Safety, Tolerability and Maximum Tolerated Dose of Oral AP23573 in Combination With Doxorubicin (8669-015)

Inclusion Criteria:

• Age ≥ 18 years with a histological/cytological diagnosis of advanced tumor, preferentially breast, sarcoma, ovarian, endometrial or other tumor types for which treatment with anthracycline therapy is indicated
• Prior cumulative doxorubicin exposure less than 400 mg/m2
• An ECOG performance status of 0 or 1
• Adequate cardiovascular function
• Measurable disease according to modified RECIST criteria
• Adequate hematological, renal and hepatic functions
• Able to understand and give voluntary written informed consent

Exclusion Criteria:

• Women who are pregnant or lactating
• Presence of active brain metastases. Patients with treated brain metastases will be eligible if they are on a stable dose of corticosteroids or are without change in brain disease status for at least 4 weeks following related therapy (e.g., whole brain radiation, surgery)
• Prior treatment with CCI-779, rapamycin, or any other mTOR inhibitor
• Prior anticancer treatment (chemotherapy, radiotherapy, hormonal, immunotherapy, biological response modifiers, signal transduction inhibitors, etc) within 4 weeks prior to the first dose of AP23573; the interval is ≥ 2 weeks for signal transduction inhibitors with a half-life known to be <24 hours, and is ≥ 6 weeks for nitrosourea or mitomycin. Exception: Concurrent treatment with LHRH agonists is allowed for patients with prostate cancer.
• Ongoing toxicity associated with prior anticancer therapy other than alopecia and ≤ Grade 1 peripheral neuropathy by NCI toxicity criteria
• Another primary malignancy within the past three years (except for non-melanoma skin cancer and cervical carcinoma in situ)
• Known or suspected hypersensitivity to any excipient contained in the study drug
• Known Grade 3 or 4 hypersensitivity to macrolide antibiotics (e.g., clarithromycin, erythromycin, azithromycin)
• Significant uncontrolled cardiovascular disease
• Any active infection requiring prescribed intervention
• Any other concurrent illness which, in the opinion of the investigator, would either compromise the patient's safety or interfere with the evaluation of the safety of the study drug
• Any pre-existing malabsorption syndrome, irritable bowel syndrome or other clinical situation which could affect oral absorption
• Concurrent treatment with immunosuppressive agents other than prescribed corticosteroids at stable doses for ≥ 2 weeks prior to first planned dose of study drug
• Concurrent treatment with medications that induce or inhibit cytochrome P450 (CYP3A)
• Inadequate recovery from any prior surgical procedure or having undergone any major surgical procedure within 2 weeks prior to the first dose of AP23573