Clinical Trials /

Atezolizumab, Cobimetinib, and Eribulin in Treating Patients With Chemotherapy Resistant Metastatic Inflammatory Breast Cancer

NCT03202316

Description:

This phase II trial studies how well atezolizumab, cobimetinib, and eribulin work in treating patients with inflammatory breast cancer that has spread to other places in the body. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Cobimetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as eribulin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving atezolizumab, cobimetinib, and eribulin may work better in treating patients with inflammatory breast cancer.

Related Conditions:
  • Inflammatory Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Atezolizumab, Cobimetinib, and Eribulin in Treating Patients With Chemotherapy Resistant Metastatic Inflammatory Breast Cancer
  • Official Title: A Phase II Study of Triple Combination of Atezolizumab + Cobimetinib + Eribulin (ACE) in Patients With Recurrent/Metastatic Inflammatory Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: 2016-0890
  • SECONDARY ID: NCI-2017-01601
  • SECONDARY ID: 2016-0890
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03202316

Conditions

  • Edema
  • Erythema
  • Peau d'Orange
  • Recurrent Inflammatory Breast Carcinoma
  • Stage IV Inflammatory Breast Carcinoma

Interventions

DrugSynonymsArms
AtezolizumabMPDL 3280A, MPDL 328OA, MPDL-3280A, MPDL3280A, MPDL328OA, RG7446, RO5541267, TecentriqTreatment (atezolizumab, cobimetinib, eribulin)
CobimetinibCotellic, GDC-0973, MEK Inhibitor GDC-0973, XL518Treatment (atezolizumab, cobimetinib, eribulin)
EribulinER-086526Treatment (atezolizumab, cobimetinib, eribulin)

Purpose

This phase II trial studies how well atezolizumab, cobimetinib, and eribulin work in treating patients with inflammatory breast cancer that has spread to other places in the body. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Cobimetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as eribulin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving atezolizumab, cobimetinib, and eribulin may work better in treating patients with inflammatory breast cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine ORR (overall response rate) of metastatic inflammatory breast cancer (mIBC)
      patients treated with this proposed combinatorial atezolizumab, cobimetinib, and eribulin
      (ACE) therapy via phase II.

      SECONDARY OBJECTIVES:

      I. To further characterize the safety and tolerability of, triple combination: ACE therapy.

      II. To determine CBR (clinical benefit rate): (stable disease [SD] + complete response [CR] +
      partial response [PR]) >= 24 weeks of mIBC patients treated with this proposed combinatorial
      therapy via phase II.

      III. To determine the duration of response (DOR). IV. To determine progression free survival
      (PFS). V. To determine 2 years overall survival (OS).

      EXPLORATORY OBJECTIVES:

      I. To determine the progressive disease (PD) biomarker changes induced by combinatorial
      therapy using liquid and tissue based assays to investigate microenvironment via multiplex
      imaging, proportional study of T cells: CD3, CD8 composition and change, macrophage (M1 and
      M2), PD-L1 expression on circulating tumor cell (CTC).

      II. To determine the immune pathway related biomarker changes induced by combinatorial
      therapy via multiplex serum cytokine assays.

      III. This translational biomarker assays will be done based on collaboration with plasma
      based ribonucleic acid (RNA) sequencing (RNA-seq) in collaboration with Lambowitz laboratory
      (lab), Oncomine next-generation sequencing (NGS) study on tumor/circulating tumor
      deoxyribonucleic acid (ctDNA) with Wistuba lab, and bioinformatics with Futreal lab.

      OUTLINE:

      Patients receive atezolizumab intravenously (IV) over about 30 minutes-1 hour every 2 weeks,
      cobimetinib orally (PO) daily for 3 weeks on, 1 week off for 4 weeks of the safety lead-in
      course. Patients then receive atezolizumab IV over about 30 minutes-1 hour every 2 weeks,
      cobimetinib PO daily for 3 weeks on, 1 week off, and eribulin IV over about 5 minutes on days
      1 and 8 of courses 1-4. Courses 1-4 repeat every 21 days and subsequent courses with
      atezolizumab and cobimetinib repeat every 28 days in the absence of disease progression or
      unacceptable toxicity.

