Clinical Trials /

M7824 and Eribulin Mesylate in Treating Patients With Metastatic Triple Negative Breast Cancer

NCT03579472

Description:

This phase Ib trial studies best dose and side effects of eribulin mesylate when given together with anti-PD-L1/TGFbetaRII fusion protein M7824 (M7824) in treating patients with triple negative breast cancer that has spread to other places in the body. Drugs used in chemotherapy, such as eribulin mesylate, 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. Immunotherapy with monoclonal antibodies, such as M7824, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving eribulin mesylate and M7824 may work better at treating triple negative breast cancer.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: M7824 and Eribulin Mesylate in Treating Participants With Metastatic Triple Negative Breast Cancer
  • Official Title: A Phase Ib Trial of M7824 and Eribulin in Patients With Metastatic Triple Negative Breast Cancer (TNBC)

Clinical Trial IDs

  • ORG STUDY ID: 2017-0500
  • SECONDARY ID: NCI-2018-01140
  • SECONDARY ID: 2017-0500
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03579472

Conditions

  • Anatomic Stage IV Breast Cancer AJCC v8
  • Estrogen Receptor Negative
  • HER2/Neu Negative
  • Progesterone Receptor Negative
  • Prognostic Stage IV Breast Cancer AJCC v8
  • Triple-Negative Breast Carcinoma

Interventions

DrugSynonymsArms
Anti-PD-L1/TGFbetaRII Fusion Protein M7824Anti-PDL1/TGFb Trap MSB0011359C, M7824, MSB0011359CTreatment (M7824, eribulin mesylate)
Eribulin MesylateB1939 Mesylate, E7389, ER-086526, Halaven, Halichondrin B AnalogTreatment (M7824, eribulin mesylate)

Purpose

This phase Ib trial studies best dose and side effects of eribulin mesylate when given together with anti-PD-L1/TGFbetaRII fusion protein M7824 (M7824) in treating participants with triple negative breast cancer that has spread to other places in the body. Drugs used in chemotherapy, such as eribulin mesylate, 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. Monoclonal antibodies, such as M7824, may interfere with the ability of tumor cells to grow and spread. Giving eribulin mesylate and M7824 may work better at treating triple negative breast cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the recommended phase II dose (RP2D) of eribulin mesylate (eribulin) when in
      combination with the fixed dose of M7824 in patients with metastatic triple-negative breast
      cancer (TNBC).

      II. To evaluate the safety and tolerability of M7824 when in combination with eribulin in
      patients with metastatic TNBC.

      SECONDARY OBJECTIVES:

      I. To determine the best overall response (BOR) rate according to Response Evaluation
      Criteria in Solid Tumors (RECIST) 1.1.

      II. To determine the overall response rate (ORR).

      EXPLORATORY OBJECTIVES:

      I. Estimation of progression-free survival (PFS) in metastatic TNBC patients treated with
      M7824 in combination with eribulin.

      II. To assess immunologic/molecular responses to M7824 in combination with eribulin in
      patients with metastatic TNBC, by performing correlative studies on tissue samples to
      evaluate systemic and tumor biomarkers of response and resistance to M7824 and eribulin.

      OUTLINE:

      Participants receive anti-PD-L1/TGFbetaRII fusion protein M7824 intravenously (IV) over 50-80
      minutes on days 1, 15, and 29, and eribulin mesylate IV over 2-5 minutes on days 1, 8, 22,
      and 29. Treatment repeats every 42 days for up to 1 year in the absence of disease
      progression or unacceptable toxicity.

      After completion of study treatment, participants are followed up at 90 days.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (M7824, eribulin mesylate)ExperimentalParticipants receive anti-PD-L1/TGFbetaRII fusion protein M7824 IV over 50-80 minutes on days 1, 15, and 29, and eribulin mesylate IV over 2-5 minutes on days 1, 8, 22, and 29. Treatment repeats every 42 days for up to 1 year in the absence of disease progression or unacceptable toxicity.
  • Anti-PD-L1/TGFbetaRII Fusion Protein M7824
  • Eribulin Mesylate

Eligibility Criteria

        Inclusion Criteria:

          -  Signed written informed consent.

