Positive data from ARIAD Pharmaceuticals' ongoing AP24534 study in advanced hematological cancer patients

Dec 8 2009

ARIAD Pharmaceuticals, Inc. (NASDAQ: ARIA) today announced positive clinical data from an ongoing Phase 1 study of its investigational, pan-BCR-ABL inhibitor, AP24534, in patients with advanced hematological cancers. The data provide strong clinical evidence of hematologic, cytogenetic and molecular anti-cancer activity of AP24534, a multi-targeted kinase inhibitor, in heavily pretreated patients with resistant and refractory chronic myeloid leukemia (CML), including those with the T315I mutation of the target protein, BCR-ABL. The data are being presented this afternoon at the 51^st Annual Meeting of the American Society of Hematology (ASH) being held in New Orleans, LA.

The primary objectives of the Phase 1 study in patients with refractory hematological cancers are to determine a maximum tolerated dose and the recommended dose for further study of AP24534 and to examine its safety and antitumor activity. The trial uses an open-label, dose-escalating design.

Forty-four patients have been enrolled to date in the study in six dosing cohorts (2, 4, 8, 15, 30 and 60 mg administered orally once daily); 40 of the patients have resistant and refractory CML or Philadelphia-chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). All of these 40 patients have been treated with, and were resistant to, the available first- and second-line targeted therapies for CML and, in most instances, with other investigational agents as well. Eighty-one percent of CML and Ph+ ALL patients in the study were resistant to at least three tyrosine kinase inhibitors, including imatinib (Gleevec^®), dasatinib (Sprycel^®), and nilotinib (Tasigna^®).

“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,” stated Jorge Cortes, M.D., professor and deputy chair, Department of Leukemia, M.D. Anderson Cancer Center and the study’s principal investigator. “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.”

Key data from the study presented at ASH include:

• Safety data show AP24534 to be well tolerated. There were no dose-limiting toxicities (DLTs) observed at dose levels lower than 60 mg.
• Of the 44 patients treated with AP24534, 28 have chronic phase CML, 5 have accelerated phase CML, 5 have blast phase CML, 2 have Ph+ ALL and 4 have non-CML hematologic malignancies. Twenty-eight patients currently remain on study, with 22 at the three highest dose levels (15, 30 and 60 mg/day).
• Of 20 chronic phase CML patients evaluable for cytogenetic response across all dose levels, 25 percent (5 of 20) demonstrated a complete cytogenetic response, 45 percent (9 of 20) experienced a major cytogenetic response, and 60 percent (12 of 20) demonstrated any cytogenetic response (i.e. major, minor or minimal response). One of four evaluable accelerated phase patients experienced a complete cytogenetic response. No response was seen in the seven blast phase or Ph+ ALL patients.
• A complete hematologic response was observed in eighty-three percent (10 of 12) of chronic phase CML patients evaluable for hematologic response. An additional 10 chronic phase patients entered the study already meeting the criteria for CHR and were maintained. A major hematologic response was observed in three of four accelerated phase patients, none of five blast phase patients, and one of two Ph+ ALL patients.

• In patients with resistant BCR-ABL mutations, hematologic, cytogenetic, and molecular responses have been observed. Of the 18 CML patients with the T315I mutation in the study, 55 percent (10 of 18) currently have chronic phase disease, and nine of these patients remain on study. Seven chronic phase patients are evaluable for response. Of them, all have achieved a complete hematologic response and 43 percent have experienced a major cytogenetic response.
• Consistent with the pre-clinical profile of AP24534 as a pan-BCR-ABL inhibitor, responses also have been seen in patients with mutations other than T315I that confer resistance to either dasatinib or nilotinib. One patient with the F359C mutation, resistant to both imatinib and nilotinib, demonstrated a complete hematologic response, complete cytogenetic response and major molecular response after three months on 15 mg of AP24534. One other patient in the study with the F317L mutation, resistant to imatinib, dasatinib and nilotinib experienced a complete cytogenetic response after three months on 60 mg of AP24534.
• There were four patients with DLTs out of 12 patients evaluable at the 60 mg dose level. The dose-limiting toxicities are chemical and clinical pancreatitis (i.e. elevated amylase and lipase, and grade 2 pancreatitis). The most common laboratory abnormalities have been mild to moderate thrombocytopenia (low platelet count) and neutropenia (low white blood cell count) which were found to be more common in patients with blast and accelerated phases of CML and Ph+ALL.
• Pharmacokinetic data indicate that blood levels have been achieved that surpass those predicted preclinically to be associated with complete inhibition of all resistant mutants. Pharmacodynamic data demonstrate sustained target inhibition at doses of 8 mg and higher against a spectrum of BCR-ABL variants. These observations included evidence of sustained target inhibition against the T315I mutant observed at dose levels of 15 mg and above.

“These are remarkable results in heavily pre-treated patients with resistant leukemia that demonstrate hematologic, cytogenetic and molecular responses to AP24534,” said Frank G. Haluska, M.D., Ph.D., vice president, clinical affairs at ARIAD. “The data provide evidence of clinical proof-of-concept of AP24534 in patients who have very few, if any, viable treatment options available to them.”

“The confirmation of anti-tumor activity by AP24534 in this patient population is strong, even in the lower dose cohorts and in those patients who have received only short courses of therapy to date. We will complete enrollment in this study and undertake additional evaluation of the data in the coming months as we consult with regulatory agencies on beginning a pivotal registration trial of AP24534 in the second half of next year,” Dr. Haluska added.