Working...
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03566485
Recruitment Status : Recruiting
First Posted : June 25, 2018
Last Update Posted : July 4, 2019
Sponsor:
Collaborators:
Genentech, Inc.
Stand Up To Cancer
Information provided by (Responsible Party):
Ingrid Mayer, MD, Vanderbilt-Ingram Cancer Center

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
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 Drug: Atezolizumab Drug: Cobimetinib Drug: Idasanutlin Phase 1 Phase 2

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.


Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : July 10, 2018
Estimated Primary Completion Date : July 2023
Estimated Study Completion Date : July 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Arm I (atezolizumab, cobimetinib)
Participants 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.
Drug: Atezolizumab
Given by IV

Drug: Cobimetinib
Given by mouth

Experimental: Arm II (atezolizumab, idasanutlin)
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.
Drug: Atezolizumab
Given by IV

Drug: Idasanutlin
Given by mouth




Primary Outcome Measures :
  1. Dose limiting toxicity (DLT) (Phase I) [ Time Frame: At 28 days ]
    Assessment of DLT for the patients in the atezolizumab and idasanutiln arm of the study

  2. Maximum tolerated dose (Phase I) [ Time Frame: At 28 days ]
    Assessment of MTD for the atezolizumab and idasanutiln combination arm of the study

  3. Recommended phase II dose (phase I) [ Time Frame: At 28 days ]
    Assessment of recommended phase II dose for the atezolizumab and idasanutiln combination arm of the study

  4. Overall response rate (ORR; by Response Evaluation Criteria in Solid Tumors [RECIST]1.1) (Phase II) [ Time Frame: Up to 28 days after completion of study treatment ]

    Assessment of clinical impact (anti-tumor effect) of the combination of atezolizumab and cobimetinib or idasanutiln in patients with metastatic ER

    + breast cancer by measure the rate (%) of complete and partial responses seen in patients with measurable disease



Secondary Outcome Measures :
  1. Clinical benefit rate (CBR) (Phase II) [ Time Frame: At 6 months ]

    Assessment of clinical impact (anti-tumor effect) of the combination of atezolizumab and cobimetinib or idasanutiln in patients with metastatic ER

    + breast cancer by measure the rate (%) of complete and partial responses + stability of disease at 6 months seen in patients with measurable disease


  2. Immune related response criteria (irRC) (Phase II) [ Time Frame: Up to 28 days after completion of study treatment ]

    Assessment of clinical impact (anti-tumor effect) of the combination of atezolizumab and cobimetinib or idasanutiln in patients with metastatic ER

    + breast cancer by measure the rate (%) of immune-related complete and partial responses seen in patients with measurable disease


  3. Progression-free survival (PFS) (Phase II) [ Time Frame: At 12 months ]

    Assessment of clinical impact (anti-tumor effect) of the combination of atezolizumab and cobimetinib or idasanutiln in patients with metastatic ER

    + breast cancer by measuring the interval (in months) between treatment initiation and disease progression


  4. Overall survival (OS) (Phase II) [ Time Frame: At 12 months ]

    Assessment of clinical impact (anti-tumor effect) of the combination of atezolizumab and cobimetinib or idasanutiln in patients with metastatic ER

    + breast cancer by measuring the interval (in months) between treatment initiation and death from any cause


  5. Incidence of adverse events (Phase II) [ Time Frame: Up to 28 days after completion of study treatment ]
    Assessment of adverse events throughout the study



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Accepts Healthy Volunteers:   No
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.

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): NCT03566485


Contacts
Layout table for location contacts
Contact: Clinical Trials Information Program 800-811-8480 cip@vanderbilt.edu

Locations
Layout table for location information
United States, Tennessee
Vanderbilt-Ingram Cancer Center Recruiting
Nashville, Tennessee, United States, 3720932
Contact: Clinical Trials Information Program    800-811-8480    cip@vanderbilt.edu   
Principal Investigator: Ingrid Mayer, MD         
Sponsors and Collaborators
Vanderbilt-Ingram Cancer Center
Genentech, Inc.
Stand Up To Cancer
Investigators
Layout table for investigator information
Principal Investigator: Ingrid Mayer, MD Vanderbilt-Ingram Cancer Center

Layout table for additonal information
Responsible Party: Ingrid Mayer, MD, Principal Investigator, Vanderbilt-Ingram Cancer Center
ClinicalTrials.gov Identifier: NCT03566485     History of Changes
Other Study ID Numbers: VICC BRE 17107
NCI-2018-01159 ( Registry Identifier: NCI, Clinical Trials Reporting Program )
First Posted: June 25, 2018    Key Record Dates
Last Update Posted: July 4, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Layout table for MeSH terms
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Atezolizumab
Antibodies, Monoclonal
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs