Ponatinib in Adult Ph+ ALL Patients With MRD Positivity or Hematological Relapse

Sponsor

Gruppo Italiano Malattie EMatologiche dell'Adulto (Other)

Overall Status

Recruiting

CT.gov ID

NCT04475731

Collaborator

(none)

Enrollment

Locations

Arm

Anticipated Duration (Months)

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 if the use of ponatinib, with or without chemotherapy, can induce a molecular remission in MRD-positive patients, in patients in hematologic and extra-hematologic relapse and in the few patients who never achieved an hematologic remission after whatever prior treatment.

Condition or Disease	Intervention/Treatment	Phase
Philadelphia-Positive ALL Acute Lymphoblastic Leukemia, in Relapse	Drug: Ponatinib	Phase 2

Detailed Description

This is a phase II interventional multicenter study for adult patients with Ph+ALL who:

Are MRD+ (i.e. BCR-ABL1/ABL1 >0.01) (or loose their molecular response) after whichever kind of previous treatment. MRD positivity is indeed regarded as a relapse/resistance, since it represents the early recognition of cases who will eventually experience an hematologic recurrence of disease.
Are in hematologic relapse after whichever kind of previous treatment.
Have never achieved an hematologic remission at least after one month of treatment.

Patients will be treated with Ponatinib at a dose of 45 mg/die per os for 28 days for 3 cycles and - if in hematologic and extra-hematologic relapse/refractoriness, clinically fit and according to medical decision - with concurrent systemic chemotherapy. In case of CMR achievement, dosing will be reduced to 30 mg. In case of toxicity, Ponatinib will be reduced to 30 (or 15) mg daily.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

67 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Ponatinib for the Management of Minimal Residual Disease (MRD) and Hematologic Relapse in Adult Ph+ Acute Lymphoblastic Leukemia (Ph+ ALL) Patients

Actual Study Start Date :

May 4, 2021

Anticipated Primary Completion Date :

Nov 1, 2022

Anticipated Study Completion Date :

Nov 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Experimental arm MRD+ Ph+ ALL adult patients will receive Ponatinib x 4 weeks x 3 courses; +/-Concomitant chemotherapy (according to hematologic status). Patients will receive the study drug until disease relapse or progression.	Drug: Ponatinib Ponatinib 45 mg/day x 4 weeks x 3 courses. +/- chemotherapy: vincristine or L-VAMP (leucovorin, vincristine, aracytin, methotrexate, prednisone)

Arm

Intervention/Treatment

Experimental: Experimental arm

MRD+ Ph+ ALL adult patients will receive Ponatinib x 4 weeks x 3 courses; +/-Concomitant chemotherapy (according to hematologic status). Patients will receive the study drug until disease relapse or progression.

Drug: Ponatinib

Ponatinib 45 mg/day x 4 weeks x 3 courses. +/- chemotherapy: vincristine or L-VAMP (leucovorin, vincristine, aracytin, methotrexate, prednisone)

Outcome Measures

Primary Outcome Measures

MRD negativity/reduction rate [After 3 months of treatment]
Rate of patients who achieve a MRD negativity/MRD reduction following treatment with either Ponatinib alone or in combination with systemic chemotherapy

Secondary Outcome Measures

Duration of CMR [at 24 months]
Duration of the CMR status after 3 months of ponatinib treatment
Hematologic remission rate [at 24 months]
The achievement of an hematologic remission in patients treated for an hematologic and extra-hematoloigc relapse and for a refractory disease.
Best molecular response [at 24 months]
Best molecular response achieved during the follow-up
Rate of AE/SAEs [at 24 months]
Safety profile in terms of incidence of grade >3 CTC-NCI side effects and toxicities (AE/SAEs).
Mutational analysis [at 24 months]
Mutational analysis in terms of occurrence, type and number of BCR-ABL1 kinase domain mutations.
Correlation between biological and MRD parameters [at 24 months]
Correlation between the achievement and duration of CMR (or MRD reduction) with the type of fusion protein (e.g. p190 or p210) and the potential occurrence of mutations, as well as with additional genomic lesions.
Disease free survival [24 months]
Time interval between the achievement of CHR after three months of ponatinib and hematologic relapse of the disease or death in CHR; patients still alive, in CHR.
Overall survival [24 months]
Time interval between treatment start and death for any cause.
Cumulative incidence of relapse [24 months]
Time interval between achievement of CHR after three months of ponatinib until the date of first hematologic relapse of the disease.
Role of hematological profile on survival outcome [at 24 months]
Identification of hematological profile on survival outcome

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Ph+ ALL patients with evidence of MRD disease or in hematologic and extra-hematologic relapse/refractoriness after any previous treatment, will be considered eligible to enter the study.
Age ≥18 years old with no upper age limit.
Adequate hepatic function 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
aspartate aminotransferase (AST) ≤2.5 × ULN.

