Bristol-Myers Squibb Company Reports Positive Results From SPRYCEL Trials UPDATE

ORLANDO, Fla., Dec. 11 /PRNewswire-FirstCall/ -- Today, Bristol-Myers Squibb Company announced results of a randomized Phase II study showing that a substantial number of patients with chronic-phase chronic myelogenous leukemia (CML) resistant to Gleevec achieved cytogenetic and hematologic responses by three months and maintained these responses through one year when treated with SPRYCEL. The open-label, multi-center international trial was designed to examine the efficacy and safety of SPRYCEL at 70 mg twice daily or an increased dose of Gleevec to 800 mg/day (patients enrolled in the trial had been previously treated with Gleevec less than or equal to 600 mg/day). Results were presented at the 48th Annual Meeting and Exposition of the American Society of Hematology (ASH).

Analysis of the data at three months and 15 months show that the number of patients who achieved and maintained a major cytogenetic response increased from 36 percent to 53 percent with SPRYCEL, and from 29 percent to 33 percent with escalated doses of Gleevec.

While the study was not powered to compare SPRYCEL to high-dose Gleevec, analysis of the data after a median follow-up of 15 months show a statistically significant difference between SPRYCEL and high-dose Gleevec in progression-free survival (length of time during which the leukemia does not progress) (p<0.0001), major and complete cytogenetic responses (p=0.023 and p=0.004, respectively) and major molecular response (p=0.038).

"This study may help answer important questions about treating resistant chronic-phase CML patients and suggests that physicians should consider treatment with SPRYCEL in patients resistant to lower doses of Gleevec," said Neil Shah, MD, PhD, Assistant Professor, Division of Hematology/Oncology, University of California, San Francisco.

Study Design and Results

This international, open-label, randomized Phase II study (START R, -017) was conducted in 23 countries. The study evaluated adult patients with chronic-phase CML who had primary or acquired resistance to 400-600 mg doses of Gleevec. Patients were randomized in a 2:1 ratio to start treatment with SPRYCEL 70 mg twice a day (bid) (n=101) or Gleevec 400 mg bid (n=49). The primary endpoint of the study was major cytogenetic response rate at 12 weeks. Secondary efficacy endpoints included duration of, and time to achieve, major cytogenetic response as well as complete hematologic response. Major cytogenetic response is defined as complete (no signs of Philadelphia chromosome-positive [Ph+] cells in the bone marrow) plus partial (less than 35 percent of Ph+ cells in the bone marrow) cytogenetic responses. Complete hematologic response is a measure of how effective a treatment is in returning blood counts to normal and occurs when blood counts appear normal and patients have no signs or symptoms of disease.

Important non-hematologic adverse events in the SPRYCEL arm included diarrhea (35%), nausea (24%), pleural effusion (17%), superficial edema (15%), vomiting (9%), pulmonary edema (3%), and muscle spasm (2%). Important non- hematologic adverse events in the Gleevec arm included superficial edema (39%), nausea (33%), diarrhea (29%), vomiting (25%), and muscle spasm (12%). Grade 3 or 4 cytopenias observed in the SPRYCEL arm included low absolute neutrophil blood count (59%), platelets (55%), leukocytes (20%), and hemoglobin (18%). Grade 3 or 4 cytopenias observed in the Gleevec arm included low absolute neutrophil white blood cells (39%), leukocytes (16%), platelets (14%), and hemoglobin (8%).

About SPRYCEL

On June 28, 2006, the U.S. Food and Drug Administration (FDA) granted accelerated approval of SPRYCEL, an oral inhibitor of multiple tyrosine kinases, for the treatment of adults in all phases of CML (chronic, accelerated, or myeloid or lymphoid blast phase) with resistance or intolerance to prior therapy, including Gleevec. The FDA also granted full approval of SPRYCEL for the treatment of adults with Philadelphia chromosome- positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy. The effectiveness of SPRYCEL is based on hematologic and cytogenetic response rates. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival.

Resistance to Gleevec is often due to mutations of BCR-ABL, BCR-ABL over- expression, or activation of new pathways. SPRYCEL is the first approved oral multiple tyrosine kinase that, at nanomolar concentrations, inhibits BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRB kinases. By targeting these kinases, SPRYCEL inhibits the overproduction of leukemia cells in the bone marrow of patients with CML and Ph+ ALL and allows normal red cell, white cell, and blood platelet production to resume.

IMPORTANT SAFETY INFORMATION

SPRYCEL is not recommended for use in pregnant women or those contemplating pregnancy. Dasatinib may cause fetal harm. Sexually active male/female patients taking SPRYCEL should use adequate contraception.

Myelosuppression: Treatment with SPRYCEL is associated with severe CTC Grade 3/4 thrombocytopenia, neutropenia, and anemia. Their occurrence is more frequent in advanced CML or Ph+ALL than in chronic phase CML. Myelosuppression was reported in patients with normal baseline laboratory values as well as in patients with preexisting laboratory abnormalities. Complete blood counts (CBC) should be performed weekly for the first 2 months and then monthly thereafter, or as clinically indicated. In clinical studies, myelosuppression was managed by dose interruption, dose reduction, or discontinuation of study therapy. Hematopoietic growth factor has been used in patients with persistent myelosuppression.

