Breast Cancer
Conditions
Keywords
HR-positive, HER2-negative, Advanced breast cancer, LEE011, ribociclib, everolimus, Afinitor, exemestane, Aromasin, CDK, CDK4, CDK6, CDK4/6, CDK4/6 inhibitor, Phase I, Phase II, ER-positive, PR-positive, Postmenopausal, adult
Brief summary
The purpose of this study is determine if the triplet combination of ribociclib, everolimus and exemastane is safe and effective in the treatment of locally advanced/metastatic breast cancer following treatment with a CDK 4/6 inhibitor
Detailed description
This trial had two phases. The purpose of Phase I dose escalation and dose de-escalation was to determine the maximum tolerated doses (MTDs) and/or identify the recommended Phase II dose (RP2D) of the combination treatment of ribociclib+ everolimus + exemestane. The dosing was continuous in adult men and postmenopausal women with HR+ HER2-negative advanced breast cancer which was resistant to the non-steroidal aromatase inhibitors, fulvestrant or tamoxifen. The purpose of the phase II portion of this trial was to evaluate the anti-tumor activity of exemestane, everolimus and ribociclib combination therapy following progression on a CDK 4/6 inhibitor. The planned duration of the study was 30 months.
Interventions
DRUGRibociclib
supplied in 50 mg, 200 mg capsules/tablets taken orally and dosed daily for 28 day cycle
DRUGEverolimus
supplied in 2.5 mg tablets taken orally, daily for 28 day cycle
DRUGExemestane
supplied in 25 mg tablets taken orally, daily for 28 day cycle
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adult men and women * Patient has a confirmed diagnosis of estrogen-receptor positive and/or progesterone receptor positive breast cancer by local laboratory and has HER2-negative breast cancer * Patient must have either measurable disease by RECIST 1.1 or bone lesions in absence of measurable disease. * ECOG Performance Status 0 - 1 * Disease refractory to either, AI, tamoxifen or fulvestrant * Previously treated on any CDK 4/6 inhibitor. * Patient has adequate bone marrow and organ function.
Exclusion criteria
* Patient with symptomatic visceral disease or any disease burden that makes the patient ineligible for endocrine therapy per the investigator's best judgment. * Patient has received more than one line of chemotherapy for advanced disease. * Previous treatment with mTOR inhibitors, or exemestane for advanced disease. * Progressed on more than one CDK 4/6 inhibitor * Patient with CNS involvement unless they are at least 4 weeks from prior therapy completion. * Clinically significant, uncontrolled heart disease and/or recent cardiac events.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Participants With Dose Limiting Toxicities by Preferred Term in Cycle 1 (28 Days) - in Phase I | Baseline up to 28 days | A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value assessed as having a reasonably possible relationship to the study medication(s) and is unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurs within the first 28 days of treatment (cycle 1) and meets any of the criteria defined in the protocol. National Cancer Institute Common Terminology Criteria for Adverse events (NCI CTCAE) version 4.03 will be used for all grading. |
| Clinical Benefit Rate as Per Central Review by Group- Phase II | From baseline up to 24 weeks | Clinical Benefit Rate (CBR) is defined as the percentage of participants with a complete response (CR) or partial response (PR) or with stable disease (SD) as per Response Evaluation Criteria in Solid Tumors (RECIST) V1.1 or Non-Complete Response or Non-Progressive Disease (NCRNPD) during first 24 weeks of first dose. CR=disappearance of all non-nodal target lesions, PR=at least a 30% decrease in the sum of diameter of all target lesions, SD=neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease (PD), PD=at least a 20% increase in the sum of diameter of all target lesions. The hypothesis was to be rejected if the lower limit of the 95% Confidence Interval for Clinical Benefit Rate (CBR) was greater than 10%. |
| Best Overall Responses (BOR) Summary Table as Per Central Review by Group - Phase II | Baseline up to 24 weeks and at 24 weeks | Complete response (CR) or partial response (PR), or stable disease (SD) at 24 weeks as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or Non-CR Non-PD (NCRNPD) at Week 24. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Summary of Progression-free Survival (PFS) (Months), as Per Central Review by Group - Phase II | Baseline up to approximately 32 months | Progression is defined as \<= 12 weeks after randomization/ start of treatment (and not qualifying for CR, PR or SD). |
| Overall Survival (OS) by Group - Phase II | Baseline up to approximately 32 months | Overall survival is the time from date of first treatment to the date of death due to any cause. If a patient is not known to have died, survival will be censored at the last date of contact. |
| Everolimus Pharmacokinetic Plasma Concentrations by Cohort - Phase I | Cycle 1,2: Day 1 and 15 - pre-dose, 2 and 4 hour post dose, Cycle 3 , Day 1 - pre-dose | Plasma concentrations; below limit of quantitation values set to zero |
| Time to Definitive Deterioration of ECOG Performance Status in One Category of the Score by Group - Phase II | Baseline up to approximately 8 months | Time to definitive deterioration of ECOG performance status in one category of score is defined as the time from the date of randomization to the date of event, which is defined as at least one score lower than the baseline. |
| Everolimus Pharmacokinetic Plasma Concentrations - Phase II | Cycle 1,2: Day 1 and 15 - pre-dose, 2 and 4 hour post dose, Cycle 3 , Day 1 - pre-dose | Plasma concentrations; below limit of quantitation values set to zero |
| Duration of Overall Response (DOR) by Group - Phase II | Baseline up to approximately 16 months | Patients whose best response is complete response (CR) or partial response (PR). The start date is the date of first documented response (CR or PR) and the end date is the date of first documented progression or death due to underlying cancer. |
| Best Overall Responses (BOR) Summary Table as Per Central Review by Cohort - Phase I | From baseline up to 24 weeks | Complete response (CR) or partial response (PR), or stable disease (SD)as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or Non-CR Non-PD (NCRNPD) |
| Clinical Benefit Rate as Per Central Review by Dose Cohort - Phase I | Baseline up to 24 weeks and at week 24 | Clinical Benefit Rate (CBR) is defined as the percentage of patients with a complete response (CR) or partial response (PR) or with stable disease (SD) at 24 weeks as per Response Evaluation Criteria in Solid Tumors (RECIST) V1.1 or Non-Complete Response Non-Progressive Disease (NCRNPD) up to Week 24 and at Week 24. |
Countries
United States
Participant flow
Pre-assignment details
Cohort A, B and C were in Phase I and Group 1 and Group 2 classification were in Phase II
Participants by arm
| Arm | Count |
|---|---|
| Cohort A Ribociclib (250 mg daily), everolimus (2.5 mg daily) and exemestane (25 mg daily) taken orally for 28 days. If no DLTs occurred, progressed to Cohort B | 8 |
| Cohort B Ribociclib (300 mg daily), everolimus (2.5 mg daily) and exemestane (25 mg daily) taken orally | 10 |
| Cohort C Ribociclib (200 mg daily), everolimus (5 mg daily) and exemestane (25 mg daily) taken orally | 7 |
| Group 1 Ribociclib (300 mg daily), everolimus (2.5 mg daily) and exemestane (25 mg daily) taken orally | 46 |
| Group 2 Ribociclib (200 mg daily), everolimus (5 mg daily) and exemestane (25 mg daily) taken orally | 33 |
| Total | 104 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Phase I | Adverse Event | 1 | 3 | 1 | 0 | 0 |
| Phase I | Physician Decision | 0 | 3 | 4 | 0 | 0 |
| Phase I | Progressive disease | 7 | 3 | 2 | 0 | 0 |
| Phase I | Protocol deviation | 0 | 1 | 0 | 0 | 0 |
| Phase II | Adverse Event | 0 | 0 | 0 | 3 | 3 |
| Phase II | Death | 0 | 0 | 0 | 1 | 0 |
| Phase II | Other | 0 | 0 | 0 | 2 | 0 |
| Phase II | Physician Decision | 0 | 0 | 0 | 8 | 5 |
| Phase II | Progressive dissease | 0 | 0 | 0 | 30 | 23 |
| Phase II | Study terminated by sponsor | 0 | 0 | 0 | 2 | 2 |
Baseline characteristics
| Characteristic | Cohort A | Cohort B | Cohort C | Group 1 | Group 2 | Total |
|---|---|---|---|---|---|---|
| Age, Customized ≥ 40 - < 50 years | 2 participants | 1 participants | 0 participants | 7 participants | 3 participants | 13 participants |
| Age, Customized <40 years | 0 participants | 2 participants | 1 participants | 4 participants | 5 participants | 12 participants |
| Age, Customized ≥ 50 - < 60 years | 3 participants | 4 participants | 2 participants | 15 participants | 11 participants | 35 participants |
| Age, Customized ≥ 60 - < 70 years | 2 participants | 2 participants | 2 participants | 14 participants | 11 participants | 31 participants |
| Age, Customized ≥ 70 years | 1 participants | 1 participants | 2 participants | 6 participants | 3 participants | 13 participants |
| Body Mass Index < 30 BMI | 5 participants | 7 participants | 2 participants | 26 participants | 19 participants | 59 participants |
| Body Mass Index ≥ 30 BMI | 3 participants | 3 participants | 4 participants | 18 participants | 11 participants | 39 participants |
| Body Mass Index Missing | 0 participants | 0 participants | 1 participants | 2 participants | 3 participants | 6 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Performance = 0 | 4 Participants | 4 Participants | 1 Participants | 27 Participants | 21 Participants | 57 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Performance = 1 | 4 Participants | 6 Participants | 6 Participants | 19 Participants | 12 Participants | 47 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Black | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants | 5 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 1 Participants | 0 Participants | 4 Participants | 0 Participants | 5 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants | 2 Participants | 0 Participants | 5 Participants | 0 Participants | 7 Participants |
| Race/Ethnicity, Customized White/Caucasian | 7 Participants | 6 Participants | 6 Participants | 36 Participants | 30 Participants | 85 Participants |
| Sex: Female, Male Female | 8 Participants | 10 Participants | 7 Participants | 46 Participants | 33 Participants | 104 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 6 / 8 | 5 / 10 | 0 / 7 | 20 / 46 | 11 / 33 |
| other Total, other adverse events | 8 / 8 | 10 / 10 | 7 / 7 | 46 / 46 | 33 / 33 |
| serious Total, serious adverse events | 3 / 8 | 3 / 10 | 5 / 7 | 11 / 46 | 5 / 33 |
Outcome results
Primary
Best Overall Responses (BOR) Summary Table as Per Central Review by Group - Phase II
Complete response (CR) or partial response (PR), or stable disease (SD) at 24 weeks as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or Non-CR Non-PD (NCRNPD) at Week 24.
Time frame: Baseline up to 24 weeks and at 24 weeks
Population: Full analysis set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort A | Best Overall Responses (BOR) Summary Table as Per Central Review by Group - Phase II | Participants with measurable disease at baseline | 35 Participants |
| Cohort A | Best Overall Responses (BOR) Summary Table as Per Central Review by Group - Phase II | Participants with non-measurable disease at baseline | 11 Participants |
| Cohort A | Best Overall Responses (BOR) Summary Table as Per Central Review by Group - Phase II | Complete response (CR) | 0 Participants |
| Cohort A | Best Overall Responses (BOR) Summary Table as Per Central Review by Group - Phase II | Partial Response (PR) | 3 Participants |
| Cohort A | Best Overall Responses (BOR) Summary Table as Per Central Review by Group - Phase II | Stable disease (SD) | 17 Participants |
| Cohort A | Best Overall Responses (BOR) Summary Table as Per Central Review by Group - Phase II | Progressive disease (PD) | 14 Participants |
| Cohort A | Best Overall Responses (BOR) Summary Table as Per Central Review by Group - Phase II | NCRNPD - Non-complete response non-progressive disease | 10 Participants |
| Cohort A | Best Overall Responses (BOR) Summary Table as Per Central Review by Group - Phase II | Unknown | 2 Participants |
| Cohort B | Best Overall Responses (BOR) Summary Table as Per Central Review by Group - Phase II | Unknown | 1 Participants |
| Cohort B | Best Overall Responses (BOR) Summary Table as Per Central Review by Group - Phase II | Participants with measurable disease at baseline | 21 Participants |
| Cohort B | Best Overall Responses (BOR) Summary Table as Per Central Review by Group - Phase II | Stable disease (SD) | 6 Participants |
| Cohort B | Best Overall Responses (BOR) Summary Table as Per Central Review by Group - Phase II | Participants with non-measurable disease at baseline | 11 Participants |
| Cohort B | Best Overall Responses (BOR) Summary Table as Per Central Review by Group - Phase II | NCRNPD - Non-complete response non-progressive disease | 10 Participants |
| Cohort B | Best Overall Responses (BOR) Summary Table as Per Central Review by Group - Phase II | Complete response (CR) | 0 Participants |
| Cohort B | Best Overall Responses (BOR) Summary Table as Per Central Review by Group - Phase II | Progressive disease (PD) | 12 Participants |
| Cohort B | Best Overall Responses (BOR) Summary Table as Per Central Review by Group - Phase II | Partial Response (PR) | 3 Participants |
Primary
Clinical Benefit Rate as Per Central Review by Group- Phase II
Clinical Benefit Rate (CBR) is defined as the percentage of participants with a complete response (CR) or partial response (PR) or with stable disease (SD) as per Response Evaluation Criteria in Solid Tumors (RECIST) V1.1 or Non-Complete Response or Non-Progressive Disease (NCRNPD) during first 24 weeks of first dose. CR=disappearance of all non-nodal target lesions, PR=at least a 30% decrease in the sum of diameter of all target lesions, SD=neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease (PD), PD=at least a 20% increase in the sum of diameter of all target lesions. The hypothesis was to be rejected if the lower limit of the 95% Confidence Interval for Clinical Benefit Rate (CBR) was greater than 10%.
Time frame: From baseline up to 24 weeks
Population: Protocol analysis set. n: Number of patients who are at the corresponding category. ORR: percentage of patients having BOR of CR/PR.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort A | Clinical Benefit Rate as Per Central Review by Group- Phase II | Overall response rate (CR+PR): | 6.5 percentage of participants |
| Cohort A | Clinical Benefit Rate as Per Central Review by Group- Phase II | CBR - CR+PR+SD (NCRNPD) by 24 weeks | 65.2 percentage of participants |
| Cohort A | Clinical Benefit Rate as Per Central Review by Group- Phase II | Disease control rate (CR+PR+SD(NCRNPD) | 65.2 percentage of participants |
| Cohort B | Clinical Benefit Rate as Per Central Review by Group- Phase II | Overall response rate (CR+PR): | 9.4 percentage of participants |
| Cohort B | Clinical Benefit Rate as Per Central Review by Group- Phase II | CBR - CR+PR+SD (NCRNPD) by 24 weeks | 59.4 percentage of participants |
| Cohort B | Clinical Benefit Rate as Per Central Review by Group- Phase II | Disease control rate (CR+PR+SD(NCRNPD) | 59.4 percentage of participants |
Primary
Participants With Dose Limiting Toxicities by Preferred Term in Cycle 1 (28 Days) - in Phase I
A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value assessed as having a reasonably possible relationship to the study medication(s) and is unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurs within the first 28 days of treatment (cycle 1) and meets any of the criteria defined in the protocol. National Cancer Institute Common Terminology Criteria for Adverse events (NCI CTCAE) version 4.03 will be used for all grading.
Time frame: Baseline up to 28 days
Population: dose limiting toxicity-determining set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort A | Participants With Dose Limiting Toxicities by Preferred Term in Cycle 1 (28 Days) - in Phase I | Febrile neutropenia Grade 3 | 1 Participants |
| Cohort A | Participants With Dose Limiting Toxicities by Preferred Term in Cycle 1 (28 Days) - in Phase I | Neutropenia Grade 4 | 0 Participants |
| Cohort A | Participants With Dose Limiting Toxicities by Preferred Term in Cycle 1 (28 Days) - in Phase I | Thrombocytopenia Grade 4 | 0 Participants |
| Cohort A | Participants With Dose Limiting Toxicities by Preferred Term in Cycle 1 (28 Days) - in Phase I | Cardiac tamponade Grade 4 | 1 Participants |
| Cohort A | Participants With Dose Limiting Toxicities by Preferred Term in Cycle 1 (28 Days) - in Phase I | Diarrhea Grade 3 | 1 Participants |
| Cohort A | Participants With Dose Limiting Toxicities by Preferred Term in Cycle 1 (28 Days) - in Phase I | Hyperglycemia Grade 4 | 0 Participants |
| Cohort B | Participants With Dose Limiting Toxicities by Preferred Term in Cycle 1 (28 Days) - in Phase I | Hyperglycemia Grade 4 | 0 Participants |
| Cohort B | Participants With Dose Limiting Toxicities by Preferred Term in Cycle 1 (28 Days) - in Phase I | Febrile neutropenia Grade 3 | 1 Participants |
| Cohort B | Participants With Dose Limiting Toxicities by Preferred Term in Cycle 1 (28 Days) - in Phase I | Cardiac tamponade Grade 4 | 0 Participants |
| Cohort B | Participants With Dose Limiting Toxicities by Preferred Term in Cycle 1 (28 Days) - in Phase I | Diarrhea Grade 3 | 0 Participants |
| Cohort B | Participants With Dose Limiting Toxicities by Preferred Term in Cycle 1 (28 Days) - in Phase I | Neutropenia Grade 4 | 1 Participants |
| Cohort B | Participants With Dose Limiting Toxicities by Preferred Term in Cycle 1 (28 Days) - in Phase I | Thrombocytopenia Grade 4 | 1 Participants |
| Cohort C | Participants With Dose Limiting Toxicities by Preferred Term in Cycle 1 (28 Days) - in Phase I | Neutropenia Grade 4 | 0 Participants |
| Cohort C | Participants With Dose Limiting Toxicities by Preferred Term in Cycle 1 (28 Days) - in Phase I | Thrombocytopenia Grade 4 | 0 Participants |
| Cohort C | Participants With Dose Limiting Toxicities by Preferred Term in Cycle 1 (28 Days) - in Phase I | Hyperglycemia Grade 4 | 1 Participants |
| Cohort C | Participants With Dose Limiting Toxicities by Preferred Term in Cycle 1 (28 Days) - in Phase I | Cardiac tamponade Grade 4 | 0 Participants |
| Cohort C | Participants With Dose Limiting Toxicities by Preferred Term in Cycle 1 (28 Days) - in Phase I | Febrile neutropenia Grade 3 | 0 Participants |
| Cohort C | Participants With Dose Limiting Toxicities by Preferred Term in Cycle 1 (28 Days) - in Phase I | Diarrhea Grade 3 | 0 Participants |
Secondary
Best Overall Responses (BOR) Summary Table as Per Central Review by Cohort - Phase I
Complete response (CR) or partial response (PR), or stable disease (SD)as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or Non-CR Non-PD (NCRNPD)
Time frame: From baseline up to 24 weeks
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort A | Best Overall Responses (BOR) Summary Table as Per Central Review by Cohort - Phase I | Participants with measurable disease at baseline | 5 Participants |
| Cohort A | Best Overall Responses (BOR) Summary Table as Per Central Review by Cohort - Phase I | Participants with non-measurable disease at baseline | 3 Participants |
| Cohort A | Best Overall Responses (BOR) Summary Table as Per Central Review by Cohort - Phase I | Complete response (CR) | 0 Participants |
| Cohort A | Best Overall Responses (BOR) Summary Table as Per Central Review by Cohort - Phase I | Partial Response (PR) | 0 Participants |
| Cohort A | Best Overall Responses (BOR) Summary Table as Per Central Review by Cohort - Phase I | Stable disease (SD) | 3 Participants |
| Cohort A | Best Overall Responses (BOR) Summary Table as Per Central Review by Cohort - Phase I | Progressive disease (PD) | 3 Participants |
| Cohort A | Best Overall Responses (BOR) Summary Table as Per Central Review by Cohort - Phase I | NCRNPD - Non-complete response non-progressive disease | 2 Participants |
| Cohort A | Best Overall Responses (BOR) Summary Table as Per Central Review by Cohort - Phase I | Unknown | 0 Participants |
| Cohort B | Best Overall Responses (BOR) Summary Table as Per Central Review by Cohort - Phase I | Complete response (CR) | 0 Participants |
| Cohort B | Best Overall Responses (BOR) Summary Table as Per Central Review by Cohort - Phase I | NCRNPD - Non-complete response non-progressive disease | 1 Participants |
| Cohort B | Best Overall Responses (BOR) Summary Table as Per Central Review by Cohort - Phase I | Partial Response (PR) | 1 Participants |
| Cohort B | Best Overall Responses (BOR) Summary Table as Per Central Review by Cohort - Phase I | Stable disease (SD) | 6 Participants |
| Cohort B | Best Overall Responses (BOR) Summary Table as Per Central Review by Cohort - Phase I | Progressive disease (PD) | 0 Participants |
| Cohort B | Best Overall Responses (BOR) Summary Table as Per Central Review by Cohort - Phase I | Participants with measurable disease at baseline | 7 Participants |
| Cohort B | Best Overall Responses (BOR) Summary Table as Per Central Review by Cohort - Phase I | Participants with non-measurable disease at baseline | 3 Participants |
| Cohort B | Best Overall Responses (BOR) Summary Table as Per Central Review by Cohort - Phase I | Unknown | 2 Participants |
| Cohort C | Best Overall Responses (BOR) Summary Table as Per Central Review by Cohort - Phase I | Complete response (CR) | 0 Participants |
| Cohort C | Best Overall Responses (BOR) Summary Table as Per Central Review by Cohort - Phase I | Participants with non-measurable disease at baseline | 3 Participants |
| Cohort C | Best Overall Responses (BOR) Summary Table as Per Central Review by Cohort - Phase I | Participants with measurable disease at baseline | 4 Participants |
| Cohort C | Best Overall Responses (BOR) Summary Table as Per Central Review by Cohort - Phase I | Partial Response (PR) | 2 Participants |
| Cohort C | Best Overall Responses (BOR) Summary Table as Per Central Review by Cohort - Phase I | NCRNPD - Non-complete response non-progressive disease | 3 Participants |
| Cohort C | Best Overall Responses (BOR) Summary Table as Per Central Review by Cohort - Phase I | Progressive disease (PD) | 0 Participants |
| Cohort C | Best Overall Responses (BOR) Summary Table as Per Central Review by Cohort - Phase I | Stable disease (SD) | 2 Participants |
| Cohort C | Best Overall Responses (BOR) Summary Table as Per Central Review by Cohort - Phase I | Unknown | 0 Participants |
Secondary
Clinical Benefit Rate as Per Central Review by Dose Cohort - Phase I
Clinical Benefit Rate (CBR) is defined as the percentage of patients with a complete response (CR) or partial response (PR) or with stable disease (SD) at 24 weeks as per Response Evaluation Criteria in Solid Tumors (RECIST) V1.1 or Non-Complete Response Non-Progressive Disease (NCRNPD) up to Week 24 and at Week 24.
Time frame: Baseline up to 24 weeks and at week 24
Population: Protocol analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort A | Clinical Benefit Rate as Per Central Review by Dose Cohort - Phase I | Disease control rate (CR+PR+SD(NCRNPD) | 62.5 percentage of participants |
| Cohort A | Clinical Benefit Rate as Per Central Review by Dose Cohort - Phase I | CBR - CR+PR+SD (NCRNPD) at 24 weeks | 0 percentage of participants |
| Cohort A | Clinical Benefit Rate as Per Central Review by Dose Cohort - Phase I | CBR - CR+PR+SD (NCRNPD) by 24 weeks | 62.5 percentage of participants |
| Cohort B | Clinical Benefit Rate as Per Central Review by Dose Cohort - Phase I | Overall response rate (CR+PR): | 10.0 percentage of participants |
| Cohort B | Clinical Benefit Rate as Per Central Review by Dose Cohort - Phase I | CBR - CR+PR+SD (NCRNPD) by 24 weeks | 80.0 percentage of participants |
| Cohort B | Clinical Benefit Rate as Per Central Review by Dose Cohort - Phase I | CBR - CR+PR+SD (NCRNPD) at 24 weeks | 0.0 percentage of participants |
| Cohort B | Clinical Benefit Rate as Per Central Review by Dose Cohort - Phase I | Disease control rate (CR+PR+SD(NCRNPD) | 80.0 percentage of participants |
| Cohort C | Clinical Benefit Rate as Per Central Review by Dose Cohort - Phase I | CBR - CR+PR+SD (NCRNPD) at 24 weeks | 28.6 percentage of participants |
| Cohort C | Clinical Benefit Rate as Per Central Review by Dose Cohort - Phase I | Overall response rate (CR+PR): | 28.6 percentage of participants |
| Cohort C | Clinical Benefit Rate as Per Central Review by Dose Cohort - Phase I | CBR - CR+PR+SD (NCRNPD) by 24 weeks | 100.0 percentage of participants |
| Cohort C | Clinical Benefit Rate as Per Central Review by Dose Cohort - Phase I | Disease control rate (CR+PR+SD(NCRNPD) | 100 percentage of participants |
Secondary
Duration of Overall Response (DOR) by Group - Phase II
Patients whose best response is complete response (CR) or partial response (PR). The start date is the date of first documented response (CR or PR) and the end date is the date of first documented progression or death due to underlying cancer.
Time frame: Baseline up to approximately 16 months
Population: Full analysis set. N=number patients included in the analysis (with confirmed CR or PR)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A | Duration of Overall Response (DOR) by Group - Phase II | 14.6 months |
| Cohort B | Duration of Overall Response (DOR) by Group - Phase II | 6.4 months |
Secondary
Everolimus Pharmacokinetic Plasma Concentrations by Cohort - Phase I
Plasma concentrations; below limit of quantitation values set to zero
Time frame: Cycle 1,2: Day 1 and 15 - pre-dose, 2 and 4 hour post dose, Cycle 3 , Day 1 - pre-dose
Population: Pharmacokinetic analysis set. Number of participants with valid samples varied across timepoints and visits
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort A | Everolimus Pharmacokinetic Plasma Concentrations by Cohort - Phase I | Cycle 1, Day 15 Pre-dose | 7.82 ng/mL |
| Cohort A | Everolimus Pharmacokinetic Plasma Concentrations by Cohort - Phase I | Cycle 1, Day 15 2 H, post dose | 15.2 ng/mL |
| Cohort A | Everolimus Pharmacokinetic Plasma Concentrations by Cohort - Phase I | Cycle 1, Day 15 4 H, post dose | 17.7 ng/mL |
| Cohort A | Everolimus Pharmacokinetic Plasma Concentrations by Cohort - Phase I | Cycle 2, Day 1 Pre-dose | 6.47 ng/mL |
| Cohort A | Everolimus Pharmacokinetic Plasma Concentrations by Cohort - Phase I | Cycle 2, Day 15 Pre-dose | 5.89 ng/mL |
| Cohort A | Everolimus Pharmacokinetic Plasma Concentrations by Cohort - Phase I | Cycle 2, Day 15 2 H post-dose | 21.8 ng/mL |
| Cohort A | Everolimus Pharmacokinetic Plasma Concentrations by Cohort - Phase I | Cycle 2, Day 15 4 H post-dose | 13.7 ng/mL |
| Cohort A | Everolimus Pharmacokinetic Plasma Concentrations by Cohort - Phase I | Cycle 3, Day 1 4 H pre-dose | 4.7 ng/mL |
| Cohort B | Everolimus Pharmacokinetic Plasma Concentrations by Cohort - Phase I | Cycle 1, Day 15 4 H, post dose | 16.2 ng/mL |
| Cohort B | Everolimus Pharmacokinetic Plasma Concentrations by Cohort - Phase I | Cycle 2, Day 15 4 H post-dose | 9.13 ng/mL |
| Cohort B | Everolimus Pharmacokinetic Plasma Concentrations by Cohort - Phase I | Cycle 2, Day 1 Pre-dose | 6.22 ng/mL |
| Cohort B | Everolimus Pharmacokinetic Plasma Concentrations by Cohort - Phase I | Cycle 2, Day 15 Pre-dose | 4.26 ng/mL |
| Cohort B | Everolimus Pharmacokinetic Plasma Concentrations by Cohort - Phase I | Cycle 2, Day 15 2 H post-dose | 14.5 ng/mL |
| Cohort B | Everolimus Pharmacokinetic Plasma Concentrations by Cohort - Phase I | Cycle 1, Day 15 Pre-dose | 8.31 ng/mL |
| Cohort B | Everolimus Pharmacokinetic Plasma Concentrations by Cohort - Phase I | Cycle 1, Day 15 2 H, post dose | 17 ng/mL |
| Cohort B | Everolimus Pharmacokinetic Plasma Concentrations by Cohort - Phase I | Cycle 3, Day 1 4 H pre-dose | 6.97 ng/mL |
| Cohort C | Everolimus Pharmacokinetic Plasma Concentrations by Cohort - Phase I | Cycle 1, Day 15 4 H, post dose | 21.5 ng/mL |
| Cohort C | Everolimus Pharmacokinetic Plasma Concentrations by Cohort - Phase I | Cycle 1, Day 15 2 H, post dose | 36.2 ng/mL |
| Cohort C | Everolimus Pharmacokinetic Plasma Concentrations by Cohort - Phase I | Cycle 1, Day 15 Pre-dose | 8.28 ng/mL |
| Cohort C | Everolimus Pharmacokinetic Plasma Concentrations by Cohort - Phase I | Cycle 2, Day 1 Pre-dose | 7.76 ng/mL |
| Cohort C | Everolimus Pharmacokinetic Plasma Concentrations by Cohort - Phase I | Cycle 2, Day 15 4 H post-dose | 26.9 ng/mL |
| Cohort C | Everolimus Pharmacokinetic Plasma Concentrations by Cohort - Phase I | Cycle 2, Day 15 2 H post-dose | 22.1 ng/mL |
| Cohort C | Everolimus Pharmacokinetic Plasma Concentrations by Cohort - Phase I | Cycle 2, Day 15 Pre-dose | 7.17 ng/mL |
| Cohort C | Everolimus Pharmacokinetic Plasma Concentrations by Cohort - Phase I | Cycle 3, Day 1 4 H pre-dose | 6.33 ng/mL |
Secondary
Everolimus Pharmacokinetic Plasma Concentrations - Phase II
Plasma concentrations; below limit of quantitation values set to zero
Time frame: Cycle 1,2: Day 1 and 15 - pre-dose, 2 and 4 hour post dose, Cycle 3 , Day 1 - pre-dose
Population: Pharmacokinetic analysis set. Number of participants with valid samples varied across timepoints and visits
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort A | Everolimus Pharmacokinetic Plasma Concentrations - Phase II | Cycle 3, Day 1 pre-dose | 193 ng/mL |
| Cohort A | Everolimus Pharmacokinetic Plasma Concentrations - Phase II | Cycle 1, Day 15 2 H post-dose | 644 ng/mL |
| Cohort A | Everolimus Pharmacokinetic Plasma Concentrations - Phase II | Cycle 1, Day 15 4 H post-dose | 583 ng/mL |
| Cohort A | Everolimus Pharmacokinetic Plasma Concentrations - Phase II | Cycle 2 Day 1 pre-dose | 199 ng/mL |
| Cohort A | Everolimus Pharmacokinetic Plasma Concentrations - Phase II | Cycle 2, Day 15 pre-dose | 245 ng/mL |
| Cohort A | Everolimus Pharmacokinetic Plasma Concentrations - Phase II | Cycle 2, Day 15 2 H post-dose | 652 ng/mL |
| Cohort A | Everolimus Pharmacokinetic Plasma Concentrations - Phase II | Cycle 2, Day 15 4 H post-dose | 642 ng/mL |
| Cohort A | Everolimus Pharmacokinetic Plasma Concentrations - Phase II | Cycle 1, Day 15 pre dose | 214 ng/mL |
| Cohort B | Everolimus Pharmacokinetic Plasma Concentrations - Phase II | Cycle 3, Day 1 pre-dose | 198 ng/mL |
| Cohort B | Everolimus Pharmacokinetic Plasma Concentrations - Phase II | Cycle 1, Day 15 pre dose | 132 ng/mL |
| Cohort B | Everolimus Pharmacokinetic Plasma Concentrations - Phase II | Cycle 2, Day 15 pre-dose | 170 ng/mL |
| Cohort B | Everolimus Pharmacokinetic Plasma Concentrations - Phase II | Cycle 1, Day 15 2 H post-dose | 372 ng/mL |
| Cohort B | Everolimus Pharmacokinetic Plasma Concentrations - Phase II | Cycle 2, Day 15 4 H post-dose | 406 ng/mL |
| Cohort B | Everolimus Pharmacokinetic Plasma Concentrations - Phase II | Cycle 1, Day 15 4 H post-dose | 323 ng/mL |
| Cohort B | Everolimus Pharmacokinetic Plasma Concentrations - Phase II | Cycle 2, Day 15 2 H post-dose | 442 ng/mL |
| Cohort B | Everolimus Pharmacokinetic Plasma Concentrations - Phase II | Cycle 2 Day 1 pre-dose | 125 ng/mL |
Secondary
Overall Survival (OS) by Group - Phase II
Overall survival is the time from date of first treatment to the date of death due to any cause. If a patient is not known to have died, survival will be censored at the last date of contact.
Time frame: Baseline up to approximately 32 months
Population: Full analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A | Overall Survival (OS) by Group - Phase II | 27.4 months |
| Cohort B | Overall Survival (OS) by Group - Phase II | NA months |
Secondary
Summary of Progression-free Survival (PFS) (Months), as Per Central Review by Group - Phase II
Progression is defined as \<= 12 weeks after randomization/ start of treatment (and not qualifying for CR, PR or SD).
Time frame: Baseline up to approximately 32 months
Population: Full analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A | Summary of Progression-free Survival (PFS) (Months), as Per Central Review by Group - Phase II | 8.0 months |
| Cohort B | Summary of Progression-free Survival (PFS) (Months), as Per Central Review by Group - Phase II | 4.7 months |
Secondary
Time to Definitive Deterioration of ECOG Performance Status in One Category of the Score by Group - Phase II
Time to definitive deterioration of ECOG performance status in one category of score is defined as the time from the date of randomization to the date of event, which is defined as at least one score lower than the baseline.
Time frame: Baseline up to approximately 8 months
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A | Time to Definitive Deterioration of ECOG Performance Status in One Category of the Score by Group - Phase II | NA median |
| Cohort B | Time to Definitive Deterioration of ECOG Performance Status in One Category of the Score by Group - Phase II | 12.0 median |