          -  Histologically confirmed metastatic triple negative breast cancer with measurable
             disease by RECIST 1.1 criteria hormone receptor (HR) defined as positive for the
             purposes of this study, if expression of estrogen receptor (ER) and/or progesterone
             receptor (PR) expression is greater than 10% by immunohistochemistry (IHC) and HER2
             negative or non-amplified is determined by the current American Society of Clinical
             Oncology-College of American Pathologists (ASCO-CAP) criteria, which are as follows:
             HER2 testing by IHC as 0 or 1+. If HER2 is 2+, ISH (in situ hybridization) must be
             performed.

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

          -  Baseline multi-gated acquisition scan (MUGA) or echocardiogram scans with left
             ventricular ejection fraction (LVEF) of > 50%.

          -  Absolute neutrophil count (ANC) >= 1500 cells/uL.

          -  White blood cell (WBC) counts > 2500/uL.

          -  Lymphocyte count >= 300/uL.

          -  Platelet count >= 100,000/uL.

          -  Hemoglobin >= 9.0 g/dL.

          -  Hepatic impairment Child-Pugh < B7.

          -  Total bilirubin =< 1.5 x upper limit of normal (ULN) with the following exception:
             patients with known Gilbert disease who have serum indirect bilirubin level =< 3 X ULN
             may be enrolled.

          -  Eribulin dose modification necessary in patients with hepatic insufficiency according
             to United Surgical Partners International (USPI).

          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3.0 x ULN with
             the following exception: patients with liver involvement: AST and/or ALT =< 5 x ULN.

          -  Alkaline phosphatase =< 2.5 x ULN with the following exception: patients with
             documented liver involvement or bone metastases: alkaline phosphatase =< 5 x ULN.

          -  Creatinine clearance >= 50 mL/min on the basis of the Cockcroft-Gault glomerular
             filtration rate estimation.

          -  International normalized ratio (INR) and activated partial thromboplastin time (aPTT)
             =< 1.5 x ULN. This applies only to 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.

          -  Women of childbearing potential must be using an adequate method of contraception to
             avoid pregnancy during the study and for at least 4 months after the last dose of
             study drugs in such a manner that the risk of pregnancy is minimized. Men on study
             also must be using contraception. Women of childbearing potential (WOCBP) are women
             who have not been postmenopausal greater than 1 year or undergone a hysterectomy or
             bilateral oophorectomy.

          -  Negative serum or urine pregnancy test for women within 72 hours of receiving the
             first dose of the study medication for women of childbearing potential.

          -  Has received no more than 5 previous lines of chemotherapy and has received at least
             two lines of chemotherapy in the metastatic setting.

        Exclusion Criteria:

          -  Women who are pregnant or breast-feeding.

          -  Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or
             anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including
             ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation
             or checkpoint pathways) for metastatic breast cancer-or- if patient has had prior
             immune-oncology therapies in the neoadjuvant or adjuvant setting within the past 12
             months.

          -  Has had major surgery within 21 days before cycle 1, day 1.

          -  Uncontrolled inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis).

          -  Myocardial infarction within 6 months before starting therapy, symptomatic congestive
             heart failure (New York Heart Association > class II), unstable angina, or unstable
             cardiac arrhythmia requiring medication.

          -  Serious intercurrent infections or non-malignant medical illness that are uncontrolled
             or the control of which may be jeopardized by this therapy.

          -  Psychiatric disorders or other conditions rendering the subject incapable of complying
             with the requirements of the protocols.

          -  History or risk of autoimmune disease, including but not limited to systemic lupus
             erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis
             associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's
             syndrome, Bell's palsy, Guillain-Barré syndrome, multiple sclerosis, autoimmune
             thyroid disease, vasculitis, or glomerulonephritis.

          -  Patients with a history of autoimmune hypothyroidism (such as atrophic thyroiditis) on
             a stable dose of thyroid replacement hormone may be eligible.

          -  Patients with uncontrolled type 1 diabetes mellitus. If on a stable insulin regimen
             may be eligible, after discussion with principal investigator.

