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01-01-2017 | Chronic myeloid leukemia | News

'Encouraging' report for CML selective BCR–ABL1 inhibitor

medwireNews: Early results for ABL001, a potent inhibitor that binds to the myristoyl site on the BCR–ABL1 kinase, suggest that the drug may be efficacious for chronic myeloid leukemia (CML) in patients with tyrosine kinase inhibitor (TKI) resistance.

The findings of the first-in-human multicenter study were presented by Timothy Hughes, from the University of Adelaide in South Australia, at the 2016 Annual Meeting & Exposition of the American Society of Hematology, held in San Diego, California, USA.

The trial determined the maximum dose of ABL001 tolerated by patients with chronic phase or accelerated phase CML, testing twice daily doses of 10, 20, 40, 80, 150 and 200 mg. The dose expansion dose was determined to be 20 or 40 mg twice daily.

In addition, dose escalation studies are ongoing for a once daily ABL001 dose and ABL001 given alongside nilotinib, imatinib or dasatinib, as well as for twice daily dosing in higher-risk patients with blast phase CML or Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL), Hughes explained.

Overall, 123 patients, aged a median of 55 years, were included, of whom 88% had chronic phase, 4% accelerated phase, and 2% blast phase CML, while 6% had ALL. Overall, 5%, 30% and 65% of patients were resistant, refractory or intolerant to one, two or at least three prior TKI therapies, respectively. T315I mutations had been detected in those who had received just one TKI agent.

In all, 46% of patients were without tyrosine kinase domain mutations, 30% had at least one of a wide range of mutations and 24% had levels too low to detect mutations.

Reporting that treatment was ongoing in 85% of 99 patients after a median of 37.6 weeks, Hughes said it was “encouraging” that few patients given serially increasing doses of once or twice daily ABL001 had come off treatment. Moreover, just four of the CML patients had so far progressed while on ABL001 monotherapy.

And analysis of eight ALL patients identified emerging mutations in just one patient, who developed several different genetic alterations including a myristoyl binding pocket mutation. There has been “surprisingly little” evidence of emerging mutations in the rest of the cohort, he commented.

Discussing adverse events possibly related to ABL001 therapy, Hughes explained that “because ABL001 is very selective for ABL and BCR–ABL it doesn’t have the same spill over into other kinases that you see in the TKIs.”

“However,” he continued, “we still see some pancreatic signal”, noting that 21% and 10% of 123 assessed patients experienced all-grade lipase and amylase increases, respectively, with grade 3 or 4 events in 10% and 1%, respectively, and three reported cases of pancreatitis. Fifteen percent of patients experienced grade 1 or 2 rash and 13% thrombocytopenia, with grade 3 or 4 for the latter reported in 6% of patients.

The dose-escalation phase involved 92 patients and dose-limiting toxicities were reported in six – grade 3 lipase elevations in three patients, plus one case each of grade 2 myalgia/arthralgia, grade 3 acute coronary event, and grade 3 bronchospasm. There was one death thought to be unrelated to ABL001 therapy.

Although the maximum tolerated dose of ABL001 has not been established, the 40 mg twice daily dose has been recommended for single-agent therapy for chronic phase CML, Hughes summarized.

Response data for the CML patients given single agent ABL001 for at least 3 months showed that 88% of the 16 patients with hematologic disease at baseline had a complete hematologic response, with a complete cytogenetic response (CCyR) achieved by 75% of the 12 patients with cytogenetic disease at entry.

In addition, 20% of 50 patients with a BCR–ABL1 >0.1% on the International Scale at baseline achieved a major molecular response (MMR), with at least a 1-log reduction achieved by 30% of the 33 patients with a BCR–ABL1 ≤10%. And the corresponding values at 12 months were 42% of 38 patients and 48% of 25 patients, respectively.

Closer analysis of the 77 patients who were resistant to their last TKI agent and treated with twice daily ABL001 showed that MMR was achieved by 13.3% at 6 months, rising to 37.5% at 12 months.

A 1-log or greater reduction at these two time points was reached by 29.4% and 42.9%, while 80% of the 10 patients with cytogenetic disease at baseline achieved CCyR within 6 months.

Ten of the 11 patients with a T315I mutation at baseline were followed-up for at least 3 months of twice daily ABL001 treatment, during which time four achieved CCyR and six maintained stable disease in the absence of CCyR or MMR, with no patient progressing to blast phase. One patient has maintained a baseline MMR for over 1 year.

“We’re seeing a stability but not a dramatic reduction”, Hughes said, adding that dose escalation is now ongoing in the T315I patients to see if a higher dose can achieve a deeper molecular response.

He described ABL001 as “generally well tolerated in heavily pretreated patients with CML resistant to or intolerant of prior TKIs”, while “clinical activity is seen in patients with nonmutant BCR-ABL1 as well as across multiple TKI-resistant mutations”.

Hughes concluded: “We think these findings are very promising and support evaluation in phase II/III clinical trials.”

By Lynda Williams

medwireNews is an independent medical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2017

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