Ponatinib With Chemotherapy for Young Adults Ph Positive Acute Lymphoblastic Leukemia

NCT02776605 | Unknown Phase 2 DMC

• 1 other identifier: PONALFIL
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 10

Brief Summary

Evaluate the response (complete hematologic response \[CHR\], complete cytogenetic response \[CCyR\], major molecular response \[MMR\] and complete molecular response \[CMR\] of the combination of ponatinib with standard chemotherapy (according to PETHEMA ALL Ph08 trial) in young patients with Ph+ (BCR-ABL) ALL. All patients are treated with: Pre-phase (maximum 7 days, -7 to -1): Prednisone 60 mg/m2/day IV over 7 days (-7 a -1) and triple intrathecal therapy (TIT) (Methotrexate \[MTX\]: 12 mg, ARA-C: 30 mg, hydrocortisone: 20 mg). 2. Induction (day 1 to day 28 or up to hematological recovery) Vincristine (VCR): 1.5 mg/m2 (maximum 2 mg) IV days 1, 8, 15 and 22. Daunorubicin (DNR): 45 mg/m2 IV days 1, 8, 15 and 22. Prednisone (PDN): 60 mg/m2/day, IV or PO, days 1 to 27. Ponatinib 30 mg, PO from day 1 to consolidation. TIT, days 1 and 22. 3. Consolidation (day 1 to day 63) Mercaptopurine (MP): 50 mg/m2, PO days 1 to 7, 28 to 35 and 56 to 63. MTX: 1,5 g/m2, IV (24 h continuous infusion) days 1, 28 and 56. VP-16: 100 mg/m2/12 h, IV, days 14 and 42. ARA-C: 1000 mg/m2/12 h, IV, days 14-15 and 42-43. TIT (MTX: 12 mg, ARA-C: 30 mg, hydrocortisone: 20 mg), , days 1, 28 and 56. Ponatinib 30 mg/d PO, from day 1 to 15 days before HSCT. 4. HSCT (performed ideally within 1 month from the end of consolidation). AlloHSCT preferred over autoHSCT (autoHSCT only indicated if alloHSCT not feasible). Myeloablative conditioning with cyclophosphamide and total body irradiation (TBI) whenever possible. 5. Post HSCT therapy After alloHSCT. Frequent monitoring of MRD (every month). I After autoHSCT: Frequent monitoring of MRD (every month).

Conditions

ALL

Outcome Measures

Primary Outcomes (2)

• Overall response

  To evaluate the response (complete hematologic response \[CHR\], complete cytogenetic response \[CCyR\], major molecular response \[MMR\] and complete molecular response \[CMR\] of the combination of ponatinib with standard chemotherapy (according to PETHEMA ALL Ph08 trial) in young patients with Ph+ (BCR-ABL) ALL.

  2 years

• Event free survival

  To evaluate the event free survival (EFS) of the combination of ponatinib with standard chemotherapy (according to PETHEMA ALL Ph08 trial) in young patients with Ph+ (BCR-ABL) ALL

  2 years

Study Arms (1)

Ponatinib

EXPERIMENTAL

1. Pre-phase (maximum 7 days, -7 to -1) with Prednisone and triple intrathecal therapy (TIT) 2. Induction (day 1 to day 28 or up to hematological recovery) Vincristine (VCR): 1.5 mg/m2 IV days 1, 8, 15 and 22. Daunorubicin (DNR): 45 mg/m2 IV days 1, 8, 15 and 22. Prednisone (PDN): 60 mg/m2/day, IV or PO, days 1 to 27. Ponatinib 30 mg, PO from day 1 to consolidation. TIT, days 1 and 22. 3. Consolidation Mercaptopurine (MP): 50 mg/m2, PO days 1 to 7, 28 to 35 and 56 to 63. MTX: 1,5 g/m2, IV days 1, 28 and 56. VP-16: 100 mg/m2/12 h, IV, days 14 and 42. ARA-C: 1000 mg/m2/12 h, IV, days 14-15 and 42-43. TIT days 1, 28 and 56. Ponatinib 30 mg/d PO, from day 1 to day 7 before HSCT". 4. HSCT (performed ideally within 1 month from the end of consolidation). 5. Post HSCT therapy (MRD monitoring)

Drug: Prednisone; Drug: Vincristine; Drug: Daunorubicin; Drug: Ponatinib; Drug: Mercaptopurine; Drug: Methotrexate; Drug: VP-16; Drug: ARA-C:; Drug: TIT; Procedure: Autologous transplantation; Procedure: Allo transplantation

Interventions

Prednisone DRUG

Prednisone 60 mg/m2/day IV over 7 days (-7 a -1) and triple intrathecal therapy (TIT)

Ponatinib

Vincristine DRUG

Vincristine (VCR): 1.5 mg/m2 (maximum 2 mg) IV days 1, 8, 15 and 22.

Ponatinib

Daunorubicin DRUG

Daunorubicin (DNR): 45 mg/m2 IV days 1, 8, 15 and 22.

Ponatinib

Ponatinib DRUG

Ponatinib 30 mg, PO from day 1 to consolidation

Ponatinib

Mercaptopurine DRUG

Mercaptopurine (MP): 50 mg/m2, PO days 1 to 7, 28 to 35 and 56 to 63.

