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

Phase 2

Active, not recruiting

• Conditions: Philadelphia-Positive ALL; Acute Lymphoblastic Leukemia, in Relapse
• Interventions: Drug: Ponatinib

• Registration Number: NCT04475731
• Lead Sponsor: Gruppo Italiano Malattie EMatologiche dell'Adulto

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.

Study Timeline

• Study First Submitted: 2020-06-25
• Study First Submitted QC: 2020-07-14
• Study First Posted: 2020-07-17
• Study Start: 2021-05-04
• Status Verified: 2024-10
• Last Update Submitted: 2024-10-21
• Last Update Posted: 2024-10-22
• Primary Completion: 2024-11
• Study Completion: 2024-11

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 67

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Experimental arm	Ponatinib	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.

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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

Trial Locations

Locations (22)

Aou Ospedali Riuniti "Umberto I - G.M. Lancisi - G. Salesi"- Ancona - Sod Clinica Ematologica; 🇮🇹 Ancona, Italy

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

Ao Di Rilievo Nazionale E Di Alta Specialità "San Giuseppe Moscati" - Avellino - Uoc Ematologia Con Unità Di Trapianto; 🇮🇹 Avellino, Italy

Aou Consorziale Policlinico - Bari - Uo Ematologia Con Trapianto; 🇮🇹 Bari, Italy

Asst Papa Giovanni Xxiii - Ospedale Di Bergamo - Sc Ematologia; 🇮🇹 Bergamo, Italy

Aou Di Bologna - Policlinico S. Orsola-Malpighi - Uoc Ematologia; 🇮🇹 Bologna, Italy

Asst Degli Spedali Civili Di Brescia - Uo Ematologia; 🇮🇹 Brescia, Italy

Aso S. Croce E Carle - Cuneo - Sc Ematologia; 🇮🇹 Cuneo, Italy

Aou Careggi - Firenze - Sod Ematologia; 🇮🇹 Firenze, Italy

Aou Policlinico "G. Martino" - Messina - Uoc Ematologia; 🇮🇹 Messina, Italy

Aulss 3 Serenissima, Ospedale Dell'Angelo - Mestre - Uo Ematologia; 🇮🇹 Mestre, Italy

Asst Grande Ospedale Metropolitano Niguarda - Milano - Sc Ematologia; 🇮🇹 Milano, Italy

Irccs Ospedale S. Raffaele - Milano - Uo Oncoematologia; 🇮🇹 Milano, Italy

Aou Federico Ii - Napoli - Uoc Ematologia; 🇮🇹 Napoli, Italy

Ao Di Perugia, Ospedale S. Maria Della Misericordia - Ematologia E Trapianto Midollo Osseo; 🇮🇹 Perugia, Italy

Ao Ospedali Riuniti Marche Nord - Ospedale San Salvatore - Pesaro - Uoc Ematologia E Centro Trapianti; 🇮🇹 Pesaro, Italy

Università Degli Studi Di Roma "Sapienza" - Dipartimento Di Medicina Traslazionale E Di Precisione - U.O.C. Ematologia; 🇮🇹 Roma, Italy

Aou "San Giovanni Di Dio E Ruggi D'Aragona" - Salerno - Uoc Ematologia E Trapianti Di Cellule Staminali Emopoietiche; 🇮🇹 Salerno, Italy

Ente Ecclesiastico Casa Sollievo Della Sofferenza - San Giovanni Rotondo - Ematologia; 🇮🇹 San Giovanni Rotondo, Italy

Aou Senese - Uoc Ematologia E Trapianti; 🇮🇹 Siena, Italy

Aou Città Della Salute E Della Scienza, Ospedale S. Giovanni Battista Molinette - Torino - Sc Ematologia 2; 🇮🇹 Torino, Italy

Aou Integrata Di Verona, Policlinico G.B. Rossi - Uoc Ematologia; 🇮🇹 Verona, Italy