NCT05306301

Ponatinib Plus Chemotherapy in Acute Lymphoblastic Leukemia Patients

Combination of Ponatinib Plus Chemotherapy As Frontline Treatment For Patients With BCR/ABL1-Like Acute Lymphoblastic Leukemia (BCR/ABL1-Like ALL)

• Status: Active Not Recruiting
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 32 (estimated)
• Sponsor: Gruppo Italiano Malattie EMatologiche dell'Adulto · Academic / Other
• Sex: All
• Age: 18 Years – 65 Years
• Healthy volunteers: Not accepted

Summary

Acute lymphoblastic leukemia (ALL) is the most frequent cancer in children, decreases in adolescence and adulthood, and a second peak can be recorded starting from the 6th decade of life. While the outcome in children is excellent, in the adolescent/adult population, the prognosis, though improved over the decades, it is still unsatisfactory and novel biologically-driven approaches are urgently needed. In this setting, thanks to the introduction of genome wide technologies, it was possible to recognize specific subset of ALL. Among those, the BCR/ABL1-like ALL are of extreme importance, since they are characterized by an unfavourable outcome and, on the other hand, can benefit of a targeted treatment, in particular with the pan-tyrosine kinase inhibitor ponatinib. The primary objective is to evaluate the clinical response - in terms of MRD negativity - in patients with a BCR/ABL1-like profile, according to the BCR/ABL1-like predictor tool, treated with Ponatinib in combination with chemotherapy.

Detailed description

This is an interventional, phase II study, foreseeing a run-in phase for adult BCR/ABL1-like ALL patients. Thirty-two newly-diagnosed B-lineage ALL cases with a BCR/ABL1-like profile will be treated (≥18 years old, up to the age of 65 years). This implies that about 100-120 B-lineage ALL patients negative at the conventional molecular screening (BCR/ABL1, ALL1/AF4, E2A/PBX1) will undergo the recently reported "BCR/ABL1 predictor" (13). The estimated timing for both the conventional and the BCR/ABL1-like screening is within the steroid pre-phase (7 days). After a steroid pre-treatment phase (prednisone: 60 mg/m2/day, day -6 up to day 0), that can occurr before enrollment during the screening period, patients who prove BCR/ABL1-like will be treated with Ponatinib in combination with a pediatric-inspired and minimal residual disease (MRD)-driven treatment scheme - as in the previous GIMEMA LAL1913 protocol (EudraCT number 2009-016075-30) -, for the first 2 cycles (C1 and C2). In order to avoid toxicity, namely thrombotic, pancreatic and hepatic events, Asparaginase will be omitted from this scheme. As for the run-in phase, patients will receive ponatinib at the dosage of 15 mg. If no relevant toxicities are observed (i.e. 2 distinct patients developing a Grade IV non hematologic toxicity related to ponatinib within the first cycle of induction, 28 days), Ponatinib will be administered at the dose of 30 mg in the remaining patients. MRD will be evaluated at week 4, 10, 16, and 22. If a donor is available (MUD and haploidentical donors allowed, HLA typing carried out as soon as possible), MRD-positive patients will proceed to an allogeneic transplant after cycle 3; otherwise, if no donor is available, they will continue treatment with 5 additional consolidation/reinduction blocks, followed by 24 28-day cycles of maintenance, as detaield in the treatment scheme. If beneficial for the patients, ponatinib will be provided until disease progression. CNS prophylaxis will be carried out throughout the course of treatment with 12 medicated rachicenteses (Methotrexate 12.5 mg, Aracytin 50 mg, Urbason 20 mg).

Conditions

• Chemotherapy
• Leukemia, Acute Lymphoblastic

Interventions

Type	Name	Description
DRUG	Ponatinib	Ponatinib is a novel, synthetic, orally-active TKI discovered using a computational and structure based drug design approach. Ponatinib was specifically designed to inhibit all clinically relevant variants of BCR-ABL1, including the T315I mutant (15-17). In vitro assays have demonstrated that Ponatinib potently inhibits the kinase enzymatic activity of the T315I ABL kinase domain, as well as that of the native (unmutated) enzyme. In leukemia cell lines expressing these BCR-ABL1 variants, Ponatinib potently inhibited BCR-ABL1 signaling, leading to the reduction of cellular proliferation and induction of apoptosis. Ponatinib also inhibits the proliferation of cell lines expressing other major clinically-observed Imatinib-resistant mutants of BCR-ABL1.

Timeline

• Start date: 2022-10-05
• Primary completion: 2026-03-01
• Completion: 2028-07-01
• First posted: 2022-04-01
• Last updated: 2026-03-06

Locations

24 sites across 1 country: Italy

Regulatory

• FDA-regulated drug study