Innovative Combination Immunotherapy for Metastatic Triple Negative Breast Cancer (TNBC): A multicenter, multi-arm Translational Breast Cancer Research Consortium study (TBCRC 047: InCITe)

Protocol # :
Stage III Breast Cancer
Stage IIIA Breast Cancer
Stage IIIB Breast Cancer
Stage IIIC Breast Cancer
Stage IV Breast Cancer
Invasive Breast Carcinoma
Recurrent Breast Carcinoma
Triple-Negative Breast Carcinoma
Unresectable Breast Carcinoma
Disease Sites
Principal Investigator
Mayer, Erica, L
Site Research Nurses
Bowers, Jordan
Campbell, Margaret
Cung, Connie
Dishman, Rachel, C.
Ficociello, Samantha
Jeon, Maryangel, H.
Kasparian, Elizabeth
Loeser, Wendy
Orechia, Meghan
Patel, Nikita

Trial Description

This phase II trial studies how well the combination of avelumab with liposomal doxorubicin
with or without binimetinib, or the combination of avelumab with sacituzumab govitecan works
in treating patients with triple negative breast cancer that is stage IV or is not able to be
removed by surgery (unresectable) and has come back (recurrent). Immunotherapy with
checkpoint inhibitors like avelumab require activation of the patient's immune system.

This trial includes a two week induction or lead-in of medications that can stimulate the
immune system. It is our hope that this induction will improve the response to immunotherapy
with avelumab. One treatment, sacituzumab Govitecan, is a monoclonal antibody called
sacituzumab linked to a chemotherapy drug called SN-38. Sacituzumab govitecan is a form of
targeted therapy because it attaches to specific molecules (receptors) on the surface of
tumor cells, known as Tumor-associated calcium signal transducer 2 (TROP2) receptors, and
delivers SN-38 to kill them. Another treatment, liposomal doxorubicin, is a form of the
anticancer drug doxorubicin that is contained in very tiny, fat-like particles. It may have
fewer side effects and work better than doxorubicin, and may enhance factors associated with
immune response. The third medication is called binimetinib, which may stop the growth of
tumor cells by blocking some of the enzymes needed for cell growth, and may help activate the
immune system. It is not yet known whether giving avelumab in combination with liposomal
doxorubicin with or without binimetinib, or the combination of avelumab with sacituzumab
govitecan will work better in treating patients with triple negative breast cancer.

Eligibility Requirements

Inclusion Criteria:

1. Signed and dated written informed consent

2. Subjects >= 18 years of age

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

4. Clinical stage IV invasive breast cancer or unresectable locoregional recurrence of
invasive breast cancer meeting the following criteria:

- Estrogen receptor (ER)/progesterone receptor (PR)-negative (=< 5% cells) by
immunohistochemistry (IHC) and human epidermal grow (HER2) negative (by IHC or
fluorescence in situ hybridization (FISH))

- Measurable disease as defined by Response Evaluation Criteria in Solid Tumors
(RECIST) version 1.1 criteria and which can be followed by computed tomography
(CT) or magnetic resonance imaging (MRI). A measurable lytic bone lesion(s)
and/or skin lesion(s) are allowed. Skin lesions must also be followed by
photography with measuring tools within the photograph at each tumor evaluation
time point. Ultrasound may be used to follow breast lesions not visible by CT
following discussion with Study Chair

- Amenable to biopsy at the time of study entry

- Known tumor/immune cell PD-L1 status by any assay

5. Adequate organ function including:

- Cardiac ejection fraction at or above the institutional lower limit of normal, as
assessed by either echocardiogram or multigated acquisition (MUGA) scan

- Absolute neutrophil count (ANC) >= 1.0 x 10^9/L (may have received growth factor)

- Platelets >= 100 x 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 x 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

- Prothrombin time (PT)/international normalized ratio (INR) =< 1.5 x ULN

- Amylase =< 1 x ULN testing is only required in patients with a history of
pancreatic disorders (Abnormality not of pancreatic origin is allowed)

- Participants with treated and controlled hypo or hyperthyroidism are eligible.

6. Male and female patients of childbearing potential must agree to use at least two
methods of acceptable contraception from 15 days prior to first trial treatment
administration until at least 30 days after study participant's final dose of study

* 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 amenorrhoeic 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

7. 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.

8. Re-enrollment of a subject that has discontinued the study as a pre-randomization
screen failure (i.e., a consented patient who was not randomized and did not receive
any study treatment) is permitted. If re-enrolled, the subject must be re-consented.
Only the screening procedures performed outside of protocol-specified timing must be
repeated; if biopsies and correlative blood samples were already obtained, and patient
has not received any systemic anti-cancer therapy since they were obtained, they do
not need to be repeated.

Exclusion Criteria:

1. More than 2 lines of chemotherapy in the metastatic setting

2. More than 1 prior line of checkpoint inhibitor therapy in the metastatic setting

3. Prior treatment with sacituzumab, govitecan

4. Concurrent anticancer therapy. Required washout from prior therapies are as follows:

- Chemotherapy: >= 14 days: antibody drug conjugants administered every 3 weeks
require a 3-week washout.

- 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
nonautoimmune conditions (e.g. delayed-type hypersensitivity reaction caused
by a contact allergen) is permitted

5. 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)

6. All subjects with central nervous system metastases and/or carcinomatous meningitis,
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 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)

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

8. Significant acute or chronic infections including, among others:

- Known history of testing positive for human immunodeficiency virus (HIV), or
acquired immunodeficiency syndrome (AIDS); testing is not required for this

- A history of a positive test for hepatitis B virus (HBV) surface antigen (and/or
core antibody) and/or confirmatory hepatitis C virus (HCV) ribonucleic acid (RNA)
(if anti-HCV antibody tested positive); testing is not required for this protocol

9. Active autoimmune disease with reasonable possibility of clinically significant
deterioration when receiving an immunostimulatory agent, per investigator discretion:

- 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) is acceptable

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

11. 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])

12. 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), uncontrolled hypertension
(systolic > 160 mmHg or diastolic > 100mmHg), or known cardiac ejection fraction below
the lower limit of institutional normal. Or any of the following occurring within 6
months (180 days) prior to first dose of avelumab: Myocardial infarction,
coronary/peripheral artery bypass graft, cerebrovascular accident or transient
ischemic attack. (Use of antihypertensive medication to control blood pressure is

13. Patients who have neuromuscular disorders that are associated with elevated creatine
kinase (CK)

14. History of acute or chronic pancreatitis

15. History or current evidence of retinal vein occlusion (RVO), or current risk factors
for RVO including uncontrolled glaucoma, ocular hypertension, history of
hyperviscosity, or hypercoagulability syndromes (patients with a history of pulmonary
embolism or deep vein thrombosis (DVT) are allowed on study if they are also on
anticoagulation as noted in (16) below) ; history of retinal degenerative disease.

16. 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 or factor Xa inhibitors are
allowed provided patients are safely able to interrupt it prior to biopsy procedures.

17. 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 5.0);
however, alopecia and sensory neuropathy grade =< 2 is acceptable

18. Known severe (grade >= 3 NCI-CTCAE v5.0) hypersensitivity reactions to monoclonal
antibodies, or history of anaphylaxis

19. 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)

20. Pregnant or breastfeeding females

21. Known current alcohol or drug abuse

22. Prisoners or subjects who are involuntarily incarcerated

23. 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.