Emerging Therapies for CML

Lay Title:    A Study to Evaluate the Efficacy of BMS-354825 for Patients with Myeloid Blast Phase Chronic Myeloid Leukemia

Description:    The primary objective of this study is to estimate complete and overall hematologic response rates to BMS-354825 in myeloid blast phase chronic myeloid leukemia (CML) subjects with primary or acquired resistance to imatinib mesylate

Eligibility:   

Inclusion Criteria:

1. Signed written informed consent
2. Subjects with Ph+ (or BCR/ABL+) myeloid blast phase chronic myeloid leukemia whose disease has primary or acquired hematologic resistance to imatinib mesylate or who are intolerant of imatinib mesylate.

Subjects are considered to have myeloid blast phase CML if they meet at least one of the following criteria:

• > 30% myeloid blast in peripheral blood or in bone marrow
• extramedullary infiltrates of leukemic cells (other than in spleen or liver) with peripheral blood myeloid blast morphology Hematologic resistance to imatinib is defined as:
  • Subjects initially diagnosed with chronic phase CML who progressed to myeloid blast phase CML while on treatment with a prescribed imatinib dose of > 400 mg/day. This includes subjects who had no response to imatinib (primary resistance) and those who responded and subsequently progressed to myeloid blast phase (acquired resistance).
  • Subjects initially diagnosed with accelerated phase CML who progressed to myeloid phase CML while on treatment with a prescribed imatinib dose of > 600 mg/day (or 400 mg to < 600 mg/day if the subject is intolerant of > 600 mg/day). This includes subjects who had no response to imatinib (primary resistance) and those who responded and subsequently progressed to myeloid blast phase (acquired resistance).
  • Subjects initially diagnosed with myeloid blast or blast phase CML who meet the criteria for myeloid blast phase crisis after at least 4 weeks of treatment prescribed at a dose of > 600 mg/day (or 400 mg to < 600 mg/day if subject is intolerant of > 600 mg/day). This 4 week treatment requirement can be shortened to 2 weeks for patients who are rapidly progressing. This includes subjects who had no response to imatinib (primary resistance) and those who responded and subsequently progressed to myeloid blast phase (acquired resistance).

Note: A subject who tolerates a dose of imatinib 400 mg/day, but is intolerant of higher doses is not considered imatinib-intolerant. Imatinib Intolerance: For purposes of defining intolerant subjects for this protocol, a subject is defined as being intolerant to imatinib if he or she had a toxicity considered at least possibly related to imatinib at a dose of 400 mg/day or lower which led to a discontinuation or therapy or can only tolerate doses < 400 mg/day.

Note: Subjects must have had prior exposure to imatinib as defined above. However, imatinib mesylate does not need to be their most recent CML treatment prior to coming on this study.

3. Available for scheduled follow-up
4. ECOG performance status score 0-2
5. Adequate hepatic function defined as: · Total bilirubin < 2.0 times the institutional upper limit of normal · Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 times the institutional upper limit normal
6. Adequate renal function defined as: · Serum creatinine < 1.5 times the institutional upper limit normal
7. Serum potassium and magnesium levels within institutional normal limits. Total serum calcium or ionized calcium level must be greater than or equal to the lower limit of normal. Subjects with low potassium, magnesium levels, total serum calcium and/or ionized calcium may be repleted to allow for protocol entry
8. Men and women, 18 years of age or older. Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for a period of at least 1 month before and at least 3 months after the study in such a manner that the risk of pregnancy is minimized. WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not postmenopausal [defined as amenorrhea > 12 consecutive months; or women on hormone replacement replacement therapy (HRT) with documented serum follicle stimulating hormone (FSH) level > 35 mIU/mL]. Even women who are using oral, implanted or injectable contraceptive hormones or mechanical products such as an intrauterine device or barrier method (diaphragm, condoms, spermicides) to prevent pregnancy or practicing abstinence or where partner is sterile (e.g., vasectomy), should be considered to be of child bearing potential. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of study medication.

