ABL001 Shows Signs of Overcoming TKI Resistance in Heavily Pretreated Patients with CML

The small molecule ABL001 exhibits rapid anti-tumor activity in heavily pretreated patients with chronic myeloid leukemia (CML), according to research presented by Oliver G. Ottmann, MD, from Cardiff University in the United Kingdom, at the 2015 ASH Annual Meeting. The interim results of the ongoing, first-in-human study provide “proof of principle of the effectiveness of allosteric inhibition of the BCR-ABL kinase in the treatment of CML,” Dr. Ottmann said.

Patients with CML often develop resistance to tyrosine kinase inhibitors (TKIs) via ABL kinase point mutations but, unlike currently available TKIs, 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,” the authors explained. “ABL001 functionally mimics this auto-regulatory role and restores negative regulation of kinase activity.”

In this multicenter, open-label, phase I, dose-escalation study, researchers examined the safety of ABL001 (administered orally as a single agent twice daily) in patients with chronic or accelerated-phase CML who were resistant or intolerant to two or more prior TKIs.

Most of the 35 patients enrolled in the study (median age = 56 years; range = 23-74 years) were also heavily pretreated: 20 (57%) had received three or more prior TKIs.

Patients received one of the following twice-daily doses: 10 mg (n=1), 20 mg (n=5), 40 mg (n=12), 80 mg (n=11), or 150 mg (n=6).

Treatment continued until disease progression, unacceptable toxicity, consent withdrawal, or death; however, at the time of data cut-off, maximum tolerated dose had not yet been reached, Dr. Ottmann noted.

In addition, 30 patients are still receiving ABL001 at doses ranging from 20 to 150 mg twice-daily; the median duration of exposure among these patients was 20.9 weeks (range = 0-49.7 weeks). Five patients discontinued treatment: one due to disease progression, three due to adverse events (AEs), and one for stem cell transplant.

The drug appeared to be well tolerated, with the majority of AEs grade 1 or 2. The most common grade 3 or 4 AEs included anemia (9%), thrombocytopenia (6%), neutropenia (6%), and increased lipase (6%).

However, the authors observed three instances of dose-limiting toxicity: one grade 3 lipase elevation, one grade 2 arthralgia at 40 mg twice-daily, and one acute coronary syndrome at 150 mg twice-daily.

Three cases of grade 2 acute pancreatitis occurred in cycle five among patients receiving higher doses (≥80 mg twice-daily). No deaths have occurred during the study.

Efficacy was analyzed through hematologic, cytogenetic, and molecular assessments, which were available for 20 patients at the time of presentation. Seventeen of these patients were resistant to prior TKIs and three were intolerant of prior TKIs.

Evidence of drug activity was noted at all dose levels. All five patients in hematologic relapse achieved complete hematologic response within three months, while nine of 11 TKI-resistant patients who achieved cytogenetic relapse (defined as >65% Philadelphia chromosome-positive metaphases at baseline) achieved a major cytogenetic response by three months. Six of these patients also achieved complete cytogenetic responses.

Of the 17 TKI-resistant patients with baseline BCR-ABL >0.1%, 11 achieved a ≥1-log reduction in BCR-ABL percentage and five achieved a major molecular response by five months after treatment with ABL001. Clinical activity was seen across TKI-resistant mutations, including Y253H and V299L.


Reference

Ottmann OG, Alimena G, DeAngelo DJ, et al. ABL001, a potent, allosteric inhibitor of BCR-ABL, exhibits safety and promising single-agent activity in a phase I study of patients with CML with failure of prior TKI therapy. Abstract #138. Presented at the 2015 ASH Annual Meeting, December 5, 2015; Orlando, Florida.

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