A Phase I Dose-Escalation Study of BMS-354825 in Patients With Refractory Solid Tumors
- Signed written informed consent
- Available for protocol-required follow-up
- ECOG performance status score 0 - 1 (See Appendix 1)
- Histologic or cytologic diagnosis of a primary solid (i.e., non-hematologic)
- Evidence (radiographic or tissue confirmation) that the disease is metastatic
- Metastatic disease which has progressed on or following currently available standard
therapies or for which no standard therapy exists. (Prior adjuvant or neoadjuvant
therapy is permitted. Prior investigational agents are permitted);
- Measurable or non-measurable disease as defined in Section 220.127.116.11
- Adequate bone marrow function defined as:
- absolute neutrophil count (neutrophil and bands) >=2,000 cells/mm3
- platelet count >=125,000 cells/mm3
- hemoglobin >=9.0 g/dl
- Adequate hepatic function defined as:
- total bilirubin <=1.5 times the institutional upper limit of normal,
- alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <=2.0 times the
institutional upper limit of normal
- Adequate renal function defined as:
- serum creatinine <=1.5 times the institutional upper normal limit
- 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. Patients with low potassium and magnesium levels may be repleted to allow for
- CD4+ T-cell counts of >=the institutional lower limit of normal.
- Prior chemo-, radio-, hormonal or immunotherapy are allowed. Patients must have
recovered from toxicity due to prior therapy i.e., toxicity has resolved to baseline
or is deemed irreversible. At least 4 weeks must have elapsed since the last
chemotherapy (6 weeks for nitrosoureas, mitomycin-C, and liposomal doxorubicin),
immunotherapy or radiotherapy and the beginning of protocol therapy. At least 2 weeks
must have elapsed since last hormonal therapy or exposure to any other "targeted"
kinase inhibitor (e.g., imatinib mesylate).
- Bleeding time <=upper limit of institutional normal or platelet aggregometry result
within the institutional normal limits
- Men and women, ages 18 and 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 prior 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 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 methods
(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
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.
- WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for
the entire study period including the period from one month prior to starting study
medication and for a period of at least 3 months after the study.
- WOCBP using a prohibited contraceptive method.
- Women who are pregnant or breastfeeding.
- Women with a positive pregnancy test on enrollment or prior to study drug
- Men who are unwilling or unable to use an acceptable method of birth control for the
entire study period and for at least 3 months after completion of study medication if
their sexual partners are WOCBP.
- Received extensive prior radiation therapy to the bone marrow. Generally, patients
should have radiation to <=25% of bone marrow-containing skeleton (see Appendix 2).
- Known brain metastasis. Patients with symptoms of brain metastasis are not eligible
unless brain metastasis are ruled out by CT or MRI.
- A serious uncontrolled medical disorder or active infection which would impair the
ability of the patient to receive protocol therapy.
- Uncontrolled or significant cardiovascular disease, including:
- A myocardial infarction within 12 months
- Uncontrolled angina within 6 months
- Congestive heart failure within 6 months
- Diagnosed or suspected congenital long QT syndrome
- Any history of clinically significant ventricular arrhythmias (such as ventricular
tachycardia, ventricular fibrillation, or torsade de pointes). Any patient with a
history of any arrhythmia should be discussed with the BMS Medical Monitor prior to
entry into the study.
- Prolonged QTc interval on pre-entry electrocardiogram (> 450 msec)
- Any history of second or third degree heart block (may be eligible if currently have
- Heart rate < 50 / minute on pre-entry electrocardiogram
- Uncontrolled hypertension.
- Dementia or altered mental status that would prohibit the understanding or rendering
of informed consent;
- History of significant bleeding disorder including:
- Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease)
- Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII
- Documented major bleeding episode from the GI tract within 6 months unless no longer
at significant risk due to surgical intervention
- Received investigational agents within 4 weeks prior to the start of protocol
- Patients currently taking drugs that are generally accepted to have a risk of causing
Torsades de Pointes including:
- Class IA antiarrhythmic agents (quinidine, procainamide, disopyramide, mexiletine)
- Class III antiarrhythmic agents ( amiodarone, sotalol, ibutilide, dofetilide)
- Macrolide antibiotics (erythromycins, clarithromycin)
- Antipsychotics (chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide)
- Tricyclic antidepressants
- Miscellaneous (cisapride, bepridil, inapsine, methadone, arsenic). Patients 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
- Patients taking medications that inhibit platelet function (e.g., aspirin,
dipyridamole, epoprostenol, eptifibatide, clopidogrel, cilostazol, abciximab,
ticlopidine, and any non-steroidal anti-inflammatory drug) or anticoagulants
(warfarin, heparin/low molecular weight heparin [e.g., danaparoid, dalteparin,
tinzaparin, enoxaparin]). Patients 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. Patients
who have discontinued other antiplatelet or anticoagulant 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.
- 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.