A Phase 1b/2, Open-label, Dose Escalation Study of Entinostat in Combination With Pembrolizumab in Patients With Non-small Cell Lung Cancer, With Expansion Cohorts in Patients With Non-small Cell Lung Cancer, Melanoma, and Mismatch Repair-Proficient Colorectal Cancer
Overview
- Phase
- Phase 1
- Intervention
- entinostat
- Conditions
- Non-Small Cell Lung Cancer
- Sponsor
- Syndax Pharmaceuticals
- Enrollment
- 191
- Locations
- 11
- Primary Endpoint
- Phase 2: Objective Response Rate (ORR), as Assessed Using Immune Response RECIST (irRECIST)
- Status
- Completed
- Last Updated
- last year
Overview
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.
Detailed Description
SNDX-275-0601 is an open-label, Phase 1b/2 study evaluating the combination of entinostat plus pembrolizumab in patients with advanced metastatic or recurrent NSCLC or melanoma or mismatch repair-proficient colorectal cancer. The study has 2 phases, a Dose Escalation/Confirmation Phase (Phase 1b) and an Expansion Phase (Phase 2). An additional cohort (Entinostat Monotherapy Immune Correlate \[EMIC\] Cohort) evaluating single agent entinostat for 2 weeks followed by the combination will also be evaluated in patients with NSCLC in the Phase 2 expansion phase. Toxicities will be assessed by the Investigator using the United States (US) National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. Dose Confirmation: The prospective MTD/RP2D identified in the Dose Escalation Phase will be confirmed in 9 patients in Dose Confirmation Cohort(s) to obtain additional AE, immune correlate, and anti-tumor activity data on entinostat in combination. Phase 2 (Expansion): In the Expansion Phase, entinostat in combination will be evaluated using the RP2D identified in the Dose Escalation/Confirmation Phase. Up to 3 Expansion Cohorts consisting of distinct subsets of patients with solid tumor cancers may be explored. Expansion cohorts may include: 1. Cohort 1: NSCLC 2. Cohort 2: Patients with NSCLC (any histology) who have previously been treated and responded and then progressed on either a PD-1 or PD-L1-blocking antibody 3. Cohort 3: Patients with melanoma who have previously been treated with and unequivocally progressed on either a PD-1 or PD-L1-blocking antibody 4. Cohort 4: Patients with CRC (mismatch repair-proficient) who have not been previously treated with a PD-1 or PD-L1 blocking antibody EMIC Cohort: 15 NSCLC patients Stage 2 of Cohort 1 will be randomly assigned to participate.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Participants with NSCLC:
- •Has histologically- or pathologically-confirmed recurrent/metastatic NSCLC.
- •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.
- •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.
- •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):
- •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
- •Participants with Melanoma:
- •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):
Exclusion Criteria
- •Participants meeting any of the following criteria are not eligible for study participation:
- •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.
- •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.
- •History of interstitial lung disease (ILD).
- •Allergy to benzamide or inactive components of entinostat.
- •History of allergies to any active or inactive ingredients of pembrolizumab or severe hypersensitivity (≥Grade 3) to pembrolizumab.
- •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.
Arms & Interventions
Phase 1b (Dose Escalation): Entinostat 3 mg Weekly + Pembrolizumab
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).
Intervention: entinostat
Phase 1b (Dose Escalation): Entinostat 3 mg Weekly + Pembrolizumab
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).
Intervention: pembrolizumab
Phase 1b (Dose Escalation): Entinostat 5 mg Weekly + Pembrolizumab
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).
Intervention: entinostat
Phase 1b (Dose Escalation): Entinostat 5 mg Weekly + Pembrolizumab
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).
Intervention: pembrolizumab
Phase 1b (Dose Confirmation): Entinostat 5 mg Weekly + Pembrolizumab
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).
Intervention: entinostat
Phase 1b (Dose Confirmation): Entinostat 5 mg Weekly + Pembrolizumab
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).
Intervention: pembrolizumab
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 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).
Intervention: entinostat
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 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).
Intervention: pembrolizumab
Phase 2, Cohort 2: Entinostat 5 mg Weekly + Pembrolizumab
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).
Intervention: entinostat
Phase 2, Cohort 2: Entinostat 5 mg Weekly + Pembrolizumab
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).
Intervention: pembrolizumab
Phase 2, Cohort 3: Entinostat 5 mg Weekly + Pembrolizumab
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).
Intervention: entinostat
Phase 2, Cohort 3: Entinostat 5 mg Weekly + Pembrolizumab
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).
Intervention: pembrolizumab
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).
Intervention: entinostat
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).
Intervention: pembrolizumab
Outcomes
Primary Outcomes
Phase 2: Objective Response Rate (ORR), as Assessed Using Immune Response RECIST (irRECIST)
Time Frame: 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 Outcomes
- Phase 1b: Recommended Phase 2 Dose (RP2D)(Day 1 through Day 21 (Cycle 1))
- Phase 2: Overall Survival(From date of randomization to the date of death (up to 765 days))
- Phase 2: Clinical Benefit Rate (CBR), as Assessed Using irRECIST(6 months)
- Phase 2: CBR, as Assessed Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)(6 months)
- Phase 2: Progression Free Survival (PFS), as Assessed Using irRECIST(6 months)
- Phase 2: PFS, as Assessed Using RECIST 1.1(6 months)
- 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))
- 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))
- Phase 2: Duration of Response, as Assessed Using irRECIST(From start date of CR or PR to date of progression (up to 765 days))
- 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))
- Phase 2: Time to Response, as Assessed Using irRECIST(From the date of randomization to date of PR or CR (up to 765 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))
- 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)
- Phase 1b: Number of Participants With at Least One Dose Limiting Toxicities (DLTs)(Day 1 through Day 21 (Cycle 1))