Phase II Front-line Ponatinib in Adult Philadelphia+/BCR-ABL+ Acute Lymphoblastic Leukemia.
Status:
Active, not recruiting
Trial end date:
2021-12-31
Target enrollment:
Participant gender:
Summary
Drug resistance resulting from emergence of Imatinib-resistant BCR-ABL clones is a
significant problem in Ph positive ALL patients because after a very good initial response to
one TKI inhibitor, many patients relapse within one year, relapse being almost always
associated with a BCR-ABL kinase domain point mutation. The patients who relapse after
treatment with one TKI can be rescued to remission with another TKI, but the second remission
is usually shorter than the previous one. A more potent TKI inhibitor, and pan-active not
only on all the BCR-ABL variants (including the second generation TKI resistant T315I
mutant), but also on others molecular targets can do better. In this context, Ponatinib is a
novel synthetic orally active tyrosine kinase inhibitor (TKI), specifically developed to
inhibit BCR-ABL, the fusion protein that is the product of the Philadelphia chromosome (Ph)
in chronic myeloid leukemia (CML) and in a subset of acute lymphoblastic leukemia (Ph+ ALL).
It potently inhibits the BCR-ABL protein as well as mutated forms of the protein that arise
in patients resistant to prior therapies with TKIs. Ponatinib has been demonstrated to
inhibit all the mutations that have been detected so far, in vitro and in vivo and to
uniformly suppress the emerge of single-mutant clones in a mutagenesis assay. In the Phase II
study, 41% of Philadelphia chromosome positive acute lymphoblastic leukemia patients treated
with Ponatinib achieved major hematologic response, 47% had a major cytogenetic response, 38%
obtained a complete cytogenetic response, showing that Ponatinib provides significant benefit
despite previous intolerance or refractoriness to other TKIs. The Phase I trial showed that
patients with a more recent diagnosis had increased rates of major molecular response: 79%
for 14 patients with 0 to 5 years since diagnosis vs. 29% for 14 patients with more than 5 to
9 years since diagnosis (P=0.02) and 27% for 15 patients with more than 9 to 24 years since
diagnosis (P=0.009). These characteristics support the hypothesis for a role of Ponatinib not
only in patients resistant to prior TKI therapy but also in untreated ALL Ph+ patients, in
order to prevent the emergence of resistant caused by the selection of mutated Ph+ clones and
in order to avoid rapid progression of the disease.
Phase:
Phase 2
Details
Lead Sponsor:
Gruppo Italiano Malattie EMatologiche dell'Adulto Incyte Corporation