          -  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: patients
             with psoriasis must have a baseline ophthalmologic exam to rule out ocular
             manifestations. Rash must cover less than 10% of body surface area (BSA). Disease is
             well controlled at baseline and only requiring low potency topical steroids (e.g.,
             hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, flucinolone 0.01%, desonide 0.05%,
             aclometasone dipropionate 0.05%). No acute exacerbations of underlying condition
             within the last 12 months (not requiring psoralen plus ultraviolet A radiation [PUVA],
             methotrexate, retinoids, biologic agents, oral calcineurin inhibitors; high potency or
             oral steroids).

          -  Patients with human immunodeficiency virus (HIV)-1 may be eligible if they meet the
             following conditions:

               -  CD4 cell count > 350 cells/mm3 obtained within 90 days prior to study start.

               -  Plasma HIV-1 ribonucleic acid (RNA) below detected limit obtained by Food and
                  Drug Administration (FDA)-approved assays for > 2 years on combination
                  anti-retroviral therapy (cART).

               -  Plasma HIV-1 RNA level of less than 40 copies/mL obtained by the Abbott m2000
                  assay or less than 20 copies/mL by Roche Taqman version (v)2.0 assay within 90
                  days prior to study start.

               -  Plasma HIV-1 RNA greater than or equal to 0.4 copies/mL by single copy assay
                  within 120 days prior to entry.

               -  Receiving a stable cART regimen containing at least 3 agents (not including
                  ritonavir if less than a 200 mg total daily dose) with no change in the
                  components of antiretroviral therapy for at least 90 days prior to study entry.

          -  Patients with prior allogeneic stem cell or solid organ transplantation.

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

          -  Patients with known active hepatitis B (defined as having a positive hepatitis B
             surface antigen [HBsAg] test at screening) or hepatitis C. Patients with past
             hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a
             negative HBsAg test and a positive antibody to hepatitis B core antigen [anti HBc]
             antibody test) are eligible. Patients positive for hepatitis C virus (HCV) antibody
             are eligible only if polymerase chain reaction is negative for HCV RNA.

          -  Known active tuberculosis.

          -  Administration of a live, attenuated vaccine within 4 weeks before cycle 1, day 1 or
             anticipation that such a live, attenuated vaccine will be required during the study.
             Influenza vaccination should be given during influenza season only (approximately
             October to March). Patients must not receive live, attenuated influenza vaccine (e.g.,
             FluMist) within 4 weeks prior to cycle 1, day 1 or at any time during the study.

          -  Treatment with systemic immunostimulatory agents (including but not limited to
             interferons or IL-2) within 4 weeks or five half-lives of the drug, whichever is
             shorter, from cycle 1 day 1.

          -  Treatment with systemic corticosteroids or other systemic immunosuppressive
             medications (including but not limited to prednisone, dexamethasone, cyclophosphamide,
             azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [TNF] agents)
             within 1 week prior to cycle 1 day 1, or anticipated requirement for systemic
             immunosuppressive medications during the trial. Patients who have received acute, low
             dose, systemic immunosuppressant medications (e.g., dexamethasone prior to the
             anthracycline-based chemotherapy for nausea) may be enrolled in the study. The use of
             inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) is allowed.

          -  Concurrent disease or condition that would interfere with study participation or
             safety, such as any of the following:

               -  Active, clinically significant infection either grade > 2 by National Cancer
                  Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03 or
                  requiring the use of parenteral anti-microbial agents within 14 days before day 1
                  of study drug.

               -  Clinically significant bleeding diathesis or coagulopathy, including known
                  platelet function disorders non-healing wound, ulcer, or bone fracture.

          -  Known hypersensitivity to any of the components of M7824 or eribulin.

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

          -  Subjects with active central nervous system (CNS) metastases causing clinical symptoms
             or metastases that require therapeutic intervention, including leptomeningeal disease,
             are excluded. Subjects with a history of treated CNS metastases (by surgery or
             radiation therapy) are not eligible unless they have fully recovered from treatment,
             demonstrated no progression for at least 2 months, and do not require continued
             steroid therapy.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Recommended phase II dose (RP2D) defined as highest dose with dose limiting toxicity (DLT) rate =< 30%
Time Frame:Up to 90 days post-treatment
Safety Issue:
Description:AEs tabulated using frequencies and percentages, by severity, by grade, and by relationship to study treatment.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

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