Clinical Trials /

Atezolizumab and Cobimetinib or Idasanutlin in Participants With Stage IV or Unresectable Recurrent Estrogen Receptor Positive Breast Cancer

NCT03566485

Description:

This phase I/II trial studies the side effects and best dose of idasanutlin when given together with atezolizumab, and to see how well atezolizumab and cobimetinib or idasanutlin work in treating participants with stage IV estrogen-receptor positive (ER+) breast cancer, or ER+ breast cancer that has come back (recurrent) and cannot be removed by surgery (unresectable). Monoclonal antibodies, such as atezolizumab, may interfere with the ability of tumor cells to grow and spread. Cobimetinib and idasanutlin may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving atezolizumab with cobimetinib or atezolizumab with idasanutlin may work better in treating participants with estrogen-receptor positive breast cancer.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Atezolizumab and Cobimetinib or Idasanutlin in Participants With Stage IV or Unresectable Recurrent Estrogen Receptor Positive Breast Cancer
  • Official Title: BRE 17107: A Phase Ib/II Trial of Atezolizumab (an Anti-PD-L1 Monoclonal Antibody) With Cobimetinib (a MEK1/2 Inhibitor) or Idasanutlin (an MDM2 Antagonist) in Metastatic ER+ Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: VICC BRE 17107
  • SECONDARY ID: NCI-2018-01159
  • NCT ID: NCT03566485

Conditions

  • Stage III Breast Cancer
  • Stage IIIA Breast Cancer
  • Stage IIIB Breast Cancer
  • Stage IIIC Breast Cancer
  • Stage IV Breast Cancer
  • Estrogen Receptor-positive
  • HER2/Neu Negative

Interventions

DrugSynonymsArms
AtezolizumabArm I (atezolizumab, cobimetinib)
CobimetinibArm I (atezolizumab, cobimetinib)
IdasanutlinArm II (atezolizumab, idasanutlin)

Purpose

This phase I/II trial studies the side effects and best dose of idasanutlin when given together with atezolizumab, and to see how well atezolizumab and cobimetinib or idasanutlin work in treating participants with stage IV estrogen-receptor positive (ER+) breast cancer, or ER+ breast cancer that has come back (recurrent) and cannot be removed by surgery (unresectable). Monoclonal antibodies, such as atezolizumab, may interfere with the ability of tumor cells to grow and spread. Cobimetinib and idasanutlin may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving atezolizumab with cobimetinib or atezolizumab with idasanutlin may work better in treating participants with estrogen-receptor positive breast cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the safety and tolerability of atezolizumab and idasanutlin in patients with
      estrogen receptor positive (ER+) metastatic breast cancer (mBC) (Phase I).

      II. To determine the anti-tumor effect of atezolizumab and cobimetinib or idasanutlin in
      patients with ER+ mBC (Phase II).

      SECONDARY OBJECTIVES:

      I. To determine the anti-tumor duration of effect of atezolizumab and cobimetinib or
      idasanutlin in patients with ER+ mBC (Phase II).

      II. To determine the safety and tolerability of atezolizumab and cobimetinib or idasanutlin
      in patients with ER+ mBC (Phase II).

      EXPLORATORY OBJECTIVES:

      I. To evaluate if CD8+ T cells are enhanced in the tumor with either MEK or MDM2 inhibition
      (Phase II).

      II. To evaluate if MHC-I/II and/or PD-L1 expression is enhanced with MEK inhibition (Phase
      II).

      III. To evaluate if T cell chemotractants (CCL5, CXCL9,10,11,13) are upregulated upon MDM2
      antagonism (Phase II).

      IV. To determine if baseline or changes in PDL1 expression, MHC expression, presence of tumor
      infiltrating lymphocytes, neoantigen expression/ mutation burden (using ribonucleic acid
      [RNA]-and whole exome sequencing), CCL5, CXCL9, CXCL10, CXCL11, and CXCL13 correlate with
      clinical outcome (Phase II).

      V. To determine if immunological activity of MEK inhibition can be tracked noninvasively
      using Zr^89-atezolizumab (Phase II).

