A Phase II Trial of Ridaforolimus and Exemestane, Compared to Ridaforolimus, Dalotuzumab and Exemestane in Participants With Breast Cancer (MK-8669-064)

Study Overview
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Brief Summary
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The purpose of the study is to evaluate the efficacy of the triplet of ridaforolimus, dalotuzumab and exemestane compared to the combination of ridaforolimus and exemestane in post-menopausal participants with breast cancer. The primary hypothesis of the study is that the triplet of ridaforolimus, dalotuzumab and exemestane will improve progression free survival (PFS) compared to ridaforolimus and exemestane.

Official Title
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A Phase II Randomized Trial of the Combination of Ridaforolimus and Exemestane, Compared to Ridaforolimus, Dalotuzumab and Exemestane in High Proliferation, Estrogen Receptor Positive Breast Cancer Patients

Conditions
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Breast Neoplasms

Intervention / Treatment
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* Drug: Ridaforolimus
* Drug: Dalotuzumab
* Drug: Exemestane


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Females with a histologically confirmed diagnosis of breast cancer that is metastatic or locally advanced (locally advanced tumors must not be amenable to surgery or radiation therapy with curative intent) with the following pathological characteristics determined locally: estrogen receptor positive and Human Epidermal Growth Factor Receptor 2 (HER-2) negative, and Ki67 (a tumor marker) ≥ 15% determined by the central study laboratory Post-menopausal With advanced breast cancer whose disease was refractory to previous letrozole or anastrozole Has at least one confirmed measurable metastatic lesion Has a performance status ≤ 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale Has a life expectancy of at least 3 months Adequate organ function Exclusion Criteria: Is receiving any other concurrent systemic tumor therapy, including hormonal agents and HER-2 inhibitors Previously received rapamycin or rapamycin analogs, including ridaforolimus, temsirolimus, or everolimus Received prior treatment with Insulin-like Growth Factor 1 Receptor (IGF-1R) inhibitors, Phosphatidylinositol 3-Kinase (PI3K) inhibitors, or other experimental agents that target PI3K, Protein Kinase B (AKT), or Mammalian Target of Rapamycin (mTOR) pathway Is receiving chronic corticosteroids administered at doses greater than those used for normal replacement therapy Has active brain metastasis or leptomeningeal carcinomatosis; patients with adequately treated brain metastases are eligible if they meet certain criteria Known allergy to macrolide antibiotics Has an active infection requiring antibiotics Significant or uncontrolled cardiovascular disease Poorly controlled Type 1 or 2 diabetes Is known to be Human Immunodeficiency Virus (HIV) positive Has a known history of active hepatitis B or C. Healthy carriers of hepatitis B are not allowed on this study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ridaforolimus + Dalotuzumab + Exemestane<br>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. | Drug: Ridaforolimus<br>* Ridaforolimus 10 mg tablet, administered PO at a dose of 10 mg (triplet) or 30 mg (doublet) depending upon randomization, on Days 1-5, 8-12, 15-19, & 22-26 of 28-day cycle.<br>* Other names: AP23573;Drug: Dalotuzumab<br>* Dalotuzumab administered 10 mg/kg IV weekly on Days 1, 8, 15, and 22 of 28-day cycle.<br>* Other names: h7C10;Drug: Exemestane<br>* Exemestane 25 mg tablet administered PO QD.<br>* Other names: Aromasin;|
| Active Comparator: Ridaforolimus + Exemestane<br>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. | Drug: Ridaforolimus<br>* Ridaforolimus 10 mg tablet, administered PO at a dose of 10 mg (triplet) or 30 mg (doublet) depending upon randomization, on Days 1-5, 8-12, 15-19, & 22-26 of 28-day cycle.<br>* Other names: AP23573;Drug: Exemestane<br>* Exemestane 25 mg tablet administered PO QD.<br>* Other names: Aromasin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1. Progression-free Survival (PFS) According to Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Based on Blinded Independent Central Review (BICR) | 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. | From Day 1 through last post-study efficacy follow-up (up to  19 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Sum of Target Lesion Diameters at Week 16 | The percent change from baseline to Week 16 in the sum of target lesion diameters as determined by anatomic imaging was defined as the line length (i.e., diameter) for each target lesion identified at baseline summed across all lesions at baseline, and separately at each post-baseline time point. The primary analysis was conducted using a constrained longitudinal data analysis (cLDA) method and target lesion measurements according to the BICR. Percent change from baseline in sum of target lesion diameters at Week 16 was reported for each treatment arm. | Baseline, Week 16 | 
| 3. Percentage of Participants With Objective Response (Objective Response Rate [ORR]) According to Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Based on Blinded Independent Central Review (BICR). | ORR was defined as the percentage of participants whose best response was complete response (CR; disappearance of all non-nodal target lesions and any pathological lymph nodes must have become normal) or partial response (PR; at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD) according to RECIST 1.1 and based on BICR. ORR 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. | From Day 1 through last post-study efficacy follow-up (up to  19 months) | 
| Overall Survival (OS) | OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of analysis were censored at the date last known to be alive. OS was analyzed using the Kaplan-Meier method and median OS (95% confidence interval [CI]) in weeks was reported for each treatment arm. Per protocol, all participants (including participants who discontinued study treatment) were followed for survival until investigator notification to discontinue. | From Day 1 through last post-study efficacy follow-up (up to  19 months) |