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Study of Oral Ridaforolimus (AP23573, MK-8669) to Treat Patients With Refractory or Advanced Malignancies (MK-8669-016 AM4)(COMPLETED)

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ClinicalTrials.gov Identifier: NCT00112372
Recruitment Status : Completed
First Posted : June 3, 2005
Last Update Posted : February 12, 2015
Sponsor:
Collaborator:
Ariad Pharmaceuticals
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Tracking Information
First Submitted Date  ICMJE June 2, 2005
First Posted Date  ICMJE June 3, 2005
Last Update Posted Date February 12, 2015
Study Start Date  ICMJE May 2005
Actual Primary Completion Date December 2008   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 29, 2013)
  • 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) ]
  • 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) ]
Original Primary Outcome Measures  ICMJE
 (submitted: June 23, 2005)
To determine the safety, tolerability and maximum tolerated dose (MTD) of AP23573 when administered orally as an enteric or film coated tablet to patients with progressive or recurrent malignancies. Three dosage regimens will be examined in this trial
Change History Complete list of historical versions of study NCT00112372 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: May 29, 2013)
  • Area Under the Curve (AUC [0-infinity]) of Ridaforolimus Administered at Different Doses and Regimens [ Time Frame: 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 [ Time Frame: Cycle 1: Days 1 & 15 or 21 (depending on dosing regimen) + Cycle 2 Day 1 ]
  • Time at Which Cmax is Reached (Tmax) at Different Doses and Regimens of Ridaforolimus [ Time Frame: Cycle 1: Days 1 & 15 or 21 (depending on dosing regimen) + Cycle 2 Day 1 ]
  • Apparent Terminal Half-Life (t½) of Ridaforolimus [ Time Frame: Cycle 1: Days 1 & 15 or 21 (depending on dosing regimen) + Cycle 2 Day 1 ]
  • Relative Phospho-4E-BP1 (p-4E-BP1) Levels as a Function of Dose [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Complete duration of study (up to approximately 42 months) ]
Original Secondary Outcome Measures  ICMJE
 (submitted: June 23, 2005)
  • Examine pharmacokinetic and pharmacodynamic characteristics of AP23573 (e.g., AP23573 blood levels, phospho-4E-BP1 levels, plasma partitioning)
  • Describe the antitumor activity of the study drug regimens
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of Oral Ridaforolimus (AP23573, MK-8669) to Treat Patients With Refractory or Advanced Malignancies (MK-8669-016 AM4)(COMPLETED)
Official Title  ICMJE 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
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Cancer
Intervention  ICMJE Drug: Ridaforolimus
10 mg tablet of ridaforolimus administered orally according to one of several different dosing regimens for a four-week treatment cycle.
Other Names:
  • AP23573
  • MK-8669
  • ridaforolimus was also known as deforolimus until May 2009
Study Arms  ICMJE Experimental: Ridaforolimus
10 mg tablet of ridaforolimus administered orally according to one of several different dosing regimens for a four-week treatment cycle.
Intervention: Drug: Ridaforolimus
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: December 20, 2007)
147
Original Enrollment  ICMJE
 (submitted: June 23, 2005)
144
Actual Study Completion Date  ICMJE March 2009
Actual Primary Completion Date December 2008   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 ≤ 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 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.

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 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.
  • 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 drug.
  • 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 ridaforolimus.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Not Provided
Removed Location Countries United States
 
Administrative Information
NCT Number  ICMJE NCT00112372
Other Study ID Numbers  ICMJE 8669-016
AP23573-05-106
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Merck Sharp & Dohme Corp.
Study Sponsor  ICMJE Merck Sharp & Dohme Corp.
Collaborators  ICMJE Ariad Pharmaceuticals
Investigators  ICMJE
Study Director: Frank Haluska, M.D. Ariad Pharmaceuticals
PRS Account Merck Sharp & Dohme Corp.
Verification Date February 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP