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

Acute Lymphoblastic Leukemia, in Relapse Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04475731
• Other study ID #: ALL2620
• Status: Recruiting
• Phase: Phase 2
• Start date: May 4, 2021
• Est. completion date: November 2024

Study information

• Verified date: February 2024
• Source: Gruppo Italiano Malattie EMatologiche dell'Adulto
• Contact: Paola Fazi
• Phone: 0670390528
• Email: p.fazi[@]gimema.it
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 67
• Est. completion date: November 2024
• Est. primary completion date: November 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Acute Lymphoblastic Leukemia, in Relapse
• Leukemia
• Leukemia, Lymphoid
• Philadelphia-Positive ALL
• Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Recurrence

Intervention

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

Locations

Country	Name	City	State
Italy	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

Sponsors (1)

Lead Sponsor	Collaborator
Gruppo Italiano Malattie EMatologiche dell'Adulto

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	MRD negativity/reduction rate	Rate of patients who achieve a MRD negativity/MRD reduction following treatment with either Ponatinib alone or in combination with systemic chemotherapy	After 3 months of treatment
Secondary	Duration of CMR	Duration of the CMR status after 3 months of ponatinib treatment	at 24 months
Secondary	Hematologic remission rate	The achievement of an hematologic remission in patients treated for an hematologic and extra-hematoloigc relapse and for a refractory disease.	at 24 months
Secondary	Best molecular response	Best molecular response achieved during the follow-up	at 24 months
Secondary	Rate of AE/SAEs	Safety profile in terms of incidence of grade >3 CTC-NCI side effects and toxicities (AE/SAEs).	at 24 months
Secondary	Mutational analysis	Mutational analysis in terms of occurrence, type and number of BCR-ABL1 kinase domain mutations.	at 24 months
Secondary	Correlation between biological and MRD parameters	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.	at 24 months
Secondary	Disease free survival	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.	24 months
Secondary	Overall survival	Time interval between treatment start and death for any cause.	24 months
Secondary	Cumulative incidence of relapse	Time interval between achievement of CHR after three months of ponatinib until the date of first hematologic relapse of the disease.	24 months
Secondary	Role of hematological profile on survival outcome	Identification of hematological profile on survival outcome	at 24 months