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New Drug Overcomes TKI Resistance in Heavily Pretreated Patients

Fuerst, Mark L.

doi: 10.1097/01.COT.0000479761.08172.8c
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ORLANDO, Florida—A new potent, specific inhibitor of BCR-ABL with a distinct mechanism of action shows rapid anti-tumor activity in heavily pretreated patients with chronic myeloid leukemia (CML), according to data reported here at the American Society of Hematology Annual Meeting (Abstract 138).

ABL001 is a small molecule designed to inhibit BCR-ABL in a different way than other tyrosine kinase inhibitors (TKIs) as it binds to a unique region of BCR-ABL, forcing a conformational change that disables the protein's active site, explained Oliver G. Ottmann, MD, of the Department of Hematology, School of Medicine, at Cardiff University in the UK.

In an interview, Ottmann said: “This new class of drug, allosteric inhibitor, inhibits TKI activity not through the classic mode, but instead to a physically remote area of the BCR-ABL protein, inducing changes in the kinase. The idea is to overcome resistance mediated by classic TKIs and point mutations.”

First-in-Human Study

The interim results of the ongoing, first-in-human study he presented provide proof of principle of the effectiveness of allosteric inhibition of the BCR-ABL kinase in the treatment of CML, he said.

Often, CML patients develop resistance to TKIs via ABL kinase point mutations. ABL001 targets the myristoyl pocket of the ABL1 kinase and inhibits proliferation of BCR-ABL–positive cells with clinically observed TKI resistance mutations.

“This pocket serves an auto-regulatory function subsequently lost upon fusion with BCR,” Ottmann said. “ABL001 functionally mimics this auto-regulatory role and restores negative regulation of kinase activity.”

In preclinical studies, ABL001 showed potent anti-tumor activity, with evidence of complete tumor regression, he noted. In animal models, the combination of ABL001 and nilotinib led to sustained tumor regression without emergence of resistant disease, even after treatment discontinuation.

Ottmann reported the results of a multicenter, open-label, Phase I dose-escalation study of ABL001 designed to examine the safety of ABL001. The drug was administered orally as a single agent twice daily in patients with chronic or accelerated-phase CML that has not responded to two or more prior TKIs due to resistance or intolerance.

Study Specifics

Of the study's 59 patients, median age of 56, almost all of them (98%) had a baseline Eastern Cooperative Oncology Group performance status of 0-1. More than half were also heavily pretreated, receiving three or more prior TKIs.

Patients were treated with the twice-daily doses of ABL001 ranging from 10 to 150 mg. Treatment continued until disease progression, unacceptable toxicity, consent withdrawal, or death; however, at the time of data cut-off, the maximum tolerated dose had not yet been reached, Ottmann noted.

“We normally see no responses at early dose levels, with responses increasing with successive doses. We saw pronounced effects at 20 mg and 40 mg daily doses.”

All 12 patients in hematologic relapse achieved a complete hematologic response within two months and two-thirds of the 12 TKI-resistant patients in cytogenetic relapse had a complete cytogenetic response within three to six months. Of the 29 patients in molecular relapse, 10 achieved a major molecular response within six months.

The study also demonstrated clinical activity across TKI-resistant mutations, such as V299L, F317L, and Y253H, Ottmann reported.

In regard to safety, there was a low rate of grade 3 or 4 adverse events. “The two most common adverse events are hematologic, such as thrombocytopenia and neutropenia—which were expected and of low frequency—and lipase reductions, which clinically exceeded grade 2. In general, the range of low-level toxicities is quite manageable,” Ottmann said.

There were five dose-limiting toxicities, including two grade 3 lipase elevation at 40 mg twice daily and 200 mg once daily, one grade 2 arthralgia at 80 mg twice daily, one acute coronary syndrome at 150 mg twice daily, and grade 3 bronchospasm at 200 mg twice daily. There were also three incidents of grade 2 acute pancreatitis during cycle 5 at doses 80 mg or higher twice daily. No patients died during the study.

In conclusion, Ottmann said: “ABL001 was generally well tolerated in heavily treated CML patients resistant to or intolerant of prior TKIs. Allosteric inhibition of BCR-ABL001 is a promising therapeutic approach in patients with CML. Enrollment to determine a recommended dose and assess safety and tolerability is ongoing.”

Next Steps

The next step is to get more experience with the drug, he said: “In terms of dose schedules, we are looking at twice- and once-daily doses as well as combining it with nilotinib to ascertain if this is tolerable and feasible. We see signs of enhanced activity with nilotinib. The drug may also combine with other BCR-ABL inhibitors, given the spectrum of mutations it inhibits.”

Ottmann noted that some patients had combinations of mutations and the presence of chromosome abnormalities, and some had received prior ponatinib.

In Phase II trials, the researchers plan to expand the experience with 40 mg doses and in patients with T315I mutations. “We do not want to choose doses that are too high, which was done in other TKI trials,” Ottmann said. “We need to understand more about the exciting mode of action of this drug and the way it interacts with other TKIs. We do not see the typical dose response seen with TKIs. We need confirmation of the way it alters sensitivity with more classic TKIs.”

Ottmann pointed out that some patients did not respond. “We hope to see rapid, deeper responses with this drug alone or in combinations with TKIs in clinical trials. For patients with more advanced disease, it may provide more effective treatment.”

Perspective from Neil Shah

In an interview, the moderator of the session that included the study, Neil Shah, MD, PhD, Professor in Hematology-Oncology and Leader of Hematopoietic Malignancies at the University of California, San Francisco, called the response data encouraging: “The fact that the drug selects for mutations that confer substantial resistance suggests that it puts pressure on the target, which is good.”

The drug was developed to complement nilotinib, but “there are not enough data to know if the doses employed so far effectively inhibit mutations to nilotinib,” Shah said. He noted that ponatinib is active against all mutations, but it has significant safety issues. “By going after a different portion of the BCR-ABL protein, we hope the new drug has better tolerability than standard TKIs, but this needs to be demonstrated.”

Early data show that 20 to 30 percent of patients have grade 1 or 2 gastrointestinal side effects with ABL001, Shah continued, adding that the extent to which it is well tolerated with nilotinib in doses to cover mutations is still unknown.

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
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