Adequate pancreatic function as defined by the following criterion:

serum lipase and amylase ≤1.5 × ULN.

For females of childbearing potential, a negative pregnancy test must be documented prior to enrollment.
Female and male patients who are fertile must agree to use an effective form of contraception with their sexual partners from enrollment through 4 months after the end of treatment.
Signed written informed consent according to ICH/EU/GCP and national local laws.

Exclusion Criteria:

WHO performance status ≤ 50% (Karnofsky) or ≥ 3 (ECOG).
Uncontrolled active HBV or HCV hepatitis, or AST/ALT ≥ 2.5 x ULN and bilirubine ≥ 1.5 x ULN not due to the disease.
History of acute pancreatitis within 1 year of study or history of chronic pancreatitis.
History of alcohol abuse.
Ongoing or active uncontrolled 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 within 6 months prior to enrollment
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 level >2.5mg/dl or glomerular filtration rate (GFR) <20 ml/min or proteinuria >3.5 g/day.
Patients who are currently receiving treatment with any of the medications listed in Appendix E if the medications cannot be either discontinued or switched to a different medication prior to starting study drug. The medications listed in Appendix E have the potential to prolong QT.

Contacts and Locations

Locations

	Site	City	Country
1	Aou Ospedali Riuniti "Umberto I - G.M. Lancisi - G. Salesi"- Ancona - Sod Clinica Ematologica	Ancona	Italy
2	Area Vasta N. 5 Ascoli Piceno - S. Benedetto Del Tronto, Presidio Ospedaliero Av5 Osp. Gen. Prov.Le "C.G.Mazzoni" - Uoc Ematologia	Ascoli Piceno	Italy
3	Ao Di Rilievo Nazionale E Di Alta Specialità "San Giuseppe Moscati" - Avellino - Uoc Ematologia Con Unità Di Trapianto	Avellino	Italy
4	Aou Consorziale Policlinico - Bari - Uo Ematologia Con Trapianto	Bari	Italy
5	Asst Papa Giovanni Xxiii - Ospedale Di Bergamo - Sc Ematologia	Bergamo	Italy
6	Aou Di Bologna - Policlinico S. Orsola-Malpighi - Uoc Ematologia	Bologna	Italy
7	Asst Degli Spedali Civili Di Brescia - Uo Ematologia	Brescia	Italy
8	Aso S. Croce E Carle - Cuneo - Sc Ematologia	Cuneo	Italy
9	Aou Careggi - Firenze - Sod Ematologia	Firenze	Italy
10	Aou Policlinico "G. Martino" - Messina - Uoc Ematologia	Messina	Italy
11	Aulss 3 Serenissima, Ospedale Dell'Angelo - Mestre - Uo Ematologia	Mestre	Italy
12	Asst Grande Ospedale Metropolitano Niguarda - Milano - Sc Ematologia	Milano	Italy
13	Irccs Ospedale S. Raffaele - Milano - Uo Oncoematologia	Milano	Italy
14	Aou Federico Ii - Napoli - Uoc Ematologia	Napoli	Italy
15	Ao Di Perugia, Ospedale S. Maria Della Misericordia - Ematologia E Trapianto Midollo Osseo	Perugia	Italy
16	Ao Ospedali Riuniti Marche Nord - Ospedale San Salvatore - Pesaro - Uoc Ematologia E Centro Trapianti	Pesaro	Italy
17	Università Degli Studi Di Roma "Sapienza" - Dipartimento Di Medicina Traslazionale E Di Precisione - U.O.C. Ematologia	Roma	Italy
18	Aou "San Giovanni Di Dio E Ruggi D'Aragona" - Salerno - Uoc Ematologia E Trapianti Di Cellule Staminali Emopoietiche	Salerno	Italy
19	Ente Ecclesiastico Casa Sollievo Della Sofferenza - San Giovanni Rotondo - Ematologia	San Giovanni Rotondo	Italy
20	Aou Senese - Uoc Ematologia E Trapianti	Siena	Italy
21	Aou Città Della Salute E Della Scienza, Ospedale S. Giovanni Battista Molinette - Torino - Sc Ematologia 2	Torino	Italy
22	Aou Integrata Di Verona, Policlinico G.B. Rossi - Uoc Ematologia	Verona	Italy