Melanoma, Mismatch Repair-Proficient Colorectal Cancer, Non-Small Cell Lung Cancer
Conditions
Brief summary
The purpose of this study is to determine the safety and tolerability of entinostat used in combination with pembrolizumab in participants with NSCLC. Additionally, the purpose of the study is to assess how effective entinostat and pembrolizumab are in combination in participants with NSCLC, Melanoma, and Mismatch-Repair Proficient CRC.
Interventions
DRUGentinostat
An orally available histone deacetylases inhibitor (HDACs)
DRUGpembrolizumab
A selective humanized monoclonal antibody (mAb)
Sponsors
Merck Sharp & Dohme LLC
Syndax Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Participants with NSCLC: 1. Has histologically- or pathologically-confirmed recurrent/metastatic NSCLC. 2. If has adenocarcinoma, required to have previously been tested for anaplastic lymphoma kinase (ALK) rearrangements and epidermal growth factor receptor (EGFR) mutations, with results available for collection in this study, and, if positive, has been treated with prior epidermal growth factor receptor (EGFR) or ALK therapy. 3. Received at least 1 chemotherapeutic regimen in the advanced/metastatic setting and experienced documented, unequivocal progressive disease by either RECIST 1.1 or clinical assessment. Additional requirements related to prior treatments applied and may have been dependent on mutational status. 4. Participants with NSCLC enrolled in Cohort 1 of the Expansion Phase should not have been previously treated with a PD-1/PD-L1-blocking antibody. Participants in Expansion Phase, Cohorts 2 (NSCLC) and 3 (Melanoma): 5. Previously treated with a PD-1/PD-L1-blocking antibody and experienced documented, unequivocal radiographic progression of disease by irRECIST, or similar criteria during or within 12 weeks after last dose of such treatment. Participants must have received at least 6 weeks of PD-1/PD-L1 therapy for Cohort 2 and at least 8 weeks of PD-1/PD-L1 therapy for Cohort 3. Participants with Melanoma: 6. In addition to having been previously treated with a PD-1/PD-L1-blocking antibody, has a histologically- or cytologically-confirmed diagnosis of unresectable or metastatic melanoma and experienced unequivocal progressive disease during treatment with a Serine/threonine-protein kinase B-Raf (BRAF) inhibitor if BRAF V600 mutation-positive. Treatment with BRAF inhibitor may occur after treatment with the checkpoint inhibitor. Participants in Expansion Phase, Cohort 4 (CRC): 7. Received at least 1 chemotherapeutic regimen in the advanced/metastatic setting and experienced documented, unequivocal progressive disease by either RECIST 1.1 or clinical assessment. Must have documented mismatch repair-proficient colon cancer as determined by either immunohistochemistry for mismatch repair proteins or polymerase chain reaction (PCR)-based functional microsatellite instability. Participants with CRC enrolled in Cohort 4 should not have been previously treated with a PD-1/PD-L1-blocking antibody (that is, pembrolizumab, nivolumab, MEDI4736, or GNE PDL1 \[MPDL3280A\]). All Participants: 8. Aged 18 years or older on the day written informed consent is given. 9. If has brain metastases, must have stable neurologic status following local therapy for at least 4 weeks without the use of steroids or on stable or decreasing dose of ≤10 milligrams (mg) daily prednisone (or equivalent), and must be without neurologic dysfunction that would confound the evaluation of neurologic and other AEs. 10. Evidence of locally recurrent or metastatic disease based on imaging studies within 28 days before the first study drug dose: * At least 1 measurable lesion ≥20 mm by conventional techniques or ≥10 mm by spiral computed tomography (CT) scan or magnetic resonance imaging (MRI), with the last imaging performed within 28 days before the first study drug dose. If there is only 1 measurable lesion and it is located in previously irradiated field, it must have demonstrated unequivocal progression according to RECIST, version 1.1. 11. If receiving radiation therapy, has a 2-week washout period following completion of the treatment prior to receiving the first study drug dose and continues to have at least 1 measurable lesion, per above criterion. 12. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 13. Has acceptable renal and hepatic function and stable hematologic and coagulation status. 14. Female participants must not be pregnant. If a participants is of childbearing potential, the participant must agree to use effective contraception, as defined in the protocol, during the study and for 120 days after the last dose of study drug. 15. If male, agrees to use an adequate method of contraception starting from the first dose of study drug through 120 days after the last dose of study drug. 16. Experienced resolution of toxic effect(s) of the most recent prior chemotherapy to Grade 1 or less (except alopecia). If participant underwent major surgery or radiation therapy of \>30 gray (Gy), they must have recovered from the toxicity and/or complications from the intervention. 17. Willing to have fresh tumor samples collected during screening and at other time points designated as mandatory, per the Schedule of Study Assessments. 18. Able to understand and give written informed consent and comply with study procedures.
