Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Also known as SNDX-275, MS-275
Entinostat · 13 trials · 34 indications
The proportion of patients that have a best overall response of complete response (CR) or partial response (PR), as assessed by RECIST 1.1.
Compare PFS between arms. PFS is defined as the time from date of randomization until the criteria for disease progression is met as defined by RECIST 1.1 or death as a result of any cause.
CBR is defined as the percentage of participants who achieved complete response (CR) or partial response (PR) or stable disease (SD) for 6 months as assessed by the investigator based on Response Evaluation Criteria in Solid Tumors (RECIST), version 1.0. CR is defined as the disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum LD since the treatment started.
PFS is defined as the number of months from the date of randomization to the earlier of progressive disease (PD) or death due to any cause.
This will be defined based on the number of "dose limiting toxicities" in participants at each dose level.
Frequency of adverse events (AEs) in participants with high-risk BC after neo-adjuvant therapy at the determined MTDC.
Severity of adverse events (AEs) in participants with high-risk BC after neo-adjuvant therapy at the determined MTDC.
PFS was defined as the number of months from randomization to progressive disease (PD) or death due to any cause, whichever occurred first. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeters (mm); the appearance of one or more new lesions; and unequivocal progression of existing non-target lesions.
A DLT was defined as the occurrence of any protocol-specified event within the first 2 cycles of treatment (from Cycle 1 Day 1 through the end of Cycle 2) of entinostat in combination with avelumab that were considered by the investigator to be at least possibly related to study drug.
Heart rate measured in beats per minute (bpm).
Change from baseline in QT interval corrected for heart rate (Qtc), PR interval (PR) and QRS complex (QRS).
Phase 1b employed a classical 3+3 design, with the determination of DLT based on entinostat in combination with atezolizumab within the first cycle of treatment (that is, between Day 1 to Day 21 of Cycle 1). Six participants were required to be treated in a dose level for it to be considered MTD or the Recommended Phase 2 Dose (RP2D). A DLT was defined as the occurrence of specific events, defined in the protocol, that were considered by the investigator to be at least possibly related to study drug using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 4.03.The DLT assessment window (Cycle 1) was the time period between Cycle 1 Day 1 until Cycle 2 Day 1 (expected to be 21 days after Cycle 1 Day 1).
Phase 1b employed a classical 3+3 design, with the determination of the RP2D based on entinostat in combination with atezolizumab within the first cycle of treatment (that is, between Day 1 to Day 21 of Cycle 1). The RP2D was defined as equal to or less than the preliminary maximum tolerated dose (MTD) and was determined in discussion with the sponsor, the study medical monitor, and dose determination phase investigators. The MTD was defined as the highest dose level at which \<33% of 6 participants experience DLT.
The duration of PFS, assessed using RECIST 1.1, was used to evaluate the efficacy of entinostat at the RP2D in combination with atezolizumab in participants with advanced triple negative breast cancer (aTNBC). It was defined as the number of months from randomization to the earlier of progressive disease or death due to any cause. One month was considered 30.4375 days. PFS (months) = (Date of Progression or Censoring - Date of Randomization + 1)/30.4375.
The ORR was defined as the percentage of participants with confirmed complete response (CR) or partial response (PR). CR: Complete disappearance of all lesions (whether measurable or not) and no new lesions. All measurable lymph nodes also must have a reduction in short axis to \<10 millimeters (mm). PR: Sum of the diameters (longest for non-nodal lesions, shortest for nodal lesions) of target and new measurable lesions decreases ≥30%. For purposes of analysis, 1 month was considered to be 30.4375 days.
The pharmacokinetics of entinostat will be analyzed from patient plasma samples: maximum plasma concentration, time of maximum plasma concentration, area under the plasma concentration-time curve from baseline to last measurable concentration and extrapolated to infinity, terminal elimination rate constant.
Safe recommended Phase 2 dose was determined based on dose-limiting toxicities (DLT) in Cycle 1. A DLT was defined as any of the following occurring in Cycle 1: Grade 3 or greater nonhematologic toxicity that was considered related to either entinostat or erlotinib or a Grade 4 hematologic toxicity lasting more than 7 days and/or resulting in a dose delay. Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 scale was used where Grade 1=mild, Grade 2=Moderate, Grade 3=Severe, medically significant, Grade 4=life-threatening and 5=death. The dose that was found to be safe is reported.
