Ponatinib Plus Reduced-intensity Chemotherapy in the First-line Treatment of Adult Patients With Ph+ ALL
NCT ID: NCT04554459
Last Updated: 2024-08-14
Study Results
Results pending
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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Recruitment Status
TERMINATED
Clinical Phase
PHASE2
Total Enrollment
4 participants
Study Classification
INTERVENTIONAL
Study Start Date
2021-02-16
Study Completion Date
2024-07-01
Brief Summary
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This is a phase II interventional trial to evaluate the efficacy of ponatinib plus reduced-intensity chemotherapy in the first-line treatment of adult patients with Ph+ acute lymphoblastic leukemia. This combination has the potential to improve the depth of molecular responses after the induction phase of treatment. Patients who achieve a complete molecular response (CMR) at week 11 will not be directed to alloSCT and will receive consolidation chemotherapy combined with ponatinib, followed by 24 months of ponatinib maintenance. The aim is to spare individuals with a low probability of relapse from overtreatment with more intensive and toxic transplant procedure.
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Detailed Description
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Primary Objective:
To evaluate the percentage of complete molecular responses (CMR) after two cycles of remission induction therapy composed of two cycles of chemotherapy plus ponatinib. CMR is defined as BCR-ABL1 below the Limit of Quantification by Droplet Digital Polymerase Chain Reaction (ddPCR).
Outline:
Pre-phase:
dexamethasone 10 mg/m2 PO (day -5 till -1), cyclophosphamide IV 200 mg/m2 (day -3 till -1), methotrexate 15 mg IT.
Induction I:
ponatinib 30 mg/day PO once daily (QD) continuously since day 1, rituximab 375 mg/m2 IV (day 1), dexamethasone 10 mg/m2 PO (day 1-2, 8-11), vincristine 2 mg IV (day 1, 8, 15), Granulocyte-Colony Stimulating Factor (G-CSF) until recovery.
Induction II:
ponatinib 30 mg/day PO QD continuously, rituximab 375 mg/m2 IV (day 23), cyclophosphamide 1000 mg/m2 IV (day 24), cytarabine 75 mg/m2 IV (day 26-29, 33-36), Granulocyte StimuG-CSF until recovery, methotrexate 15 mg IT (day 26, 33) methotrexate 15 mg + cytarabine 40 mg + dexamethasone 4 mg IT (day 40). Week 11: Primary endpoint assessment.
Consolidation I (week 12):
ponatinib 30 mg/day PO QD continuously, rituximab 375 mg/m2 IV (day 1), dexamethasone 10 mg/m2 PO (day 1-4), vindesine 3 mg/m2 IV (day 2), methotrexate 1.5 g/m2 IV (day 2), cytarabine 2x 2 g/m2 IV (day 5), G-CSF until recovery, methotrexate 15 mg + cytarabine 40 mg + dexamethasone 4 mg IT (day 8). Patients in complete molecular response at week 11 will be treated with 5 additional blocks of chemotherapy followed by maintenance therapy; patients with molecular failure at week 11 will end the study and be directed to alloSCT.
Consolidation II (week 18):
ponatinib 15 mg/day PO QD continuously, rituximab 375 mg/m2 IV (day 1), cyclophosphamide 500 mg/m2 IV (day 2,3), etoposide (VP-16) 75 mg/m2 IV (day 2,3), methotrexate 15 mg + cytarabine 40 mg + dexamethasone 4 mg IT (day 1).
Consolidation III+V (weeks 24 and 36):
ponatinib 15 mg/day PO QD continuously, rituximab 375 mg/m2 IV (day 1), methotrexate 1.5 g/m2 IV (day 2), vincristine 1 mg IV (day 2), 6-mercaptopurine 60 mg/m2 PO (day 2-8), methotrexate 15 mg + cytarabine 40 mg + dexamethasone 4 mg IT at day 1.
Consolidation IV+VI (weeks 30+40):
ponatinib 15 mg/day PO QD continuously, rituximab 375 mg/m2 IV (day 1), dexamethasone 10 mg/m2 PO (day 1-4), cytarabine 1.5 g/m2 IV (day 1+3+5), methotrexate 15 mg + cytarabine 40 mg + dexamethasone 4 mg IT (day 1). Maintenance: ponatinib 15 mg/day PO QD continuously 24 months. (Doses of IV methotrexate and cytarabine are reduced in patients \>55 years.)
To evaluate the percentage of complete molecular responses (CMR) after two cycles of remission induction therapy composed of two cycles of chemotherapy plus ponatinib. CMR is defined as BCR-ABL1 below the Limit of Quantification by Droplet Digital Polymerase Chain Reaction (ddPCR).
Outline:
Pre-phase:
dexamethasone 10 mg/m2 PO (day -5 till -1), cyclophosphamide IV 200 mg/m2 (day -3 till -1), methotrexate 15 mg IT.
Induction I:
ponatinib 30 mg/day PO once daily (QD) continuously since day 1, rituximab 375 mg/m2 IV (day 1), dexamethasone 10 mg/m2 PO (day 1-2, 8-11), vincristine 2 mg IV (day 1, 8, 15), Granulocyte-Colony Stimulating Factor (G-CSF) until recovery.
Induction II:
ponatinib 30 mg/day PO QD continuously, rituximab 375 mg/m2 IV (day 23), cyclophosphamide 1000 mg/m2 IV (day 24), cytarabine 75 mg/m2 IV (day 26-29, 33-36), Granulocyte StimuG-CSF until recovery, methotrexate 15 mg IT (day 26, 33) methotrexate 15 mg + cytarabine 40 mg + dexamethasone 4 mg IT (day 40). Week 11: Primary endpoint assessment.
Consolidation I (week 12):
ponatinib 30 mg/day PO QD continuously, rituximab 375 mg/m2 IV (day 1), dexamethasone 10 mg/m2 PO (day 1-4), vindesine 3 mg/m2 IV (day 2), methotrexate 1.5 g/m2 IV (day 2), cytarabine 2x 2 g/m2 IV (day 5), G-CSF until recovery, methotrexate 15 mg + cytarabine 40 mg + dexamethasone 4 mg IT (day 8). Patients in complete molecular response at week 11 will be treated with 5 additional blocks of chemotherapy followed by maintenance therapy; patients with molecular failure at week 11 will end the study and be directed to alloSCT.
Consolidation II (week 18):
ponatinib 15 mg/day PO QD continuously, rituximab 375 mg/m2 IV (day 1), cyclophosphamide 500 mg/m2 IV (day 2,3), etoposide (VP-16) 75 mg/m2 IV (day 2,3), methotrexate 15 mg + cytarabine 40 mg + dexamethasone 4 mg IT (day 1).
Consolidation III+V (weeks 24 and 36):
ponatinib 15 mg/day PO QD continuously, rituximab 375 mg/m2 IV (day 1), methotrexate 1.5 g/m2 IV (day 2), vincristine 1 mg IV (day 2), 6-mercaptopurine 60 mg/m2 PO (day 2-8), methotrexate 15 mg + cytarabine 40 mg + dexamethasone 4 mg IT at day 1.
Consolidation IV+VI (weeks 30+40):
ponatinib 15 mg/day PO QD continuously, rituximab 375 mg/m2 IV (day 1), dexamethasone 10 mg/m2 PO (day 1-4), cytarabine 1.5 g/m2 IV (day 1+3+5), methotrexate 15 mg + cytarabine 40 mg + dexamethasone 4 mg IT (day 1). Maintenance: ponatinib 15 mg/day PO QD continuously 24 months. (Doses of IV methotrexate and cytarabine are reduced in patients \>55 years.)
Conditions
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Acute Lymphoblastic Leukemia, Adult
Ph+ ALL
Newly Diagnosed
Study Design
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Allocation Method
NA
Intervention Model
SINGLE_GROUP
Primary Study Purpose
TREATMENT
Blinding Strategy
NONE
Study Groups
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ponatinib plus reduced-intensity chemotherapy
ponatinib plus reduced-intensity chemotherapy in first-line treatment of Adult Ph+ ALL
Group Type
EXPERIMENTAL
Ponatinib 15 MG Oral Tablet
Intervention Type
DRUG
ponatinib plus reduced-intensity chemotherapy in first-line treatment of Adult Ph+ ALL
Interventions
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Ponatinib 15 MG Oral Tablet
ponatinib plus reduced-intensity chemotherapy in first-line treatment of Adult Ph+ ALL
Intervention Type
DRUG
Other Intervention Names
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Iclusig
AP24534
L01XE24
Eligibility Criteria
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Inclusion Criteria
* Patients with newly diagnosed, previously untreated, Ph-positive \[either t(9;22) and/or BCR-ABL positive\] B-precursor acute lymphoblastic leukemia;
* Age more than 18 years;
* Eligible to intensive chemotherapy, due to general health status;
* ECOG (Eastern Cooperative Oncology Group) performance status ≤2;
* Absence of significant liver disease, as defined by the following criteria: total serum bilirubin ≤1.5 x upper limit of normal (ULN), unless due to Gilbert's syndrome, alanine aminotransferase (ALT) ≤2.5 × ULN or ≤5 x ULN if leukemic involvement of the liver is present, and aspartate aminotransferase (AST) ≤2.5 × ULN or ≤5 x ULN if leukemic involvement of the liver is present;
* Adequate pancreatic function as defined by serum amylase and lipase ≤1.5 × ULN;
* Diagnostic sample of bone marrow (or peripheral blood with \>50% of blasts) available for central MRD assessment;
* Subject has provided written informed consent prior to any screening procedure.
* Age more than 18 years;
* Eligible to intensive chemotherapy, due to general health status;
* ECOG (Eastern Cooperative Oncology Group) performance status ≤2;
* Absence of significant liver disease, as defined by the following criteria: total serum bilirubin ≤1.5 x upper limit of normal (ULN), unless due to Gilbert's syndrome, alanine aminotransferase (ALT) ≤2.5 × ULN or ≤5 x ULN if leukemic involvement of the liver is present, and aspartate aminotransferase (AST) ≤2.5 × ULN or ≤5 x ULN if leukemic involvement of the liver is present;
* Adequate pancreatic function as defined by serum amylase and lipase ≤1.5 × ULN;
* Diagnostic sample of bone marrow (or peripheral blood with \>50% of blasts) available for central MRD assessment;
* Subject has provided written informed consent prior to any screening procedure.
Exclusion Criteria
* Lymphoid blast crisis of chronic myelocytic leukemia (CML);
* Active serious infection not controlled by oral or intravenous antibiotics;
* Active known hepatitis B virus (HBV) or hepatitis C virus (HCV) or positive HIV serology;
* History of acute pancreatitis within 1 year of study or history of chronic pancreatitis;
* Uncontrolled hypertriglyceridemia (triglycerides \> 5.1 µmol/L);
* Clinically significant, uncontrolled or active cardiovascular disease, specifically including, but not restricted to: any history of myocardial infarction, stroke, or revascularization; unstable angina or transient ischemic attack within 6 months prior to enrolment; congestive heart failure within 6 months prior to enrolment or left ventricular ejection fraction (LVEF) less than lower limit of normal per local institutional standards; history of clinically significant (as determined by the treating physician) atrial arrhythmia; any history of ventricular arrhythmia; any history of venous thromboembolism including deep venous thrombosis or pulmonary embolism;
* Uncontrolled hypertension (diastolic blood pressure \>90 mmHg; systolic \>140 mmHg). Patients with hypertension should be under treatment on study entry to effect blood pressure control;
* Creatinine levels \> 160 µmol/L or estimated creatinine clearance of \< 50 mL/min;
* GI disease and/or major GI surgery that may significantly alter the absorption of study drug
* Hypersensitivity to the active substance or to any of the excipients, especially galactose intolerance.
* Taking any medications or herbal supplements that are known to be strong inhibitors of CYP3A4 within at least 14 days before the first dose of ponatinib;
* Female patients who are pregnant or breast feeding or patients of childbearing potential not willing to use a highly effective method of contraception during the study and for 3 months following the last dose of study drug;
* Male patients whose sexual partner(s) are women of childbearing potential who are not willing to use a highly effective method of contraception, one of which includes a condom, during the study;
* Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention;
* Any concurrent severe and/or uncontrolled medical condition, which could, in the opinion of the investigator, compromise participation in the study;
* Concurrent participation in another clinical study with an investigational medical product.
* Active serious infection not controlled by oral or intravenous antibiotics;
* Active known hepatitis B virus (HBV) or hepatitis C virus (HCV) or positive HIV serology;
* History of acute pancreatitis within 1 year of study or history of chronic pancreatitis;
* Uncontrolled hypertriglyceridemia (triglycerides \> 5.1 µmol/L);
* Clinically significant, uncontrolled or active cardiovascular disease, specifically including, but not restricted to: any history of myocardial infarction, stroke, or revascularization; unstable angina or transient ischemic attack within 6 months prior to enrolment; congestive heart failure within 6 months prior to enrolment or left ventricular ejection fraction (LVEF) less than lower limit of normal per local institutional standards; history of clinically significant (as determined by the treating physician) atrial arrhythmia; any history of ventricular arrhythmia; any history of venous thromboembolism including deep venous thrombosis or pulmonary embolism;
* Uncontrolled hypertension (diastolic blood pressure \>90 mmHg; systolic \>140 mmHg). Patients with hypertension should be under treatment on study entry to effect blood pressure control;
* Creatinine levels \> 160 µmol/L or estimated creatinine clearance of \< 50 mL/min;
* GI disease and/or major GI surgery that may significantly alter the absorption of study drug
* Hypersensitivity to the active substance or to any of the excipients, especially galactose intolerance.
* Taking any medications or herbal supplements that are known to be strong inhibitors of CYP3A4 within at least 14 days before the first dose of ponatinib;
* Female patients who are pregnant or breast feeding or patients of childbearing potential not willing to use a highly effective method of contraception during the study and for 3 months following the last dose of study drug;
* Male patients whose sexual partner(s) are women of childbearing potential who are not willing to use a highly effective method of contraception, one of which includes a condom, during the study;
* Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention;
* Any concurrent severe and/or uncontrolled medical condition, which could, in the opinion of the investigator, compromise participation in the study;
* Concurrent participation in another clinical study with an investigational medical product.
Minimum Eligible Age
18 Years
Maximum Eligible Age
99 Years
Eligible Sex
ALL
Accepts Healthy Volunteers
No
Sponsors
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CZECRIN - Czech Clinical Research Infrastructure Network
UNKNOWN
Sponsor Role
collaborator
Institute of Hematology and Blood Transfusion, Czech Republic
OTHER
Sponsor Role
lead
Responsible Party
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Responsibility Role
SPONSOR
Principal Investigators
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Cyril Salek, MD
Role: PRINCIPAL_INVESTIGATOR
Institute of Hematology and Blood Transfusion, Czech Republic
Locations
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University Hospital Brno, Internal hematology and oncology clinic
Brno, , Czechia
Site Status
University Hospital Hradec Kralove, The 4th Department of Internal Medicine - Hematology
Hradec Králové, , Czechia
Site Status
University Hospital Olomouc, Hematooncology Clinic
Olomouc, , Czechia
Site Status
University Hospital Ostrava, Hematooncology Clinic
Ostrava, , Czechia
Site Status
University Hospital Plzen, Hematology and Oncology Department
Plzeň-Lochotín, , Czechia
Site Status
University Hospital Kralovske Vinohrady, Internal Hematology Clinic
Prague, , Czechia
Site Status
Institute of Hematology and Blood Transfusion
Prague, , Czechia
Site Status
Countries
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Czechia
References
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Rousselot P, Coude MM, Gokbuget N, Gambacorti Passerini C, Hayette S, Cayuela JM, Huguet F, Leguay T, Chevallier P, Salanoubat C, Bonmati C, Alexis M, Hunault M, Glaisner S, Agape P, Berthou C, Jourdan E, Fernandes J, Sutton L, Banos A, Reman O, Lioure B, Thomas X, Ifrah N, Lafage-Pochitaloff M, Bornand A, Morisset L, Robin V, Pfeifer H, Delannoy A, Ribera J, Bassan R, Delord M, Hoelzer D, Dombret H, Ottmann OG; European Working Group on Adult ALL (EWALL) group. Dasatinib and low-intensity chemotherapy in elderly patients with Philadelphia chromosome-positive ALL. Blood. 2016 Aug 11;128(6):774-82. doi: 10.1182/blood-2016-02-700153. Epub 2016 Apr 27.
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Salek C, Folber F, Fronkova E, Prochazka B, Marinov I, Cetkovsky P, Mayer J, Doubek M; Czech Leukemia Study Group - for Life. Early MRD response as a prognostic factor in adult patients with acute lymphoblastic leukemia. Eur J Haematol. 2016 Mar;96(3):276-84. doi: 10.1111/ejh.12587. Epub 2015 Jun 22.
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Short NJ, Jabbour E, Sasaki K, Patel K, O'Brien SM, Cortes JE, Garris R, Issa GC, Garcia-Manero G, Luthra R, Thomas D, Kantarjian H, Ravandi F. Impact of complete molecular response on survival in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 2016 Jul 28;128(4):504-7. doi: 10.1182/blood-2016-03-707562. Epub 2016 May 27.
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Schultz KR, Bowman WP, Aledo A, Slayton WB, Sather H, Devidas M, Wang C, Davies SM, Gaynon PS, Trigg M, Rutledge R, Burden L, Jorstad D, Carroll A, Heerema NA, Winick N, Borowitz MJ, Hunger SP, Carroll WL, Camitta B. Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a children's oncology group study. J Clin Oncol. 2009 Nov 1;27(31):5175-81. doi: 10.1200/JCO.2008.21.2514. Epub 2009 Oct 5.
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Tanguy-Schmidt A, Rousselot P, Chalandon Y, Cayuela JM, Hayette S, Vekemans MC, Escoffre M, Huguet F, Rea D, Delannoy A, Cahn JY, Vernant JP, Ifrah N, Dombret H, Thomas X. Long-term follow-up of the imatinib GRAAPH-2003 study in newly diagnosed patients with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia: a GRAALL study. Biol Blood Marrow Transplant. 2013 Jan;19(1):150-5. doi: 10.1016/j.bbmt.2012.08.021. Epub 2012 Sep 6.
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Vignetti M, Fazi P, Cimino G, Martinelli G, Di Raimondo F, Ferrara F, Meloni G, Ambrosetti A, Quarta G, Pagano L, Rege-Cambrin G, Elia L, Bertieri R, Annino L, Foa R, Baccarani M, Mandelli F. Imatinib plus steroids induces complete remissions and prolonged survival in elderly Philadelphia chromosome-positive patients with acute lymphoblastic leukemia without additional chemotherapy: results of the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) LAL0201-B protocol. Blood. 2007 May 1;109(9):3676-8. doi: 10.1182/blood-2006-10-052746. Epub 2007 Jan 9.
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Wetzler M, Watson D, Stock W, Koval G, Mulkey FA, Hoke EE, McCarty JM, Blum WG, Powell BL, Marcucci G, Bloomfield CD, Linker CA, Larson RA. Autologous transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia achieves outcomes similar to allogeneic transplantation: results of CALGB Study 10001 (Alliance). Haematologica. 2014 Jan;99(1):111-5. doi: 10.3324/haematol.2013.085811. Epub 2013 Sep 27.
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Yanada M, Takeuchi J, Sugiura I, Akiyama H, Usui N, Yagasaki F, Kobayashi T, Ueda Y, Takeuchi M, Miyawaki S, Maruta A, Emi N, Miyazaki Y, Ohtake S, Jinnai I, Matsuo K, Naoe T, Ohno R; Japan Adult Leukemia Study Group. High complete remission rate and promising outcome by combination of imatinib and chemotherapy for newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia: a phase II study by the Japan Adult Leukemia Study Group. J Clin Oncol. 2006 Jan 20;24(3):460-6. doi: 10.1200/JCO.2005.03.2177. Epub 2005 Dec 12.
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BACKGROUND
Chalandon Y, Thomas X, Hayette S, Cayuela JM, Abbal C, Huguet F, Raffoux E, Leguay T, Rousselot P, Lepretre S, Escoffre-Barbe M, Maury S, Berthon C, Tavernier E, Lambert JF, Lafage-Pochitaloff M, Lheritier V, Chevret S, Ifrah N, Dombret H; Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL). Randomized study of reduced-intensity chemotherapy combined with imatinib in adults with Ph-positive acute lymphoblastic leukemia. Blood. 2015 Jun 11;125(24):3711-9. doi: 10.1182/blood-2015-02-627935. Epub 2015 Apr 15.
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RESULT
Dorer DJ, Knickerbocker RK, Baccarani M, Cortes JE, Hochhaus A, Talpaz M, Haluska FG. Impact of dose intensity of ponatinib on selected adverse events: Multivariate analyses from a pooled population of clinical trial patients. Leuk Res. 2016 Sep;48:84-91. doi: 10.1016/j.leukres.2016.07.007. Epub 2016 Jul 22.
Reference Type
RESULT
Jabbour E, Kantarjian H, Ravandi F, Thomas D, Huang X, Faderl S, Pemmaraju N, Daver N, Garcia-Manero G, Sasaki K, Cortes J, Garris R, Yin CC, Khoury JD, Jorgensen J, Estrov Z, Bohannan Z, Konopleva M, Kadia T, Jain N, DiNardo C, Wierda W, Jeanis V, O'Brien S. Combination of hyper-CVAD with ponatinib as first-line therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia: a single-centre, phase 2 study. Lancet Oncol. 2015 Nov;16(15):1547-1555. doi: 10.1016/S1470-2045(15)00207-7. Epub 2015 Sep 30.
Reference Type
RESULT
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Other Identifiers
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Pona-CELL
Identifier Type: -
Identifier Source: org_study_id
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