Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Also known as deforolimus, MK-8669, ridaforolimus was also known as deforolimus until May 2009, Ridaforolimus Tablet, Ridaforolimus Intravenous (IV) Infusion, ridaforolimus, deforolimus (until May 2009), ridaforolimus (MK8669)
AP23573 · 25 trials · 31 indications
PFS was defined as the time from randomization to progressive disease, or death, whichever occurs first. Response was assessed according to RECIST 1.1 by BICR. According to RECIST 1.1, progressive disease (PD) was defined as a 20% relative increase in the sum of diameters (SOD) of target lesions, taking as reference the nadir SOD and an absolute increase of \>5 mm in the SOD, or the appearance of new lesions. PFS was analyzed using the Kaplan-Meier method and median PFS (95% confidence interval \[CI\]) in weeks was reported for each treatment arm. Per protocol, participants remained on assigned treatment until disease progression. Participants who discontinued study treatment for reasons other than disease progression continued to be assessed by imaging until objective documentation of progression. All participants (including participants who discontinued study treatment) were followed for survival until investigator notification to discontinue.
Progression free survival is defined as the time from randomization to progressive disease or death, which ever occurs earlier.
Progression free rate at 6 months is defined as the proportion of participants who are a complete response (CR, disappearance of all target lesions), partial response (PR, at least a 30% decrease in the sum of the longest diameter of target lesions) or stable disease (does not qualify for PR or progressive disease) at 6 months from the date of the first study drug administration.
Tlag is the time taken for ridaforolimus to appear in systemic circulation following oral administration. The median and full range (minimum, maximum) for Tlag after a single dose of ridafolorlimus are presented.
AUC0-∞ represents the total exposure to ridaforolimus and its average blood concentration multiplied by the total amount of time (extrapolated to infinity) that ridaforolimus was in the body. The (geometric) mean was calculated based on the back-transformed least-squares mean and the 95% confidence interval was determined from a linear mixed-effect model, containing a fixed effect for day and a random effect for participant, performed on natural log-transformed values. The geometric mean and back-transformed 95% confidence interval are presented for AUC0-∞.
AUC0-24hr represents the total exposure to ridaforolimus and its average blood concentration multiplied by the total amount of time (extrapolated to 24 hours) that ridaforolimus was in the body. The (geometric) mean was calculated based on the back-transformed least-squares mean and the 95% confidence interval was determined from a linear mixed-effect model, containing a fixed effect for day and a random effect for participant, performed on natural log-transformed values. The geometric means and back-transformed 95% confidence intervals after a single dose of ridaforolimus and after multiple doses of ridaforolimus are presented for AUC0-24hr.
Cmax is the peak blood plasma concentration following a dose of ridaforolimus. The (geometric) mean was calculated based on the back-transformed least-squares mean and the 95% confidence interval was determined from a linear mixed-effect model, containing a fixed effect for day and a random effect for participant, performed on natural log-transformed values. The geometric means and back-transformed 95% confidence intervals after a single dose of ridaforolimus and after multiple doses of ridaforolimus are presented for Cmax.
C24hr is the concentration of ridaforolimus in the blood 24 hours after a dose of ridaforolimus. The (geometric) mean was calculated based on the back-transformed least-squares mean and the 95% confidence interval was determined from a linear mixed-effect model, containing a fixed effect for day and a random effect for participant, performed on natural log-transformed values. The geometric means and back-transformed 95% confidence intervals after a single dose of ridaforolimus and after multiple doses of ridaforolimus are presented for C24hr.
Tmax is the time at which the Cmax of ridaforolimus is reached. The medians and ranges (minimum, maximum) for Tmax after a single dose of ridaforolimus and after multiple doses of ridaforolimus are presented.
t½ is the time that it takes for the concentration of ridaforolimus in the body to decrease by half. The (harmonic) means and 95% confidence intervals for t1/2 after a single dose of ridaforolimus and after multiple doses of ridaforolimus are presented.
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.
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.
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.
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.
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.
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.
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.
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.
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.
