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
II. To evaluate the safety and tolerability of M7824 when in combination with eribulin in
patients with metastatic TNBC.
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).
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.
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.
- 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
- 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
- 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.
- 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
- 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
- Patients with human immunodeficiency virus (HIV)-1 may be eligible if they meet the
- 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