Randomized Phase 2 Study of Atezolizumab and Entinostat in Patients With aTN Breast Cancer With Phase 1b Lead In

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety and tolerability of entinostat used in combination with atezolizumab in participants with Advanced Triple Negative Breast Cancer (aTNBC). Additionally, the purpose of the study is to assess how effective entinostat and atezolizumab are in combination in participants with aTNBC.

Detailed Description
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SNDX-275-0602 is a Phase 1b/2 study evaluating the combination of entinostat plus atezolizumab in participants with aTNBC. The study has 2 phases: an open-label Dose Determination Phase (Phase 1b) followed by an Expansion Phase (Phase 2). The Expansion Phase will evaluate the efficacy and safety of entinostat when administered at the RP2D with atezolizumab in participants with aTNBC in a randomized, double-blind, placebo-controlled setting. Safety will be assessed during the study by documentation of AEs, clinical laboratory tests, physical examinations, vital sign measurements, electrocardiograms (ECGs), and Eastern Cooperative Oncology Group (ECOG) performance status. Adverse events of special interest (AESI) will be collected and reviewed in a manner consistent with serious adverse event reporting procedures.

Official Title
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A Randomized, Placebo-controlled, Double-blind, Multicenter Phase 2 Study of Atezolizumab With or Without Entinostat in Patients With Advanced Triple Negative Breast Cancer, With a Phase 1b Lead in Phase

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Entinostat
* Drug: Atezolizumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has histologically or cytologically confirmed triple negative breast carcinoma that is either metastatic (stage IV of the TNM classification) or locally recurrent and not amenable to local curative treatment. Evidence of measurable, locally recurrent or metastatic disease based on imaging studies within 28 days before the first dose of study drug. Has received at least 1, but no more than 2, prior lines of systemic therapy for locally recurrent and/or metastatic disease. If participant has a history of treated asymptomatic CNS metastases they are eligible, provided they meet all of the following criteria: participant has measurable disease outside CNS; participant does not have metastases to midbrain, pons, medulla or spinal cord; participant is not on corticosteroids as therapy for CNS disease (anticonvulsants at a stable dose are allowed); participant has not had whole-brain radiation within 6 weeks prior to study enrollment; participant has stable CNS disease as demonstrated by at least 4 weeks of stability between the last intervention scan and the study screening scan. ECOG performance status of 0 or 1. Has acceptable, applicable laboratory parameters. Female participants must not be pregnant; willing to use 2 methods of birth control/abstinence if applicable through 120 days after the last dose of study drug. Experienced resolution of toxic effect(s) of the most recent prior anti-cancer therapy to Grade <1 (except alopecia or neuropathy). Able to understand and give written informed consent and comply with study procedures. Exclusion Criteria: Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug. Active autoimmune disease including active diverticulitis, symptomatic peptic ulcer disease, colitis, or inflammatory bowel disease that has required systemic treatment in past 2 years. Previously treated with a PD-1/PD-L1-blocking antibody or a histone deacetylase inhibitor. 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 participant to participate, in the opinion of the treating Investigator, including, but not limited to: history of immune deficiencies or autoimmune disease; myocardial infarction or arterial thromboembolic events within 6 months prior to screening or severe or unstable angina, New York Heart Association (NYHA) Class III or IV disease, or a QTc interval > 470 msec; uncontrolled hypertension or diabetes mellitus; another known malignancy that is progressing or requires active treatment; active infection requiring systemic therapy; known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Any contraindication to oral agents or significant nausea and vomiting, malabsorption, or significant small bowel resection that, in the opinion of the investigator, would preclude adequate absorption. Received a live vaccine within 30 days of the first dose of treatment. Prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to enrollment or who has not recovered from AEs due to mAb agents administered more than 4 weeks earlier. Prior chemotherapy within 3 weeks, targeted small molecule therapy or radiation therapy within 2 weeks prior to enrollment, or who has not recovered (i.e., ≤Grade 1 at enrollment) from AEs due to a previously administered agent. Received transfusion of blood products or administration of colony stimulating factors within 4 weeks prior to the first dose of treatment. 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 study drug. Currently receiving treatment with any other agent listed on the prohibited medication list. If female, is pregnant, breastfeeding, or expecting to conceive starting with the screening visit through 120 days after the last dose of study drug. Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies). Known active hepatitis B or hepatitis C. Allergy to benzamide or inactive components of entinostat. History of allergies to any active or inactive ingredients of atezolizumab. Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Entinostat plus Atezolizumab<br>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. | Drug: Entinostat<br>* An orally available histone deacetylases inhibitor (HDAC).<br>* Other names: MS-275;Drug: Atezolizumab<br>* A humanized, engineered monoclonal antibody of IgG1 isotype against the protein programmed cell death ligand 1 (PD-L1).<br>* Other names: MPDL3280A;|
| Placebo Comparator: Placebo plus Atezolizumab<br>Participants in this arm will receive placebo in combination with atezolizumab 1200 mg. | Drug: Atezolizumab<br>* A humanized, engineered monoclonal antibody of IgG1 isotype against the protein programmed cell death ligand 1 (PD-L1).<br>* Other names: MPDL3280A;Drug: Placebo<br>* A pill containing no active drug ingredient<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b: Participants Experiencing DLT | 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). | Up to 21 days after Cycle 1 Day 1 | 
| Phase 1b: Determination of the RP2D | 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. | Up to 21 days after Cycle 1 Day 1 | 
| Phase 2 Expansion: Duration of Progression-free Survival (PFS) Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | 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. | Up to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 2 Expansion: Duration of PFS Using Immune Response RECIST (irRECIST) | The duration of PFS, assessed using irRECIST, was used to evaluate the efficacy of entinostat at the RP2D in combination with atezolizumab in participants with 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. | Up to 1 year | 
| Phase 2 Expansion: Overall Response Rate (ORR) Using RECIST 1.1 and irRECIST | ORR was defined as the crude percentage of participants achieving a best overall response of complete response (CR) or partial response (PR) assessed using RECIST 1.1 and irRECIST. ORR calculated as: (number of participants with best overall response as CR or PR)/total number of participants. The overall response was determined locally by the investigator at each scheduled assessment. | Up to 1 year | 
| Phase 2 Expansion: Clinical Benefit Rate (CBR) Using RECIST 1.1 and irRECIST | CBR was estimated based on the crude percentage of participants in each treatment arm whose best overall response during the course of study treatment was CR, PR, or stable disease (SD) lasting for at least 24 weeks (measured from the date of randomization to the last date where SD was reported). | Up to 1 year | 
| Phase 2 Expansion: Overall Survival (OS) | OS was defined as the number of months from randomization to date of death from any cause. Participants who were alive or lost to follow-up as of a data analysis cutoff date were right-censored. One month was considered 30.4375 days. OS (months) = (Date of Death/Censoring - Date of Randomization + 1)/30.4375 | Up to 5 years | 
| Phase 2 Expansion: Duration of Response (DOR) | DOR was defined as the number of months from the date where a CR/PR (based on RECIST 1.1) or immune response CR (irCR)/immune response PR (irPR) was firstly observed, to the first date that recurrent or progressive disease was documented. | Up to 2 years | 
| Phase 2 Expansion: Time To Response (TTR) | TTR was defined for the subset of participants that achieved best overall response of confirmed CR/PR or confirmed irCR/irPR as the number of months from date of randomization to date of the initial documented response of CR/PR (based on RECIST 1.1) or irCR/irPR (based on irRECIST). | Up to 2 years |