| Arm | Type | Description |
|---|---|---|
| Ridaforolimus | EXPERIMENTAL | - |
| Placebo | PLACEBO_COMPARATOR | - |
| Ridaforolimus + Dalotuzumab + Exemestane | EXPERIMENTAL | Participants receive ridaforolimus 10 mg orally (PO) every 5 days (QD x 5) plus dalotuzumab 10 mg/kg intravenously (IV) every week (QW) plus exemestane 25 mg PO every day (QD) in 28-day cycles until documented disease progression or unacceptable toxicity. |
| Ridaforolimus + Exemestane | ACTIVE_COMPARATOR | Participants receive ridaforolimus 30 mg PO QD x 5 plus exemestane 25 mg PO QD treatment in 28-day cycles until documented disease progression or unacceptable toxicity. |
| Part A: ridaforolimus + dalotuzumab | EXPERIMENTAL | Approximately 15 patients will be enrolled to the ridaforolimus-dalotuzumab combination treatment arm. Subsequent Patients are randomly assigned in a 1:1 ratio to treatment with the ridaforolimus (20 mg daily five days a week)/dalotuzumab (intravenous infusion 10 mg/kg once weekly) combination therapy or cross-over to exemestane single-therapy treatment. |
| Part A: exemestane | ACTIVE_COMPARATOR | Exemestane 25 mg daily; single-agent therapy. |
| Part B: ridaforolimus + dalotuzumab | EXPERIMENTAL | Patients are randomly assigned in a 1:1 ratio to treatment with the ridaforolimus (20 mg daily five days a week)/dalotuzumab (intravenous infusion 10 mg/kg once weekly) combination therapy or cross-over to one of two single-therapy treatments (ridaforolimus alone or dalotuzumab alone). With the implementation of Amendment 3, this study arm will not be opened. |
| Part B: ridaforolimus | EXPERIMENTAL | Ridaforolimus; 40 mg daily five days a week, single-agent therapy. With the implementation of Amendment 3, this study arm will not be opened. |
| Part B: dalotuzumab | EXPERIMENTAL | Dalotuzumab intravenous infusion 10 mg/kg weekly; single-agent therapy. With the implementation of Amendment 3, this study arm will not be opened. |
| Ridaforolimus 40 mg | EXPERIMENTAL | - |
| Open Label | EXPERIMENTAL | ridaforolimus (MK8669)+ bicalutamide |
| 1 | EXPERIMENTAL | 40 mg once daily oral tablets for 5 days followed by 2 days without ridaforolimus |
| 2 | ACTIVE_COMPARATOR | Investigator's choice of: oral medroxyprogesterone acetate tablets 200 mg daily or oral megestrol acetate tablets 40 mg 4 times per day (160 mg daily) OR Chemotherapy - carboplatin, paclitaxel, doxorubicin, pegylated liposomal doxorubicin or topotecan administered as a single agent or as a doublet, and will be administered at doses and schedules chosen by the investigator |
| Ridaforolimus 20 mg + MK-2206 90 mg | EXPERIMENTAL | - |
| Ridaforolimus 20 mg + MK-2206 135 mg | EXPERIMENTAL | - |
| Ridaforolimus 30 mg + MK-2206 90 mg | EXPERIMENTAL | - |
| Ridaforolimus 30 mg + MK-2206 135 mg | EXPERIMENTAL | - |
| Ridaforolimus 30 mg + MK-2206 200 mg | EXPERIMENTAL | - |
| Ridaforolimus 40 mg + MK-2206 135 mg | EXPERIMENTAL | - |
| Ridaforolimus 40 mg + MK-2206 200 mg | EXPERIMENTAL | - |
| Ridaforolimus 20 mg + MK-0752 1800 mg | EXPERIMENTAL | No longer recruiting as of 19 July 2012 |
| Ridaforolimus 30 mg + MK-0752 1800 mg | EXPERIMENTAL | No longer recruiting as of 19 July 2012 |
| Ridaforolimus 40 mg + MK-0752 1800 mg | EXPERIMENTAL | No longer recruiting as of 19 July 2012 |
| Ridaforolimus + Dalotuzumab | EXPERIMENTAL | Ridaforolimus (MK-8669) + Dalotuzumab (MK-0646) |
| Dalotuzumab | EXPERIMENTAL | Dalotuzumab (MK-0646) |
| All Participants | EXPERIMENTAL | In Part 1, all participants received a single oral dose of 2 mg midazolam on Day -2. On Days 1-5, all participants received daily single oral doses of ridaforolimus 40 mg ( 4 x 10 mg tablets). On Day 5, all participants received a single oral dose of 2 mg midazolam coadministered with the dose of ridaforolimus. Participants had the option to continue into Part 2 of this study. |
| Pt 1. Placebo/Ridaforolimus 100 mg; Pt 2. Ridaforolimus 40 mg | EXPERIMENTAL | \[Pt 1, Day 1\]: 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. |
| 3 | EXPERIMENTAL | 40mg QDx5/wk ridaforolimus plus 15mg/kg Q3wks bevacizumab for 3 weeks |
| Cohort 1: Ridaforolimus 6.25 mg | EXPERIMENTAL | - |
| Cohort 2: Ridaforolimus 12.5 mg | EXPERIMENTAL | - |
| Cohort 3: Ridaforolimus 25 mg | EXPERIMENTAL | - |
| Cohort 4: Ridaforolimus 50 mg | EXPERIMENTAL | - |
| Cohort 5: Ridaforolimus 100 mg | EXPERIMENTAL | - |
| Cohort 6: Ridaforolimus 75 mg | EXPERIMENTAL | - |
| Name | Type | Description |
|---|---|---|
| ridaforolimus | DRUG | Four 10 mg tablets taken by mouth for 5 days per week continuously |
| Placebo | DRUG | Four 10 mg tablets taken by mouth for 5 days per week continuously |
