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

A Phase 1B, Sequential Cohort, Dose Escalation Trial to Determine the Safety, Tolerability and Maximum Tolerated Dose of Oral AP23573 in Combination With Doxorubicin

This study is designed to determine the safety, tolerability and maximum tolerated dose of Oral AP23573 in combination with Doxorubicin

The primary objective is to determine the maximum tolerated dose (MTD) of AP23573 in combination with doxorubicin, to characterize the safety profile of AP23573 in combination with doxorubicin, and to examine the pharmacokinetics of AP23573 and doxorubicin when given in combination to patients with advanced malignancies.

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