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

NCT02708680 | Completed Phase 1 Results DMC

• 1 other identifier: SNDX-275-0602
• Study Type: interventional
• Target: 89
• Locations: 2 countries
• Sites: 29

Brief Summary

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.

Conditions

Breast Cancer

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (6)

• Phase 2 Expansion: Duration of PFS Using Immune Response RECIST (irRECIST)

  Up to 1 year

• Phase 2 Expansion: Overall Response Rate (ORR) Using RECIST 1.1 and irRECIST

  Up to 1 year

• Phase 2 Expansion: Clinical Benefit Rate (CBR) Using RECIST 1.1 and irRECIST

  Up to 1 year

• Phase 2 Expansion: Overall Survival (OS)

  Up to 5 years

• Phase 2 Expansion: Duration of Response (DOR)

  Up to 2 years

Study Arms (2)

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.

Drug: Entinostat; Drug: Atezolizumab

Placebo plus Atezolizumab

PLACEBO COMPARATOR

Participants in this arm will receive placebo in combination with atezolizumab 1200 mg.

Drug: Atezolizumab; Drug: Placebo

Interventions

Entinostat DRUG

An orally available histone deacetylases inhibitor (HDAC).

Also known as: SNDX-275, MS-275

Entinostat plus Atezolizumab

Atezolizumab DRUG

A humanized, engineered monoclonal antibody of IgG1 isotype against the protein programmed cell death ligand 1 (PD-L1).

Also known as: MPDL3280A

Entinostat plus Atezolizumab; Placebo plus Atezolizumab

Placebo DRUG

A pill containing no active drug ingredient

Placebo plus Atezolizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Syndax Pharmaceuticals: lead
• Roche Pharma AG: collaborator

Study Sites (29)

UAB Comprehensive Cancer Center

Birmingham, Alabama, 35201, United States

Location

CBCC Global Research at Comprehensive Blood and Cancer Center

Bakersfield, California, 93309, United States

Location

St. Jude Medical Center

Fullerton, California, 92835, United States

Location

Los Angeles Hematology Oncology Medical Group

Glendale, California, 91204, United States

Location

Torrance Memorial Cancer Care Associates

Redondo Beach, California, 90277, United States

Location

SLO Oncology and Hematology Health Center

San Luis Obispo, California, 93401, United States

Location

Central Coast Medical Oncology Group

Santa Maria, California, 93454, United States

Location

UCLA Hematology/Oncology - Santa Monica

Santa Monica, California, 90404, United States

Location

Saint Mary's Regional Cancer Center

Grand Junction, Colorado, 81501, United States

Location

Office of Human Research

Hollywood, Florida, 33020, United States

Location

Orlando Health, Inc.

Orlando, Florida, 32806, United States

Location

Ft. Wayne Hematology and Oncology

Fort Wayne, Indiana, 46804, United States

Location

Ft. Wayne Medical Oncology & Hematology, Inc

Fort Wayne, Indiana, 46845, United States

Location

Cancer Center of Kansas

Wichita, Kansas, 67214, United States

Location

Frauenshuh Cancer Center at Park Nicollet Health Service

Saint Louis Park, Minnesota, 55426, United States

Location

Saint Barnabas Medical Cancer Center

Livingston, New Jersey, 07039, United States

Location

Hope Women's Cancer Centers

Asheville, North Carolina, 28806, United States

Location

Wake Forest Baptist Medical Center

Winston-Salem, North Carolina, 27157, United States

Location

Texas Oncology-Baylor Charles A. Sammons Cancer Center

Dallas, Texas, 75201, United States

Location

Cancer Center of Adjara Autonomous Republic

Batumi, Adjara, 6010, Georgia

Location

Saint Nikolozi Surgery and Oncological Centre

Kutaisi, Imereti, 4600, Georgia

Location

Unimed Adjara - Oncology Center

Kutaisi, Imereti, 4600, Georgia

Location

Health House

Tbilisi, 0144, Georgia

Location

Institute of Clinical Oncology

Tbilisi, 0159, Georgia

Location

New Vision University Hospital

Tbilisi, 0159, Georgia

Location

Cancer Research Center

Tbilisi, 0177, Georgia

Location

S. Khechinashvili, University Hospital

Tbilisi, 0179, Georgia

Location

Multiprofile Clinic Consilium Medulla

Tbilisi, 0186, Georgia

Location

Research Institute of Clinical Medicine

Tbilisi, 4600, Georgia

Location

MeSH Terms

Conditions

Breast Neoplasms

Interventions

entinostat; atezolizumab

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Results Point of Contact

• Title: Kate Madigan, MD, Chief Medical Officer
• Organization: Syndax Pharmaceuticals, Inc.

kmadigan@syndax.com

858-888-3798

Study Officials

• Dennis Slamon, MD

  University of California, Los Angeles

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 9, 2016
• First Posted: March 15, 2016
• Study Start: May 1, 2016
• Primary Completion: March 31, 2021
• Study Completion: March 31, 2021
• Last Updated: December 4, 2024
• Results First Posted: September 14, 2023

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (19); GE (10)