Exclusion criteria
Participants meeting any of the following criteria are not eligible for study participation: 1. Diagnosis of immunodeficiency or receiving systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug. The use of physiologic doses of corticosteroids may be approved after consultation with the Sponsor. 2. Active autoimmune disease that has required systemic treatment in past 2 years (that is, with disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (for example, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment. 3. History of interstitial lung disease (ILD). 4. Allergy to benzamide or inactive components of entinostat. 5. History of allergies to any active or inactive ingredients of pembrolizumab or severe hypersensitivity (≥Grade 3) to pembrolizumab. 6. History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating Investigator, including, but not limited to: * Myocardial infarction or arterial thromboembolic events within 6 months prior to baseline or severe or unstable angina, New York Heart Association (NYHA) Class III or IV disease, or a QTc interval \> 470 milliseconds (msec). * Uncontrolled heart failure or hypertension, uncontrolled diabetes mellitus, or uncontrolled systemic infection. * Another known additional malignancy that is progressing or requires active treatment (excluding adequately treated basal cell carcinoma, squamous cell of the skin, cervical intraepithelial neoplasia \[CIN\]/cervical carcinoma in situ or melanoma in situ, or ductal carinoma in situ of the breast). Prior history of other cancer is allowed, as long as there is no active disease within the prior 5 years. * Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis. * Active infection requiring systemic therapy. * Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Note: Participants with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging \[using the identical imaging modality for each assessment, either MRI or CT scan\] for at least 4 weeks prior to the first dose of study drug and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 2 weeks prior to the first dose of study drug or are on stable or decreasing dose of ≤10 mg daily prednisone (or equivalent). This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability. 7. Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study. 8. Currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment. 9. Received a live virus vaccination within 30 days of the first dose of treatment. 10. Prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to baseline or who has not recovered (that is, ≤Grade 1 or at baseline) from AEs due to agents administered more than 4 weeks earlier. 11. Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study baseline or who has not recovered (that is, ≤Grade 1 or at baseline) from AEs due to a previously administered agent. Note: Participants with ≤Grade 2 neuropathy or ≤Grade 2 alopecia are an exception to this criterion and may qualify for the study. Note: If participant underwent major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy. 12. Received transfusion of blood products (including platelets or red blood cells) or administration of colony stimulating factors (including granulocyte-colony stimulating factor \[G-CSF\], granulocyte macrophage-colony stimulating factor \[GM-CSF\], or recombinant erythropoietin) within 4 weeks prior to the first dose of study drug. 13. Currently receiving treatment with any other agent listed on the prohibited medication list such as valproic acid, or other systemic cancer agents within 14 days of the first dose of treatment. 14. If female, is pregnant, breastfeeding, or expecting to conceive, or if male, expect to father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study drug. 15. Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies). 16. Known active hepatitis B (for example, hepatitis B surface antigen-reactive) or hepatitis C (for example, hepatitis C virus ribonucleic acid \[qualitative\]). 17. For CRC expansion cohort, no prior history of malignant bowel obstruction requiring hospitalization in the 6 months prior to enrollment 18. For the CRC expansion cohort, history of uncontrolled ascites, defined as symptomatic ascites and/or repeated paracenteses for symptom control in the past 3 months.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 2: Objective Response Rate (ORR), as Assessed Using Immune Response RECIST (irRECIST) | From date of randomization to date of progression (up to 765 days) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 2: CBR, as Assessed Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 6 months | The CBR was defined as the percentage of participants with a confirmed CR, PR, or SD lasting for at least 6 months. CR: Disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Disappearance of all non-target lesions and normalisation of tumour marker level. All lymph nodes must be non-pathological in size (\<10 mm short axis). PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. |
| Phase 2: Progression Free Survival (PFS), as Assessed Using irRECIST | 6 months | PFS was defined as the number of months from randomization to PD or death due to any cause, whichever occurred first. PD: Sum of the diameters (longest for non-nodal lesions, shortest for nodal lesions) of target and new measurable lesions increases ≥20% (compared to nadir), confirmed by a repeat, consecutive observation at least 4 weeks from the date first documented. Number of participants without evidence of progression or death at Month 6 are reported. |
| Phase 2: PFS, as Assessed Using RECIST 1.1 | 6 months | PFS was defined as the number of months from randomization to 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 mm; the appearance of one or more new lesions; and unequivocal progression of existing non-target lesions. Number of participants without evidence of progression or death at Month 6 are reported. |
| Phase 2: PFS Duration, as Determined by the Local Investigator Using irRECIST | From date of randomization to PD or death due to any cause (up to 765 days) | PFS was defined as the number of months from randomization to PD or death due to any cause, whichever occurred first. PD: Sum of the diameters (longest for non-nodal lesions, shortest for nodal lesions) of target and new measurable lesions increases ≥20% (compared to nadir), confirmed by a repeat, consecutive observation at least 4 weeks from the date first documented. For purposes of analysis, 1 month was considered to be 30.4375 days. |
