Renal Cell Carcinoma, Metastatic
Conditions
Keywords
ESK981
Brief summary
The objective of the trial is to determine the clinical efficacy of ESK981 in combination with nivolumab therapy in patients with metastatic renal cell carcinoma (RCC).
Detailed description
The study was terminated early due to changes in the RCC treatment landscape which limited the patient population. Due to this early termination no subjects were enrolled into Cohort B.
Interventions
DRUGESK981
ESK981: 160 mg (4 capsules) PO daily for 5 consecutive days followed by a 2-day off drug in each week, repeated weekly in 4-week (28-day) cycles
DRUGNivolumab
480 mg/dose IV, Day 1 of each 28-day cycle
Sponsors
University of Michigan Rogel Cancer Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
There are 2 cohorts for accrual with Cohort A being accrued first. Cohort B will follow and will have 2 stages of accrual. Cohort A will accrue 11 patients to monotherapy treatment. Then Cohort B will begin accrual of 17 patients to the first stage and if the interim permits, the second stage will accrue an additional 19 patients.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologic diagnosis of renal cell carcinoma (any histology except medullary carcinoma or collecting duct carcinoma is acceptable) with radiologic or histologic evidence of metastatic disease. * Prior treatment with up to one (and only one) anti-VEGF or VEGFR inhibitor (small molecule or antibody). * Must have measurable disease as per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) criteria. * Must be of age ≥ 18 years at time of informed consent. * Ability to understand and the willingness to sign a written informed consent. * Karnofsky Performance Status ≥60. (The Karnofsky Performance Status Scale is an assessment tool for functional impairment. It can be used to compare effectiveness of different therapies and to assess the prognosis in individual patients. In most serious illnesses, the lower the Karnofsky score, the worse the likelihood of survival.) * Most recent systemic therapy or most recent radiation therapy ≥ 2 weeks of first study drug dose. * Recovery to baseline or \< Grade 1 CTCAE v.4.03 from toxicities related to any prior treatments, unless AE(s) are clinically non-significant and/or stable on supportive therapy. * Women of childbearing potential must have a negative serum or urine pregnancy test within 28 days prior to registration. * Adequate organ and marrow function
Exclusion criteria
* Prior treatment for metastatic disease with \>1 anti-VEGF/VEGFR inhibitor. * Prior treatment with anti-PD/PD-L1/CTLA4/IDO antibody (for Cohort B patients only) or ESK981 (for Cohort A and Cohort B patients). * Prior mTOR inhibitors or glutaminase inhibitors are allowed. * Untreated brain metastases or spinal cord compression. * Uncontrolled hypertension defined as blood pressure \>150/90 despite at least 2 anti-hypertensive medication(s) as assessed by 2 blood pressure readings taken at least 1 hour apart during screening. * Major surgical procedure or significant traumatic injury within 6 weeks prior to study registration (\> 6 weeks prior to registration is permitted as long as they have fully recovered from any such procedure). * History of another primary malignancy except for: malignancy treated with curative intent and no known active disease for ≥2 years, adequately treated non-melanoma skin cancer without current evidence of active disease, adequately treated carcinoma in situ without current evidence of active disease, Gleason ≤6 prostate cancer. * Angina, myocardial infarction symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack, arterial embolism, pulmonary embolism, percutaneous angioplasty or coronary arterial bypass surgery within the past 3 months. * History of gastrointestinal perforation or fistula in the past 6 months, or while previously on antiangiogenic therapy, unless underlying risk has been resolved (e.g. through surgical resection or repair). * The patient has known hypersensitivity to gelatin or lactose monohydrate. * The patient has received any investigational drug within 28 days prior to registration or 5 half-lives of the investigational drug, whichever is shorter. * History of bleeding disorders (e.g. pulmonary hemorrhage, significant hemoptysis, menometrorrhagia not responding to hormonal treatment) ≤ 6 weeks before Cycle 1 Day1. * The patient is on a chronic daily medication known to be a severe or moderate inhibitor or inducer by Micromedex of CYP1A2, CYP2C8, or CYP3A4 at registration. * Systemic corticosteroids greater than the equivalent of 10 mg of prednisone or equivalent alternative steroid (except physiologic dose for adrenal replacement therapy) or other immunosuppressive agents (such as cyclosporine or methotrexate) and any other medications that could potentially impact the efficacy or safety of the study as judged by the treating investigator are NOT permitted from time of registration to subjects completing protocol therapy unless clinically indicated to manage adverse events or life threatening or serious conditions as determined by the treating investigator. * Have any condition that, in the opinion of the investigator, would compromise the ability of the subject to meet or perform study requirements.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 1. The Percentage of Patients That Respond to Treatment With the Combination of ESK981 Monotherapy and Nivolumab Therapy (Cohort B). | Up to 24 months after last dose of study treatment | The percentage of patients in Cohort B that achieve a complete response (CR) or partial response (PR). Response will be assessed by combined Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and Immune-related (ir)RECIST. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Percentage of Patients That Respond to Treatment With ESK981 Monotherapy (Cohort A). | Up to 24 months after last dose of study treatment, 5 month treatment duration on average, no CR or PR responses were recorded. | The percentage of patients in Cohort A that achieve a complete response (CR) or partial response (PR). Response will be assessed by RECIST v1.1. |
| Median Overall Survival Time | Up to 24 months after last dose of study treatment | Overall survival time measured from start of treatment until up to 24 months after the last dose of study treatment in Cohort A (ESK981 monotherapy) and in Cohort B (combination of ESK981 and nivolumab therapy). |
| Progression Free Survival Time | Up to 24 months after last dose of study treatment | Measured from start of treatment to time of progression or death, or up to 24 months after the last dose of study treatment in Cohort A (ESK981 monotherapy) and in Cohort B (combination of ESK981 and nivolumab therapy). Disease progression will be assessed by RECIST v1.1 in Cohort A and by combined RECIST v1.1/irRECIST in Cohort B. |
| Duration of Therapy | Up to approximately 24 months after treatment start | Measured from the first to the last dose of study treatment in Cohort A (ESK981 monotherapy) and in Cohort B (combination of ESK981 and nivolumab therapy). |
| Duration of Response | Up to 24 months after last dose of study treatment | Measured from the time of complete response (CR) or partial response (PR) (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented. Response will be assessed by RECIST v1.1 (Cohort A) and by combined RECIST v1.1/irRECIST (Cohort B). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| ESK981 Monotherapy ESK981: 160 mg (4 capsules) PO daily for 5 consecutive days followed by a 2-day off drug in each week, repeated weekly in 4-week (28-day) cycles
ESK981: ESK981: 160 mg (4 capsules) PO daily for 5 consecutive days followed by a 2-day off drug in each week, repeated weekly in 4-week (28-day) cycles | 8 |
| ESK981 and Nivolumab ESK981: 160 mg (4 capsules) PO daily for 5 consecutive days followed by a 2-day off drug in each week, repeated weekly in 4-week (28-day) cycles
Nivolumab: 480 mg/dose IV, Day 1 of each 28-day cycle
ESK981: ESK981: 160 mg (4 capsules) PO daily for 5 consecutive days followed by a 2-day off drug in each week, repeated weekly in 4-week (28-day) cycles
Nivolumab: 480 mg/dose IV, Day 1 of each 28-day cycle | 0 |
| Total | 8 |
Baseline characteristics
| Characteristic | ESK981 Monotherapy | Total |
|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 4 Participants |
| Age, Continuous | 66 years | 66 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 7 Participants | 7 Participants |
| Region of Enrollment United States | 8 participants | 8 participants |
| Sex: Female, Male Female | 3 Participants | 3 Participants |
| Sex: Female, Male Male | 5 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 8 | 0 / 0 |
| other Total, other adverse events | 8 / 8 | 0 / 0 |
| serious Total, serious adverse events | 2 / 8 | 0 / 0 |
Outcome results
Primary
1. The Percentage of Patients That Respond to Treatment With the Combination of ESK981 Monotherapy and Nivolumab Therapy (Cohort B).
The percentage of patients in Cohort B that achieve a complete response (CR) or partial response (PR). Response will be assessed by combined Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and Immune-related (ir)RECIST.
Time frame: Up to 24 months after last dose of study treatment
Population: No patients were enrolled in the ESK984 and Nivolumab combo arm (cohort B)
Secondary
Duration of Response
Measured from the time of complete response (CR) or partial response (PR) (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented. Response will be assessed by RECIST v1.1 (Cohort A) and by combined RECIST v1.1/irRECIST (Cohort B).
Time frame: Up to 24 months after last dose of study treatment
Population: There were no responses to therapy
Secondary
Duration of Therapy
Measured from the first to the last dose of study treatment in Cohort A (ESK981 monotherapy) and in Cohort B (combination of ESK981 and nivolumab therapy).
Time frame: Up to approximately 24 months after treatment start
Population: No patients were enrolled into the combo arm (cohort B)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ESK981 and Nivolumab (Cohort B) | Duration of Therapy | 2.1 Months |
Secondary
Median Overall Survival Time
Overall survival time measured from start of treatment until up to 24 months after the last dose of study treatment in Cohort A (ESK981 monotherapy) and in Cohort B (combination of ESK981 and nivolumab therapy).
Time frame: Up to 24 months after last dose of study treatment
Population: No patients were enrolled in the ESK984 and Nivolumab combo arm (cohort B)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ESK981 and Nivolumab (Cohort B) | Median Overall Survival Time | 24.5 Months |
Secondary
Progression Free Survival Time
Measured from start of treatment to time of progression or death, or up to 24 months after the last dose of study treatment in Cohort A (ESK981 monotherapy) and in Cohort B (combination of ESK981 and nivolumab therapy). Disease progression will be assessed by RECIST v1.1 in Cohort A and by combined RECIST v1.1/irRECIST in Cohort B.
Time frame: Up to 24 months after last dose of study treatment
Population: No patients were enrolled into the combo arm (cohort B)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ESK981 and Nivolumab (Cohort B) | Progression Free Survival Time | 1.7 months |
Secondary
The Percentage of Patients That Respond to Treatment With ESK981 Monotherapy (Cohort A).
The percentage of patients in Cohort A that achieve a complete response (CR) or partial response (PR). Response will be assessed by RECIST v1.1.
Time frame: Up to 24 months after last dose of study treatment, 5 month treatment duration on average, no CR or PR responses were recorded.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ESK981 and Nivolumab (Cohort B) | The Percentage of Patients That Respond to Treatment With ESK981 Monotherapy (Cohort A). | 0 Participants |