Metastatic Renal Cell Carcinoma
Conditions
Brief summary
This study will compare the effects of Enzastaurin plus Sunitinib versus Sunitinib alone in metastatic Renal Cell Cancer.
Detailed description
This is a multicenter, Phase 2 study of enzastaurin and sunitinib versus placebo and sunitinib as first-line therapy in participants with metastatic renal cell carcinoma, containing 2 parts. Part 1 is a safety lead-in study with 12 participants and possible dose escalation. Part 2 is a randomized, double-blind, Phase 2 study in 110 participants.
Interventions
DRUGEnzastaurin
Administered orally
DRUGSunitinib
Administered orally
DRUGPlacebo
Administered orally
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants with metastatic Renal Cell Carcinoma (RCC) who have not received prior treatment with systemic (adjuvant or neoadjuvant) therapy for RCC (including targeted therapy such as tyrosine kinase inhibitors or bevacizumab, immunotherapy, chemotherapy, hormonal, or investigational therapy) * Histologically confirmed RCC with metastases with a component of clear (conventional) cell histology * Evidence of unidimensional measurable disease, measured by computed tomography (CT) scan or magnetic resonance imaging (MRI) * Primary tumor has been surgically removed by nephrectomy or nephron-sparing surgery * Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 * Participants must sign an informed consent document
Exclusion criteria
* Have received prior treatment with sunitinib or enzastaurin * Have received treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry * Have had any of the following within 12 months prior to study drug administration: * myocardial infarction, * severe/unstable angina, * coronary/peripheral artery bypass graft, * symptomatic congestive heart failure (CHF), * cerebrovascular accident, * transient ischemic attack, or * pulmonary embolism * Note: Ongoing treatment with therapeutic doses of Coumadin® (warfarin) or a derivative of Coumadin or phenprocoumon is not allowed, but prophylactic, low-dose Coumadin (≤ 2 mg daily) for deep vein thrombosis is allowed. In such cases, prothrombin time/international normalization ratio (PT/INR) should be very closely monitored as clinically indicated * Ongoing cardiac arrhythmias \>New York Health Association Class II, atrial fibrillation of any grade, or prolongation of the QTc interval to \>450 millisecond (msec) for males or \>470 msec for females. * Have uncontrolled hypertension \[\>150/100 millimeter of mercury (mm/Hg) despite optimal medical therapy\], or history of poor compliance with antihypertensive treatment * Require concomitant use of potent Cytochrome P450 3A4 (CYP3A4) inducer, for example, rifampicin or potent CYP3A inhibitors, such as ketoconazole. * Significant surgery or radiation therapy \<4 weeks of starting study treatment. Prior palliative radiotherapy to metastatic lesion(s) is/are permitted, provided there is at least 1 measurable lesion that has not been irradiated * Participants who are pregnant or breast feeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) in Part 2 | Randomization to Measured Progressive Disease (PD) (Up to 24 Months) | Progression-free survival (PFS) was defined as the number of months between the date of randomization and the date of first documented disease progression or the date of death due to any cause, whichever came first. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) in Part 2 | Randomization to Death from Any Cause (Up to 24 Months) | OS time was defined as the number of months between the date of randomization and the date of death due to any cause. |
| Time-To-Tumor Progression in Part 2 | Randomization to the Date of Objective Progressive Disease or Date of Death due to Study Disease, whichever came first (Up to 24 Months) | Time to tumor progression (TTP) at initial treatment was defined as the number of months between date of randomization and the date of first documented disease progression or the date of death due to disease under study, whichever came first. |
| Number of Participants With Adverse Events (AEs) or Serious AEs (SAEs) in Part 1 | Randomization to Study Completion (Up to 6 Cycles) | Clinically significant events were defined as serious adverse events, regardless of causality. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Event module. |
| Pharmacokinetics (PK): Area Under Concentration Time Curve During One Dosing Interval at Steady State (AUCτ,ss) of Enzastaurin + Metabolite (LSN326020) + Total Analytes in Part 1 | Cycle 1 Day 15: Predose, 2, 4, and 6 - 8 hours, Up to 12 Hours Post dose | Pharmacokinetics (PK) was assessed in participants to determine the area under the concentration time curve during one dosing interval at steady state (AUCτ,ss) of Enzastaurin, LSN326020 and total Analytes. τ equals 12 hours for Enzastaurin, LSN326020 and total Analytes. |
| PK: Maximum Concentration at Steady State (Cmax,ss) of Enzastaurin + LSN326020 + Total Analytes in Part 1 | Cycle 1 Day 15: Predose, 2, 4, and 6 - 8 hours, Up to 12 Hours Post dose | PK was assessed in participants to determine the maximum concentration at steady state (Cmax, ss) of Enzastaurin + LSN326020 + total analytes. |
Countries
Austria, France, Italy, Poland
Participant flow
Pre-assignment details
Part 1 completers finished 3 or more cycles and included those with progressive disease. Part 2 was not performed and was not activated due to sponsor broad decision to not pursue enzastaurin in solid tumors.
Participants by arm
| Arm | Count |
|---|---|
| Modified Regimen A (Cohort 1) On cycle 1, day 1 a loading dose 125 milligram (mg) of Enzastaurin was administered by mouth orally, (BID) twice a day, followed by Enzastaurin 125 mg administered, twice a day, Days 2 through 42 of a 6-week cycle Sunitinib 50 mg was administered orally, once daily, Days 1-28, then rest (no drug given) Days 29-42. | 11 |
| Regimen A (Cohort 2) Enzastaurin was given on Day 1 of Cycle 1 as a loading dose of 1125 mg (3 tablets of 125 mg each, taken 3 times a day with at least 4 hours between doses), followed by daily total dose of 500 mg (2 tablets of 125 mg each, BID) continuously until disease progression, unacceptable toxicity, death, or discontinuation from the study for any other reason.
Sunitinib 50 mg was administered orally, once daily, Days 1-28, then rest (no drug given) Days 29-42. | 6 |
| Total | 17 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 3 |
Baseline characteristics
| Characteristic | Modified Regimen A (Cohort 1) | Total | Regimen A (Cohort 2) |
|---|---|---|---|
| Age, Continuous | 60.1 years STANDARD_DEVIATION 5.44 | 59.6 years STANDARD_DEVIATION 6.42 | 58.5 years STANDARD_DEVIATION 8.42 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants | 17 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 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 | 11 Participants | 17 Participants | 6 Participants |
| Region of Enrollment Austria | 1 Participants | 2 Participants | 1 Participants |
| Region of Enrollment France | 1 Participants | 2 Participants | 1 Participants |
| Region of Enrollment Italy | 3 Participants | 3 Participants | 0 Participants |
| Region of Enrollment Poland | 6 Participants | 10 Participants | 4 Participants |
| Sex: Female, Male Female | 5 Participants | 6 Participants | 1 Participants |
| Sex: Female, Male Male | 6 Participants | 11 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 11 / 11 | 6 / 6 |
| serious Total, serious adverse events | 3 / 11 | 1 / 6 |
Outcome results
Primary
Progression Free Survival (PFS) in Part 2
Progression-free survival (PFS) was defined as the number of months between the date of randomization and the date of first documented disease progression or the date of death due to any cause, whichever came first.
Time frame: Randomization to Measured Progressive Disease (PD) (Up to 24 Months)
Population: Zero participants data were collected. Part 2 was not activated due to sponsor broad decision to not pursue Enzastaurin in solid tumors.
Secondary
Number of Participants With Adverse Events (AEs) or Serious AEs (SAEs) in Part 1
Clinically significant events were defined as serious adverse events, regardless of causality. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Event module.
Time frame: Randomization to Study Completion (Up to 6 Cycles)
Population: All randomized participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Enzastaurin + Sunitinib | Number of Participants With Adverse Events (AEs) or Serious AEs (SAEs) in Part 1 | AEs | 11 Participants |
| Enzastaurin + Sunitinib | Number of Participants With Adverse Events (AEs) or Serious AEs (SAEs) in Part 1 | SAEs | 3 Participants |
| Sunitinib + Placebo | Number of Participants With Adverse Events (AEs) or Serious AEs (SAEs) in Part 1 | AEs | 6 Participants |
| Sunitinib + Placebo | Number of Participants With Adverse Events (AEs) or Serious AEs (SAEs) in Part 1 | SAEs | 1 Participants |
Secondary
Overall Survival (OS) in Part 2
OS time was defined as the number of months between the date of randomization and the date of death due to any cause.
Time frame: Randomization to Death from Any Cause (Up to 24 Months)
Population: Zero participant data were collected. Part 2 was not activated due to sponsor broad decision to not pursue Enzastaurin in solid tumors.
Secondary
Pharmacokinetics (PK): Area Under Concentration Time Curve During One Dosing Interval at Steady State (AUCτ,ss) of Enzastaurin + Metabolite (LSN326020) + Total Analytes in Part 1
Pharmacokinetics (PK) was assessed in participants to determine the area under the concentration time curve during one dosing interval at steady state (AUCτ,ss) of Enzastaurin, LSN326020 and total Analytes. τ equals 12 hours for Enzastaurin, LSN326020 and total Analytes.
Time frame: Cycle 1 Day 15: Predose, 2, 4, and 6 - 8 hours, Up to 12 Hours Post dose
Population: All randomized participants who received at least one dose of study drug and had evaluable PK data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Enzastaurin + Sunitinib | Pharmacokinetics (PK): Area Under Concentration Time Curve During One Dosing Interval at Steady State (AUCτ,ss) of Enzastaurin + Metabolite (LSN326020) + Total Analytes in Part 1 | Enzastaurin | 12000 nanomole*hour/liter (nmol*hr/L) | Geometric Coefficient of Variation 144 |
| Enzastaurin + Sunitinib | Pharmacokinetics (PK): Area Under Concentration Time Curve During One Dosing Interval at Steady State (AUCτ,ss) of Enzastaurin + Metabolite (LSN326020) + Total Analytes in Part 1 | LSN326020 | 8820 nanomole*hour/liter (nmol*hr/L) | Geometric Coefficient of Variation 76 |
| Enzastaurin + Sunitinib | Pharmacokinetics (PK): Area Under Concentration Time Curve During One Dosing Interval at Steady State (AUCτ,ss) of Enzastaurin + Metabolite (LSN326020) + Total Analytes in Part 1 | Total Analytes | 21400 nanomole*hour/liter (nmol*hr/L) | Geometric Coefficient of Variation 101 |
| Sunitinib + Placebo | Pharmacokinetics (PK): Area Under Concentration Time Curve During One Dosing Interval at Steady State (AUCτ,ss) of Enzastaurin + Metabolite (LSN326020) + Total Analytes in Part 1 | Enzastaurin | 22600 nanomole*hour/liter (nmol*hr/L) | Geometric Coefficient of Variation 91 |
| Sunitinib + Placebo | Pharmacokinetics (PK): Area Under Concentration Time Curve During One Dosing Interval at Steady State (AUCτ,ss) of Enzastaurin + Metabolite (LSN326020) + Total Analytes in Part 1 | LSN326020 | 12200 nanomole*hour/liter (nmol*hr/L) | Geometric Coefficient of Variation 73 |
| Sunitinib + Placebo | Pharmacokinetics (PK): Area Under Concentration Time Curve During One Dosing Interval at Steady State (AUCτ,ss) of Enzastaurin + Metabolite (LSN326020) + Total Analytes in Part 1 | Total Analytes | 35200 nanomole*hour/liter (nmol*hr/L) | Geometric Coefficient of Variation 82 |
Secondary
PK: Maximum Concentration at Steady State (Cmax,ss) of Enzastaurin + LSN326020 + Total Analytes in Part 1
PK was assessed in participants to determine the maximum concentration at steady state (Cmax, ss) of Enzastaurin + LSN326020 + total analytes.
Time frame: Cycle 1 Day 15: Predose, 2, 4, and 6 - 8 hours, Up to 12 Hours Post dose
Population: All randomized participants who received at least one dose of study drug and had evaluable PK data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Enzastaurin + Sunitinib | PK: Maximum Concentration at Steady State (Cmax,ss) of Enzastaurin + LSN326020 + Total Analytes in Part 1 | Enzastaurin | 1310 nanomole/liter (nmol/L) | Geometric Coefficient of Variation 109 |
| Enzastaurin + Sunitinib | PK: Maximum Concentration at Steady State (Cmax,ss) of Enzastaurin + LSN326020 + Total Analytes in Part 1 | LSN326020 | 816 nanomole/liter (nmol/L) | Geometric Coefficient of Variation 72 |
| Enzastaurin + Sunitinib | PK: Maximum Concentration at Steady State (Cmax,ss) of Enzastaurin + LSN326020 + Total Analytes in Part 1 | Total Analytes | 2130 nanomole/liter (nmol/L) | Geometric Coefficient of Variation 88 |
| Sunitinib + Placebo | PK: Maximum Concentration at Steady State (Cmax,ss) of Enzastaurin + LSN326020 + Total Analytes in Part 1 | Total Analytes | 3740 nanomole/liter (nmol/L) | Geometric Coefficient of Variation 65 |
| Sunitinib + Placebo | PK: Maximum Concentration at Steady State (Cmax,ss) of Enzastaurin + LSN326020 + Total Analytes in Part 1 | Enzastaurin | 2650 nanomole/liter (nmol/L) | Geometric Coefficient of Variation 71 |
| Sunitinib + Placebo | PK: Maximum Concentration at Steady State (Cmax,ss) of Enzastaurin + LSN326020 + Total Analytes in Part 1 | LSN326020 | 1140 nanomole/liter (nmol/L) | Geometric Coefficient of Variation 64 |
Secondary
Time-To-Tumor Progression in Part 2
Time to tumor progression (TTP) at initial treatment was defined as the number of months between date of randomization and the date of first documented disease progression or the date of death due to disease under study, whichever came first.
Time frame: Randomization to the Date of Objective Progressive Disease or Date of Death due to Study Disease, whichever came first (Up to 24 Months)
Population: Zero participant data were collected. Part 2 was not activated due to sponsor broad decision to not pursue Enzastaurin in solid tumors.