| Phase 2: PFS Duration, as Determined by the Local Investigator Using RECIST 1.1 | From date of randomization to PD or death due to any cause (up to 765 days) | PFS was defined as the number of months from randomization to PD or death due to any cause, whichever occurred first. PD: Sum of the diameters (longest for non-nodal lesions, shortest for nodal lesions) of target and new measurable lesions increases ≥20% (compared to nadir), confirmed by a repeat, consecutive observation at least 4 weeks from the date first documented. For purposes of analysis, 1 month was considered to be 30.4375 days. |
| Phase 2: Overall Survival | From date of randomization to the date of death (up to 765 days) | Overall survival was defined as the number of months from randomization to the date of death (due to any cause). For purposes of analysis, 1 month was considered to be 30.4375 days. |
| Phase 2: Clinical Benefit Rate (CBR), as Assessed Using irRECIST | 6 months | The CBR was defined as the percentage of participants with a confirmed CR, PR, or stable disease (SD) lasting for at least 6 months. 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 mm. PR: Sum of the diameters (longest for non-nodal lesions, shortest for nodal lesions) of target and new measurable lesions decreases ≥30%. SD: Sum of the diameters (longest for nonnodal lesions, shortest for nodal lesions) of target and new measurable lesions neither CR, PR, (compared to baseline) or progressive disease (PD) (compared to nadir). |
| Phase 2: Duration of Response, as Assessed Using RECIST 1.1 | From start date of CR or PR to date of progression (up to 765 days) | Duration of response was defined as number of months from start date of CR or PR (whichever occurred first) and subsequently confirmed, to the first date that recurrent or progressive disease was documented. CR: Disappearance of all target lesions and any pathological lymph nodes (target or non-target) must have reduction in short axis to \<10 mm. Disappearance of all non-target lesions and normalisation of tumour marker level. All lymph nodes must be non-pathological in size (\<10 mm short axis). PR: At least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. PD: At least a 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, sum must also demonstrate an absolute increase of ≥5 mm; appearance of one or more new lesions; and unequivocal progression of existing non-target lesions. For purposes of analysis, 1 month was considered to be 30.4375 days. |
| Phase 2: Time to Response, as Assessed Using irRECIST | From the date of randomization to date of PR or CR (up to 765 days) | Time to response was defined as the number of months from the randomization date to the first date the participant achieved a PR or CR (whichever response occurred first and was subsequently confirmed). CR: Disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Disappearance of all non-target lesions and normalisation of tumour marker level. All lymph nodes must be non-pathological in size (\<10 mm short axis). PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. For purposes of analysis, 1 month was considered to be 30.4375 days. |
| Phase 2: Time to Response, as Assessed Using RECIST 1.1 | From the date of randomization to date of PR or CR (up to 765 days) | Time to response was defined as the number of months from the randomization date to the first date the participant achieved a PR or CR (whichever response occurred first and was subsequently confirmed). CR: Disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Disappearance of all non-target lesions and normalisation of tumour marker level. All lymph nodes must be non-pathological in size (\<10 mm short axis). PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. For purposes of analysis, 1 month was considered to be 30.4375 days. |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), AEs Resulting in the Permanent Discontinuation of Study Drug, and Death | From first dose of study drug up to 765 days | An adverse event (AE) was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. SAEs included death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized the participant and required medical intervention to prevent 1 of the outcomes listed in this definition. TEAEs were defined as AEs that started on or after the first administration of study drug and within 30 days of the last administration of any study treatment. A summary of serious and non-serious AEs regardless of causality is located in 'Reported Adverse Events module'. For purposes of analysis, 1 month was considered to be 30.4375 days. |
| Phase 1b: Number of Participants With at Least One Dose Limiting Toxicities (DLTs) | Day 1 through Day 21 (Cycle 1) | A DLT was defined as the occurrence of any protocol-specified event in the first cycle of treatment (Day 1 through Day 21) of entinostat in combination with avelumab that were considered by the investigator to be at least possibly related to study drug. |
| Phase 1b: Recommended Phase 2 Dose (RP2D) | Day 1 through Day 21 (Cycle 1) | The RP2D was determined in discussion with the Sponsor, Medical Monitor, and Dose Determination Phase Investigators. Additionally, observations related to immune correlates, and any cumulative toxicity observed after multiple cycles might be included in the rationale supporting the RP2D. The RP2D could be equal to or less than the preliminary maximum tolerated dose (MTD). The MTD was defined as the highest dose level at which \<33% of 6 participants experienced DLT. |
| Phase 2: Duration of Response, as Assessed Using irRECIST | From start date of CR or PR to date of progression (up to 765 days) | Duration of response was defined as number of months from start date of CR or PR (whichever occurred first) and subsequently confirmed, to the first date that recurrent or progressive disease was documented. CR: Disappearance of all target lesions and any pathological lymph nodes (target or non-target) must have reduction in short axis to \<10 mm. Disappearance of all non-target lesions and normalisation of tumour marker level. All lymph nodes must be non-pathological in size (\<10 mm short axis). PR: At least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. PD: At least a 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, sum must also demonstrate an absolute increase of ≥5 mm; appearance of one or more new lesions; and unequivocal progression of existing non-target lesions. For purposes of analysis, 1 month was considered to be 30.4375 days. |
Countries
United States
Participant flow
Recruitment details
The study was conducted in 2 phases, a Dose Escalation/Confirmation Phase (Phase 1b) and an Expansion Phase (Phase 2).
Pre-assignment details
Per protocol, 9 participants in the Confirmation Phase who rolled over to Cohort 2, and the other 7 participants who rolled over to Cohort 1 in the Expansion Phase, were counted in the Expansion Phase Population rather than in the Escalation/Confirmation Phase Population for the purpose of collecting data.
