Breast Neoplasms
Conditions
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.
Interventions
DRUGRidaforolimus
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.
DRUGDalotuzumab
Dalotuzumab administered 10 mg/kg IV weekly on Days 1, 8, 15, and 22 of 28-day cycle.
DRUGExemestane
Exemestane 25 mg tablet administered PO QD.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Participant flow
Pre-assignment details
Of 196 screened participants, 80 were randomized to either ridaforolimus plus dalotuzumab plus exemestane or ridaforolimus plus exemestane.
Participants by arm
| Arm | Count |
|---|---|
| Ridaforolimus + Dalotuzumab + Exemestane Participants received 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. | 40 |
| Ridaforolimus + Exemestane Participants received 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. | 40 |
| Total | 80 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 5 | 3 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Non-Compliance With Study Drug | 1 | 1 |
| Overall Study | Physician Decision | 2 | 2 |
| Overall Study | Progressive Disease | 23 | 27 |
| Overall Study | Transfer Off Study | 4 | 5 |
| Overall Study | Withdrawal by Subject | 4 | 2 |
Baseline characteristics
| Characteristic | Ridaforolimus + Exemestane | Total | Ridaforolimus + Dalotuzumab + Exemestane |
|---|---|---|---|
| Age, Continuous | 57.7 Years STANDARD_DEVIATION 11.8 | 59.2 Years STANDARD_DEVIATION 10.6 | 60.7 Years STANDARD_DEVIATION 9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 8 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 34 Participants | 69 Participants | 35 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 14 Participants | 23 Participants | 9 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 4 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 24 Participants | 50 Participants | 26 Participants |
| Sex: Female, Male Female | 40 Participants | 80 Participants | 40 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 39 | 2 / 40 |
| other Total, other adverse events | 39 / 39 | 40 / 40 |
| serious Total, serious adverse events | 8 / 39 | 17 / 40 |
Outcome results
Primary
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.
Time frame: From Day 1 through last post-study efficacy follow-up (up to ~19 months)
Population: All randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ridaforolimus + Dalotuzumab + Exemestane | 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) | 23.29 Weeks |
| Ridaforolimus + Exemestane | 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) | 31.86 Weeks |
Comparison: Hazard ratio (HR) and p-value for treatment difference based on Cox regression model with Efron tie handling for treatment comparison (Ridaforolimus + Dalotuzumab + Exemestane arm versus Ridaforolimus + Exemestane arm).p-value: 0.56580% CI: [0.81, 1.72]Regression, Cox
Secondary
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.
Time frame: From Day 1 through last post-study efficacy follow-up (up to ~19 months)
Population: All randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ridaforolimus + Dalotuzumab + Exemestane | 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). | 15.0 Percentage of Participants |
| Ridaforolimus + Exemestane | 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). | 25.0 Percentage of Participants |
Comparison: Miettinen and Nurminen's method was used to compare ORR between the two treatment arms (Ridaforolimus + Dalotuzumab + Exemestane arm versus Ridaforolimus + Exemestane arm), and to calculate a p-value and 95% confidence interval (CI) for the difference in response rates.p-value: 0.26795% CI: [-27.8, 8]Miettinen and Nurminen's Method
Secondary
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.
Time frame: From Day 1 through last post-study efficacy follow-up (up to ~19 months)
Population: All randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ridaforolimus + Dalotuzumab + Exemestane | Overall Survival (OS) | NA Weeks |
| Ridaforolimus + Exemestane | Overall Survival (OS) | NA Weeks |
Comparison: HR and p-value for treatment difference based on Cox regression model with Efron tie handling for treatment comparison (Ridaforolimus + Dalotuzumab + Exemestane arm versus Ridaforolimus + Exemestane arm).p-value: 0.56295% CI: [0.46, 4.13]Regression, Cox
Secondary
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.
Time frame: Baseline, Week 16
Population: All randomized participants with available Week 16 target lesion measurements.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ridaforolimus + Dalotuzumab + Exemestane | Percent Change From Baseline in Sum of Target Lesion Diameters at Week 16 | -19.3 percent change | Standard Deviation 20.4 |
| Ridaforolimus + Exemestane | Percent Change From Baseline in Sum of Target Lesion Diameters at Week 16 | -10.7 percent change | Standard Deviation 28.5 |