A Study of Ridaforolimus in Pediatric Participants With Advanced Solid Tumors (MK-8669-056)

A Phase I Study of Ridaforolimus in Pediatric Patients With Advanced Solid Tumors

The main objectives of this trial are to determine the recommended dose of ridaforolimus for pediatric participants with advanced solid tumors by measuring the number of participants experiencing dose-limiting toxicities (DLTs) while on different doses of ridaforolimus, and to characterize the pharmacokinetics of ridaforolimus in these participants. The primary hypotheses of this study are that 1) the DLTs observed will be dose-dependent and allow for definition of a maximum tolerated dose (MTD) and 2) at a safe and well tolerated dose, ridaforolimus geometric mean (GM) Day-5 blood area under the concentration-time curve at 24 hours (AUC0-24) exceeds 75% (or 1304-ng*hr/mL) of the estimated GM Day-5, 40-mg AUC0-24 in adults.

Study-related visits concluded in August 2013. Participants who did not have disease progression, adequately tolerated therapy, and continued to meet eligibility criteria for 6 months after the enrollment period had been completed could continue treatment in an extension phase until they met discontinuation criteria or voluntarily withdrew.

Study Overview

• Status: Terminated
• Conditions: Solid Tumors
• Intervention / Treatment: Drug: Ridaforolimus

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

• Histologic or cytologic diagnosis of a malignant solid tumor, including tumors of the central nervous system and lymphoma, that have progressed despite standard therapy or for which no effective standard therapy is known. Participants who have received standard therapy and continue to have biopsy-proven residual stable disease are eligible
• Measurable or non-measurable disease
• Must be able to swallow tablets
• Performance Status: Lansky Play Scale ≥70 for children <10 years of age; Karnofsky score ≥70 for children ≥10 to <16 years; or Eastern Cooperative Oncology Group (ECOG) Status 0-2 for patients age 16 and older
• Adequate organ function
• For females of reproductive potential, a negative pregnancy test must be documented within 72 hours of receiving the first dose of study medication
• Participants of reproductive potential must agree to use (or have their partner use) adequate contraception throughout the study, starting with Visit 1 through 30 days after the last dose of study drug

Exclusion criteria:

• Currently receiving any other investigational agents or using any investigational devices
• Leukemia
• Participant previously received ridaforolimus, rapamycin, or other rapamycin analogs
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to ridaforolimus
• Persistent acute toxicity from previous therapy ≥Grade 2 (excluding alopecia, neuropathy, or hearing loss)
• Uncontrolled intercurrent illness despite adequate therapy
• Pregnant or breastfeeding
• Requirement for concurrent treatment with medications that are inducers or inhibitors of cytochrome P450 (CYP3A)
• Poorly controlled Type 1 or 2 diabetes

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ridaforolimus 22 mg/m^2; Participants receive 22 mg/m^2 of ridaforolimus administered orally for 5 consecutive days each week (2 days rest) in consecutive 28-day cycles for up to six months. Eligible participants can receive additional treatment in an extension phase of the study.	Drug: Ridaforolimus; Oral administration of 10 mg enteric-coated tablets at doses of 22 mg/m^2, 28 mg/m^2, or 33 mg/m^2 based on body surface area (BSA), once daily for 5 consecutive days each week in consecutive 28-day cycles.; Other Names: MK-8669
Experimental: Ridaforolimus 28 mg/m^2; Participants receive 28 mg/m^2 of ridaforolimus administered orally for 5 consecutive days each week (2 days rest) in consecutive 28-day cycles for up to six months. Eligible participants can receive additional treatment in an extension phase of the study.	Drug: Ridaforolimus; Oral administration of 10 mg enteric-coated tablets at doses of 22 mg/m^2, 28 mg/m^2, or 33 mg/m^2 based on body surface area (BSA), once daily for 5 consecutive days each week in consecutive 28-day cycles.; Other Names: MK-8669
Experimental: Ridaforolimus 33 mg/m^2; Participants receive 33 mg/m^2 of ridaforolimus administered orally for 5 consecutive days each week (2 days rest) in consecutive 28-day cycles for up to six months. Eligible participants can receive additional treatment in an extension phase of the study.	Drug: Ridaforolimus; Oral administration of 10 mg enteric-coated tablets at doses of 22 mg/m^2, 28 mg/m^2, or 33 mg/m^2 based on body surface area (BSA), once daily for 5 consecutive days each week in consecutive 28-day cycles.; Other Names: MK-8669

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Experiencing a Dose Limiting Toxicity (DLT) According to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v.4.0)	DLT defined using NCI-CTCAE v.4.0 as any of the following events occurring during the first 28-day cycle that were possibly, probably, or definitely study drug-related: Grade 4 neutropenia for ≥5 days; Grade 3-4 neutropenia associated with fever, antibiotics, or hospitalization for infection; Grade 4 thrombocytopenia for ≥5 days or requiring platelet transfusion; ≥Grade 3 hyperglycemia for ≥5 days despite management; ≥Grade 3 diarrhea for >24 hours despite management; ≥Grade 3 nausea or vomiting despite management; any other Grade ≥3 non-hematological toxicity persisting despite management (except alopecia, transient electrolyte abnormalities, transient Grade 3 liver function test elevations, and Grade 3 neurotoxicity for participants with baseline Grade 3 neurotoxicity); inability to complete DLT assessment period, interruption in dosing for >10 dosing days during DLT assessment period, or any delay in the initiation of the next cycle for >10 dosing days due to any related toxicity.	Cycle 1 (cycle = 28 days)
Area Under the Concentration-Time Curve of Ridaforolimus From Time 0 to 24 Hours (AUC0-24 hr)	AUC is a measure of the amount of drug in the blood over time. Whole blood samples were collected pre-dose (within 5 minutes of ridaforolimus administration) and post-dose at specified time points on Day 5 of the first week of Cycle 1 to determine AUC0-24 hr.	Day 5 of Cycle 1 [28-day cycle]: pre-dose (0.0 hours) and 0.5, 1.0, 2.0, 4.0, 8.0, and 24.0 hours after administration of ridaforolimus

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Pearson AD, Federico SM, Aerts I, Hargrave DR, DuBois SG, Iannone R, Geschwindt RD, Wang R, Haluska FG, Trippett TM, Geoerger B. A phase 1 study of oral ridaforolimus in pediatric patients with advanced solid tumors. Oncotarget. 2016 Dec 20;7(51):84736-84747. doi: 10.18632/oncotarget.12450.

Study record dates

Study Major Dates

• Study Start (Actual): January 30, 2012
• Primary Completion (Actual): August 20, 2013
• Study Completion (Actual): May 25, 2018

Study Registration Dates

• First Submitted: September 7, 2011
• First Submitted That Met QC Criteria: September 7, 2011
• First Posted (Estimate): September 9, 2011

Study Record Updates

• Last Update Posted (Actual): March 1, 2019
• Last Update Submitted That Met QC Criteria: February 27, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms
• Other Study ID Numbers: 8669-056; 2011-000729-55 (EudraCT Number); MK-8669-056 (Other Identifier: Merck Protocol Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf