A Phase I/IIa, Sequential Cohort, Dose Escalation Trial to Determine the Safety, Tolerability and Maximum Tolerated Dose of AP23573 When Administered Orally in Patients With Refractory or Advanced Malignancies
- Male or female patients ≥18 years of age.
- Patients with a histological/cytological diagnosis of unresectable or metastatic
cancer that is refractory to standard therapies or for which no standard therapy
- Patients must must have measurable or nonmeasurable lesions assessable using an
appropriate radiographical procedure (e.g., computed tomography (CT) or magnetic
resonance imaging (MRI) scans).
- Fertile male or female patients who agree to use approved barrier methods of
contraception (non hormonal methods).
- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
- Adequate renal and hepatic function, defined as: *Total serum bilirubin ≤ 2 x upper
limit of normal (ULN) for the institution; * (aspartate aminotransferase (AST) and/or
alanine aminotransferase (ALT) ≤ 2.5 x ULN for the institution (≤ 5 x if due to
hepatic metastases); *Serum albumin ≥ 2 g/dL; Serum creatinine ≤ 2 x ULN for the
- Adequate bone marrow function, defined as: * absolute neutrophil count (ANC) ≥ 1.5 x
10^9/L; *Platelet count ≥ 100 x 10^9/L
- Serum cholesterol < 350 mg/dL and triglycerides < 400 mg/dL.
- Anticipated life expectancy of ≥ 3 months.
- Able to give and understand a written informed consent.
For the Phase IIa segment, patients must meet the following additional criteria:
- Patients with a histological/cytological diagnosis of metastatic and/or unresectable
sarcoma within one of the following histological subgroups:
- Bone sarcomas
- Presence of at least one measurable lesion that:
- Can be accurately measured in at least one dimension with longest diameter ≥20
mm using conventional techniques or ≥10 mm with spiral CT scan (or otherwise at
least twice the reconstruction interval for CT or MRI scans).
- Previously irradiated lesions may be considered to be measurable provided: 1)
there has been documented progression of the lesion(s) since completion of
radiotherapy, and 2) the criteria for measurability as outlined above are met.
- ECOG performance status ≤1
- Patients with active central nervous system (CNS) metastases or leptomeningeal
disease, not controlled by prior surgery or radiotherapy.
- Prior therapy with rapamycin, rapamycin analogs, or known sensitivity to these
- Prior anticancer treatment, standard or experimental, within 4 weeks prior to the
first dose of ridaforolimus (except luteinizing hormone releasing hormone (LH-RH)
agonists); 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.
- Concomitant treatment with medications that induce, inhibit, or are metabolized by
cytochrome P450 (CYP3A). Patients should be off these medications 2 weeks prior to
the first dose of ridaforolimus.
- Ongoing toxicity associated with prior anticancer therapy (except peripheral
neuropathy of ≤ grade 1 by National Cancer Institute (NCI) Terminology Criteria and
- Another primary malignancy within the past three years (except in situ carcinoma).
- Known or suspected hypersensitivity to any excipient contained in the study drug.
- Known Grade 3 or 4 hypersensitivity to macrolide antibiotics (e.g., clarithromycin,
- Significant uncontrolled cardiovascular disease.
- Active infection requiring systemic therapy.
- Women who are pregnant or lactating.
- Known human immunodeficiency virus (HIV) infection .
- Other life-threatening illness, any medical condition, or organ system dysfunction,
which, in the opinion of the Investigator and Sponsor, would either compromise the
patient's safety or interfere with evaluation of the safety of ridaforolimus, or
could interfere with the absorption of the oral study drug.
- Concurrent treatment with immunosuppressive agents other than prescribed
corticosteroids at stable doses for ≥ 2 weeks prior to first planned dose of study
- Inadequate recovery from any prior surgical procedure or having undergone any major
surgical procedure within the last 3 to 4 weeks prior to the first dose of