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

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ClinicalTrials.gov Identifier: NCT02708680
Recruitment Status : Active, not recruiting
First Posted : March 15, 2016
Last Update Posted : October 26, 2018
Sponsor:
Collaborator:
Roche Pharma AG
Information provided by (Responsible Party):
Syndax Pharmaceuticals

Brief Summary:
The purpose of this study is to determine the safety and tolerability of entinostat used in combination with atezolizumab in patients 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 patients with aTNBC.

Condition or disease Intervention/treatment Phase
Breast Cancer Drug: entinostat Drug: atezolizumab Drug: Placebo Phase 1 Phase 2

Detailed Description:

SNDX-275-0602 is a Phase 1b/2 study evaluating the combination of entinostat plus atezolizumab in patients 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 patients with aTNBC in a randomized, double-blind, placebo-controlled setting. Up to 88 evaluable patients are anticipated if the study completes all phases of evaluation (up to 18 patients for Phase 1b, up to 70 patients for Phase 2). Up to 30 study centers in the US and Europe may participate.

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 88 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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
Study Start Date : May 2016
Estimated Primary Completion Date : January 2019
Estimated Study Completion Date : January 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Active Comparator: Entinostat plus Atezolizumab
Patients in this arm will receive entinostat at the RP2D in combination with atezolizumab
Drug: entinostat
An orally available histone deacetylases inhibitor (HDAC)
Other Names:
  • SNDX-275
  • MS-275

Drug: atezolizumab
A humanized, engineered monoclonal antibody of IgG1 isotype against the protein programmed cell death ligand 1 (PD-L1).
Other Name: MPDL3280A

Placebo Comparator: Placebo plus Atezolizumab
Patients in this arm will receive placebo in combination with atezolizumab
Drug: atezolizumab
A humanized, engineered monoclonal antibody of IgG1 isotype against the protein programmed cell death ligand 1 (PD-L1).
Other Name: MPDL3280A

Drug: Placebo
A pill containing no active drug ingredient




Primary Outcome Measures :
  1. Determination of DLT and the MTD and/or RP2D [ Time Frame: In approximately 3 months ]
    Phase 1 Dose Determination - Up to 18 patients will be enrolled in this phase of the study which employs a classical 3+3 design, with the determination of DLT and the MTD and/or RP2D based on entinostat in combination with atezolizumab in C1

  2. Duration of Progression-free survival using RECIST 1.1 [ Time Frame: In approximately 1 year ]
    To perform an evaluation of the efficacy of entinostat at the RP2D in combination with atezolizumab in patients with aTNBC, as determined by the duration of progression-free survival (PFS).


Secondary Outcome Measures :
  1. Progression-free survival based on immune response RECIST (irRECIST) [ Time Frame: In approximately 1 year ]
    PFS status in each patient. PFS is defined as the number of months from the date of the first dose of study drug to the earliest of documented PD or death due to any cause without prior progression.

  2. Overall response rate (ORR) based on RECIST 1.1 and irRECIST [ Time Frame: In approximately 1 year ]
    ORR is Complete Response + Partial Response; based on RECIST 1.1 and irRECIST

  3. Clinical benefit rate (CBR) based on RECIST 1.1 and irRECIST [ Time Frame: In approximately 1 year ]
    CBR is Complete Response + Partial Response + Stable Disease for at least 24 weeks; based on RECISST 1.1 and irRECIST

  4. Overall survival (OS) [ Time Frame: In approximately 2 years ]
    OS status in each patient. OS is defined as the number of months from the first dose of study drug to the date of death due to any cause.

  5. Duration of response (DOR) [ Time Frame: In approximately 2 years ]
    In patients with best overall response of CR or PR; number of months from the start date of the response (and subsequently confirmed) to the first date that recurrent disease or PD is documented.

  6. Time to response (TTR) [ Time Frame: In approximately 2 years ]
    In patients with best overall response of CR or PR



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. 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.
  2. Evidence of measurable, locally recurrent or metastatic disease based on imaging studies within 28 days before the first dose of study drug.
  3. Has received at least 1, but no more than 2, prior lines of systemic therapy for locally recurrent and/or metastatic disease.
  4. If patient has a history of treated asymptomatic CNS metastases they are eligible, provided they meet all of the following criteria: Patient has measurable disease outside CNS; Patient does not have metastases to midbrain, pons, medulla or spinal cord; Patient is not on corticosteroids as therapy for CNS disease (anticonvulsants at a stable dose are allowed); Patient has not had whole-brain radiation within 6 weeks prior to study enrollment; Patient has stable CNS disease as demonstrated by at least 4 weeks of stability between the last intervention scan and the study screening scan
  5. ECOG performance status of 0 or 1.
  6. Has acceptable, applicable laboratory parameters.
  7. Female subjects 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
  8. Experienced resolution of toxic effect(s) of the most recent prior anti-cancer therapy to Grade <1 (except alopecia or neuropathy).
  9. Able to understand and give written informed consent and comply with study procedures.

Exclusion Criteria:

  1. 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.
  2. Active autoimmune disease including active diverticulitis, symptomatic peptic ulcer disease, colitis, or inflammatory bowel disease that has required systemic treatment in past 2 years
  3. Previously treated with a PD-1/PD-L1-blocking antibody or a histone deacetylase inhibitor
  4. History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient'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: 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.
  5. 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.
  6. Received a live vaccine within 30 days of the first dose of treatment.
  7. 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.
  8. 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.
  9. Received transfusion of blood products or administration of colony stimulating factors within 4 weeks prior to the first dose of treatment.
  10. 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.
  11. Currently receiving treatment with any other agent listed on the prohibited medication list
  12. If female, is pregnant, breastfeeding, or expecting to conceive starting with the screening visit through 120 days after the last dose of study drug.
  13. Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).
  14. Known active hepatitis B or hepatitis C
  15. Allergy to benzamide or inactive components of entinostat.
  16. History of allergies to any active or inactive ingredients of atezolizumab.
  17. Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02708680


  Show 29 Study Locations
Sponsors and Collaborators
Syndax Pharmaceuticals
Roche Pharma AG
Investigators
Principal Investigator: Dennis Slamon, MD University of California, Los Angeles

Responsible Party: Syndax Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02708680     History of Changes
Other Study ID Numbers: SNDX-275-0602
First Posted: March 15, 2016    Key Record Dates
Last Update Posted: October 26, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: An independent data safety monitoring board (DSMB) will be established for the Phase 2 portion of this study to act in an advisory capacity to the Sponsor with respect to safeguarding the interests of trial patients and assessing the safety of the interventions administered during the trial.

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Atezolizumab
Entinostat
Antibodies, Monoclonal
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Histone Deacetylase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action