Clinical trial NCT04475731: Ponatinib in Adult Ph+ ALL Patients With MRD Positivity or Hematological Relapse
Official title: Ponatinib for the Management of Minimal Residual Disease (MRD) and Hematologic Relapse in Adult Ph+ Acute Lymphoblastic Leukemia (Ph+ ALL) Patients
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Philadelphia-Positive ALL
Acute Lymphoblastic Leukemia, in Relapse
Lead sponsor: Gruppo Italiano Malattie EMatologiche dell'Adulto
Sponsor class: OTHER
First posted: 2020-07-17
Enrollment: 67
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: Inclusion Criteria:

1. 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.
2. Age ≥18 years old with no upper age limit.
3. 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.
4. Adequate pancreatic function as defined by the following criterion:

   - serum lipase and amylase ≤1.5 × ULN.
5. For females of childbearing potential, a negative pregnancy test must be documented prior to enrollment.
6. 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.
7. Signed written informed consent according to ICH/EU/GCP and national local laws.

Exclusion Criteria:

1. WHO performance status ≤ 50% (Karnofsky) or ≥ 3 (ECOG).
2. Uncontrolled active HBV or HCV hepatitis, or AST/ALT ≥ 2.5 x ULN and bilirubine ≥ 1.5 x ULN not due to the disease.
3. History of acute pancreatitis within 1 year of study or history of chronic pancreatitis.
4. History of alcohol abuse.
5. Ongoing or active uncontrolled infections.
6. Uncontrolled hypertriglyceridemia (triglycerides \>450 mg/dL).
7. 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.
8. Taking medications that are known to be associated with Torsades de Pointes.
9. 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.
10. Creatinine level \>2.5mg/dl or glomerular filtration rate (GFR) \<20 ml/min or proteinuria \>3.5 g/day.
11. 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.

Primary outcomes:
measure: MRD negativity/reduction rate
timeFrame: After 3 months of treatment
Secondary outcomes:
measure: Duration of CMR
timeFrame: at 24 months
measure: Hematologic remission rate
timeFrame: at 24 months
measure: Best molecular response
timeFrame: at 24 months
measure: Rate of AE/SAEs
timeFrame: at 24 months
measure: Mutational analysis
timeFrame: at 24 months
measure: Correlation between biological and MRD parameters
timeFrame: at 24 months
measure: Disease free survival
timeFrame: 24 months
measure: Overall survival
timeFrame: 24 months
measure: Cumulative incidence of relapse
timeFrame: 24 months
measure: Role of hematological profile on survival outcome
timeFrame: at 24 months
Other outcomes:
Locations:
city: Ancona
country: Italy
facility: Aou Ospedali Riuniti "Umberto I - G.M. Lancisi - G. Salesi"- Ancona - Sod Clinica Ematologica
city: Ascoli Piceno
country: Italy
facility: Area Vasta N. 5 Ascoli Piceno - S. Benedetto Del Tronto, Presidio Ospedaliero Av5 Osp. Gen. Prov.Le "C.G.Mazzoni" - Uoc Ematologia
city: Avellino
country: Italy
facility: Ao Di Rilievo Nazionale E Di Alta Specialità "San Giuseppe Moscati" - Avellino - Uoc Ematologia Con Unità Di Trapianto
city: Bari
country: Italy
facility: Aou Consorziale Policlinico - Bari - Uo Ematologia Con Trapianto
city: Bergamo
country: Italy
facility: Asst Papa Giovanni Xxiii - Ospedale Di Bergamo - Sc Ematologia
city: Bologna
country: Italy
facility: Aou Di Bologna - Policlinico S. Orsola-Malpighi - Uoc Ematologia
city: Brescia
country: Italy
facility: Asst Degli Spedali Civili Di Brescia - Uo Ematologia
city: Cuneo
country: Italy
facility: Aso S. Croce E Carle - Cuneo - Sc Ematologia
city: Firenze
country: Italy
facility: Aou Careggi - Firenze - Sod Ematologia
city: Messina
country: Italy
facility: Aou Policlinico "G. Martino" - Messina - Uoc Ematologia
city: Mestre
country: Italy
facility: Aulss 3 Serenissima, Ospedale Dell'Angelo - Mestre - Uo Ematologia
city: Milano
country: Italy
facility: Asst Grande Ospedale Metropolitano Niguarda - Milano - Sc Ematologia
city: Milano
country: Italy
facility: Irccs Ospedale S. Raffaele - Milano - Uo Oncoematologia
city: Napoli
country: Italy
facility: Aou Federico Ii - Napoli - Uoc Ematologia
city: Perugia
country: Italy
facility: Ao Di Perugia, Ospedale S. Maria Della Misericordia - Ematologia E Trapianto Midollo Osseo
city: Pesaro
country: Italy
facility: Ao Ospedali Riuniti Marche Nord - Ospedale San Salvatore - Pesaro - Uoc Ematologia E Centro Trapianti
city: Roma
country: Italy
facility: Università Degli Studi Di Roma "Sapienza" - Dipartimento Di Medicina Traslazionale E Di Precisione - U.O.C. Ematologia
city: Salerno
country: Italy
facility: Aou "San Giovanni Di Dio E Ruggi D'Aragona" - Salerno - Uoc Ematologia E Trapianti Di Cellule Staminali Emopoietiche
city: San Giovanni Rotondo
country: Italy
facility: Ente Ecclesiastico Casa Sollievo Della Sofferenza - San Giovanni Rotondo - Ematologia
city: Siena
country: Italy
facility: Aou Senese - Uoc Ematologia E Trapianti
city: Torino
country: Italy
facility: Aou Città Della Salute E Della Scienza, Ospedale S. Giovanni Battista Molinette - Torino - Sc Ematologia 2
city: Verona
country: Italy
facility: Aou Integrata Di Verona, Policlinico G.B. Rossi - Uoc Ematologia
Study officials:
References: