Metastatic Cancer, Renal Cancer
Conditions
Keywords
PD-L1 inhibitor
Brief summary
This study will assess the immunomodulatory activity of entinostat in patients with advanced renal cell carcinoma receiving the PD-L1 inhibitor atezolizumab. The overall hypothesis is that entinostat will increase the immune response and anti-tumor effect induced by the PD-L1 inhibition by suppressing Treg function. We have chosen renal cell carcinoma that has been reported to respond to PD1/PD-L 1 inhibition. The schedule of entinostat is based on our previous experience with this agent. Based on our working hypothesis that low dose HDAC inhibitors will have a suppressive function on Tregs but not on T effector cells, the starting dose of entinostat will be 1 mg and will be escalated up to 5 mg rather than the 10 mg dose. The combination also with bevacizumab will provide an effective VEGF inhibition that may potentiate the immune response and anti-tumor effect induced by atezolizumab. The proposed dose and schedule for atezolizumab and bevacizumab has been shown to be well tolerated in prior Phase/I/II studies and is currently tested in a Phase III randomized study in patients with renal cell carcinoma with sunitinib as a control arm. The highest proposed dose level for entinostat (5 mg) represents 50% of the recommended Phase II dose for this compound as a single agent.
Detailed description
This is a Phase l/II, open-label, safety, pharmacodynamics and efficacy study of atezolizumab in combination with entinostat and bevacizumab in patients with advanced renal cell carcinoma. This clinical study will be composed of a Dose Finding Phase (Phase I) and a two-stage Phase (Phase II) portion. In Phase 1 Combination Phase), patients will be treated with oral entinostat every 7 days, with bevacizumab at the fixed dose of 15 mg/kg IV every 3 weeks and with atezolizumab at the fixed dose of 1200 mg IV every 3 weeks. Each cycle length is 21 days. Three dose levels of entinostat will be tested in 3-design patient cohorts according to the 3 + 3 standard design (1 mg, 3 mg and 5 mg). For the Dose Finding Phase, the starting dose level of pill be 1 mg by mouth every 7 days. The first dose level will have a minimum of 3 patients treated (unless the first 2 patients experience DLT(s) before the 3rd patient is enrolled). DLTs attributable to entinostat and/or bevacizumab and/or atezolizumab will be evaluated during the first 21 days of the combination treatment. If a DLT occurs in 1 patient treated at the starting dose level, a minimum of 3 additional patients will be treated at this dose level. If DLTs occur in 2 or more of the first 6 patients, the study will be terminated. If a DLT occurs in 1 out of 6 patients, 3 additional patients will be treated at the next dose level (level 2). If no DLTs occur at the starting dose level 1, 3 additional patients will be treated at the next dose level (level 2). If no DLTs occur at the dose level 2, 3 additional patients will be treated at the next dose level (level 3). If no DLTs occur at dose level 3, this dose level will be recommended for the Phase II portion of the study. Patients who experience Grade ≥ 3 toxicity and recover to ≤ Grade 1 (or to pretreatment baseline level toxicity) may continue treatment at the next lower level. The Phase II Dose will be RP2D of entinostat (i.e., the highest tested dose that is declared safe and tolerable by the Investigators and Sponsor-Investigator). Once the RP2D is identified, the Phase II portion (Simon's two stage design) will be opened. During Phase II, Cohorts A and B will have a Run-In period with entinostat for one cycle followed by atezolizumab and bevacizumab for the second cycle, and then the Combination Phase. The reason for the Run-In period is to obtain data on the immunomodulatory effects of entinostat separately from bevacizumab and atezolizumab. The run-in period will be optional for patients, including those who are rapidly progressing, or if it is in the patient's best interest clinically as determined by the treating physician's discretion. In Stage I, 27 patients with prior treatments will be enrolled in two Phase II cohorts: 18 treatment naïve (anti-PD1/PDL1 naïve) patients (Cohort A), and 9 anti-PD1 resistant (defined as patients who have been on PD1 inhibitors for at least 3 months and have progressed by either clinical or radiographic assessment) patients (Cohort B). If ≥ 5 responses are observed and confirmed in Cohort A, Stage II will be conducted with 15 additional patients. In Cohort B, if any patients has a response that is observed and confirmed, Stage II will be conducted with 7 additional patients. Patients will be treated on Cohort B with the same combination therapy as in Cohort A. Cohort B is a pilot arm which aims to test atezolizumab in anti-PD1 resistant patients. If there is no response to atezolizumab, then the RP2D dose of entinostat will be added to the standard dose of atezolizumab. If there is a response to atezolizumab, patients will continue to be treated with atezolizumab alone. The RP2D is the dose of entinostat, atezolizumab, and bevacizumab in combination chosen for further clinical development. Further experience in the Dose Expansion Cohort may result in a RP2D dose lower than the MTD. Objectives: 1. Primary Phase I: To assess the safety and tolerability of atezolizumab in combination with entinostat and bevacizumab in patients with advanced renal cell carcinoma. 2. Primary Phase II: To assess the objective response rate of atezolizumab in combination with entinostat and bevacizumab in anti-PD 1 naïve patients and atezolizumab in combination with entinostat in anti-PD 1 resistant patients with advanced renal cell carcinoma. 3. Secondary: To assess the objective response rate (Phase I only), progression-free survival and overall survival. 4. Correlative: To characterize PD-L1/2, immune cell subsets, and miRs in tumor and/or blood in correlation with response.
Interventions
DRUGAtezolizumab
Atezolizumab will be given intravenously every 3 weeks at 1200 mg.
DRUGBevacizumab
Bevacizumab will be given intravenously every 3 weeks at 15 mg/kg.
DRUGEntinostat
Entinostat will be given orally every 7 days at 1, 3, or 5 mg depending upon phase. In Phase I, dose levels will be tested in up to 3 cohorts starting at 1 mg. In Phase II, the dose will be the recommended phase II dose that was determined during Phase I (i.e., 1, 3, or 5 mg).
Sponsors
Roberto Pili
Genentech, Inc.
Syndax 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
Patients must meet the following criteria for study entry: * Signed Informed Consent Form (ICF) * Ability and willingness to comply with the requirements of the study protocol * Age ≥ 18 years * Measurable disease per RECIST v1.1 (see Appendix 4) for patients with solid malignancies or patients with bone disease must have disease evaluable by bone scan and/or PET scan * Metastatic renal cell carcinoma o During Phase I - All prior treatments or none are allowed * During Phase II/Cohort A - No prior treatments with PD1 or PDL1 inhibitors allowed * During Phase II/Cohort B - Must have at least one prior treatment with a PD1 or PDL1 inhibitor for metastatic disease for at least 3 months and have progressed by either clinical or radiographic assessment * Life expectancy of at least 6 months * Adequate hematologic and end organ function, defined by the following laboratory results obtained within 14 days prior to the first study treatment (Cycle 1, Day 1): * Absolute neutrophil count (ANC) ≥ 1500 cells/microL * White blood cell (WBC) counts \> 2500/microL * Lymphocyte count ≥ 300/microL * Platelet count ≥ 100,000/microL; for patients with hematologic malignancies, platelet count ≥ 75,000/microL * Hemoglobin ≥ 9.0 g/dL * Total bilirubin ≤ 1.5 x upper limit of normal (ULN) with the following exception: Patients with known Gilbert disease who have serum bilirubin level ≤ 3 x ULN may be enrolled. Direct bilirubin ≤ ULN for patients with total bilirubin levels \> 1.5 x ULN \- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN with the following exception: Patients with liver involvement: AST and/or ALT ≤ 5 x ULN \- Alkaline phosphatase (ALP) ≤ 2.0 x ULN with the following exception: Patients with documented liver involvement or bone metastases: ALP ≤ 5 x ULN * Serum creatinine ≤ 1.25 x ULN or creatinine clearance ≥ 60 mL/min on the basis of the Cockcroft-Gault glomerular filtration rate estimation: (140 - age) x (weight in kg) x (0.85 if female) / 72 x (serum creatinine in mg/dL) * Urine dipstick for proteinuria \< 2+ or 24-hour urine protein \< 1 g of protein is demonstrated * International Normalized Ratio (INR) and activated Partial Thromboplastin Time (aPTT) ≤ 1.5 x ULN This applies only to patients who do not receive therapeutic anticoagulation; patients receiving therapeutic anticoagulation (such as low-molecular-weight heparin or warfarin) should be on a stable dose. • If a female of childbearing potential, negative serum blood pregnancy test during screening and a negative urine pregnancy test ≤ 3 days prior to receiving the first dose of study drug. If the screening serum test is done ≤ 3 days prior to receiving the first dose of study drug, a urine test is not required. * Non-childbearing potential is defined as (by other than medical reasons): * ≥ 45 years of age and has not had menses for \> 2 years * Amenorrheic for \< 2 years without a hysterectomy and/or oophorectomy and a follicle-stimulating hormone value in the postmenopausal range upon pre-study (screening) evaluation * Post hysterectomy or oophorectomy. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. * For female patients of childbearing potential and male patients with partners of childbearing potential, agreement (by patient and/or partner) to use two forms of highly effective contraception (i.e., one that results in a low failure rate \[\< 1% per year\] when used consistently and correctly) and to continue its use for 150 days after the last dose of all study drugs (atezolizumab, entinostat, and bevacizumab). * Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
Exclusion criteria
Patients who meet any of the following criteria will be excluded from study entry. General
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase I: Recommended Phase II Dose of Entinostat | 21 days | Three dose levels of entinostat (1 mg, 3 mg and 5 mg) were tested according to the 3 + 3 standard design. The starting dose level of entinostat was 1 mg orally every 7 days. DLTs attributable to entinostat and/or bevacizumab and/or atezolizumab were evaluated during the first 21 days of the combination treatment. If a DLT occurs in 1 patient treated at the starting dose level, a minimum of 3 additional patients will be treated at this dose level. If DLTs occur in 2 or more of the first 6 patients, the study will be terminated. If a DLT occurs in 1 out of 6 patients, 3 additional patients will be treated at the next dose level (level 2). If no DLTs occur at the starting dose level 1, 3 additional patients will be treated at the next dose level (level 2). The process is repeated for dose level 2. If no DLTs occur at dose level 3 or if 1 DLT occurs out of 6 patients, then this dose level will be recommended for the Phase II portion of the study. |
| Phase II: Percentage of Patients With Objective Response | Up to 1 year | Percentage of patients who achieved a complete response or partial response to treatment as measured per RECIST 1.1. Complete response: Disappearance of all target lesions. Partial response: At least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase I: Percentage of Patients With Objective Response | Up to 1 year | Percentage of patients who achieved a complete response or partial response to treatment as measured per RECIST 1.1. Complete response: Disappearance of all target lesions. Partial response: At least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter. |
| Phase II: Median Progression-free Survival | Up to 4.5 years | Progression free survival was defined as the time from on treatment date to date of recurrence of any type or death from any cause. Patients who did not experience recurrence or death were censored at their last evaluation date. The Kaplan-Meier method was used to determine the median and 95% confidence interval. |
| Phase II: Median Overall Survival | Up to 5.5 years | Overall survival was defined as the time from on treatment date to death due to any cause. Patients who remained alive were censored at their last known alive date. The Kaplan-Meier method was used to determine the median and 95% confidence interval. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase I - Dose Level 1 Open to patients meeting eligibility criteria with advanced renal cell carcinoma and ANY or NO prior treatments.
Patients in Phase I Dose Level 1 will be treated with atezolizumab, bevaciuzmab, and entinostat at a dose of 1 mg.
Atezolizumab will be given intravenously every 3 weeks at 1200 mg. Bevacizumab will be given intravenously every 3 weeks at 15 mg/kg. Entinostat will be given orally every 7 days at 1 mg. | 6 |
| Phase I - Dose Level 2 Open to patients meeting eligibility criteria with advanced renal cell carcinoma and ANY or NO prior treatments.
Patients in Phase I Dose Level 2 will be treated with atezolizumab, bevaciuzmab, and entinostat at a dose of 3 mg.
Atezolizumab will be given intravenously every 3 weeks at 1200 mg. Bevacizumab will be given intravenously every 3 weeks at 15 mg/kg. Entinostat will be given orally every 7 days at 3 mg. | 6 |
| Phase I - Dose Level 3 Open to patients meeting eligibility criteria with advanced renal cell carcinoma and ANY or NO prior treatments.
Patients in Phase I Dose Level 3 will be treated with atezolizumab, bevaciuzmab, and entinostat at a dose of 5 mg.
Atezolizumab will be given intravenously every 3 weeks at 1200 mg. Bevacizumab will be given intravenously every 3 weeks at 15 mg/kg. Entinostat will be given orally every 7 days at 5 mg. | 6 |
| Phase II - Cohort A Open to patients meeting eligibility criteria with advanced renal cell carcinoma and NO prior treatments.
Patients in Cohort A will be treated with atezolizumab, bevaciuzmab, and the recommended phase II dose of 5 mg of entinostat.
Atezolizumab will be given intravenously every 3 weeks at 1200 mg. Bevacizumab will be given intravenously every 3 weeks at 15 mg/kg. Entinostat will be given orally every 7 days at 5 mg. | 12 |
| Phase II - Cohort B Open to patients meeting eligibility criteria with advanced renal cell carcinoma and at least one prior treatment with a PD1 or PDL1 inhibitor.
Patients in Cohort B will be treated with atezolizumab, bevaciuzmab, and the recommended phase II dose of 5 mg of entinostat.
Atezolizumab will be given intravenously every 3 weeks at 1200 mg. Bevacizumab will be given intravenously every 3 weeks at 15 mg/kg. Entinostat will be given orally every 7 days at 5 mg. | 1 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 3 | 5 | 0 |
| Overall Study | Disease progression, refractory disease | 4 | 4 | 2 | 2 | 1 |
| Overall Study | Disease progression, relapse | 1 | 0 | 0 | 3 | 0 |
| Overall Study | Moved out of state | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Needed an alternative therapy prohibited by protocol | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Newly diagnosed cancer | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Physician Decision | 1 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Phase I - Dose Level 2 | Phase I - Dose Level 3 | Phase II - Cohort A | Phase I - Dose Level 1 | Phase II - Cohort B | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 3 Participants | 4 Participants | 0 Participants | 0 Participants | 8 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 3 Participants | 8 Participants | 6 Participants | 1 Participants | 23 Participants |
| Age, Continuous | 56.8 years STANDARD_DEVIATION 8.9 | 63.1 years STANDARD_DEVIATION 12 | 59.4 years STANDARD_DEVIATION 9.9 | 51.3 years STANDARD_DEVIATION 9 | 54.1 years | 57.9 years STANDARD_DEVIATION 10.1 |
| ECOG Performance Status 0 | 3 Participants | 5 Participants | 9 Participants | 3 Participants | 1 Participants | 21 Participants |
| ECOG Performance Status 1 | 3 Participants | 1 Participants | 3 Participants | 3 Participants | 0 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 5 Participants | 11 Participants | 5 Participants | 1 Participants | 28 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) White | 6 Participants | 5 Participants | 11 Participants | 6 Participants | 0 Participants | 28 Participants |
| Region of Enrollment United States | 6 participants | 6 participants | 12 participants | 6 participants | 1 participants | 31 participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 2 Participants | 1 Participants | 0 Participants | 7 Participants |
| Sex: Female, Male Male | 4 Participants | 4 Participants | 10 Participants | 5 Participants | 1 Participants | 24 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 / 6 | 5 / 6 | 4 / 6 | 4 / 12 | 1 / 1 |
| other Total, other adverse events | 6 / 6 | 6 / 6 | 6 / 6 | 12 / 12 | 1 / 1 |
| serious Total, serious adverse events | 3 / 6 | 5 / 6 | 6 / 6 | 6 / 12 | 0 / 1 |
Outcome results
Primary
Phase II: Percentage of Patients With Objective Response
Percentage of patients who achieved a complete response or partial response to treatment as measured per RECIST 1.1. Complete response: Disappearance of all target lesions. Partial response: At least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter.
Time frame: Up to 1 year
Population: Patients who received at least one cycle of study drugs and had at least one post-baseline evaluation. Patients who were treated at Dose Level 3 in Phase I were assigned to the applicable Phase II cohort for efficacy analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I - Dose Escalation | Phase II: Percentage of Patients With Objective Response | 62.5 percentage of participants |
| Phase II - Cohort B | Phase II: Percentage of Patients With Objective Response | 33.3 percentage of participants |
Primary
Phase I: Recommended Phase II Dose of Entinostat
Three dose levels of entinostat (1 mg, 3 mg and 5 mg) were tested according to the 3 + 3 standard design. The starting dose level of entinostat was 1 mg orally every 7 days. DLTs attributable to entinostat and/or bevacizumab and/or atezolizumab were evaluated during the first 21 days of the combination treatment. If a DLT occurs in 1 patient treated at the starting dose level, a minimum of 3 additional patients will be treated at this dose level. If DLTs occur in 2 or more of the first 6 patients, the study will be terminated. If a DLT occurs in 1 out of 6 patients, 3 additional patients will be treated at the next dose level (level 2). If no DLTs occur at the starting dose level 1, 3 additional patients will be treated at the next dose level (level 2). The process is repeated for dose level 2. If no DLTs occur at dose level 3 or if 1 DLT occurs out of 6 patients, then this dose level will be recommended for the Phase II portion of the study.
Time frame: 21 days
Population: Patients who received at least one cycle of study drugs and had at least one post-baseline evaluation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I - Dose Escalation | Phase I: Recommended Phase II Dose of Entinostat | 5 mg |
Secondary
Phase II: Median Overall Survival
Overall survival was defined as the time from on treatment date to death due to any cause. Patients who remained alive were censored at their last known alive date. The Kaplan-Meier method was used to determine the median and 95% confidence interval.
Time frame: Up to 5.5 years
Population: Patients who received at least one cycle of study drugs and had at least one post-baseline evaluation. Patients who were treated at Dose Level 3 in Phase I were assigned to the applicable Phase II cohort for efficacy analyses.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I - Dose Escalation | Phase II: Median Overall Survival | 51.6 months |
| Phase II - Cohort B | Phase II: Median Overall Survival | 31.2 months |
Secondary
Phase II: Median Progression-free Survival
Progression free survival was defined as the time from on treatment date to date of recurrence of any type or death from any cause. Patients who did not experience recurrence or death were censored at their last evaluation date. The Kaplan-Meier method was used to determine the median and 95% confidence interval.
Time frame: Up to 4.5 years
Population: Patients who received at least one cycle of study drugs and had at least one post-baseline evaluation. Patients who were treated at Dose Level 3 in Phase I were assigned to the applicable Phase II cohort for efficacy analyses.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I - Dose Escalation | Phase II: Median Progression-free Survival | 13.7 months |
| Phase II - Cohort B | Phase II: Median Progression-free Survival | 9.8 months |
Secondary
Phase I: Percentage of Patients With Objective Response
Percentage of patients who achieved a complete response or partial response to treatment as measured per RECIST 1.1. Complete response: Disappearance of all target lesions. Partial response: At least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter.
Time frame: Up to 1 year
Population: Patients who received at least one cycle of study drugs and had at least one post-baseline evaluation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I - Dose Escalation | Phase I: Percentage of Patients With Objective Response | 50 percentage of patients |
| Phase II - Cohort B | Phase I: Percentage of Patients With Objective Response | 20 percentage of patients |
| Phase I - Dose Level 3 | Phase I: Percentage of Patients With Objective Response | 83.3 percentage of patients |