Exclusion Criteria:

1. WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period of at least 1 month before and for at least 3 months after completion of the study medication.
2. WOCBP using a prohibited contraceptive method
3. Women who are pregnant or breastfeeding
4. Women with a positive pregnancy test on enrollment or prior to study drug administration
5. Men whose sexual partners are WOCBP, who are unwilling or unable to use an acceptable method to avoid pregnancy of his partner for the entire study period and for at least 3 months after completion of study medication
6. Subjects who are eligible and willing to undergo transplantation during the screening period
7. A serious uncontrolled medical disorder or active infection that would impair the ability of the subjects to receive protocol therapy
8. Uncontrolled or significant cardiovascular disease, including: a) A myocardial infarction within 6 months b) Uncontrolled angina within 3 months c) Congestive heart failure within 3 months d) Diagnosed or suspected congenital long QT syndrome e) Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or torsade de pointes). Any subject with a history of any arrhythmia should be discussed with the BMS Medical Monitor prior to entry into the study. a) Prolonged QTc interval on pre-entry electrocardiogram (> 450 msec) on Bazatt's correction. However, if Bazatt's correction is high (i.e., > 450 msec) and Fridericia is < 450 msec, the subject is eligible. g) Any history of second or third degree heart block (may be eligible if currently have a pacemaker) h) Heart rate consistently < 50 beats/minute on pre-entry electrocardiograms i) Uncontrolled hypertension
9. Dementia or altered mental status that would prohibit the understanding or rendering of informed consent
10. History of significant bleeding disorder unrelated to CML, including: a) Diagnosed congenital bleeding disorder (e.g., von Willebrand's disease) b) Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies) c) Clinically significant bleeding from the GI tract within 6 months
11. Concurrent incurable malignancy other than CML
12. Evidence of organ dysfunction or digestive dysfunction that would prevent administration of study therapy
13. Subjects who received any of the following: a) imatinib mesylate within 7 days b) interferon or cytarabine within 14 days c) a targeted small molecule anti-cancer agent within 14 days d) any other investigational or antineoplastic agent other than hydroxyurea or anagrelide within 28 days before starting treatment with BMS-354825
14. Subjects currently taking the following drugs that are generally accepted to have a risk of causing Torsades de Pointes including: a) quinidine, procainamide, disopyramide b) amiodarone, sotalol, ibutilide, dofetilide c) erythromycins, clarithromycin d) chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide e) cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, halofantrine, levomethadyl, panetamidine, sparfloxacin, lidoflazine Subjects who have discontinued any of these medications must have a wash-out period of at least 5 days or at least 5 half-lives of the drug (whichever is greater) prior to the first dose of BMS-354825.
15. Subjects taking medications that irreversibly inhibit platelet function (i.e., aspirin, dipryidamolde, epoprostenol, epitfibatide, clopidogrel, cilostazol, abciximab, ticlopidine) or anticoagulants (warfarin, heparin/low molecular weight heparin [e.g., danaparoid, dalteparin, tinzaparing, enoxaparin]). Exceptions are for subjects taking anagrelide for thrombocytosis due to CML, low-dose warfarin for prophylaxis to prevent catheter thrombosis, and for heparin-flushes for IV lines. Subjects who have discontinued aspirin must have a wash-out period of at least 7 days for low-dose aspirin (< 325 mg/day) or 14 days for higher-dose aspirin (> 325 mg/day) prior to the first dose of BMS-354825. Subjects who have discontinued other antiplatelet or anticoagulant medication must have a wash-out period of at least 5 days or at least 5 half-lives of the drug (whichever is greater) prior to the first dose of BMS-354825.
16. Prior therapy with BMS-354825
17. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious disease) illness must not be enrolled into this study.

Study Type: Subjects with Gleevec resistance or intolerance will be screened to determine if they are eligible for study participation. Once enrolled patients will be dosed on a twice-a-day 70 mg continuous schedule. Patients will return to the clinic for weekly visits to collect data on safety and efficacy.

Please see UCLA's Jonsson Comprehensive Cancer Centre