇺🇸Nashville, Tennessee, United States
Texas Tech University Health Sciences Center-Amarillo
🇺🇸Amarillo, Texas, United States
Dell Children's Medical Center of Central Texas
🇺🇸Austin, Texas, United States
Driscoll Children's Hospital
🇺🇸Corpus Christi, Texas, United States
Medical City Dallas Hospital
🇺🇸Dallas, Texas, United States
UT Southwestern/Simmons Cancer Center-Dallas
🇺🇸Dallas, Texas, United States
El Paso Children's Hospital
🇺🇸El Paso, Texas, United States
Cook Children's Medical Center
🇺🇸Fort Worth, Texas, United States
Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
🇺🇸Houston, Texas, United States
M D Anderson Cancer Center
🇺🇸Houston, Texas, United States
Covenant Children's Hospital
🇺🇸Lubbock, Texas, United States
UMC Cancer Center / UMC Health System
🇺🇸Lubbock, Texas, United States
Children's Hospital of San Antonio
🇺🇸San Antonio, Texas, United States
Methodist Children's Hospital of South Texas
🇺🇸San Antonio, Texas, United States
University of Texas Health Science Center at San Antonio
🇺🇸San Antonio, Texas, United States
Scott and White Memorial Hospital
🇺🇸Temple, Texas, United States
Primary Children's Hospital
🇺🇸Salt Lake City, Utah, United States
University of Vermont and State Agricultural College
🇺🇸Burlington, Vermont, United States
University of Virginia Cancer Center
🇺🇸Charlottesville, Virginia, United States
Inova Fairfax Hospital
🇺🇸Falls Church, Virginia, United States
Children's Hospital of The King's Daughters
🇺🇸Norfolk, Virginia, United States
Naval Medical Center - Portsmouth
🇺🇸Portsmouth, Virginia, United States
Virginia Commonwealth University/Massey Cancer Center
🇺🇸Richmond, Virginia, United States
Carilion Children's
🇺🇸Roanoke, Virginia, United States
Seattle Children's Hospital
🇺🇸Seattle, Washington, United States
Providence Sacred Heart Medical Center and Children's Hospital
🇺🇸Spokane, Washington, United States
Mary Bridge Children's Hospital and Health Center
🇺🇸Tacoma, Washington, United States
Madigan Army Medical Center
🇺🇸Tacoma, Washington, United States
Edwards Comprehensive Cancer Center
🇺🇸Huntington, West Virginia, United States
West Virginia University Healthcare
🇺🇸Morgantown, West Virginia, United States
Saint Vincent Hospital Cancer Center Green Bay
🇺🇸Green Bay, Wisconsin, United States
University of Wisconsin Carbone Cancer Center - University Hospital
🇺🇸Madison, Wisconsin, United States
Marshfield Medical Center-Marshfield
🇺🇸Marshfield, Wisconsin, United States
Children's Hospital of Wisconsin
🇺🇸Milwaukee, Wisconsin, United States
John Hunter Children's Hospital
🇦🇺Hunter Regional Mail Centre, New South Wales, Australia
Sydney Children's Hospital
🇦🇺Randwick, New South Wales, Australia
The Children's Hospital at Westmead
🇦🇺Westmead, New South Wales, Australia
Queensland Children's Hospital
🇦🇺South Brisbane, Queensland, Australia
Princess Margaret Hospital for Children
🇦🇺Perth, Western Australia, Australia
Perth Children's Hospital
🇦🇺Perth, Western Australia, Australia
St. Anna Children's Hospital
🇦🇹Vienna, Austria
Hospitals Leuven
🇧🇪Leuven, Flemish Brabant, Belgium
Alberta Children's Hospital
🇨🇦Calgary, Alberta, Canada
University of Alberta Hospital
🇨🇦Edmonton, Alberta, Canada
British Columbia Children's Hospital
🇨🇦Vancouver, British Columbia, Canada
CancerCare Manitoba
🇨🇦Winnipeg, Manitoba, Canada
IWK Health Centre
🇨🇦Halifax, Nova Scotia, Canada
McMaster Children's Hospital at Hamilton Health Sciences
🇨🇦Hamilton, Ontario, Canada
Kingston Health Sciences Centre
🇨🇦Kingston, Ontario, Canada
Children's Hospital
🇨🇦London, Ontario, Canada
Children's Hospital of Eastern Ontario
🇨🇦Ottawa, Ontario, Canada
Hospital for Sick Children
🇨🇦Toronto, Ontario, Canada
The Montreal Children's Hospital of the MUHC
🇨🇦Montreal, Quebec, Canada
Centre Hospitalier Universitaire Sainte-Justine
🇨🇦Montreal, Quebec, Canada
Centre Hospitalier Universitaire de Sherbrooke-Fleurimont
🇨🇦Sherbrooke, Quebec, Canada
Jim Pattison Children's Hospital
🇨🇦Saskatoon, Saskatchewan, Canada
Saskatoon Cancer Centre
🇨🇦Saskatoon, Saskatchewan, Canada
CHU de Quebec-Centre Hospitalier de l'Universite Laval (CHUL)
🇨🇦Quebec, Canada
Hospital Roberto del Rio-Universidad de Chile
🇨🇱Santiago, Chile
University Hospital Motol
🇨🇿Praha, Czechia
Tampere University Hospital
🇫🇮Tampere, Finland
CHU Hopital Sud
🇫🇷Rennes, France
University Medical Center chleswig- Campus Kiel
🇩🇪Kiel, Schleswig-Holstein, Germany
Universitätsklinik Eppendorf
🇩🇪Hamburg, Germany
Hong Kong Children's Hospital
ðŸ‡ðŸ‡°Kowloon Bay, Kowloon, Hong Kong
Schneider Children's Medical Center of Israel
🇮🇱Petah-Tikva, Central District, Israel
Clinica Pediatrica Università Milano-Bicocca Ospedale S. Gerardo/Fondazione MBBM
🇮🇹Monza, Italy
Princess Máxima Center for Pediatric Oncology
🇳🇱Utrecht, Netherlands
Starship Children's Hospital
🇳🇿Grafton, Auckland, New Zealand
Christchurch Hospital
🇳🇿Christchurch, New Zealand
HIMA San Pablo Oncologic Hospital
🇵🇷Caguas, Puerto Rico
San Jorge Children's Hospital
🇵🇷San Juan, Puerto Rico
University Pediatric Hospital
🇵🇷San Juan, Puerto Rico
King Faisal Specialist Hospital and Research Centre
🇸🇦Riyadh, Saudi Arabia
Skane University Hospital
🇸🇪Lund, Scania, Sweden
University Children's Hospital
🇨ðŸ‡Zurich, Switzerland