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

This study has been completed.
Sponsor:
Collaborator:
Ariad Pharmaceuticals
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier:
NCT00112372
First received: June 2, 2005
Last updated: March 10, 2014
Last verified: March 2014
  Purpose

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.


Condition Intervention Phase
Cancer
Drug: Ridaforolimus
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Merck Sharp & Dohme Corp.:

Primary Outcome Measures:
  • 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) ] [ Designated as safety issue: Yes ]
  • Length of Exposure to Ridaforolimus [ Time Frame: Complete duration of study (up to approximately 42 months) ] [ Designated as safety issue: Yes ]
  • Cumulative Dose of Ridaforolimus [ Time Frame: Complete duration of study (up to approximately 42 months) ] [ Designated as safety issue: Yes ]
  • Number of Participants With Dose Limiting Toxicity (DLT) [ Time Frame: Cycle 1 (Day 1 to Day 28) ] [ Designated as safety issue: Yes ]
  • Efficacy (Clinical Benefit Rate [CBR]) of Ridaforolimus in Advanced Sarcoma [ Time Frame: Complete duration of study (up to approximately 42 months) ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • Apparent Terminal Half-Life (t½) of Ridaforolimus [ Time Frame: Cycle 1: Days 1 & 15 or 21 (depending on dosing regimen) + Cycle 2 Day 1 ] [ Designated as safety issue: No ]
  • 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) ] [ Designated as safety issue: No ]
  • Plasma Partitioning [ Time Frame: Cycle 1: Days 1 & 15 or 21 (depending on dosing regimen) + Cycle 2 Day 1 ] [ Designated as safety issue: No ]
  • Efficacy (Antitumor Activity, as Measured by CBR) of the Study Drug Regimens [ Time Frame: Complete duration of study (up to approximately 42 months) ] [ Designated as safety issue: No ]

Enrollment: 147
Study Start Date: May 2005
Study Completion Date: March 2009
Primary Completion Date: December 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Ridaforolimus
10 mg tablet of ridaforolimus administered orally according to one of several different dosing regimens for a four-week treatment cycle.
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

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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 ≤ 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00112372

Sponsors and Collaborators
Merck Sharp & Dohme Corp.
Ariad Pharmaceuticals
Investigators
Study Director: Frank Haluska, M.D. Ariad Pharmaceuticals
  More Information

Publications:
Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT00112372     History of Changes
Other Study ID Numbers: 8669-016, AP23573-05-106
Study First Received: June 2, 2005
Last Updated: March 10, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Merck Sharp & Dohme Corp.:
unresectable
metastatic
cancer
recurrent
malignancies
progressive

Additional relevant MeSH terms:
Neoplasms
Sirolimus
Anti-Bacterial Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Antibiotics, Antineoplastic
Antineoplastic Agents
Antifungal Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on August 21, 2014