PONALFIL: Ponatinib With Chemotherapy for Young Adults Ph Positive Acute Lymphoblastic Leukemia

Sponsor

PETHEMA Foundation (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT02776605

Collaborator

(none)

Enrollment

Locations

Arm

Anticipated Duration (Months)

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
ALL	Drug: Prednisone Drug: Vincristine Drug: Daunorubicin Drug: Prednisone Drug: Ponatinib Drug: Mercaptopurine Drug: Methotrexate Drug: VP-16 Drug: ARA-C: Drug: TIT Drug: Ponatinib Procedure: Autologous transplantation Procedure: Allo transplantation	Phase 2

Detailed Description

Objectives Primary

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.
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. Secondary

To evaluate the rate of patients receiving an allogeneic hematopoietic stem cell transplant (alloHSCT) in first CR
To evaluate the frequency of MMR and CMR at the time of alloHSCT
To evaluate the transplant-related mortality (TRM)
To evaluate the CR duration and overall survival (OS) of the combination of ponatinib with standard chemotherapy (according to PETHEMA ALL Ph08 trial) in young patients with Ph+ (BCR-ABL) ALL.
To evaluate the outcome measures (CR duration, OS and EFS) in context of those observed in the PETHEMA ALL Ph08 trial.
To observe the type and number of BCR-ABL kinase domain mutations developing during and after the study.
To evaluate side effects, adverse events (AE) and serious AE (SAE).

Interventions:

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).

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.
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.
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.
Post HSCT therapy After alloHSCT. Frequent monitoring of MRD (every month). If MRD negative: no therapy. If MRD positive, Ponatinib 30 mg/d, po, until 2 yr. after HSCT. The ponatinib dose will be reduced to 15 mg/d in the second year in patients with sustained molecular response. After autoHSCT: Frequent monitoring of MRD (every month). All patients will receive Ponatinib: 30 mg/d, PO, mercaptopurine, (40 mg/m2/d, PO) and methotrexate (15 mg/m2/week, IM), during the first year after HSCT. The ponatinib dose will be reduced to 15 mg/d in the second year in patients with sustained molecular response.

Study Design

Study Type:

Interventional

Actual Enrollment :

30 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Concurrent Ponatinib With Chemotherapy for Young Adults With Newly Diagnosed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

Actual Study Start Date :

Jun 1, 2016

Actual Primary Completion Date :

Aug 5, 2020

Anticipated Study Completion Date :

Aug 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ponatinib Pre-phase (maximum 7 days, -7 to -1) with Prednisone and triple intrathecal therapy (TIT) 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. 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". HSCT (performed ideally within 1 month from the end of consolidation). Post HSCT therapy (MRD monitoring)	Drug: Prednisone Prednisone 60 mg/m2/day IV over 7 days (-7 a -1) and triple intrathecal therapy (TIT) Drug: Vincristine Vincristine (VCR): 1.5 mg/m2 (maximum 2 mg) IV days 1, 8, 15 and 22. Drug: Daunorubicin Daunorubicin (DNR): 45 mg/m2 IV days 1, 8, 15 and 22. Drug: Prednisone Prednisone (PDN): 60 mg/m2/day, IV or PO, days 1 to 27. Drug: Ponatinib Ponatinib 30 mg, PO from day 1 to consolidation Drug: Mercaptopurine Mercaptopurine (MP): 50 mg/m2, PO days 1 to 7, 28 to 35 and 56 to 63. Drug: Methotrexate MTX: 1,5 g/m2, IV (24 h continuous infusion) days 1, 28 and 56 Drug: VP-16 VP-16: 100 mg/m2/12 h, IV, days 14 and 42 Drug: ARA-C: ARA-C: 1000 mg/m2/12 h, IV, days 14-15 and 42-43. Drug: TIT TIT (MTX: 12 mg, ARA-C: 30 mg, hydrocortisone: 20 mg), , days 1, 28 and 56. Drug: Ponatinib Ponatinib 30 mg/d PO, from day 1 to 15 days before HSCT. Procedure: Autologous transplantation Myeloablative conditioning with cyclophosphamide and total body irradiation (TBI) whenever possible and autologous transplantation Procedure: Allo transplantation Myeloablative conditioning with cyclophosphamide and total body irradiation (TBI) whenever possible and allo transplantation

Arm

Intervention/Treatment

Experimental: Ponatinib

Pre-phase (maximum 7 days, -7 to -1) with Prednisone and triple intrathecal therapy (TIT) 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. 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". HSCT (performed ideally within 1 month from the end of consolidation). Post HSCT therapy (MRD monitoring)

Drug: Prednisone

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

Drug: Vincristine

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

Drug: Daunorubicin

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

Drug: Prednisone

Prednisone (PDN): 60 mg/m2/day, IV or PO, days 1 to 27.

Drug: Ponatinib

Ponatinib 30 mg, PO from day 1 to consolidation

Drug: Mercaptopurine

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

Drug: Methotrexate

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

Drug: VP-16

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

Drug: ARA-C:

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

Drug: TIT

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

Drug: Ponatinib

Ponatinib 30 mg/d PO, from day 1 to 15 days before HSCT.

Procedure: Autologous transplantation

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

Procedure: Allo transplantation

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

Outcome Measures

Primary Outcome Measures

Overall response [2 years]
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.
Event free survival [2 years]
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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 55 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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

Exclusion Criteria:

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.
Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy.
Patients who are pregnant or breast feeding and adults of reproductive potential not employing an effective method of birth control (women of childbearing potential must have a negative serum pregnancy test within 48 hrs. prior to administration of Ponatinib). Postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. Male and female patients must agree to employ an effective barrier method of birth control throughout the study and for up to 4 months following discontinuation of study drugs.
Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention.
Patients unwilling or unable to comply with the protocol

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Hospital Germans Trias i Pujol	Badalona	Spain
2	Hospital Clinic	Barcelona	Spain	08036
3	Hospital 12 de Octubre	Madrid	Spain
4	Hospital Virgen de la Victoria	Málaga	Spain
5	Hospital Clinico Universitario de Salamanca	Salamanca	Spain
6	Hospital Marques de Valdecilla	Santander	Spain
7	C H Santiago de Compostela	Santiago de Compostela	Spain
8	Hospital Virgen del Rocio	Sevilla	Spain
9	Hospital Clinico de Valencia	Valencia	Spain
10	Hospital La Fe	Valencia	Spain