Data Promising for Oral AP24534 in Refractory CML and Other Hematologic Malignancies

New Orleans, LA — A multi-target kinase inhibitor, known as AP24534, has shown strong clinical evidence of hematologic, cytogenetic, and molecular anti-cancer activity in heavily pretreated patients with resistant and refractory chronic myeloid leukemia (CML), including in those with the T315I mutation of the target protein, BCR-ABL. Patients with the T315I mutation have demonstrated resistance to imatinib (Gleevec) and second-generation tyrosine kinase inhibitors nilotinib (Tasigna) and dasatinib (Sprycel), making it critical to find an effective treatment for these patients. According to Jorge Cortes, MD, professor and deputy chair, Department of Leukemia, M.D. Anderson Cancer Center, who served as the study’s lead investigator, “The initial findings from this study show AP24534 to be well tolerated and to produce beneficial anti-leukemia activity in patients who have failed prior tyrosine kinase inhibitor therapy for CML.”

The phase I study has enrolled 44 patients to date. Of these, 28 have CML chronic phase (CP), 5 have CML accelerated phase (AP), 5 have CML in the blast phase (BP), 2 have Philadelphia-chromosome positive (Ph+) acute lymphoblastic leukemia (ALL), and 4 have other hematologic malignancies.In an effort to determine the maximum tolerated dose and examine efficacy, the study features six dosing cohorts, with patients receiving 2 mg, 4 mg, 8 mg, 15 mg, 30 mg, or 60 mg of oral AP24534 once daily. At the time data was presented, 28 patients remained in the study, 22 of whom were receiving one of the three highest dosages of AP24534.

A total of 20 patients with CML-CP evaluable for cytogenetic response (CyR) across all dosing levels; 60% (n = 12) of patients demonstrated some level of CyR. One-quarter (n = 5) had complete CyR and 45% (n = 9) had major CyR. No response was observed in any of the CML-BP or Ph+ ALL patients. Of the 12 CML-CP patients evaluable for hematologic response, 83% (n = 10) had a complete hematologic response (CHR); 3 of 4 patients with CML-AP had a major hematologic response. As was seen with CyR, none of the patients with CML-BP had a hematologic response; 1 of the 2 Ph+ ALL patients demonstrated hematologic response. CyR, hematologic response, and molecular response was observed in patients with resistant BCR-ABL mutations.

Looking at the subset of CML patients (n = 18) with a T315I mutation, 55% (n = 10) currently have CML-CP, of which 9 remain on the study and 7 are evaluable for response. All 7 of the evaluable patients have achieved CHR. The investigators also observed responses in patients with mutations other than T315I, including a patient with a F359C mutation, known to be resistant to imatinib and nilotinib. This patient experienced CHR, CCyR, and major molecular response after 3 months of treatment at the 15-mg dose of AP24534.

AP24534 was generally well tolerated. Side effects associated with the drug included nausea, fatigue and dry eye, anorexia, arthralgia, dizziness, dry mouth, headache, hot flush, myalgia, vomiting, and QTc prolongation (observed in 1 patient in the 2-mg cohort and 1 patient in the 4-mg cohort). Grade 3-4 thrombocytopenia occurred in 36% of patients and grade 3-4 neutropenia in 41%, with both of these hematologic toxicities occurring more frequently in patients with advanced stages of CML or baseline cytopenia.

Dr Cortes concluded, “Pending further clinical trials, AP24534 appears to represent a potential significant advance for CML patients who have become resistant or refractory to currently available therapies and who are in great need of new treatment options.” This includes CML-CP and CML-AP patients with the T315I mutation. ASH Abstract 643.

Study investigators have ownership in, received support, or have other affiliations with ARIAD, Novartis, BMS, Celgene, and Genzyme.

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