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

• ClinicalTrials.gov Identifier: NCT01605396
• Recruitment Status: Completed
• First Posted: May 24, 2012
• Results First Posted: March 25, 2019
• Last Update Posted: March 25, 2019
• Sponsor: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Merck Sharp & Dohme LLC

Tracking Information

• First Submitted Date: May 22, 2012
• First Posted Date: May 24, 2012
• Results First Submitted Date: February 15, 2019
• Results First Posted Date: March 25, 2019
• Last Update Posted Date: March 25, 2019
• Actual Study Start Date: July 4, 2012
• Actual Primary Completion Date: February 19, 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 21, 2019)

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) [ Time Frame: 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.

• Original Primary Outcome Measures (submitted: May 22, 2012): Progression-free Survival (PFS) [ Time Frame: Baseline until disease progression, assessed throughout entire study duration (up to approximately 27 months) ]

Current Secondary Outcome Measures (submitted: March 21, 2019)

• Percent Change From Baseline in Sum of Target Lesion Diameters at Week 16 [ Time Frame: 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). [ Time Frame: 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) [ Time Frame: 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.

Original Secondary Outcome Measures (submitted: May 22, 2012)

• Percent Reduction in Sum of Target Lesion Sizes [ Time Frame: Baseline to Week 16 ]
• Objective response rate (ORR) [ Time Frame: Baseline until participant no longer responds to treatment, assessed throughout entire study duration (up to approximately 27 months) ]
• Overall survival (OS) [ Time Frame: Baseline until death, assessed throughout entire study duration (up to approximately 27 months) ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Phase II Trial of Ridaforolimus and Exemestane, Compared to Ridaforolimus, Dalotuzumab and Exemestane in Participants With Breast Cancer (MK-8669-064)
• Official Title: 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
• 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 Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Breast Neoplasms

Intervention

• Drug: Ridaforolimus
  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.
  Other Names:

  • MK-8669
  • AP23573
• Drug: Dalotuzumab
  Dalotuzumab administered 10 mg/kg IV weekly on Days 1, 8, 15, and 22 of 28-day cycle.
  Other Names:

  • MK-0646
  • h7C10
• Drug: Exemestane
  Exemestane 25 mg tablet administered PO QD.
  Other Name: Aromasin

Study Arms

• Experimental: Ridaforolimus + Dalotuzumab + 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.
  Interventions:

  • Drug: Ridaforolimus
  • Drug: Dalotuzumab
  • Drug: Exemestane
• Active Comparator: Ridaforolimus + 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.
  Interventions:

  • Drug: Ridaforolimus
  • Drug: Exemestane

• Publications *: Rugo HS, Tredan O, Ro J, Morales SM, Campone M, Musolino A, Afonso N, Ferreira M, Park KH, Cortes J, Tan AR, Blum JL, Eaton L, Gause CK, Wang Z, Im E, Mauro DJ, Jones MB, Denker A, Baselga J. A randomized phase II trial of ridaforolimus, dalotuzumab, and exemestane compared with ridaforolimus and exemestane in patients with advanced breast cancer. Breast Cancer Res Treat. 2017 Oct;165(3):601-609. doi: 10.1007/s10549-017-4375-5. Epub 2017 Jul 5.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 18, 2017): 80
• Original Estimated Enrollment (submitted: May 22, 2012): 150
• Actual Study Completion Date: March 15, 2018
• Actual Primary Completion Date: February 19, 2014 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Not Provided
• Removed Location Countries: Belgium, Colombia, Czech Republic, Denmark, France, Germany, Israel, Italy, Korea, Republic of, Peru, Portugal, Spain, Sweden, Taiwan, United States

Administrative Information

• NCT Number: NCT01605396
• Other Study ID Numbers: 8669-064; 2012-000335-11 ( EudraCT Number ); MK-8669-064 ( Other Identifier: Merck )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
• URL: http://engagezone.msd.com/ds_documentation.php

• Current Responsible Party: Merck Sharp & Dohme LLC
• Original Responsible Party: Same as current
• Current Study Sponsor: Merck Sharp & Dohme LLC
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme LLC

• PRS Account: Merck Sharp & Dohme LLC
• Verification Date: March 2019