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

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