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

January 11, 2024 updated by: Institute of Hematology and Blood Transfusion, Czech Republic

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

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.

Study Overview

Status

Suspended

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Estimated)

32

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Czechia
      • Brno, Czechia, 60200
        • University Hospital Brno, Internal hematology and oncology clinic
      • Hradec Králové, Czechia, 50005
        • University Hospital Hradec Kralove, The 4th Department of Internal Medicine - Hematology
      • Olomouc, Czechia
        • University Hospital Olomouc, Hematooncology Clinic
      • Ostrava, Czechia, 70852
        • University Hospital Ostrava, Hematooncology Clinic
      • Plzeň-Lochotín, Czechia, 304 60
        • University Hospital Plzen, Hematology and Oncology Department
      • Praha, Czechia, 10034
        • University Hospital Kralovske Vinohrady, Internal Hematology Clinic
      • Praha, Czechia, 128 00
        • Institute of Hematology and Blood Transfusion

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 99 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Complete Molecular Response
Time Frame: 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
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)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
CR and CRi
Time Frame: 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)
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
PFS
Time Frame: 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)
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
OS
Time Frame: 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)
Time from the day 1 (starting of the 1st Induction Course) until the date of death from any cause, assessed up to 36 months
AlloSCT in the first complete remission
Time Frame: 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
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)
Severity and occurence of adverse events related to ponatinib
Time Frame: During the ponatinib treatment up to 30 days after end of treatment
Severity and occurence of adverse events related to ponatinib treatment
During the ponatinib treatment up to 30 days after end of treatment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Institute of Hematology and Blood Transfusion, Czech Republic

Collaborators

CZECRIN - Czech Clinical Research Infrastructure Network

Investigators

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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 16, 2021

Primary Completion (Actual)

September 1, 2023

Study Completion (Estimated)

July 1, 2024

Study Registration Dates

First Submitted

September 4, 2020

First Submitted That Met QC Criteria

September 14, 2020

First Posted (Actual)

September 18, 2020

Study Record Updates

Last Update Posted (Estimated)

January 15, 2024

Last Update Submitted That Met QC Criteria

January 11, 2024

Last Verified

August 1, 2023

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Pona-CELL

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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