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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

Phase 1
18 Years
Not Enrolling

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Trial Information

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

The advent of oral anticancer therapy has created a means to reduce dependency on a system
for treating cancer that relies on hospital-based services to administer treatment. While
known disadvantages of oral therapies such as potential variable absorption, unpredictable
bioavailability and sometimes poor patient compliance pose challenges, the use of orally
administered compounds permits investigation of alternative or varied dose regimens, which
may ultimately enhance overall patient care.

Ridaforolimus is currently being studied in phase 1 and phase II clinical trials in patients
with advanced cancers. Thus far, these trials have demonstrated that ridaforolimus has a
favorable safety profile and possesses anticancer activity when administered as a 30-minute
intravenous (IV) infusion daily x 5 every-two-weeks or on a weekly schedule. The primary
objective of this current phase I trial is to study the safety and tolerability of an orally
administered dosage form of ridaforolimus. This will be accomplished by an ascending dose
study of several dosage regimens in patients with advanced malignancies.

Inclusion Criteria:

- 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

- Leiomyosarcomas

- Liposarcomas

- 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

Exclusion Criteria:

- 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,
erythromycin, azithromycin).

- 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

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum Tolerated Dose (MTD) of Ridaforolimus When Administered Orally as an Enteric or Film Coated Tablet to Patients With Progressive or Recurrent Malignancies

Outcome Time Frame:

Cycle 1 (Day 1 to Day 28)

Safety Issue:


Principal Investigator

Frank Haluska, M.D.

Investigator Role:

Study Director

Investigator Affiliation:

Ariad Pharmaceuticals


United States: Food and Drug Administration

Study ID:




Start Date:

May 2005

Completion Date:

March 2009

Related Keywords:

  • Cancer
  • unresectable
  • metastatic
  • cancer
  • recurrent
  • malignancies
  • progressive
  • Neoplasms