AMN107, Novel Inhibitor of Bcr-Abl, Has Activity in Imatinib-Resistant Chronic Myelogenous Leukemia

ATLANTA—A phase I study of AMN107 (Novartis) in Philadelphia-positive (Ph+) chronic myelogenous leukemia (CML) and acute lymphocytic leukemia (ALL) shows the new agent induces responses in patients with imatinib (Gleevec)-resistant Bcr-Abl mutations, according to a presentation at the 47th Annual Meeting of the American Society of Hematology (abstract 37).

Although imatinib offers 5-year survival rates of 90% to 95% and cytogenetic complete response rates of 70% to 80% in CML, imatinib resistance occurs at 4% per year, said Hagop M. Kantarjian, MD, professor of medicine and Leukemia Department chair at M.D. Anderson Cancer Center. Furthermore, resistance progresses to accelerated or blastic phase at 2% per year. Abl mutations are detected in 40% of resistance cases. "More potent Bcr-Abl or Abl and Src inhibitors may overcome resistance and improve prognosis," Dr. Kantarjian said.

AMN107 is 10 to 50 times more potent than imatinib and inhibits 32 of 33 known imatinib-resistant Bcr-Abl mutations (all but the T315I mutation). Its pharmacokinetic profile favors oral administration, and in animal models of CML it prevents and delays disease development and improves survival.

Study Protocol

Dr. Kantarjian's study enrolled 119 patients at three centers. It included CML patients in chronic phase (CP), accelerated phase (AP) and blastic phase (BP), and relapsed or refractory Ph+ ALL patients. The maximum tolerated dose (MTD) was defined as the dose at which 33% of subjects experience grade 3-4 toxicity on the first cycle. AMN107 doses between 50 and 1,200 mg daily, and 400 and 600 mg twice daily were explored. Abl mutations were found in 43% of cases. The median highest imatinib dose in prior treatment had been 800 mg. Median duration of AMN107 treatment was 152 days.

After quickly escalating doses, investigators realized that plasma levels of AMN107 remained the same between 400 mg and 1,200 mg. Dividing doses, they saw toxicities develop with 600 mg twice daily and decided that 400 mg twice daily, which allowed 40% to 50% higher plasma levels, is the appropriate dose for pivotal trials in CML.

Dr. Kantarjian reported that among 20 CML patients in chronic phase, complete hematologic responses with normalization of blood counts were found in 92%, suppression of Ph+ cells in 53%, and disappearance of Ph+ cells in 35%.

"As expected, those who had been in accelerated or blastic phase still had impressive results, but not as good," he commented at an ASH press briefing. Among 56 patients in accelerated phase, complete hematologic responses were found in 76%, Ph+ suppression in 55%, with complete suppression in 14%. In 24 blast phase patients, hematologic responses were reported in 42%, Ph+ suppression in 29%, and complete Ph+ suppression in 4% (1 patient). Patients responded equally, with or without mutations.

Among 10 ALL patients with active status, one (10%) responded to AMN107. Among three ALL patients with minimal residual disease (PCR positive), one (33%) responded.

The most common severe adverse event was low white blood cell counts found in 20% of patients, a proportion lower than is found with imatinib, Dr. Kantarjian pointed out. Temporary bil-irubin increases, which subsided even with continued treatment, were also reported. "In newly diagnosed patients, this would be quite safe. . . . So we are excited about this drug. It is safe and active," Dr. Kantarjian commented. Pivotal trials are currently being completed.

Press conference moderator Brian Drucker, MD, Oregon Health & Science University Cancer Institute, Portland, stated, "The consensus is that the T315I mutation is resistant to all the existing kinase inhibitors that bind to ATP." The mutation appears to alter the molecular entry point where drugs penetrate, closing off the entry. "So if we want to overcome that resistance, we need to develop kinase inhibitors that bind outside that site," Dr. Drucker said.

Dr. Kantarjian suggested that in view of the fact that the T315I mutation tends to occur later in the course of CML disease, use of multiple kinase inhibitors either in sequence or in an upfront combination in a "hit early and hit hard" strategy might prevent the mutation from occurring. It may be possible, thereafter, to stimulate the immune system with "vaccine-like" strategies, he said.