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

Sponsor
Institute of Hematology and Blood Transfusion, Czech Republic (Other)
Overall Status
Recruiting
CT.gov ID
NCT04554459
Collaborator
CZECRIN - Czech Clinical Research Infrastructure Network (Other)
32
Enrollment
7
Locations
1
Arm
66.5
Anticipated Duration (Months)
4.6
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease Intervention/Treatment Phase
  • Drug: Ponatinib 15 MG Oral Tablet
 Phase 2

Detailed Description

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.)

Study Design

Study Type:
Interventional
Anticipated Enrollment :
32 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Ponatinib Plus Reduced-intensity Chemotherapy in the First-line Treatment of Adult Patients With Ph-positive Acute Lymphoblastic Leukemia
Actual Study Start Date :
Feb 16, 2021
Anticipated Primary Completion Date :
Sep 1, 2024
Anticipated Study Completion Date :
Sep 1, 2026

Arms and Interventions

Arm Intervention/Treatment
Experimental: ponatinib plus reduced-intensity chemotherapy

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

Drug: Ponatinib 15 MG Oral Tablet
ponatinib plus reduced-intensity chemotherapy in first-line treatment of Adult Ph+ ALL
Other Names:
  • Iclusig
  • AP24534
  • L01XE24

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Complete Molecular Response [At week 11 (acceptable window + 1 wk); after completion of two induction courses and before starting of the 1st Consolidation cycle (each induction course is 23 days with continuing ponatinib treatment till the outcome assessing)]

      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

    Secondary Outcome Measures

    1. CR and CRi [CR and CRi at the end of the 1st Induction Course (Day 23) and at week 11 (acceptable window + 1wk) after completion of the 2nd Induction Course and before starting of the 1st Consolidation Cycle]

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

    2. PFS [Time from the day of CR/CRi documentation until the date of relapse, or death from any cause whichever came first, assessed up to 36 months]

      Progression Free Survival (PFS)

    3. OS [Time from the day 1 (starting of the 1st Induction Course) until the date of death from any cause, assessed up to 36 months]

      Overall Survival (OS)

    4. AlloSCT in the first complete remission [At week 11 (acceptable window + 1 wk); after completion of two induction courses and before starting of the 1st Consolidation cycle (each induction course is 23 days with continuing ponatinib treatment till the outcome assessing)]

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

    5. Severity and occurence of adverse events related to ponatinib [During the ponatinib treatment up to 30 days after end of treatment]

      Severity and occurence of adverse events related to ponatinib treatment

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 99 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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.

    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.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 University Hospital Brno, Internal hematology and oncology clinic Brno Czechia 60200
    2 University Hospital Hradec Kralove, The 4th Department of Internal Medicine - Hematology Hradec Králové Czechia 50005
    3 University Hospital Olomouc, Hematooncology Clinic Olomouc Czechia
    4 University Hospital Ostrava, Hematooncology Clinic Ostrava Czechia 70852
    5 University Hospital Plzen, Hematology and Oncology Department Plzeň-Lochotín Czechia 304 60
    6 University Hospital Kralovske Vinohrady, Internal Hematology Clinic Praha Czechia 10034
    7 Institute of Hematology and Blood Transfusion Praha Czechia 128 00

    Sponsors and Collaborators

    • Institute of Hematology and Blood Transfusion, Czech Republic
    • CZECRIN - Czech Clinical Research Infrastructure Network

    Investigators

    • Principal Investigator: Cyril Salek, MD, Institute of Hematology and Blood Transfusion, Czech Republic

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    Responsible Party:
    Institute of Hematology and Blood Transfusion, Czech Republic
    ClinicalTrials.gov Identifier:
    NCT04554459
    Other Study ID Numbers:
    • Pona-CELL
    First Posted:
    Sep 18, 2020
    Last Update Posted:
    Aug 4, 2022
    Last Verified:
    Aug 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    No
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:
    Leukemia
    Precursor Cell Lymphoblastic Leukemia-Lymphoma
    Leukemia, Lymphoid
    Ponatinib

    Study Results

    No Results Posted as of Aug 4, 2022