The aim of the study is to evaluate the efficacy of Ponatinib, either alone or in combination with chemotherapy, in inducing remission in patients: MRD positive (persistent or relapsed), patients after haematological and extra-haematological relapse and patients who do not have never achieved remission after any previous treatment.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fondazione Gimema Franco Mandelli Onlus, Fondazione Gimema Franco Mandelli Onlus

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

4 May 2021 → ongoing

Decision date (initial)

2024-09-18

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Fondazione GIMEMA Franco Mandelli Onlus · Incyte Biosciences International

External identifiers

EU CT number

2024-516868-28-00

EudraCT number

2020-003912-28

ClinicalTrials.gov

NCT04475731

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Therapy

The primary objective of this study is to evaluate the rate of patients obtaining a MRD negativity/MRD reduction following treatment with either ponatinib alone or in combination with systemic chemotherapy after 3 months of treatment. Since both MRD+ and hematologically and extra-hematologically relapsed/refractory patients will be considered, the primary objective will be analyzed separately in the two groups of MRD+ and hematologically and extra-hematologically relapsed/refractory patients.

Secondary objectives 10

1. The duration of CMR, if achieved.
2. The achievement of an hematologic remission in patients treated for an hematologic and extra-hematoloigc relapse and for a refractory disease.
3. The best molecular response.
4. Safety profile.
5. Mutational analysis.
6. The correlation between biological and MRD parameters.
7. Disease-free survival (DFS).
8. Overall Survival (OS).
9. Cumulative Incidence of relapse (CIR).
10. Role of clinical and biological parameters on survival outcome.

Conditions and MedDRA coding

Ph+ Acute Lymphoblastic Leukemia

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

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 11

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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint is the 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 endpoints 10

1. Duration of CMR, if applicable.
2. Rate of patients who achieve an hematologic remission in patients treated for an hematologic and extra-hematoloigc relapse and for a refractory disease.
3. The best molecular response achieved during the study.
4. Safety profile in terms of incidence of grade >3 CTC-NCI side effects and toxicities (AE/SAEs).
5. Mutational analysis in terms of occurrence, type and number of BCR-ABL1 kinase domain mutations.
6. 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
7. DFS at 24 months.
8. OS at 24 months
9. CIR at 24 months.
10. Role of clinical and biological assessment at baseline, type of fusion protein (p190 vs p210) and presence of additional genomic lesions and mutations, duration on CMR, OS and DFS.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 6

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fondazione Gimema Franco Mandelli Onlus

Sponsor organisation

Fondazione Gimema Franco Mandelli Onlus

Address

Via Casilina 5

City

Rome

Postcode

00182

Country

Italy

Scientific contact point

Organisation

Fondazione Gimema Franco Mandelli Onlus

Contact name

Data center

Public contact point

Organisation

Fondazione Gimema Franco Mandelli Onlus

Contact name

Data center

Third parties 1

Fondazione Gimema Franco Mandelli Onlus

Sponsor organisation

Fondazione Gimema Franco Mandelli Onlus

Address

Via Casilina 5

City

Rome

Postcode

00182

Country

Italy

Locations

1 EU/EEA country · 51 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 8 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications