A Study to Evaluate the Effect of MK-8669 (Ridaforolimus) on QTc Interval in Participants With Advanced Cancer (MK-8669-037)

A Clinical Trial to Assess the Effect of Ridaforolimus (AP23573; MK-8669) on QTc Interval in Patients

To assess the potential for ridaforolimus to prolong the QTc interval (an effect on the electrical activity of the heart) in participants with advanced cancer. This study will be done in 2 parts. Part 1 (Pt 1) will evaluate the effect of a single 100 mg dose of ridaforolimus on QT interval in participants with advanced cancer. Fridericias's correction (QTcF) will be used. In Part 2 (Pt 2), participants will receive ridaforolimus at the current therapeutic dose (40 mg x 5 days).

Study Overview

• Status: Completed
• Conditions: Metastatic or Locally Advanced Cancer
• Intervention / Treatment: Drug: Ridaforolimus 100 mg; Drug: Ridaforolimus 40 mg; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Participant must have metastatic or locally advanced cancer which has failed to respond to standard therapy or no therapy exists.
• If the participant is a female, she must be postmenopausal or if she is of childbearing potential she must have blood pregnancy tests during the study and be willing to use 2 methods of contraception.
• If the participant is male and has female partners of child-bearing potential, he must agree to use a medically acceptable method of contraception during the study and for 30 days after the last dose of study drug.

Exclusion Criteria:

• Participant has had chemotherapy, radiotherapy or biological therapy within the past 4 weeks.
• Participant is currently receiving other anti-cancer therapy.
• Participant is currently participating or has participated in a study with an investigation drug or device within the last 30 days.
• Participant has a primary central nervous system tumor or active brain metastases.
• Participant has a psychiatric disorder.
• Participant uses illegal drugs.
• Participant is pregnant or breastfeeding.
• Participant is known to be human immunodeficiency virus (HIV) positive.
• Participant has a known history of Hepatitis B or C.
• Participant has newly diagnosed diabetes.
• Participant has an active infection.
• Participant is unable to swallow capsules.
• Participant has received a blood transfusion with one week of study entry.
• Participant has a history of cardiac problems including heart failure, myocardial infarction, unstable angina, congestive heart failure or cardiac arrhythmia.
• Participant has a known sensitivity to the components of the study drug.
• Participant has not adequately recovered from any prior surgical procedure.
• Participant does not agree to refrain from use of herbal remedies and consumption of grapefruit juice for 2 weeks prior to and during the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: Single

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Pt 1. Placebo/Ridaforolimus 100 mg; Pt 2. Ridaforolimus 40 mg; [Pt 1, Day 1]: Participants received a single dose of placebo (10 oral tablets) on Day 1 of Part 1. [Pt 1, Day 2]: Following completion of Part 1 / Day 1, participants received a single dose of ridaforolimus 100 mg (10 x 10 mg oral tablets) on Day 2 of Part 1. Following completion of Part 1 / Day 2, participants entered a washout period of ≥5 days before the first dose Part 2. [Pt 2]: Following completion of Part 1, participants received ridaforolimus 40 mg (4 x 10 mg oral tablets) given once daily (QD) for 5 consecutive days followed by 2 days off-drug.

Drug: Ridaforolimus 100 mg; Part 1: A single oral dose of 100 mg ridaforolimus (10 x 10 mg tablets) was given on Day 2.; Other Names: AP23573; MK-8669; deforolimus (until May 2009); Drug: Ridaforolimus 40 mg; Part 2 (optional): Ridaforolimus 40 mg (4 x 10 mg tablets) was received on a regimen of daily oral doses for 5 consecutive days followed by 2 days off-drug.; Other Names: AP23573; MK-8669; deforolimus (until May 2009); Drug: Placebo; Part 1: A single oral dose of placebo (10 x placebo tablets) was given on Day 1.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1. Mean Change From Baseline in Rate-Corrected (Fridericia's) QT Interval (QTcF) at 0.5 Hours	The mean change from baseline (CFB) in QTcF at 0.5 hours post-dose was assessed. At baseline (pre-dose) and at 0.5 hours post-dose, 5 replicate electrocardiograms (ECGs) were collected to reduce measurement variability. The 5 replicate QTcF values were averaged to calculate the QTcF value for each participant. Further, each participant served as their own control for the calculation of CFB in QTcF after placebo and ridaforolimus 100 mg dosing. Additionally, CFB in QTcF after single ridaforolimus 100 mg dosing for each participant was adjusted for the CFB in QTcF observed after placebo dosing.	Baseline and 0.5 hours post-dose on Days 1 & 2 of Part 1
Part 1. Mean Change From Baseline in Rate-Corrected (Fridericia's) QT Interval (QTcF) at 1 Hour	The mean change from baseline (CFB) in QTcF at 1 hour post-dose was assessed. At baseline (pre-dose) and at 1 hour post-dose, 5 replicate electrocardiograms (ECGs) were collected to reduce measurement variability. The 5 replicate QTcF values were averaged to calculate the QTcF value for each participant. Further, each participant served as their own control for the calculation of CFB in QTcF after placebo and ridaforolimus 100 mg dosing. Additionally, CFB in QTcF after single ridaforolimus 100 mg dosing for each participant was adjusted for the CFB in QTcF observed after placebo dosing.	Baseline and 1 hour post-dose on Days 1 & 2 of Part 1
Part 1. Mean Change From Baseline in Rate-Corrected (Fridericia's) QT Interval (QTcF) at 2 Hours	The mean change from baseline (CFB) in QTcF at 2 hours post-dose was assessed. At baseline (pre-dose) and at 2 hours post-dose, 5 replicate electrocardiograms (ECGs) were collected to reduce measurement variability. The 5 replicate QTcF values were averaged to calculate the QTcF value for each participant. Further, each participant served as their own control for the calculation of CFB in QTcF after placebo and ridaforolimus 100 mg dosing. Additionally, CFB in QTcF after single ridaforolimus 100 mg dosing for each participant was adjusted for the CFB in QTcF observed after placebo dosing.	Baseline and 2 hours post-dose on Days 1 & 2 of Part 1
Part 1. Mean Change From Baseline in Rate-Corrected (Fridericia's) QT Interval (QTcF) at 3 Hours	The mean change from baseline (CFB) in QTcF at 3 hours post-dose was assessed. At baseline (pre-dose) and at 3 hours post-dose, 5 replicate electrocardiograms (ECGs) were collected to reduce measurement variability. The 5 replicate QTcF values were averaged to calculate the QTcF value for each participant. Further, each participant served as their own control for the calculation of CFB in QTcF after placebo and ridaforolimus 100 mg dosing. Additionally, CFB in QTcF after single ridaforolimus 100 mg dosing for each participant was adjusted for the CFB in QTcF observed after placebo dosing.	Baseline and 3 hours post-dose on Days 1 & 2 of Part 1
Part 1. Mean Change From Baseline in Rate-Corrected (Fridericia's) QT Interval (QTcF) at 4 Hours	The mean change from baseline (CFB) in QTcF at 4 hours post-dose was assessed. At baseline (pre-dose) and at 4 hours post-dose, 5 replicate electrocardiograms (ECGs) were collected to reduce measurement variability. The 5 replicate QTcF values were averaged to calculate the QTcF value for each participant. Further, each participant served as their own control for the calculation of CFB in QTcF after placebo and ridaforolimus 100 mg dosing. Additionally, CFB in QTcF after single ridaforolimus 100 mg dosing for each participant was adjusted for the CFB in QTcF observed after placebo dosing.	Baseline and 4 hours post-dose on Days 1 & 2 of Part 1
Part 1. Mean Change From Baseline in Rate-Corrected (Fridericia's) QT Interval (QTcF) at 6 Hours	The mean change from baseline (CFB) in QTcF at 6 hours post-dose was assessed. At baseline (pre-dose) and at 6 hours post-dose, 5 replicate electrocardiograms (ECGs) were collected to reduce measurement variability. The 5 replicate QTcF values were averaged to calculate the QTcF value for each participant. Further, each participant served as their own control for the calculation of CFB in QTcF after placebo and ridaforolimus 100 mg dosing. Additionally, CFB in QTcF after single ridaforolimus 100 mg dosing for each participant was adjusted for the CFB in QTcF observed after placebo dosing.	Baseline and 6 hours post-dose on Days 1 & 2 of Part 1
Part 1. Mean Change From Baseline in Rate-Corrected (Fridericia's) QT Interval (QTcF) at 8 Hours	The mean change from baseline (CFB) in QTcF at 8 hours post-dose was assessed. At baseline (pre-dose) and at 8 hours post-dose, 5 replicate electrocardiograms (ECGs) were collected to reduce measurement variability. The 5 replicate QTcF values were averaged to calculate the QTcF value for each participant. Further, each participant served as their own control for the calculation of CFB in QTcF after placebo and ridaforolimus 100 mg dosing. Additionally, CFB in QTcF after single ridaforolimus 100 mg dosing for each participant was adjusted for the CFB in QTcF observed after placebo dosing.	Baseline and 8 hours post-dose on Days 1 & 2 of Part 1
Part 1. Mean Change From Baseline in Rate-Corrected (Fridericia's) QT Interval (QTcF) at 10 Hours	The mean change from baseline (CFB) in QTcF at 10 hours post-dose was assessed. At baseline (pre-dose) and at 10 hours post-dose, 5 replicate electrocardiograms (ECGs) were collected to reduce measurement variability. The 5 replicate QTcF values were averaged to calculate the QTcF value for each participant. Further, each participant served as their own control for the calculation of CFB in QTcF after placebo and ridaforolimus 100 mg dosing. Additionally, CFB in QTcF after single ridaforolimus 100 mg dosing for each participant was adjusted for the CFB in QTcF observed after placebo dosing.	Baseline and 10 hours post-dose on Days 1 & 2 of Part 1
Part 1. Mean Change From Baseline in Rate-Corrected (Fridericia's) QT Interval (QTcF) at 24 Hours	The mean change from baseline (CFB) in QTcF at 24 hours post-dose was assessed. At baseline (pre-dose) and at 24 hours post-dose, 5 replicate electrocardiograms (ECGs) were collected to reduce measurement variability. The 5 replicate QTcF values were averaged to calculate the QTcF value for each participant. Further, each participant served as their own control for the calculation of CFB in QTcF after placebo and ridaforolimus 100 mg dosing. Additionally, CFB in QTcF after single ridaforolimus 100 mg dosing for each participant was adjusted for the CFB in QTcF observed after placebo dosing.	Baseline and 24 hours post-dose on Days 1 & 2 of Part 1