      OUTLINE: This is a phase 1, dose-escalation study of idasanutlin followed by a phase II
      study. Participants are assigned to 1 of 2 arms.

      ARM I: Participants with TP53 gene mutation receive atezolizumab intravenously (IV) over 60
      minutes starting with day 15 of course 1 and then on days 1 and 15 of subsequent courses, and
      cobimetinib orally (PO) daily on days 1-21. Courses repeat every 28 days in the absence of
      disease progression or unacceptable toxicity.

      ARM II: Participants without TP53 gene mutation receive atezolizumab IV over 60 minutes
      starting with day 15 of course 1 and then on days 1 and 15 of subsequent courses, and
      idasanutlin PO daily on days 1-5. Courses repeat every 28 days in the absence of disease
      progression or unacceptable toxicity.

      After completion of study treatment, participants are followed for 28 days.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (atezolizumab, cobimetinib)ExperimentalParticipants with TP53 gene mutation receive atezolizumab IV over 60 minutes starting with day 15 of course 1 and then on days 1 and 15 of subsequent courses, and cobimetinib PO daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Atezolizumab
  • Cobimetinib
Arm II (atezolizumab, idasanutlin)ExperimentalParticipants without TP53 gene mutation receive atezolizumab IV over 60 minutes starting with day 15 of course 1 and then on days 1 and 15 of subsequent courses, and idasanutlin PO daily on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Atezolizumab
  • Idasanutlin

Eligibility Criteria

        Inclusion Criteria:

          -  Signed and dated written informed consent.

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.

          -  Clinical stage IV invasive mammary carcinoma or unresectable locoregional recurrence
             of invasive mammary carcinoma that is:

               -  ER/progesterone receptor (PR)-positive (> 1% cells) by immunohistochemistry (IHC)
                  and HER2 negative per American Society of Clinical Oncology (ASCO) guidelines (by
                  IHC or fluorescence in situ hybridization [FISH])

               -  Previously exposed to an aromatase inhibitor (AI) or a selective
                  estrogen-receptor modulator/ downregulator (SERM; SERD) + a CDK4/6 inhibitor

               -  Measurable disease as defined by Response Evaluation Criteria in Solid Tumors
                  (RECIST) version 1.1 criteria that has not been previously irradiated and which
                  can be followed by computed tomography (CT) or magnetic resonance imaging (MRI).

               -  Amenable to biopsy at the time of study entry.

          -  Absolute neutrophil count (ANC) >= 1.5 × 10^9/L.

          -  Platelets >= 100 × 10^9/L.

          -  Hemoglobin >= 9/g/dL (may have been transfused).

          -  Total serum bilirubin =< 1.5 times upper limit of normal (ULN).

          -  Aspartate aminotransferase (AST/serum glutamic oxaloacetic transaminase [SGOT]) and
             alanine aminotransferase (ALT/serum glutamate pyruvate transaminase [SGPT]) =< 2.5 ×
             ULN (or =< 5 x ULN if liver metastases are present).

          -  Serum creatinine =< 1.5 x ULN or estimated creatinine clearance >= 50 mL/min as
             calculated using the Cockcroft-Gault (CG) equation.

          -  Thyroid stimulating hormone (TSH) =< 1 x ULN.

          -  Amylase =< 1 x ULN.

          -  Lipase =< 1 x ULN.

          -  Creatine kinase (CPK) =< 1.5 x ULN.

          -  Left ventricular ejection fraction (LVEF) (echocardiogram [echo]) >= lower limit of
             normal (LLN).

          -  Female patients of childbearing potential must agree to use at least two methods of
             acceptable contraception with a failure rate of < 1% per year from 15 days prior to
             first trial treatment administration until at least 5 months after study participant's
             final dose of study drugs.

             * Note: Females of childbearing potential are defined as those who are not surgically
             sterile or post-menopausal (i.e. patient has not had a bilateral tubal ligation, a
             bilateral oophorectomy, or a complete hysterectomy; or has not been amenorrheic for 12
             months without an alternative medical cause). Post-menopausal status in females under
             55 years of age should be confirmed with a serum follicle-stimulating hormone (FSH)
             level within laboratory reference range for postmenopausal women.

          -  Patients unable to read/write in English are eligible to participate in the overall
             study but will not participate in the patient-reported outcome questionnaires
             throughout the trial.

          -  Re-enrollment of a subject that has discontinued the study as a pre-treatment screen
             failure (i.e. a consented patient who did not receive study drugs) is permitted. If
             re-enrolled, the subject must be re-consented. Only the screening procedures performed
             outside of protocol-specified timing must be repeated.

        Exclusion Criteria:

          -  Prior therapy with anti-PD-L1 and anti-PD1 antibodies, MEK inhibitors or MDM2
             antagonists.

          -  No more than 3 lines of chemotherapy in the metastatic setting.

          -  No concurrent anticancer therapy. Required washout from prior therapy:

               -  Endocrine therapy: no required wash-out

               -  Chemotherapy: 14 days

               -  Major surgery: 14 days (provided wound healing is adequate)

               -  Radiation: 7 days

               -  Investigational/biologic therapy (half-life =< 40 hours): 14 days

               -  Investigational/biologic therapy (half-life > 40 hours): 28 days.

          -  Use of corticosteroids or immunosuppressive medication is exclusionary, except the
             following in the absence of active autoimmune disease:

               -  Subjects are permitted the use of corticosteroids with minimal systemic
                  absorption (e.g. topical, ocular, intra articular, intranasal, and inhaled);

               -  Systemic corticosteroids at physiologic doses =< 10 mg/day of prednisone or
                  equivalent are permitted;

               -  Adrenal replacement steroid doses including doses > 10 mg daily prednisone are
                  permitted;

               -  A brief (less than 3 weeks) course of corticosteroids for prophylaxis (e.g. CT
                  scan premedication against contrast dye allergy) or for treatment of
                  non-autoimmune conditions (e.g. delayed-type hypersensitivity reaction caused by
                  a contact allergen) is permitted.

          -  Previous malignant disease other than breast cancer within the last 5 years, with the
             exception of basal or squamous cell carcinoma of the skin, cervical carcinoma in situ,
             or low-risk cancers considered curatively treated (i.e. complete remission achieved at
             least 2 years prior to first dose of study drugs and additional therapy not required
             while receiving study treatment).

          -  All subjects with brain metastases, except those meeting the following criteria:

               -  Brain metastases that have been treated locally and are clinically stable for at
                  least 2 weeks prior to enrollment

               -  No history of intracranial or spinal cord hemorrhage

               -  No evidence of interim central nervous system (CNS) disease progression

               -  Metastasis to the midbrain, pons, and medulla

               -  No ongoing neurological symptoms that are related to the brain localization of
                  the disease (sequelae that are a consequence of the treatment of the brain
                  metastases are acceptable.

               -  Subjects must be either off steroids or on a stable or decreasing dose of =< 10
                  mg daily prednisone (or equivalent).

          -  Receipt of any organ transplantation including allogeneic stem-cell transplantation.

          -  Significant acute or chronic infections including, among others:

               -  Known history of testing positive for human immunodeficiency virus (HIV), or
                  acquired immunodeficiency syndrome (AIDS).

               -  Active tuberculosis.

               -  Positive test for hepatitis B virus (HBV) surface antigen (and/or core antibody)
                  and/or confirmatory hepatitis C virus (HCV) RNA (if anti-HCV antibody tested
                  positive).

          -  Active autoimmune disease with reasonable possibility of clinically significant
             deterioration when receiving an immunostimulatory agent:

               -  Subjects with type 1 diabetes mellitus, vitiligo, psoriasis, hypo- or
                  hyperthyroid disease not requiring immunosuppressive treatment are eligible.

               -  Subjects requiring hormone replacement with corticosteroids are eligible if the
                  steroids are administered only for the purpose of hormonal replacement and at
                  doses =< 10 mg or 10 mg equivalent prednisone per day.

               -  Administration of steroids through a route known to result in a minimal systemic
                  exposure (topical, intranasal, intro-ocular, or inhalation) are acceptable.

          -  Interstitial lung disease that is symptomatic or which may interfere with the
             detection or management of suspected drug-related pulmonary toxicity.

          -  Uncontrolled asthma (defined as having 3 or more of the following features of
             partially controlled asthma within 28 days prior to starting study treatment: Daytime
             symptoms more than twice per week, any limitation of activities, any nocturnal
             symptoms/awaking, need for reliever/rescue inhaler more than twice per week, or known
             lung function [peak expiratory flow (PEF) or forced expiratory volume in 1 second
             (FEV1)] without administration of a bronchodilator that is < 80% predicted or personal
             best [if known]).

          -  Current symptomatic congestive heart failure (New York Heart Association > class II),
             unstable cardiac arrhythmia requiring therapy (e.g. medication or pacemaker), unstable
             angina (e.g. new, worsening or persistent chest discomfort), or uncontrolled
             hypertension (systolic > 160 mmHg or diastolic > 100mmHg). Or any of the following
             occurring within 6 months (180 days) prior to first dose of study drugs: myocardial
             infarction, coronary/peripheral artery bypass graft, cerebrovascular accident or
             transient ischemic attack. (Use of antihypertensive medication to control blood
             pressure is allowed.)

          -  Concurrent treatment with a non-permitted drug as well as foods or supplements that
             are strong or moderate CYP3A4 enzyme inducers or inhibitors. Any of the above has to
             be discontinued at least 7 days prior to cycle 1/ day 1 of study treatment.

          -  Requirement of anticoagulant therapy with oral vitamin K antagonists such as Coumadin
             (warfarin). Low-dose anticoagulants for the maintenance of patency in a central venous
             access device or the prevention of deep vein thrombosis or pulmonary embolism is
             allowed. Therapeutic use of low molecular weight heparin is allowed provided patients
             are safely able to interrupt it prior to biopsy procedures.

          -  Persisting toxicity related to prior therapy that has not reduced to grade 1 (National
             Cancer Institute Common Toxicity Criteria for Adverse Events [NCI CTCAE] version
             4.03); however, alopecia and sensory neuropathy grade =< 2 is acceptable.

          -  Known severe (grade >= 3 NCI-CTCAE) hypersensitivity reactions to monoclonal
             antibodies, or history of anaphylaxis.

          -  Vaccination within 28 days of the first dose of study drugs and while on trial is
             prohibited, except for administration of inactivated vaccines (for example,
             inactivated influenza vaccine).

          -  Pregnant or breastfeeding females.

          -  Known current alcohol or drug abuse.

          -  Prisoners or subjects who are involuntarily incarcerated.

          -  Known psychiatric condition, social circumstance, or other medical condition
             reasonably judged by the patient's study physician to unacceptably increase the risk
             of study participation; or to prohibit the understanding or rendering of informed
             consent or anticipated compliance with scheduled visits, treatment schedule,
             laboratory tests and other study requirements.

          -  Known risk factors for ocular toxicity, consisting of any of the following:

               -  presence of serous retinopathy within 6 months of protocol enrollment

               -  presence of retinal vein occlusion (RVO) within 6 months of protocol enrollment.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose limiting toxicity (DLT) (Phase I)
Time Frame:At 28 days
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Clinical benefit rate (CBR) (Phase II)
Time Frame:At 6 months
Safety Issue:
Description:
Measure:Immune related response criteria (irRC) (Phase II)
Time Frame:Up to 28 days after completion of study treatment
Safety Issue:
Description:
Measure:Progression-free survival (PFS) (Phase II)
Time Frame:At 12 months
Safety Issue:
Description:
Measure:Overall survival (OS) (Phase II)
Time Frame:At 12 months
Safety Issue:
Description:
Measure:Incidence of adverse events (Phase II)
Time Frame:Up to 28 days after completion of study treatment
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Vanderbilt-Ingram Cancer Center

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