      After completion of the study treatment, patients are followed for 3 months and then every 6
      months for at least 2 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (atezolizumab, cobimetinib, eribulin)ExperimentalPatients receive atezolizumab IV over about 30 minutes-1 hour every 2 weeks, cobimetinib PO daily for 3 weeks on, 1 week off for 4 weeks of the safety lead-in course. Patients then receive atezolizumab IV over about 30 minutes-1 hour every 2 weeks, cobimetinib PO daily for 3 weeks on, 1 week off, and eribulin IV over about 5 minutes on days 1 and 8 of courses 1-4. Courses 1-4 repeat every 21 days and subsequent courses with atezolizumab and cobimetinib repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Atezolizumab
  • Cobimetinib
  • Eribulin

Eligibility Criteria

        Inclusion Criteria:

          -  Signed informed consent form (ICF) and comply with the requirements of the study
             protocol

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

          -  Confirmed diagnosis of inflammatory breast cancer according to international consensus
             criteria: (1) onset: rapid onset of breast erythema, edema, and/or peau d'orange,
             and/or warm breast, with or without an underlying breast mass (2) duration: history of
             such findings no more than 6 months (3) extent: erythema occupying at least 1/3 of
             whole breast (4) pathology: pathologic confirmation of invasive carcinoma

          -  Patients with recurrent or metastatic IBC after standard systemic therapy are
             eligible; patients who have disease progression while receiving standard anthracycline
             or taxane based neoadjuvant therapy are also eligible. a. patients with HER2-positive
             disease must have had at least 2 lines of anti-HER2 therapy, including Perjeta and
             Kadcyla; b. prior eribulin treatment is allowed

          -  Have at least one metastatic lesion amendable for biopsy (core, punch, or fine needle
             aspiration [FNA]); if the patient only has lymph nodes, these are considered amenable
             but will not be biopsied

          -  At least one site of measurable disease (per Response Evaluation Criteria in Solid
             Tumors [RECIST] 1.1), local or distant

          -  Any estrogen receptor (ER), progesterone receptor (PR), HER2 status

          -  Absolute neutrophil count (ANC) >= 1500 cells/uL (obtained within 14 days prior to the
             first study treatment [PD window day 1])

          -  White blood cell (WBC) counts > 2500/uL (obtained within 14 days prior to the first
             study treatment [PD window, day 1])

          -  Lymphocyte count >= 300/uL (obtained within 14 days prior to the first study treatment
             [PD window day 1])

          -  Platelet count >= 100,000/uL (obtained within 14 days prior to the first study
             treatment [PD window day 1])

          -  Hemoglobin >= 9.0 g/dL (obtained within 14 days prior to the first study treatment [PD
             window day 1])

          -  Total bilirubin =< 1.5 x upper limit of normal (ULN) with the following the exception
             that patients with known Gilbert disease who have serum bilirubin level =< 3 x ULN may
             be enrolled (obtained within 14 days prior to the first study treatment [cycle 1, day
             1])

          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN with
             the exception that patients with liver involvement: AST and/or ALT =< 5 x ULN
             (obtained within 14 days prior to the first study treatment [cycle 1, day 1])

          -  Alkaline phosphatase =< 2.5 x ULN with the exception that patients with documented
             liver involvement or bone metastases: alkaline phosphatase =< 5 x ULN (obtained within
             14 days prior to the first study treatment [cycle 1, day 1])

          -  Serum creatinine =< 1.5 x ULN or creatinine clearance >= 50 mL/min on the basis of the
             Cockcroft-Gault glomerular filtration rate estimation (obtained within 14 days prior
             to the first study treatment [cycle 1, day 1])

          -  For women of childbearing potential or male subjects: agreement to remain abstinent
             (refrain from heterosexual intercourse) or use contraceptive methods that result in a
             failure rate of < 1% per year, during the treatment period and for at least 5 months
             after the last dose of treatment

          -  International normalized ratio (INR) and activated partial thromboplastin time (aPTT)
             =< 1.5 x ULN for patients who do not receive therapeutic anticoagulation

          -  Patients receiving therapeutic anticoagulation (such as low-molecular-weight heparin
             or warfarin) should be on a stable dose

          -  Left ventricular ejection fraction >= 50% measured by multigated acquisition (MUGA)
             scan or echocardiogram

        Exclusion Criteria:

          -  Any approved anticancer therapy for treatment purpose is not allowed, or need to be
             stopped at least 2 weeks prior to initiation of study treatment; however, the
             following are allowed: a. endocrine therapy (selective estrogen receptor modulator
             [SERM], aromatase inhibitor, fulvestrant) b. palliative radiotherapy for bone
             metastases > 1 week prior to study treatment c. stable brain metastasis and
             asymptomatic treated central nervous system (CNS) metastases are allowed, patient must
             show stable disease by CNS radiographic study >= 4 weeks from completion of
             radiotherapy and >= 2 weeks from discontinuation of corticosteroids

          -  Adverse events (AEs) from prior anticancer therapy that have not resolved to grade =<
             1 except for alopecia and neuropathy

          -  Grade 3 or above neuropathy induced from prior treatment, that is not resolved to
             grade 2 or below despite best supportive care

          -  Known clinically significant liver disease, including active viral, alcoholic, or
             other hepatitis; cirrhosis; fatty liver; and inherited liver disease

          -  Pregnancy, lactation, or breastfeeding

          -  Known hypersensitivity to Chinese hamster ovary cell products or other recombinant
             human antibodies

          -  Inability to comply with study and follow-up procedures

          -  Active or history of autoimmune disease or immune deficiency, including, but not
             limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus
             erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid
             antibody syndrome, Wegener granulomatosis, Sjogren's syndrome, Guillain-Barre
             syndrome, or multiple sclerosis, with the following exception: a. patients with a
             history of autoimmune hypothyroidism who are on thyroid replacement hormone are
             eligible for the study; b. patients with controlled type 1 diabetes mellitus who are
             on an insulin regimen are eligible for the study; c. patients with eczema, psoriasis,
             lichen simplex chronicus of vitiligo with dermatologic manifestations only (e.g.,
             patients with psoriatic arthritis would be excluded) are permitted provided that they
             meet the following conditions: i. rash must cover < 10% of body surface area.; ii.
             disease is well controlled at baseline and requires only low-potency topical
             corticosteroids; iii. no occurrence of acute exacerbations of the underlying condition
             requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic
             agents, oral calcineurin inhibitors, or high potency or oral corticosteroids within
             the previous 12 months

          -  Acute exacerbations of underlying condition within the last 12 months (requiring
             psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids, biologic
             agents, oral calcineurin inhibitors; high potency or oral steroids)

          -  Known history of idiopathic pulmonary fibrosis, pneumonitis (including drug induced),
             organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing
             pneumonia, etc.), or evidence of active pneumonitis on screening chest computed
             tomography (CT) scan; but history of radiation pneumonitis in the radiation field
             (fibrosis) is permitted

          -  Any other diseases, metabolic dysfunction, physical examination finding, or clinical
             laboratory finding giving reasonable suspicion of a disease or condition that
             contraindicates the use of an investigational drug or that may affect the
             interpretation of the results or render the patient at high risk from treatment
             complications

          -  Known history of human immunodeficiency virus (HIV) infection or active hepatitis B
             (chronic or acute) or hepatitis C infection; but: a. patients positive for hepatitis C
             virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative
             for hepatitis C virus (HCV) RNA; b. patients with past or resolved hepatitis B
             infection (defined as having a negative hepatitis B surface antigen [HBsAg] test and a
             positive anti-HBc [antibody to hepatitis B core antigen] antibody test) are eligible,
             but should sample for hepatitis B virus (HBV) DNA and referral to virologist to
             monitor for HBV reactivation

          -  Active tuberculosis based on history, symptoms, physical exam, imaging

          -  Severe infections within 4 weeks prior to study treatment, including but not limited
             to hospitalization for complications of infection, bacteremia, or severe pneumonia

          -  Signs or symptoms of infection within 2 weeks prior to study treatment

          -  Received oral or IV antibiotics within 2 weeks prior to study treatment; but patients
             receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection
             or chronic obstructive pulmonary disease) are eligible

          -  Major surgical procedure within 28 days prior to study treatment or anticipation of
             need for a major surgical procedure during the course of the study

          -  Patients must agree not to receive any live, attenuated influenza vaccine (e.g.,
             FluMist) within 28 days prior to receiving study treatment, during treatment or within
             5 months following the last dose of atezolizumab

          -  Malignancies other than the disease under study within 5 years prior to study
             treatment, with the exception of those with a negligible risk of metastasis or death
             and with expected curative outcome (such as adequately treated carcinoma in situ of
             the cervix, basal or squamous cell skin cancer, or ductal carcinoma in situ treated
             surgically with curative intent) or undergoing active surveillance per
             standard-of-care management (e.g., chronic lymphocytic leukemia Rai Stage 0)

          -  History of or evidence of retinal pathology on ophthalmologic examination that is
             considered a risk factor for neurosensory retinal detachment/central serous
             chorioretinopathy (CSCR), retinal vein occlusion (RVO), or neovascular macular
             degeneration

          -  Patients will be excluded if they currently have the following risk factors for
             retinal vein occlusion (RVO): (1) uncontrolled glaucoma with intra-ocular pressures >=
             21 mmHg (2) serum cholesterol >= grade 2 (3) hypertriglyceridemia >= grade 2 (4)
             hyperglycemia (fasting) >= grade 2

          -  Patients with congestive heart failure, congenital long QT syndrome; bradyarrhythmias,
             drugs known to prolong the QT interval unless the principal investigator and/or
             attending physician deems the risk for QT prolongation to be low

          -  The following foods/supplements are prohibited at least 7 days prior to initiation of
             and during study treatment: (1) St. John's wort or hyperforin (potent CYP3A4 enzyme
             inducer) (2) grapefruit juice (potent cytochrome P450 CYP3A4 enzyme inhibitor)

          -  Prior treatment with anti-PD-1, or anti-PD-L1 therapeutic antibody or pathway
             targeting agents; but patients who have received prior treatment with anti·CTLA-4 may
             be enrolled, provided the following requirements are met: (1) minimum of 12 weeks from
             the first dose of anti-CTLA-4 and > 6 weeks from the last dose; (2) no history of
             severe immune-related adverse effects from anti-CTLA 4 (National Cancer Institute
             [NCI] Common Terminology for Cancer Adverse Effects CTCAE] grade 3 and 4)

          -  Treatment with systemic immunostimulatory agents (including but not limited to
             interferon [IFN]-a or interleukin [IL]-2) within 6 weeks or five half-lives of the
             drug (whichever is shorter) prior to study treatment

          -  Treatment with investigational agent within 4 weeks prior to study treatment (or
             within five half lives of the investigational product, whichever is longer)

          -  Treatment with systemic immunosuppressive medications (including but not limited to
             prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor
             necrosis factor [anti-TNF] agents) within 2 weeks prior to study treatment; but: a.
             patients who have received acute, low dose, systemic immunosuppressant medications
             (e.g., a one-time dose of dexamethasone for nausea) may be enrolled; b. the use of
             inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients
             with orthostatic hypotension or adrenocortical insufficiency is allowed

          -  History of severe allergic, anaphylactic, or other hypersensitivity reactions to
             chimeric or humanized antibodies or fusion proteins

          -  Patients with prior solid organ transplantation on anti-immunosuppressant
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate (ORR) calculated per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
Time Frame:Up to 2 years
Safety Issue:
Description:ORR is defined as the rate of patients who achieved partial response or complete response as the best response. All tumor response will be evaluated by RECIST 1.1. The ORR will be estimated along with 95% confidence intervals. Logistic regression model will be used to assess other variables' effect on the best ORR.

Secondary Outcome Measures

Measure:Incidence of dose limiting toxicity (DLT) of cobimetinib and atezolizumab evaluated according to Common Terminology Criteria for Adverse Events version 4.0 (safety lead-in)
Time Frame:Up to 7 weeks
Safety Issue:
Description:DLT is defined as any treatment-emergent adverse events (AEs) occurring during the first 7 weeks (progressive disease window and cycle 1) not clearly attributable to a cause other than the study drugs.
Measure:Clinical benefit rate (CBR) defined as the rate of patients who achieved complete response, partial response, and stable disease for >= 24 weeks as the best response of treatment
Time Frame:Up to 2 years
Safety Issue:
Description:CBR is defined as the rate of patients who achieved complete response, partial response, and stable disease for >= 24 weeks as the best response of treatment.
Measure:Duration of response (DOR) defined as the period measured from the date of the first occurrence of a complete response (CR) or partial response (PR) (whichever status is recorded first) until the first date that progressive disease or death is documented
Time Frame:Up to 2 years
Safety Issue:
Description:Patients who have not progressed and who have not died by the date of data cutoff for analysis will be censored at the time of last tumor assessment date. If no tumor assessments were performed after the date of the first occurrence of a CR or PR, DOR will be censored at the date of the first occurrence of a CR or PR plus remaining stable response from that time point.
Measure:Progression free survival (PFS)
Time Frame:From date of treatment start until date of first documented disease progression or death, whichever occurs first, assessed up to 2 years
Safety Issue:
Description:Data from patients who have not experienced disease progression or death will be censored at the last tumor assessment date and known to be free of disease progression. Data from patients with no post-baseline tumor assessment will be censored at the treatment start date plus 1 day. PFS will be estimated using the Kaplan-Meier method and the comparison between or among patient's characteristic groups will be evaluated by log-rank test. The Cox regression model may be applied to assess the effect of covariates of interest on PFS.
Measure:Overall survival (OS)
Time Frame:At 2 years
Safety Issue:
Description:OS will be estimated using the Kaplan-Meier method and the comparison between or among patient's characteristic groups will be evaluated by log-rank test. The Cox regression model may be applied to assess the effect of covariates of interest on OS.
Measure:Pharmacodynamic markers
Time Frame:Up to 2 years
Safety Issue:
Description:Biomarker changes induced by combinatorial therapy using liquid and tissue based assays to investigate microenvironment via multiplex imaging, proportional study of T cells: CD3, CD8 composition and change, macrophage (M1and M2), PD-L1 expression on circulating tumor cell will be measured. Immune pathway related biomarker changes induced by combinatorial therapy via multiplex serum cytokine assays will be determined. This translational biomarker assays will be done based on collaboration with plasma based ribonucleic acid (RNA) sequencing (RNA-seq) in collaboration with Lambowitz laboratory (lab), Oncomine next-generation sequencing (NGS) study on tumor/circulating tumor deoxyribonucleic acid (ctDNA) with Wistuba lab, and bioinformatics with Futreal lab.
Measure:Incidence of adverse events
Time Frame:Up to 2 years
Safety Issue:
Description:Detailed safety and tolerability of the combination of cobimetinib, atezolizumab, and eribulin will be assessed. Toxicity data will be summarized by frequency tables.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

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