Participants by arm
| Arm | Count |
|---|---|
| Phase 1b (Dose Escalation): Entinostat 3 mg Weekly + Pembrolizumab Participants with NSCLC received entinostat 3 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). | 6 |
| Phase 2, Cohort 1: Entinostat 5 mg Weekly + Pembrolizumab Participants with NSCLC with squamous cell or adenocarcinoma histology who had not been 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). | 18 |
| Phase 2, Cohort 2: Entinostat 5 mg Weekly + Pembrolizumab Participants with NSCLC (any histology) who had previously been treated with and unequivocally progressed on either 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). | 76 |
| Phase 2, Cohort 3: Entinostat 5 mg Weekly + Pembrolizumab Participants with melanoma who had previously been treated with and unequivocally progressed on either 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). | 53 |
| Phase 2, Cohort 4: Entinostat 5 mg Weekly + Pembrolizumab 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). | 38 |
| Total | 191 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Dose Escalation/Confirmation (Phase 1b) | Death | 4 | 0 | 0 | 0 | 0 | 0 | 0 |
| Expansion (Phase 2) | Death | 0 | 0 | 0 | 6 | 37 | 29 | 24 |
| Expansion (Phase 2) | Lost to Follow-up | 0 | 0 | 0 | 0 | 3 | 3 | 2 |
| Expansion (Phase 2) | Withdrawal by Subject | 0 | 0 | 0 | 7 | 25 | 4 | 2 |
Baseline characteristics
| Characteristic | Phase 2, Cohort 1: Entinostat 5 mg Weekly + Pembrolizumab | Phase 2, Cohort 2: Entinostat 5 mg Weekly + Pembrolizumab | Phase 2, Cohort 3: Entinostat 5 mg Weekly + Pembrolizumab | Phase 1b (Dose Escalation): Entinostat 3 mg Weekly + Pembrolizumab | Phase 2, Cohort 4: Entinostat 5 mg Weekly + Pembrolizumab | Total |
|---|---|---|---|---|---|---|
| Age, Customized Age 44 years and younger | 1 Participants | 1 Participants | 6 Participants | 0 Participants | 6 Participants | 14 Participants |
| Age, Customized Age 45 to 64 years | 7 Participants | 35 Participants | 23 Participants | 1 Participants | 24 Participants | 90 Participants |
| Age, Customized Age 65 to 74 years | 7 Participants | 25 Participants | 14 Participants | 5 Participants | 6 Participants | 57 Participants |
| Age, Customized Age 75 years and older | 3 Participants | 15 Participants | 10 Participants | 0 Participants | 2 Participants | 30 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 | 2 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 3 Participants | 3 Participants | 1 Participants | 5 Participants | 12 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 | 1 Participants | 5 Participants | 2 Participants | 1 Participants | 1 Participants | 10 Participants |
| Race (NIH/OMB) White | 15 Participants | 66 Participants | 47 Participants | 4 Participants | 32 Participants | 164 Participants |
| Sex: Female, Male Female | 8 Participants | 36 Participants | 21 Participants | 1 Participants | 14 Participants | 80 Participants |
| Sex: Female, Male Male | 10 Participants | 40 Participants | 32 Participants | 5 Participants | 24 Participants | 111 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 | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 6 / 6 | 0 / 7 | 1 / 9 | 8 / 18 | 41 / 76 | 31 / 53 | 25 / 38 |
| other Total, other adverse events | 6 / 6 | 7 / 7 | 9 / 9 | 18 / 18 | 75 / 76 | 52 / 53 | 37 / 38 |
| serious Total, serious adverse events | 4 / 6 | 4 / 7 | 2 / 9 | 10 / 18 | 33 / 76 | 24 / 53 | 14 / 38 |
Outcome results
Primary
Phase 2: Objective Response Rate (ORR), as Assessed Using Immune Response RECIST (irRECIST)
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.
Time frame: From date of randomization to date of progression (up to 765 days)
Population: Full analysis set (FAS) included all enrolled participants excluding those that did not receive at least 1 dose of entinostat and pembrolizumab or lacked baseline data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 2, Cohort 1: Entinostat 5 mg Weekly + Pembrolizumab | Phase 2: Objective Response Rate (ORR), as Assessed Using Immune Response RECIST (irRECIST) | 22.2 percentage of participants |
| Phase 2, Cohort 2: Entinostat 5 mg Weekly + Pembrolizumab | Phase 2: Objective Response Rate (ORR), as Assessed Using Immune Response RECIST (irRECIST) | 9.2 percentage of participants |
| Phase 2, Cohort 3: Entinostat 5 mg Weekly + Pembrolizumab | Phase 2: Objective Response Rate (ORR), as Assessed Using Immune Response RECIST (irRECIST) | 18.9 percentage of participants |
| Phase 2, Cohort 4: Entinostat 5 mg Weekly + Pembrolizumab | Phase 2: Objective Response Rate (ORR), as Assessed Using Immune Response RECIST (irRECIST) | 5.4 percentage of participants |
Secondary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), AEs Resulting in the Permanent Discontinuation of Study Drug, and Death
An adverse event (AE) was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. SAEs included death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized the participant and required medical intervention to prevent 1 of the outcomes listed in this definition. TEAEs were defined as AEs that started on or after the first administration of study drug and within 30 days of the last administration of any study treatment. A summary of serious and non-serious AEs regardless of causality is located in 'Reported Adverse Events module'. For purposes of analysis, 1 month was considered to be 30.4375 days.
Time frame: From first dose of study drug up to 765 days
Population: Safety analysis set included all participants who received at least 1 dose of either study drug, entinostat, or pembrolizumab.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 2, Cohort 1: Entinostat 5 mg Weekly + Pembrolizumab | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), AEs Resulting in the Permanent Discontinuation of Study Drug, and Death | AEs Resulting in the Permanent Discontinuation of Study Drug | 1 Participants |
| Phase 2, Cohort 1: Entinostat 5 mg Weekly + Pembrolizumab | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), AEs Resulting in the Permanent Discontinuation of Study Drug, and Death | SAEs | 4 Participants |
| Phase 2, Cohort 1: Entinostat 5 mg Weekly + Pembrolizumab | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), AEs Resulting in the Permanent Discontinuation of Study Drug, and Death | TEAEs | 6 Participants |
| Phase 2, Cohort 1: Entinostat 5 mg Weekly + Pembrolizumab | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), AEs Resulting in the Permanent Discontinuation of Study Drug, and Death | AEs Resulting in Death | 1 Participants |
| Phase 2, Cohort 2: Entinostat 5 mg Weekly + Pembrolizumab | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), AEs Resulting in the Permanent Discontinuation of Study Drug, and Death | AEs Resulting in the Permanent Discontinuation of Study Drug | 2 Participants |
| Phase 2, Cohort 2: Entinostat 5 mg Weekly + Pembrolizumab | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), AEs Resulting in the Permanent Discontinuation of Study Drug, and Death | TEAEs | 7 Participants |
| Phase 2, Cohort 2: Entinostat 5 mg Weekly + Pembrolizumab | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), AEs Resulting in the Permanent Discontinuation of Study Drug, and Death | SAEs | 4 Participants |
| Phase 2, Cohort 2: Entinostat 5 mg Weekly + Pembrolizumab | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), AEs Resulting in the Permanent Discontinuation of Study Drug, and Death | AEs Resulting in Death | 0 Participants |
| Phase 2, Cohort 3: Entinostat 5 mg Weekly + Pembrolizumab | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), AEs Resulting in the Permanent Discontinuation of Study Drug, and Death | SAEs | 2 Participants |
| Phase 2, Cohort 3: Entinostat 5 mg Weekly + Pembrolizumab | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), AEs Resulting in the Permanent Discontinuation of Study Drug, and Death | TEAEs | 9 Participants |
| Phase 2, Cohort 3: Entinostat 5 mg Weekly + Pembrolizumab | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), AEs Resulting in the Permanent Discontinuation of Study Drug, and Death | AEs Resulting in Death | 1 Participants |
| Phase 2, Cohort 3: Entinostat 5 mg Weekly + Pembrolizumab | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), AEs Resulting in the Permanent Discontinuation of Study Drug, and Death | AEs Resulting in the Permanent Discontinuation of Study Drug | 1 Participants |
| Phase 2, Cohort 4: Entinostat 5 mg Weekly + Pembrolizumab | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), AEs Resulting in the Permanent Discontinuation of Study Drug, and Death | AEs Resulting in the Permanent Discontinuation of Study Drug | 7 Participants |
| Phase 2, Cohort 4: Entinostat 5 mg Weekly + Pembrolizumab | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), AEs Resulting in the Permanent Discontinuation of Study Drug, and Death | TEAEs | 18 Participants |
| Phase 2, Cohort 4: Entinostat 5 mg Weekly + Pembrolizumab | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), AEs Resulting in the Permanent Discontinuation of Study Drug, and Death | SAEs | 10 Participants |
| Phase 2, Cohort 4: Entinostat 5 mg Weekly + Pembrolizumab | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), AEs Resulting in the Permanent Discontinuation of Study Drug, and Death | AEs Resulting in Death | 3 Participants |
| Phase 2, Cohort 2: Entinostat 5 mg Weekly + Pembrolizumab | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), AEs Resulting in the Permanent Discontinuation of Study Drug, and Death | AEs Resulting in the Permanent Discontinuation of Study Drug | 19 Participants |
| Phase 2, Cohort 2: Entinostat 5 mg Weekly + Pembrolizumab | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), AEs Resulting in the Permanent Discontinuation of Study Drug, and Death | TEAEs | 75 Participants |
| Phase 2, Cohort 2: Entinostat 5 mg Weekly + Pembrolizumab | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), AEs Resulting in the Permanent Discontinuation of Study Drug, and Death | SAEs | 33 Participants |
| Phase 2, Cohort 2: Entinostat 5 mg Weekly + Pembrolizumab | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), AEs Resulting in the Permanent Discontinuation of Study Drug, and Death | AEs Resulting in Death | 3 Participants |
| Phase 2, Cohort 3: Entinostat 5 mg Weekly + Pembrolizumab | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), AEs Resulting in the Permanent Discontinuation of Study Drug, and Death | TEAEs | 53 Participants |
| Phase 2, Cohort 3: Entinostat 5 mg Weekly + Pembrolizumab | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), AEs Resulting in the Permanent Discontinuation of Study Drug, and Death | SAEs | 24 Participants |
| Phase 2, Cohort 3: Entinostat 5 mg Weekly + Pembrolizumab | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), AEs Resulting in the Permanent Discontinuation of Study Drug, and Death | AEs Resulting in Death | 2 Participants |
| Phase 2, Cohort 3: Entinostat 5 mg Weekly + Pembrolizumab | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), AEs Resulting in the Permanent Discontinuation of Study Drug, and Death | AEs Resulting in the Permanent Discontinuation of Study Drug | 8 Participants |
| Phase 2, Cohort 4: Entinostat 5 mg Weekly + Pembrolizumab | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), AEs Resulting in the Permanent Discontinuation of Study Drug, and Death | AEs Resulting in Death | 1 Participants |
| Phase 2, Cohort 4: Entinostat 5 mg Weekly + Pembrolizumab | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), AEs Resulting in the Permanent Discontinuation of Study Drug, and Death | SAEs | 14 Participants |
| Phase 2, Cohort 4: Entinostat 5 mg Weekly + Pembrolizumab | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), AEs Resulting in the Permanent Discontinuation of Study Drug, and Death | TEAEs | 37 Participants |
| Phase 2, Cohort 4: Entinostat 5 mg Weekly + Pembrolizumab | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), AEs Resulting in the Permanent Discontinuation of Study Drug, and Death | AEs Resulting in the Permanent Discontinuation of Study Drug | 7 Participants |
Secondary
Phase 1b: Number of Participants With at Least One Dose Limiting Toxicities (DLTs)
A DLT was defined as the occurrence of any protocol-specified event in the first cycle of treatment (Day 1 through Day 21) of entinostat in combination with avelumab that were considered by the investigator to be at least possibly related to study drug.
Time frame: Day 1 through Day 21 (Cycle 1)
Population: Safety analysis set included all participants who received at least 1 dose of either study drug, entinostat, or pembrolizumab.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 2, Cohort 1: Entinostat 5 mg Weekly + Pembrolizumab | Phase 1b: Number of Participants With at Least One Dose Limiting Toxicities (DLTs) | 0 Participants |
| Phase 2, Cohort 2: Entinostat 5 mg Weekly + Pembrolizumab | Phase 1b: Number of Participants With at Least One Dose Limiting Toxicities (DLTs) | 1 Participants |
| Phase 2, Cohort 3: Entinostat 5 mg Weekly + Pembrolizumab | Phase 1b: Number of Participants With at Least One Dose Limiting Toxicities (DLTs) | 0 Participants |
Secondary
Phase 1b: Recommended Phase 2 Dose (RP2D)
The RP2D was determined in discussion with the Sponsor, Medical Monitor, and Dose Determination Phase Investigators. Additionally, observations related to immune correlates, and any cumulative toxicity observed after multiple cycles might be included in the rationale supporting the RP2D. The RP2D could be equal to or less than the preliminary maximum tolerated dose (MTD). The MTD was defined as the highest dose level at which \<33% of 6 participants experienced DLT.
Time frame: Day 1 through Day 21 (Cycle 1)
Population: Safety analysis set included all participants who received at least 1 dose of either study drug, entinostat, or pembrolizumab.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 2, Cohort 1: Entinostat 5 mg Weekly + Pembrolizumab | Phase 1b: Recommended Phase 2 Dose (RP2D) | 5 mg |
Secondary
Phase 2: CBR, as Assessed Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
The CBR was defined as the percentage of participants with a confirmed CR, PR, or SD lasting for at least 6 months. CR: Disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Disappearance of all non-target lesions and normalisation of tumour marker level. All lymph nodes must be non-pathological in size (\<10 mm short axis). PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Time frame: 6 months
Population: FAS included all enrolled participants excluding those that did not receive at least 1 dose of entinostat and pembrolizumab or lacked baseline data. Data were not censored for CBR analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 2, Cohort 1: Entinostat 5 mg Weekly + Pembrolizumab | Phase 2: CBR, as Assessed Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 22.2 percentage of participants |
| Phase 2, Cohort 2: Entinostat 5 mg Weekly + Pembrolizumab | Phase 2: CBR, as Assessed Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 14.5 percentage of participants |
| Phase 2, Cohort 3: Entinostat 5 mg Weekly + Pembrolizumab | Phase 2: CBR, as Assessed Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 30.2 percentage of participants |
| Phase 2, Cohort 4: Entinostat 5 mg Weekly + Pembrolizumab | Phase 2: CBR, as Assessed Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 2.7 percentage of participants |
Secondary
Phase 2: Clinical Benefit Rate (CBR), as Assessed Using irRECIST
The CBR was defined as the percentage of participants with a confirmed CR, PR, or stable disease (SD) lasting for at least 6 months. 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 mm. PR: Sum of the diameters (longest for non-nodal lesions, shortest for nodal lesions) of target and new measurable lesions decreases ≥30%. SD: Sum of the diameters (longest for nonnodal lesions, shortest for nodal lesions) of target and new measurable lesions neither CR, PR, (compared to baseline) or progressive disease (PD) (compared to nadir).
Time frame: 6 months
Population: FAS included all enrolled participants excluding those that did not receive at least 1 dose of entinostat and pembrolizumab or lacked baseline data. Data were not censored for CBR analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 2, Cohort 1: Entinostat 5 mg Weekly + Pembrolizumab | Phase 2: Clinical Benefit Rate (CBR), as Assessed Using irRECIST | 33.3 percentage of participants |
| Phase 2, Cohort 2: Entinostat 5 mg Weekly + Pembrolizumab | Phase 2: Clinical Benefit Rate (CBR), as Assessed Using irRECIST | 14.5 percentage of participants |
| Phase 2, Cohort 3: Entinostat 5 mg Weekly + Pembrolizumab | Phase 2: Clinical Benefit Rate (CBR), as Assessed Using irRECIST | 35.8 percentage of participants |
| Phase 2, Cohort 4: Entinostat 5 mg Weekly + Pembrolizumab | Phase 2: Clinical Benefit Rate (CBR), as Assessed Using irRECIST | 8.1 percentage of participants |
Secondary
Phase 2: Duration of Response, as Assessed Using irRECIST
Duration of response was defined as number of months from start date of CR or PR (whichever occurred first) and subsequently confirmed, to the first date that recurrent or progressive disease was documented. CR: Disappearance of all target lesions and any pathological lymph nodes (target or non-target) must have reduction in short axis to \<10 mm. Disappearance of all non-target lesions and normalisation of tumour marker level. All lymph nodes must be non-pathological in size (\<10 mm short axis). PR: At least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. PD: At least a 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, sum must also demonstrate an absolute increase of ≥5 mm; appearance of one or more new lesions; and unequivocal progression of existing non-target lesions. For purposes of analysis, 1 month was considered to be 30.4375 days.
Time frame: From start date of CR or PR to date of progression (up to 765 days)
Population: FAS included all enrolled participants excluding those that did not receive at least 1 dose of entinostat and pembrolizumab or lacked baseline data. Here, 'Overall number of participants analyzed' = participants who achieved objective response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 2, Cohort 1: Entinostat 5 mg Weekly + Pembrolizumab | Phase 2: Duration of Response, as Assessed Using irRECIST | 15.61 months |
| Phase 2, Cohort 2: Entinostat 5 mg Weekly + Pembrolizumab | Phase 2: Duration of Response, as Assessed Using irRECIST | 10.10 months |
| Phase 2, Cohort 3: Entinostat 5 mg Weekly + Pembrolizumab | Phase 2: Duration of Response, as Assessed Using irRECIST | 25.49 months |
| Phase 2, Cohort 4: Entinostat 5 mg Weekly + Pembrolizumab | Phase 2: Duration of Response, as Assessed Using irRECIST | 7.33 months |
Secondary
Phase 2: Duration of Response, as Assessed Using RECIST 1.1
Duration of response was defined as number of months from start date of CR or PR (whichever occurred first) and subsequently confirmed, to the first date that recurrent or progressive disease was documented. CR: Disappearance of all target lesions and any pathological lymph nodes (target or non-target) must have reduction in short axis to \<10 mm. Disappearance of all non-target lesions and normalisation of tumour marker level. All lymph nodes must be non-pathological in size (\<10 mm short axis). PR: At least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. PD: At least a 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, sum must also demonstrate an absolute increase of ≥5 mm; appearance of one or more new lesions; and unequivocal progression of existing non-target lesions. For purposes of analysis, 1 month was considered to be 30.4375 days.
Time frame: From start date of CR or PR to date of progression (up to 765 days)
Population: FAS included all enrolled participants excluding those that did not receive at least 1 dose of entinostat and pembrolizumab or lacked baseline data. Here, 'Overall number of participants analyzed' = participants who achieved objective response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 2, Cohort 1: Entinostat 5 mg Weekly + Pembrolizumab | Phase 2: Duration of Response, as Assessed Using RECIST 1.1 | NA months |
| Phase 2, Cohort 2: Entinostat 5 mg Weekly + Pembrolizumab | Phase 2: Duration of Response, as Assessed Using RECIST 1.1 | 10.14 months |
| Phase 2, Cohort 3: Entinostat 5 mg Weekly + Pembrolizumab | Phase 2: Duration of Response, as Assessed Using RECIST 1.1 | 25.49 months |
Secondary
Phase 2: Overall Survival
Overall survival was defined as the number of months from randomization to the date of death (due to any cause). For purposes of analysis, 1 month was considered to be 30.4375 days.
Time frame: From date of randomization to the date of death (up to 765 days)
Population: FAS included all enrolled participants excluding those that did not receive at least 1 dose of entinostat and pembrolizumab or lacked baseline data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 2, Cohort 1: Entinostat 5 mg Weekly + Pembrolizumab | Phase 2: Overall Survival | 25.20 months |
| Phase 2, Cohort 2: Entinostat 5 mg Weekly + Pembrolizumab | Phase 2: Overall Survival | 11.73 months |
| Phase 2, Cohort 3: Entinostat 5 mg Weekly + Pembrolizumab | Phase 2: Overall Survival | 12.52 months |
| Phase 2, Cohort 4: Entinostat 5 mg Weekly + Pembrolizumab | Phase 2: Overall Survival | 9.79 months |
Secondary
Phase 2: PFS, as Assessed Using RECIST 1.1
PFS was defined as the number of months from randomization to 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 mm; the appearance of one or more new lesions; and unequivocal progression of existing non-target lesions. Number of participants without evidence of progression or death at Month 6 are reported.
Time frame: 6 months
Population: FAS included all enrolled participants excluding those that did not receive at least 1 dose of entinostat and pembrolizumab or lacked baseline data. Data were censored for PFS analysis based on prespecified analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 2, Cohort 1: Entinostat 5 mg Weekly + Pembrolizumab | Phase 2: PFS, as Assessed Using RECIST 1.1 | 3 Participants |
| Phase 2, Cohort 2: Entinostat 5 mg Weekly + Pembrolizumab | Phase 2: PFS, as Assessed Using RECIST 1.1 | 17 Participants |
| Phase 2, Cohort 3: Entinostat 5 mg Weekly + Pembrolizumab | Phase 2: PFS, as Assessed Using RECIST 1.1 | 17 Participants |
| Phase 2, Cohort 4: Entinostat 5 mg Weekly + Pembrolizumab | Phase 2: PFS, as Assessed Using RECIST 1.1 | 2 Participants |
Secondary
Phase 2: PFS Duration, as Determined by the Local Investigator Using irRECIST
PFS was defined as the number of months from randomization to PD or death due to any cause, whichever occurred first. PD: Sum of the diameters (longest for non-nodal lesions, shortest for nodal lesions) of target and new measurable lesions increases ≥20% (compared to nadir), confirmed by a repeat, consecutive observation at least 4 weeks from the date first documented. For purposes of analysis, 1 month was considered to be 30.4375 days.
Time frame: From date of randomization to PD or death due to any cause (up to 765 days)
Population: FAS included all enrolled participants excluding those that did not receive at least 1 dose of entinostat and pembrolizumab or lacked baseline data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 2, Cohort 1: Entinostat 5 mg Weekly + Pembrolizumab | Phase 2: PFS Duration, as Determined by the Local Investigator Using irRECIST | 2.76 months |
| Phase 2, Cohort 2: Entinostat 5 mg Weekly + Pembrolizumab | Phase 2: PFS Duration, as Determined by the Local Investigator Using irRECIST | 2.83 months |
| Phase 2, Cohort 3: Entinostat 5 mg Weekly + Pembrolizumab | Phase 2: PFS Duration, as Determined by the Local Investigator Using irRECIST | 4.40 months |
| Phase 2, Cohort 4: Entinostat 5 mg Weekly + Pembrolizumab | Phase 2: PFS Duration, as Determined by the Local Investigator Using irRECIST | 1.91 months |
Secondary
Phase 2: PFS Duration, as Determined by the Local Investigator Using RECIST 1.1
PFS was defined as the number of months from randomization to PD or death due to any cause, whichever occurred first. PD: Sum of the diameters (longest for non-nodal lesions, shortest for nodal lesions) of target and new measurable lesions increases ≥20% (compared to nadir), confirmed by a repeat, consecutive observation at least 4 weeks from the date first documented. For purposes of analysis, 1 month was considered to be 30.4375 days.
Time frame: From date of randomization to PD or death due to any cause (up to 765 days)
Population: FAS included all enrolled participants excluding those that did not receive at least 1 dose of entinostat and pembrolizumab or lacked baseline data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 2, Cohort 1: Entinostat 5 mg Weekly + Pembrolizumab | Phase 2: PFS Duration, as Determined by the Local Investigator Using RECIST 1.1 | 2.76 months |
| Phase 2, Cohort 2: Entinostat 5 mg Weekly + Pembrolizumab | Phase 2: PFS Duration, as Determined by the Local Investigator Using RECIST 1.1 | 2.69 months |
| Phase 2, Cohort 3: Entinostat 5 mg Weekly + Pembrolizumab | Phase 2: PFS Duration, as Determined by the Local Investigator Using RECIST 1.1 | 2.96 months |
| Phase 2, Cohort 4: Entinostat 5 mg Weekly + Pembrolizumab | Phase 2: PFS Duration, as Determined by the Local Investigator Using RECIST 1.1 | 1.91 months |
Secondary
Phase 2: Progression Free Survival (PFS), as Assessed Using irRECIST
PFS was defined as the number of months from randomization to PD or death due to any cause, whichever occurred first. PD: Sum of the diameters (longest for non-nodal lesions, shortest for nodal lesions) of target and new measurable lesions increases ≥20% (compared to nadir), confirmed by a repeat, consecutive observation at least 4 weeks from the date first documented. Number of participants without evidence of progression or death at Month 6 are reported.
Time frame: 6 months
Population: FAS included all enrolled participants excluding those that did not receive at least 1 dose of entinostat and pembrolizumab or lacked baseline data. Data were censored for PFS analysis based on prespecified analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 2, Cohort 1: Entinostat 5 mg Weekly + Pembrolizumab | Phase 2: Progression Free Survival (PFS), as Assessed Using irRECIST | 3 Participants |
| Phase 2, Cohort 2: Entinostat 5 mg Weekly + Pembrolizumab | Phase 2: Progression Free Survival (PFS), as Assessed Using irRECIST | 17 Participants |
| Phase 2, Cohort 3: Entinostat 5 mg Weekly + Pembrolizumab | Phase 2: Progression Free Survival (PFS), as Assessed Using irRECIST | 20 Participants |
| Phase 2, Cohort 4: Entinostat 5 mg Weekly + Pembrolizumab | Phase 2: Progression Free Survival (PFS), as Assessed Using irRECIST | 3 Participants |
Secondary
Phase 2: Time to Response, as Assessed Using irRECIST
Time to response was defined as the number of months from the randomization date to the first date the participant achieved a PR or CR (whichever response occurred first and was subsequently confirmed). CR: Disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Disappearance of all non-target lesions and normalisation of tumour marker level. All lymph nodes must be non-pathological in size (\<10 mm short axis). PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. For purposes of analysis, 1 month was considered to be 30.4375 days.
Time frame: From the date of randomization to date of PR or CR (up to 765 days)
Population: FAS included all enrolled participants excluding those that did not receive at least 1 dose of entinostat and pembrolizumab or lacked baseline data. Here, 'Overall number of participants analyzed' = participants who achieved objective response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 2, Cohort 1: Entinostat 5 mg Weekly + Pembrolizumab | Phase 2: Time to Response, as Assessed Using irRECIST | 4.30 months |
| Phase 2, Cohort 2: Entinostat 5 mg Weekly + Pembrolizumab | Phase 2: Time to Response, as Assessed Using irRECIST | 2.83 months |
| Phase 2, Cohort 3: Entinostat 5 mg Weekly + Pembrolizumab | Phase 2: Time to Response, as Assessed Using irRECIST | 1.95 months |
| Phase 2, Cohort 4: Entinostat 5 mg Weekly + Pembrolizumab | Phase 2: Time to Response, as Assessed Using irRECIST | 4.17 months |
Secondary
Phase 2: Time to Response, as Assessed Using RECIST 1.1
Time to response was defined as the number of months from the randomization date to the first date the participant achieved a PR or CR (whichever response occurred first and was subsequently confirmed). CR: Disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Disappearance of all non-target lesions and normalisation of tumour marker level. All lymph nodes must be non-pathological in size (\<10 mm short axis). PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. For purposes of analysis, 1 month was considered to be 30.4375 days.
Time frame: From the date of randomization to date of PR or CR (up to 765 days)
Population: FAS included all enrolled participants excluding those that did not receive at least 1 dose of entinostat and pembrolizumab or lacked baseline data. Here, 'Overall number of participants analyzed' = participants who achieved objective response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 2, Cohort 1: Entinostat 5 mg Weekly + Pembrolizumab | Phase 2: Time to Response, as Assessed Using RECIST 1.1 | 4.29 months |
| Phase 2, Cohort 2: Entinostat 5 mg Weekly + Pembrolizumab | Phase 2: Time to Response, as Assessed Using RECIST 1.1 | 2.83 months |
| Phase 2, Cohort 3: Entinostat 5 mg Weekly + Pembrolizumab | Phase 2: Time to Response, as Assessed Using RECIST 1.1 | 1.95 months |