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

Phase 2

Completed

• Conditions: Breast Neoplasms
• Interventions: Drug: Ridaforolimus; Drug: Dalotuzumab; Drug: Exemestane

• Registration Number: NCT01605396
• Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2012-05-22
• Study First Submitted QC: 2012-05-22
• Study First Posted: 2012-05-24
• Study Start: 2012-07-04
• Primary Completion: 2014-02-19
• Study Completion: 2018-03-15
• Results First Submitted: 2019-02-15
• Status Verified: 2019-03
• Results First Submitted QC: 2019-03-21
• Last Update Submitted: 2019-03-21
• Results First Posted: 2019-03-25
• Last Update Posted: 2019-03-25

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Female
• Target Recruitment: 80

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Ridaforolimus + Dalotuzumab + Exemestane	Ridaforolimus	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 + Dalotuzumab + Exemestane	Dalotuzumab	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	Ridaforolimus	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.
Ridaforolimus + Dalotuzumab + Exemestane	Exemestane	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	Exemestane	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.

Primary Outcome Measures

Name	Time	Method
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)	From Day 1 through last post-study efficacy follow-up (up to ~19 months)	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.

Secondary Outcome Measures

Name	Time	Method
Percent Change From Baseline in Sum of Target Lesion Diameters at Week 16	Baseline, 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.
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).	From Day 1 through last post-study efficacy follow-up (up to ~19 months)	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.
Overall Survival (OS)	From Day 1 through last post-study efficacy follow-up (up to ~19 months)	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.