| Dalotuzumab | DRUG | Dalotuzumab administered 10 mg/kg IV weekly on Days 1, 8, 15, and 22 of 28-day cycle. |
| Exemestane | DRUG | Exemestane 25 mg tablet administered PO QD. |
| ridaforolimus + dalotuzumab | DRUG | Ridaforolimus 20 mg once daily (QD) five days a week, with the possibility of escalation to 30 mg once daily (QD) after the first cycle and dalotuzumab intravenous infusion 10 mg/kg once weekly (QW). Treatment will continue until disease progression. |
| ridaforolimus (MK8669) | DRUG | Three 10 mg tablets administered daily for 5 consecutive days each week followed by 2 days without ridaforolimus and one 50 mg tablet of bicalutamide administered once daily for 7 days each week. Treatment will continue until disease progression. |
| Comparator: Placebo | DRUG | Three tablets of matching placebo to ridaforolimus administered daily for 5 consecutive days each week followed by 2 days without matching placebo and on 50 mg tablet of bicalutamide administered once daily for 7 days each week. Treatment will continue until disease progression. |
| open-label ridaforolimus (MK8669) | DRUG | Single dose of three 10 mg tablets ridaforolimus on Day 1, and 50 mg bicalutamide once daily starting on Day 2. On Day 8, patients will begin taking three 10 mg tablets of ridaforolimus daily for 5 consecutive days each week followed by 2 days without ridaforolimus and one 50 mg tablet of bicalutamide once daily for 7 days each week. Treatment will continue until disease progression. |
| medroxyprogesterone acetate tablets OR megestrol acetate | DRUG | oral medroxyprogesterone acetate tablets 200 mg daily OR oral megestrol acetate tablets 40 mg 4 times per day (160 mg daily) |
| chemotherapy | DRUG | Chemotherapy - carboplatin, paclitaxel, doxorubicin, pegylated liposomal doxorubicin or topotecan administered as a single agent or as a doublet, and will be administered at doses and schedules chosen by the investigator |
| trastuzumab | DRUG | single intravenous infusion every week; initial dose of 4 mg/kg over 90 minutes, then 2 mg/kg over 30 minutes |
| MK-0752 | DRUG | 300 mg capsule, orally, 6 capsules per dose, once each week. |
| MK-2206 | DRUG | Tablets (5 mg, 25 mg, and 200 mg) to equal starting dose of 90 mg and escalating to 200 mg per dose, orally, once each week. |
| Midazolam | DRUG | A single oral dose of midazolam 2 mg (1 mL of 2 mg/mL syrup) was given on Day -2 and Day 5. |
| Ridaforolimus 100 mg | DRUG | Part 1: A single oral dose of 100 mg ridaforolimus (10 x 10 mg tablets) was given on Day 2. |
| Ridaforolimus 40 mg | DRUG | 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. |
| bevacizumab | DRUG | IV infusion |
| Comparator: ridaforolimus + dalotuzumab | DRUG | Starting dose of oral ridaforolimus is 10 mg/day, QD, for five days. Dose rising up to 40 mg/day, QD for five days. Dose range for intravenous dalotuzumab is 7.5 mg/kg/week, 10 mg/kg/week or 7.5 mg/kg/every 14 days. Dalotuzumab will be given as an IV infusion over 1 or 2 hour(s). |
| Doxorubicin | DRUG | administered at 60 mg/m2 intravenously every 3 weeks |
| AP23573 | DRUG | ridaforolimus |
Inclusion Criteria: * Confirmed diagnosis of metastatic soft-tissue or bone sarcoma * Ongoing complete response, partial response, or stable disease (RECIST) after a minimum of 4 cycles (and maximum of 12 months) of any one first, second, or third line of prior cytotoxic chemotherapy for metastatic...
AP23573 is an investigational small molecule being studied for the treatment of malignant glioma, including glioblastoma and gliosarcoma. It was evaluated in a Phase 1 clinical trial in patients with progressive or recurrent glioma. The drug is not approved and remains in clinical development.
AP23573 is being developed by Merck & Company, Inc., which trades under the ticker symbol MRK. The company sponsored a Phase 1 clinical trial of the drug in patients with malignant glioma. Merck is the sole developer of AP23573.
AP23573 is in Phase 1 clinical development. A single Phase 1 trial of the drug has been completed in patients with progressive or recurrent glioma. The drug is investigational and has not been approved by regulatory authorities.
AP23573 has been studied in one clinical trial, identified as NCT00087451. This Phase 1 study, titled "Safety Study of AP23573 in Patients With Progressive or Recurrent Glioma (8669-023)", was completed in the United States and enrolled 11 participants aged 18 years and older.
AP23573 is the sole name provided for this investigational drug. No alternative names have been identified for this compound. It is being developed by Merck & Company, Inc. for the treatment of malignant glioma.