PFS rate at 4 months was defined as the percentage of participants who are progression-free at 4 months.
| Arm | Type | Description |
|---|---|---|
| Pembrolizumab and Entinostat | EXPERIMENTAL | - |
| High Dose Interleukin 2 | ACTIVE_COMPARATOR | HD IL-2 600,000 IU/kg Every 8 hours on Days 1-5 and Days 15-19 |
| High Dose Interleukin 2 plus Entinostat | EXPERIMENTAL | HD IL-2 600,000 IU/kg Every 8 hours on Days 1-5 and Days 15-19 plus Entinostat 5 mg orally every 2 weeks starting Day -14 |
| Entinostat 5 mg + AI | EXPERIMENTAL | Entinostat 5 mg tablet orally every week on Days 1, 8. 15 and 22 of each 28-day treatment cycle in combination with continued treatment with AI therapy at labeled dose and schedule until disease progression or unacceptable toxicity. |
| Exemestane 25 mg + Entinostat 5 mg | EXPERIMENTAL | Exemestane (Aromasin®) 25 mg tablets orally once daily plus an entinostat 5 mg tablet orally once per week on Days 1, 8, 15 and 22 of each 28-day treatment cycle until development of progressive disease (PD) or unacceptable toxicity or closure of the study by the Sponsor, whichever occurred first. |
| Exemestane 25 mg + Placebo | PLACEBO_COMPARATOR | Exemestane (Aromasin®) 25 mg tablets orally once daily plus a placebo-matching entinostat tablet orally once per week on Days 1, 8, 15 and 22 of each 28-day treatment cycle until development of progressive disease (PD) or unacceptable toxicity or closure of the study by the Sponsor, whichever occurred first. |
| Entinostat and Capecitabine | EXPERIMENTAL | Dose escalation of the combination of entinostat and capecitabine in MBC patients. This dose will be given to MBC patients and to BC patients with residual invasive disease after neoadjuvant chemotherapy and surgery. The dose combinations include: Combination 1: 3 mg/week entinostat, 800 mg/m2 twice a day for 14 days of capecitabine Combination 2: 5 mg/week entinostat, 800 mg/m2 twice a day for 14 days of capecitabine Combination 3: 3 mg/week entinostat, 1000 mg/m2 twice a day for 14 days of capecitabine Combination 4: 5 mg/week entinostat, 1000 mg/m2 twice a day for 14 days of capecitabine If a participant experiences unacceptable side effects, he or she will receive the next lowest dose combination. If he or she is on Combination 1, he or she will stop study treatment. |
| Entinostat plus Avelumab | ACTIVE_COMPARATOR | Avelumab is administered intravenously (IV) on Day 1 of each 14-day cycle in combination with Entinostat administration on Day 1 and Day 8 of each cycle at the Maximum tolerated Dose (MTD)/RP2D as determined in the Phase Ib (Dose Determination) part of the study. |
| Placebo plus Avelumab | PLACEBO_COMPARATOR | Avelumab is administered intravenously (IV) on Day 1 of each 14-day cycle in combination with placebo administered on Day 1 and Day 8 of each cycle. |
| ENT 1mg daily with pembro every 3 weeks | ACTIVE_COMPARATOR | Entinostat daily in combination with pembrolizumab every three weeks |
| ENT 5mg weekly with pembro every 3 weeks | ACTIVE_COMPARATOR | Entinostat once weekly in combination with pembrolizumab every three weeks |
| ENT 10mg bi-weekly with pembro every 3 weeks | ACTIVE_COMPARATOR | Entinostat once every other week in combination with pembrolizumab every three weeks |
| Entinostat | ACTIVE_COMPARATOR | Participants received a single oral supratherapeutic dose of 15 mg entinostat under fasted conditions. |
| Placebo | PLACEBO_COMPARATOR | Participants received a single dose of placebo-matching entinostat under fasted conditions. |
| Cohort 1 | ACTIVE_COMPARATOR | Cohort 1 will evaluate exemestane's effect on the PK of entinostat. Each treatment cycle is 28 days. |
| Cohort 2 | ACTIVE_COMPARATOR | Cohort 2 will enroll when Cohort 1 enrollment is complete. Cohort 2 will evaluate entinostat's effect on the PK of exemestane. Each treatment cycle is 28 days. |
| Entinostat plus Atezolizumab | ACTIVE_COMPARATOR | Participants in this arm will receive entinostat in combination with atezolizumab. Phase 1b Dose Determination: The initial 3 to 6 participants will receive entinostat at a starting dose of 5 milligrams (mg) (Dose Group 1) on Days 1, 8, and 15 along with atezolizumab 1200 mg via intravenous (IV) infusion on Day 1 of each 21-day cycle. If the 5 mg dose exceeds the maximum tolerated dose (MTD), then a 3 mg dose of entinostat (Dose Group -1) will be evaluated in the same manner. If the -1 dose level exceeds the MTD, then a 2 mg dose of entinostat (Dose Group -2) will be evaluated. Phase 2 Dose Expansion: Participants will receive the RP2D identified in the Dose Determination Phase. |
| Placebo plus Atezolizumab | PLACEBO_COMPARATOR | Participants in this arm will receive placebo in combination with atezolizumab 1200 mg. |
| Phase 1b (Dose Escalation): Entinostat 3 mg Weekly + Pembrolizumab | EXPERIMENTAL | Participants with NSCLC will receive entinostat 3 mg administered orally weekly (Days 1, 8, and 15 of each 21-day cycle) along with pembrolizumab 200 mg via intravenous (IV) infusion once every 3 weeks (Day 1 of each 21-day cycle). |
| Phase 1b (Dose Escalation): Entinostat 5 mg Weekly + Pembrolizumab | EXPERIMENTAL | Participants with NSCLC will receive entinostat 5 mg administered orally weekly (Days 1, 8, and 15 of each 21-day cycle) along with pembrolizumab 200 mg via IV infusion once every 3 weeks (Day 1 of each 21-day cycle). |
| Phase 1b (Dose Confirmation): Entinostat 5 mg Weekly + Pembrolizumab | EXPERIMENTAL | Participants with NSCLC will receive entinostat 5 mg administered orally weekly (Days 1, 8, and 15 of each 21-day cycle) along with pembrolizumab 200 mg via IV infusion once every 3 weeks (Day 1 of each 21-day cycle). |
| Phase 2, Cohort 1: Entinostat 5 mg Weekly + Pembrolizumab | EXPERIMENTAL | Participants with NSCLC with squamous cell or adenocarcinoma histology who had not been treated with a programmed cell death receptor-1 (PD-1)- or programmed cell death ligand-1 (PD-L1)-blocking antibody, will receive entinostat 5 mg administered orally weekly (Days 1, 8, and 15 of each 21-day cycle) along with pembrolizumab 200 mg via IV infusion once every 3 weeks (Day 1 of each 21-day cycle). |
| Phase 2, Cohort 2: Entinostat 5 mg Weekly + Pembrolizumab | EXPERIMENTAL | Participants with NSCLC (any histology) who has previously been treated with and unequivocally progressed on either a PD-1- or PD-L1-blocking antibody, will receive entinostat 5 mg administered orally weekly (Days 1, 8, and 15 of each 21-day cycle) along with pembrolizumab 200 mg via IV infusion once every 3 weeks (Day 1 of each 21-day cycle). |
| Phase 2, Cohort 3: Entinostat 5 mg Weekly + Pembrolizumab | EXPERIMENTAL | Participants with melanoma who has previously been treated with and unequivocally progressed on either a PD-1- or PD-L1-blocking antibody, will receive entinostat 5 mg administered orally weekly (Days 1, 8, and 15 of each 21-day cycle) along with pembrolizumab 200 mg via IV infusion once every 3 weeks (Day 1 of each 21-day cycle). |
| Phase 2, Cohort 4: Entinostat 5 mg Weekly + Pembrolizumab | EXPERIMENTAL | Participants with CRC (mismatch repair-proficient) who had not been previously treated with a PD-1- or PD-L1-blocking antibody, received entinostat 5 mg administered orally weekly (Days 1, 8, and 15 of each 21-day cycle) along with pembrolizumab 200 mg via IV infusion once every 3 weeks (Day 1 of each 21-day cycle). |
| entinostat C1D1 fed | EXPERIMENTAL | Entinostat: Beginning C1D1 fed; C1D15 fasted. Erlotinib: NSCLC pts beginning C2D1,150 mg, po, qd. Exemestane: Breast cancer pts beginning C2D1,25 mg, po, qd. |
| entinostat C1D1 fasted | EXPERIMENTAL | Entinostat: Beginning C1D1 fasted; C1D15 fed. Erlotinib: NSCLC pts beginning C2D1,150 mg, po, qd. Exemestane: Breast cancer pts beginning C2D1,25 mg, po, qd. |
| Lead-in Phase: Erlotinib + Entinostat 5 mg | EXPERIMENTAL | Erlotinib 150 mg, tablets, orally, daily plus entinostat 5 mg, tablets, orally, on Days 1 and 15 of each 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Lead-in Phase. |
| Lead-in Phase: Erlotinib + Entinostat 10 mg | EXPERIMENTAL | Erlotinib 150 mg tablets, orally, daily plus entinostat 10 mg, tablets, orally, on Days 1 and 15 of each 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Lead-in Phase. |
| Double-blind Phase: Erlotinib + Entinostat 10 mg | EXPERIMENTAL | Erlotinib 150 mg, tablets, orally, daily plus entinostat 10 mg, tablets, orally, on Day 1 and 15 of a 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Double-blind Phase. |
| Double-blind Phase: Erlotinib + Placebo | PLACEBO_COMPARATOR | Erlotinib 150 mg, tablets, orally, daily plus placebo matching entinostat, tablets, orally, on Days 1 and 15 of each 28-day cycle until disease progression or intolerable toxicities for up to 6 cycles in the Double-blind Phase. |
| Crossover Phase: Erlotinib + Entinostat 10 mg | EXPERIMENTAL | Participants in the Double-blind Phase Erlotinib + Placebo arm who experienced disease progression crossed over to receive open-label erlotinib 150 mg, tablets, orally, daily plus entinostat 10 mg, tablets, orally, on Days 1 and 15 of each 28-day cycle until disease progression or intolerable toxicities. |
| Name | Type | Description |
|---|---|---|
| Pembrolizumab | DRUG | 200 mg administered intravenously (IV) every third week until progression or unacceptable toxicity for a maximum of 24 months |
| Entinostat | DRUG | 5 mg by mouth (PO) once weekly until progression or unacceptable toxicity for a maximum of 24 months |
| Interleukin-2 | DRUG | In the event of clinical benefit after a course of HD IL-2 (stable disease or tumor shrinkage) patients will receive a second treatment course of HD IL-2 therapy. Patients with evidence of tumor shrinkage after the 2nd HD IL-2 treatment course may receive a 3rd treatment course of HD IL-2. |
| Aromatase Inhibitor (AI) Therapy | DRUG | AI therapy at labeled dose and schedule as prescribed in clinical practice. AI therapies include: Arimidex® (anastrozole) 1 mg/day by mouth (PO), Fermara® (letrozole) 2.5 mg/day PO , Aromasin® (exemestane) 25 mg/day PO. |
| exemestane | DRUG | Exemestane 25 mg tablet orally once daily |
| Placebo | DRUG | Placebo-matching entinostat tablet orally once per week |
| Capecitabine | DRUG | In metastatic breast cancer patients, capecitabine will be taken by mouth starting at 800 mg/m2 twice a day for 14 days per cycle and increase to 1000 mg/m2 (for 14 days per cycle) in the absence of unacceptable side effects. The safe dose (when combined with capecitabine) will be confirmed in additional metastatic breast cancer patients and breast cancer patients with residual invasive disease following neoadjuvant chemotherapy and surgery. |
| avelumab | DRUG | A fully human antibody of the immunoglobulin (Ig) G1 isotype that targets and blocks Programmed death-ligand 1 (PD-L1), the ligand for Programmed cell death protein 1 (PD-1) receptor. |
| Atezolizumab | DRUG | A humanized, engineered monoclonal antibody of IgG1 isotype against the protein programmed cell death ligand 1 (PD-L1). |
| Erlotinib | DRUG | Erlotinib: NSCLC pts beginning C2D1,150 mg, po, qd. |
Inclusion Criteria: * Age above 18 years. * Signed and dated written informed consent before the start of specific protocol procedures. * ECOG PS 0-1 * Histologically/cytologically confirmed stage IV uveal melanoma * Measurable disease by computed tomography (CT) or Magnetic Resonance Imaging (MRI)...
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Entinostat is an investigational small molecule being studied in oncology for several tumor types, including ER-positive and metastatic breast cancer, epithelial ovarian cancer, lung cancer, and metastatic uveal melanoma. It is also being evaluated in renal cell carcinoma in combination with high dose IL-2. It is not an approved therapy.
Entinostat targets histone deacetylases, specifically HDAC1, HDAC2, HDAC3, HDAC5, HDAC6, and HDAC7. It acts as an HDAC inhibitor, a class of small molecule agents studied in oncology. This target profile is the basis for its investigation across multiple solid tumor and blood-related cancer settings.
Entinostat is being developed by Syndax Pharmaceuticals, Inc., which trades under the ticker SNDX. The company is the sponsor of the clinical program evaluating the agent across breast cancer, ovarian cancer, lung cancer, and other solid tumor indications.
Entinostat is in Phase 2 clinical development and is investigational. It has not been approved by the FDA. The program includes completed Phase 1 studies and an active Phase 2 study, with a total of three completed trials and one active trial across the development program.
Entinostat has been studied in NCT03501381, a Phase 2 trial combining high dose IL-2 in renal cell carcinoma that is active and not recruiting, and in completed trials NCT03473639 in high risk breast cancer with capecitabine, NCT02915523 in advanced epithelial ovarian cancer with avelumab, and NCT02909452 in advanced solid tumors with pembrolizumab.
Across the reported Entinostat clinical program, total enrollment is 280 patients. The trials include randomized, double-blind, active-controlled designs, and at least one study used biomarker selection. Enrollment ranged from 13 patients in the breast cancer pilot study to 140 patients in the ovarian cancer study.