Potential new alternative in CML when TKI therapy fails
ASH Annual Meeting
Photo courtesy of ASH
ORLANDO, FL—ABL001, an allosteric inhibitor of BCR-ABL1, has shown early evidence of single-agent activity in a multicenter, first-in-human, first-in-class trial of heavily treated patients with chronic myeloid leukemia (CML) that is resistant to or intolerant of prior tyrosine kinase inhibitors (TKIs), even at the lowest dose evaluated.
ABL001 and classical TKIs exhibit complementary mutation profiles, with ABL001 showing activity against TKI resistance mutations.
When combined with nilotinib in a mouse model of CML, ABL001 prevented the emergence of resistant disease even after treatment was discontinued.
“This produces a new therapeutic concept—that of allosteric inhibition,” said Oliver G. Ottmann, MD, of Cardiff University in the UK.
The ABL001 binding site is located in a region remote from the kinase domain and has the potential to combine with TKIs for greater pharmacologic control of BCR-ABL1.
“This obviously has the opportunity both for combining different treatments and for overcoming resistance to one or the other,” Dr Ottmann added.
Based on preliminary pharmacokinetic data and preclinical evidence, investigators proceeded to evaluate ABL001 in a phase 1 dose-escalation and dose-expansion study.
Their primary objective was to determine the maximum tolerated dose (MTD) in humans and the recommended dose for expansion (RDE). Secondary objectives were to evaluate the safety, tolerability, preliminary anti-CML activity, and pharmacokinetic and pharmacodynamic profile.
Dr Ottmann presented the findings during the 2015 ASH Annual Meeting as abstract 138.*
Study design
Patients received ABL001 orally as a single agent twice a day (BID) continuously until disease progression, unacceptable toxicity, consent withdrawal, or death.
The dose-escalation schema followed a Bayesian logistic regression model based on dose-limiting toxicities during cycle 1. Doses ranged from 10 mg to 200 mg BID.
A subsequent dose-expansion phase was planned to augment the data generated in the dose-escalation phase and to include patients with Ph-positive acute lymphoblastic leukemia resistant or intolerant to prior TKI therapy.
Dr Ottmann noted that there were 2 protocol amendments. The first amendment was made to include a once-daily (QD) dosing of ABL001 at 120 mg and 200 mg. The second amendment was made to evaluate the combination of 40 mg of ABL001 BID with nilotinib at 300 mg BID.
Inclusion/exclusion criteria
Patients had to be at least 18 years old with CML in chronic or accelerated phase. They had to have failed at least 2 prior TKIs or be intolerant of TKIs. Their performance status had to be 0–2.
Patients were excluded from the trial if they had an absolute neutrophil count less than 500/mm3, a platelet count less than 50,000/mm3, bilirubin level more than 1.5 x the upper limit of normal (ULN) or more than 3.0 x ULN in patients with Gilberts syndrome.
Their aspartate aminotransferase or alanine aminotransferase could not be above 3 x ULN, and creatinine could not be above 1.5 x ULN.
Patients were also excluded if they needed treatment with strong inhibitors or inducers of CYP3A4 or its substrates with narrow therapeutic index.
Patient demographics
Fifty-nine patients were enrolled on the trial at the time of the presentation and they had “typical” characteristics of patients at this stage, Dr Ottmann said.
Their median age was 56 (range, 23–78). Almost two-thirds (61%) were male and 39% female.
All but 1 patient had an ECOG performance status of 0, and patients had a median of 3.5 (range, 2–5) prior lines of therapy. Twenty-four patients (41%) had 2 prior TKIs, and 35 (59%) had 3 or more TKIs. Forty-five patients (76%) were resistant and 14 (24%) were intolerant to their prior TKI.