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Experiencing an Adverse Event (AE)	The number of participants experiencing an AE was assessed. An AE was defined as any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE. Participants experiencing AEs were counted under the treatment they received when the AE occurred. Participants experiencing AEs during the washout period between Part 1 and Part 2 are counted in the "Pt 1, Day 2. Ridaforolimus 100 mg" arm.	Up to 7 months
Number of Participants Discontinuing Study Treatment Due to an Adverse Event	The number of participants discontinuing study treatment due to an AE was assessed. An AE was defined as any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE. Participants discontinuing study treatment due to an AE were counted as discontinuing under the treatment they received when the AE occurred.	Up to 6 months

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Lush RM, Patnaik A, Sullivan D, Papadopoulos KP, Trucksis M, McCrea J, Cerchio K, Li X, Stroh M, Selverian D, Orford K, Ebbinghaus S, Agrawal N, Iwamoto M, Wagner JA, Tolcher A. A single supratherapeutic dose of ridaforolimus does not prolong the QTc interval in patients with advanced cancer. Cancer Chemother Pharmacol. 2012 Oct;70(4):567-74. doi: 10.1007/s00280-012-1942-7. Epub 2012 Aug 10.

Study record dates

Study Major Dates

• Study Start (Actual): April 28, 2009
• Primary Completion (Actual): October 30, 2009
• Study Completion (Actual): April 30, 2010

Study Registration Dates

• First Submitted: March 31, 2009
• First Submitted That Met QC Criteria: April 1, 2009
• First Posted (Estimate): April 2, 2009

Study Record Updates

• Last Update Posted (Actual): May 6, 2019
• Last Update Submitted That Met QC Criteria: May 1, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Physiological Effects of Drugs; Anti-Infective Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Sirolimus
• Other Study ID Numbers: 8669-037; 2009_569 (Other Identifier: NIH); MK-8669-037 (Other Identifier: Merck Protocol Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf