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ponatinib plus reduced-intensity chemotherapy in first-line treatment of Adult Ph+ ALL

Ponatinib 15 MG Oral Tablet

Cyril Salek, MD

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.

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.)

Ponatinib Plus Reduced-intensity Chemotherapy in the First-line Treatment of Adult Patients With Ph+ ALL

Ponatinib Plus Reduced-intensity Chemotherapy in the First-line Treatment of Adult Patients With Ph-positive Acute Lymphoblastic Leukemia

Percentage of patients with Complete Molecular Response (CMR) after 2 cycles of induction therapy composed by reduced chemotherapy and ponatinib. Minimal Residual Disease (MRD) tested by quantification of BCR-ABL1 transcript using ddPCR method

Complete Remission (CR) and Complete Remission with incomplete blood count recovery(CRi)

Percentage of patients with suboptimal molecular response after completion of 2 induction course containing ponatinib

Severity and occurence of adverse events related to ponatinib treatment

CZECRIN - Czech Clinical Research Infrastructure Network

Institute of Hematology and Blood Transfusion, Czech Republic

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Ponatinib Plus Reduced-intensity Chemotherapy in the First-line Treatment of Adult Patients With Ph+ ALL	NCT04554459	Acute Lymphobla... Ph+ ALL Newly Diagnosed	Ponatinib 15 MG...	18 Years - 99 Years	Institute of Hematology and Blood Transfusion, Czech Republic
Ponatinib Plus Reduced-intensity Chemotherapy in the First-line Treatment of Adult Patients With Ph+ ALL	NCT04554459	Acute Lymphobla... Ph+ ALL Newly Diagnosed	Ponatinib 15 MG...	18 Years - 99 Years	Institute of Hematology and Blood Transfusion, Czech Republic

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