Ponatinib

Methotrexate DRUG

MTX: 1,5 g/m2, IV (24 h continuous infusion) days 1, 28 and 56

Ponatinib

VP-16 DRUG

VP-16: 100 mg/m2/12 h, IV, days 14 and 42

Ponatinib

ARA-C: DRUG

ARA-C: 1000 mg/m2/12 h, IV, days 14-15 and 42-43.

Ponatinib

TIT DRUG

TIT (MTX: 12 mg, ARA-C: 30 mg, hydrocortisone: 20 mg), , days 1, 28 and 56.

Ponatinib

Autologous transplantation PROCEDURE

Myeloablative conditioning with cyclophosphamide and total body irradiation (TBI) whenever possible and autologous transplantation

Ponatinib

Allo transplantation PROCEDURE

Myeloablative conditioning with cyclophosphamide and total body irradiation (TBI) whenever possible and allo transplantation

Ponatinib

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Age 18-55 yr.
• De novo Ph+ (BCR-ABL)ALL
• ECOG score ≤2 unless due to ALL
• 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 lipase and amylase ≤1.5 × ULN.
• No history of dyslipidemia, hypertension, thrombotic events or cardiac disease.
• For females of childbearing potential, a negative pregnancy test must be documented prior to randomization. Female and male patients who are fertile must agree to use an effective form of contraception with their sexual partners from randomization through 4 months after the end of treatment.
• informed consent signed, according to national regulation
• Patients aged between 56 and 60 years may be selected who could be included in the study with the authorization of the Coordinating Investigator with the consolidation treatment modified as follows:
• Mercaptopurine (MP): 50 mg / m2, PO on days 1 to 7, 28 to 35 and 56 to 63 MTX: 0.75 g / m2, IV (continuous infusion 24 h) on days 1, 28 and 56 ARA-C: 500 mg / m2 / 12 h, IV, days 14-15 and 42-43 TIT (MTX: 12 mg, ARA-C: 30 mg, hydrocortisone: 20 mg), days 1, 28 and 56 Ponatinib 30 mg / d PO, from day 1 to 7 days before HSCT

You may not qualify if:

• Lymphoid blast crisis of CML,
• WHO performance status ≤ 50% (Karnofsky) or ≥ 3 (ECOG).
• Active HBV or HCV hepatitis, or AST/ALT ≥ 2.5 x ULN and bilirubin ≥ 1.5 x ULN.
• History of acute pancreatitis within 1 year of study or history of chronic pancreatitis.
• History of alcohol abuse.
• Ongoing or active infections.
• Uncontrolled hypertriglyceridemia (triglycerides \>450 mg/dL).
• 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 enrollment Congestive heart failure within 6 months prior to enrollment, 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 mm Hg; systolic \>140 mm Hg). Patients with hypertension should be under treatment on study entry to effect blood pressure control.
• Taking medications that are known to be associated with torsades de pointes.
• 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.
• Creatinine levels \> 2.5mg/dl or glomerular filtration rate (GFR) \< 20 ml/min or proteinuria \>3.5 g/day.
• Gastrointestinal (GI) function impairment, or a GI disease that may significantly alter the absorption of study drugs.
• Patients who are currently receiving treatment with any of the medications with potential to prolong QT interval (listed in Appendix 4) if the medications cannot be either discontinued or switched to a different medication prior to starting study drug.
• Patients who have received any investigational drug ≤ 4 weeks.

Sponsors & Collaborators

• PETHEMA Foundation: lead

Study Sites (10)

Hospital Germans Trias i Pujol

Badalona, Spain

Location

Hospital Clinic

Barcelona, 08036, Spain

Location

Hospital 12 de Octubre

Madrid, Spain

Location

Hospital Virgen de la Victoria

Málaga, Spain

Location

Hospital Clinico Universitario de Salamanca

Salamanca, Spain

Location

Hospital Marques de Valdecilla

Santander, Spain

Location

C H Santiago de Compostela

Santiago de Compostela, Spain

Location

Hospital Virgen del Rocio

Seville, Spain

Location

Hospital Clinico de Valencia

Valencia, Spain

Location

Hospital La Fe

Valencia, Spain

Location

Related Publications (1)

• Ribera JM, Garcia-Calduch O, Ribera J, Montesinos P, Cano-Ferri I, Martinez P, Esteve J, Esteban D, Garcia-Fortes M, Alonso N, Gonzalez-Campos J, Bermudez A, Torrent A, Genesca E, Mercadal S, Martinez-Lopez J, Garcia-Sanz R. Ponatinib, chemotherapy, and transplant in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood Adv. 2022 Sep 27;6(18):5395-5402. doi: 10.1182/bloodadvances.2022007764.

  PMID: 35675590 DERIVED

MeSH Terms

Interventions

Prednisone; Vincristine; Daunorubicin; ponatinib; Mercaptopurine; Methotrexate; Etoposide; Cytarabine; Transplantation, Autologous

Intervention Hierarchy (Ancestors)

Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Aminoglycosides; Glycosides; Carbohydrates; Sulfhydryl Compounds; Sulfur Compounds; Purines; Aminopterin; Pterins; Pteridines; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Glucosides; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Transplantation; Surgical Procedures, Operative

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: May 16, 2016
• First Posted: May 18, 2016
• Study Start: June 1, 2016
• Primary Completion: August 5, 2020
• Study Completion: August 1, 2023
• Last Updated: February 18, 2022

Record last verified: 2022-02

Locations

ES (10)