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
Overview
- Phase
- Phase 1
- Intervention
- Ridaforolimus
- Conditions
- Cancer
- Sponsor
- Merck Sharp & Dohme LLC
- Enrollment
- 147
- Primary Endpoint
- Number of Participants With Dose Limiting Toxicity (DLT)
- Status
- Completed
- Last Updated
- 11 years ago
Overview
Brief Summary
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.
Detailed Description
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.
Investigators
Eligibility Criteria
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 exists.
- •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 ≤
- •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 institution
- •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.
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 agents.
- •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 alopecia).
- •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.
Arms & Interventions
Ridaforolimus
10 mg tablet of ridaforolimus administered orally according to one of several different dosing regimens for a four-week treatment cycle.
Intervention: Ridaforolimus
Outcomes
Primary Outcomes
Number of Participants With Dose Limiting Toxicity (DLT)
Time Frame: Cycle 1 (Day 1 to Day 28)
Efficacy (Clinical Benefit Rate [CBR]) of Ridaforolimus in Advanced Sarcoma
Time Frame: Complete duration of study (up to approximately 42 months)
Maximum Tolerated Dose (MTD) of Ridaforolimus When Administered Orally as an Enteric or Film Coated Tablet to Patients With Progressive or Recurrent Malignancies
Time Frame: Cycle 1 (Day 1 to Day 28)
Length of Exposure to Ridaforolimus
Time Frame: Complete duration of study (up to approximately 42 months)
Cumulative Dose of Ridaforolimus
Time Frame: Complete duration of study (up to approximately 42 months)
Secondary Outcomes
- Time at Which Cmax is Reached (Tmax) at Different Doses and Regimens of Ridaforolimus(Cycle 1: Days 1 & 15 or 21 (depending on dosing regimen) + Cycle 2 Day 1)
- Apparent Terminal Half-Life (t½) of Ridaforolimus(Cycle 1: Days 1 & 15 or 21 (depending on dosing regimen) + Cycle 2 Day 1)
- Area Under the Curve (AUC [0-infinity]) of Ridaforolimus Administered at Different Doses and Regimens(Cycle 1: Days 1 & 15 or 21 (depending on dosing regimen) + Cycle 2 Day 1)
- Maximum Concentration (Cmax) of Ridaforolimus Administered at Different Doses and Regimens(Cycle 1: Days 1 & 15 or 21 (depending on dosing regimen) + Cycle 2 Day 1)
- Efficacy (Antitumor Activity, as Measured by CBR) of the Study Drug Regimens(Complete duration of study (up to approximately 42 months))
- Relative Phospho-4E-BP1 (p-4E-BP1) Levels as a Function of Dose(Screening, Cycle 1 Days 1, 2, 11, 15, 16, 22 + Cycle 2 Day 1 or Screening, Cycle 1 Days 1, 2, 11, 21 + Cycle 2 Day 1 (depending on dosing regimen))
- Plasma Partitioning(Cycle 1: Days 1 & 15 or 21 (depending on dosing regimen) + Cycle 2 Day 1)