Potential new alternative in CML when TKI therapy fails

All but 1 patient had chronic phase CML, 18 (31%) were TKD nonmutated, 14 (24%) were mutated, and 17 (46%) were not evaluable.

Patient disposition

Of the 43 patients in the monotherapy BID cohort, 1 was treated at the 10 mg dose level, 5 at the 20 mg level, 12 at the 40 mg level, 12 at the 80 mg level, 8 at the 150 mg level, and 5 at the 200 mg level. They had a median duration of drug exposure ranging from 25 weeks to 67 weeks.

Of the 11 patients in the monotherapy QD group, 5 were treated at the 120 mg dose level and 6 at the 200 mg level. Their drug exposure was a median of 26 weeks for those receiving 120 mg and 9.8 weeks for those receiving the 200 mg dose.

And the 5 patients in the ABL001-plus-nilotinib group had a median of 6.3 weeks of drug exposure.

“We had a remarkably low rate of discontinuation to date,” Dr Ottmann pointed out.

Ten patients discontinued therapy, all in the monotherapy BID group, 1 at 10 mg, 2 at 40 mg, 2 at 80 mg, 3 at 150 mg, and 2 at 200 mg.

Seven patients discontinued for adverse events. Two patients withdrew consent, and 1 patient in the 40 mg group had disease progression, which is “quite remarkable in a phase 1,” Dr Ottmann said.

Pharmacokinetic profile

ABL001 is rapidly absorbed in a median of 2 to 3 hours, and there is a dose-proportional increase in exposure following single and repeated dosing.

The drug has an approximately 2-fold or lower accumulation on repeated dosing and a short elimination half-life of 5 to 6 hours.

Safety

“We have excellent tolerability,” Dr Ottmann said, with a small number of grade 3/4 adverse events (AEs).

Grade 3/4 AEs considered to be drug-related were mostly associated with hematologic suppression. Four patients (7%) had thrombocytopenia, 4 (7%) neutropenia, 3 (5%) anemia, 4 (7%) lipase increase, and 1 (2%) hypercholesterolemia.

AEs of all grades suspected of being related to the study drug and occurring in 5% or more of patients included thrombocytopenia (19%), neutropenia (15%), anemia (10%), nausea/vomiting/diarrhea (29%), arthralgia/myalgia (20%), rash (17%), fatigue (15%), lipase increase (14%), headache (14%), pruritus (10%), dry skin (7%), hypophosphatemia (7%), and acute pancreatitis (5%).

“The pancreatitis was reversible upon interruption or discontinuation of the drug,” Dr Ottmann explained.

There were 5 dose-limiting toxicities. Two patients had grade 3 lipase elevation in the 40 mg BID and 200 mg QD cohorts. One patient had grade 2 myalgia/arthralgia at 80 mg BID, 1 patient had a grade 3 acute coronary event at 150 mg BID, and 1 patient had a grade 3 bronchospasm at 200 mg BID.

No deaths occurred on the study, and the dose escalation is still ongoing.

Response

Twenty-nine patients with 3 months or more of follow-up were evaluable for response.

Twelve patients, who at baseline had hematologic relapse, achieved complete hematologic response within 2 months, and 8 who had cytogenetic relapse at baseline achieved a complete cytogenetic response within 3 to 6 months.

Of the 29 patients who had molecular relapse at baseline, 10 (34.5%) achieved a molecular response within 6 months, 7 (24.1%) had 1 log or more reduction in BCR-ABL1, 9 (31.0%) had less than a log reduction, and 3 (10.3%) had no reduction.

“The obvious question from the preclinical data,” Dr Ottmann said, “is do the mutations respond?”

And ABL001 has shown clinical activity across TKI-resistant mutations, such as V299L, F317L, and Y253H.