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

NCT04554459 | Terminated Phase 2

• 1 other identifier: Pona-CELL
• Study Type: interventional
• Target: 4
• Locations: 1 country
• Sites: 7

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.

Conditions

Acute Lymphoblastic Leukemia, Adult; Ph+ ALL; Newly Diagnosed

Outcome Measures

Primary Outcomes (1)

• Complete Molecular Response

  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 Outcomes (5)

• 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

• 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 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

  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

  During the ponatinib treatment up to 30 days after end of treatment

Study Arms (1)

ponatinib plus reduced-intensity chemotherapy

EXPERIMENTAL

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

Drug: Ponatinib 15 MG Oral Tablet

Interventions

Ponatinib 15 MG Oral Tablet DRUG

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

Also known as: Iclusig, AP24534, L01XE24

ponatinib plus reduced-intensity chemotherapy

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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;

Sponsors & Collaborators

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

Study Sites (7)

University Hospital Brno, Internal hematology and oncology clinic

Brno, 60200, Czechia

Location

University Hospital Hradec Kralove, The 4th Department of Internal Medicine - Hematology

Hradec Králové, 50005, Czechia

Location

University Hospital Olomouc, Hematooncology Clinic

Olomouc, Czechia

Location

University Hospital Ostrava, Hematooncology Clinic

Ostrava, 70852, Czechia

Location

University Hospital Plzen, Hematology and Oncology Department

Plzeň-Lochotín, 304 60, Czechia

Location

University Hospital Kralovske Vinohrady, Internal Hematology Clinic

Prague, 10034, Czechia

Location

Institute of Hematology and Blood Transfusion

Prague, 128 00, Czechia

Location

Related Publications (33)

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  PMID: 25878120 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.

  PMID: 27505637 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.

  PMID: 26432046 RESULT

Related Links

• Acute Lymphocytic Leukemia
• Ponatinib

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Interventions

ponatinib; Tablets

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Dosage Forms; Pharmaceutical Preparations

Study Officials

• Cyril Salek, MD

  Institute of Hematology and Blood Transfusion, Czech Republic

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 4, 2020
• First Posted: September 18, 2020
• Study Start: February 16, 2021
• Primary Completion: September 1, 2023
• Study Completion: July 1, 2024
• Last Updated: August 14, 2024

Record last verified: 2023-08

Data Sharing

• IPD Sharing: Will not share

Locations

CZ (7)