Hemorrhage: Dasatinib caused platelet dysfunction in vitro and thrombocytopenia in humans. Severe CNS hemorrhage, including fatalities occurred in 1% of patients. Severe GI hemorrhage occurred in 7% of patients and generally required treatment interruptions and transfusions. Other cases of severe hemorrhage occurred in 4% of patients. Most bleeding events were associated with severe thrombocytopenia. Caution is advised in patients required to take medications that inhibit platelet function or anticoagulants.

Fluid Retention: Fluid retention was severe in 9% of patients, including pleural and pericardial effusions reported in 5% and 1%, respectively. Severe ascites and generalized edema were each reported in 1%. Severe pulmonary edema was reported in 1% of patients. Patients who develop symptoms suggestive of pleural effusion (dyspnea or dry cough) should be evaluated by chest x-ray. Severe pleural effusion may require oxygen therapy and thoracentesis. Fluid retention was typically managed by supportive care measures that include diuretics or short courses of steroids.

QT Prolongation: In vitro data suggest that dasatinib has the potential to prolong cardiac ventricular repolarization (QT interval). Nine patients had QTc prolongation as an adverse event. Three patients (<1%) experienced a QTcF >500 msec. SPRYCEL should be administered with caution in patients who have or may develop prolongation of QTc including patients with hypokalemia, hypomagnesemia, or congenital long QT syndrome and patients taking anti- arrhythmic drugs, other medicinal products that lead to QT prolongation, or cumulative high-dose anthracycline therapy. Hypokalemia or hypomagnesemia should be corrected prior to dasatinib administration.

Drug Interactions: Dasatinib is a CYP3A4 substrate. Drugs that may increase dasatinib concentrations are: CYP3A4 inhibitors (eg, ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir, atazanavir, indinavir, nefazodone, nelfinavir, saquinavir, and telithromycin). Concomitant use of dasatinib and drugs that inhibit CYP3A4 should be avoided. If systemic administration of a potent CYP3A4 inhibitor cannot be avoided, close monitoring for toxicity and dose reduction should be considered. Drugs that may decrease dasatinib concentrations are: CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital). Alternative agents with less enzyme induction potential should be used or a dose increase of SPRYCEL should be considered. St. John's Wort (Hypericum perforatum) may decrease dasatinib plasma concentrations unpredictably. Patients taking SPRYCEL should not take St. John's Wort.

Dasatinib is a time-dependent inhibitor of CYP3A4. Drugs that may have their plasma concentration altered by dasatinib are: CYP3A4 substrates with a narrow therapeutic index (eg, alfentanil, astemizole, terfenadine, cisapride, cyclosporine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, or ergot alkaloids [ergotamine, dihydroergotamine]) should be administered with caution.

Long-term suppression of gastric acid secretion by use of H2 blockers or proton pump inhibitors (eg, famotidine and omeprazole) is likely to reduce dasatinib exposure. Therefore, concomitant use of H2 blockers or proton pump inhibitors with SPRYCEL is not recommended. The use of antacids should be considered. Simultaneous administration of SPRYCEL and antacids should be avoided. If antacid therapy is needed, the antacid dose should be administered at least 2 hours prior to or 2 hours after the dose of SPRYCEL.

Nursing Mothers: Women who are taking SPRYCEL should avoid breast- feeding.

Adverse Reactions: The safety data reflect exposure to SPRYCEL in 911 patients with leukemia from one Phase I and five Phase II clinical studies. The majority of SPRYCEL-treated patients experienced adverse drug reactions at some time. Drug was discontinued for adverse drug reactions in 6% of patients in chronic phase, 5% in accelerated phase, and 11% in myeloid blast phase CML and in 6% in lymphoid blast phase CML or Ph+ ALL.

The most frequently reported adverse events included fluid retention events, such as pleural effusion, gastrointestinal events including diarrhea, nausea, abdominal pain and vomiting and bleeding events. The most frequently reported serious adverse events (SAEs) included pyrexia (9%), pleural effusion (8%), febrile neutropenia (7%), gastrointestinal bleeding (6%), pneumonia (6%), thrombocytopenia (5%), dyspnea (4%), anemia (3%), diarrhea (2%), and cardiac failure (3%).

Grade 3/4 elevations of transaminases or bilirubin were reported in all patients, with increased frequency in patients with myeloid or lymphoid blast CML or Ph+ ALL. Elevations in transaminases or bilirubin were managed with dose reduction or interruption. Grade 3/4 hypocalcemia was reported in patients with all phases of CML, but with an increased frequency in patients with myeloid or lymphoid blast CML or Ph+ ALL. Patients developing Grade 3/4 hypocalcemia during the course of SPRYCEL therapy often had recovery with oral calcium supplementation.

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global pharmaceutical and related health care products company whose mission is to extend and enhance human life.

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