Study of Triple Combination of Atezolizumab + Cobimetinib + Eribulin (ACE) in Patients With Recurrent/Metastatic Inflammatory Breast Cancer

Study Groups:

If you are found to be eligible to take part in this study, you will be enrolled in 1 of 2
study groups: Group A or Group B. Both groups will receive the same drugs at the same
schedule, and the same dose of atezolizumab and eribulin. However, Group A may receive a
different dose of cobimetinib. Up to 9 participants will be in Group A and 24 participants
will be in Group B.

If you are enrolled in Group A, the dose of cobimetinib you receive will depend on when you
join this study. The first group of participants will receive the highest dose level of
cobimetinib. The next new group will receive the same dose of cobimetinib if no intolerable
side effects were seen. If intolerable side effects were seen, then the next new group will
receive a lower level dose. This will continue until the highest tolerable dose of
cobimetinib is found.

If you are enrolled in Group B, you will receive cobimetinib at the highest tolerable dose
found in Group A.

Study Drug Administration:

The pre-cycle is 4 weeks, Cycles 1-4 are 21 days (about 3 weeks), and Cycles 5 and beyond are
28 days (about 4 weeks).

During the pre-cycle, you will receive atezolizumab and cobimetinib only. During Cycles 1-4,
you will receive all 3 study drugs. Starting at Cycle 5, you will only receive atezolizumab
and cobimetinib

You will receive atezolizumab by vein over about 30 minutes every 2 weeks while on study.
However, your first infusion will be given over about 1 hour.

You will take cobimetinib by mouth at the same time every day with or without food on a 3
weeks on, 1 week off schedule. This means you will take the study drug every day for 3 weeks
in a row and then will not take cobimetinib for 1 week. If a dose of cobimetinib is missed or
if you vomit a dose, do not take a "make-up" dose. Wait and take your next dose as scheduled.

You will receive eribulin by vein over about 5 minutes on Days 1 and 8 of Cycles 1-4.

Length of Study:

You may continue taking atezolizumab and cobimetinib for as long as the study doctor thinks
is in your best interest. You may receive up to 4 cycles of eribulin. You will no longer be
able to take the study drugs if the disease gets worse, if intolerable side effects occur, or
if you are unable to follow study directions.

Your participation in this study will be over after follow-up.

Study Visits:

During Week 1 of the pre-cycle, you will have a physical exam.

During Week 1 of each cycle:

- You will have a physical exam.

- Blood (about 1 tablespoon) will be drawn for routine tests.

Before Cycle 1:

- You will have a tumor biopsy for biomarker testing.

- Blood (about 3 tablespoons) will be drawn for cytokine and biomarker testing.

Before Cycles 2 and 5 and then every 3 cycles after that (Cycles 8, 11,14, and so on):

- You will have an eye exam.

- You will have an ECHO or MUGA.

- Starting at Cycle 5, blood (about 3 tablespoons) will be drawn for cytokine and
biomarker testing.

- Starting at Cycle 5, you will have imaging scans.

Before Cycle 3:

- Blood (about 3 tablespoons) will be drawn for cytokine and biomarker testing.

- You will have imaging scans.

On Day 8 of Cycles 1-4, blood (about 1 tablespoon) will be drawn for routine tests.

End of Study:

After your last dose of study drugs:

- You will have a physical exam.

- Blood (about 4-5 tablespoons) will be drawn for routine, cytokine, and biomarker
testing.

- You will have an ECHO or MUGA.

- You will have imaging scans.

- If you have not had one in the last 3 cycles, you will have an eye exam.

Follow-Up:

For about 3 months after the last dose of study drugs or until you start another anticancer
therapy, you will be asked about your health and any side effects you may have had. You may
be asked during a routine clinic visit or you may be called by a member of the study staff.
If you are called, each call should last about 2 minutes.

About every 6 months for at least 2 years after you stop taking the study drugs, you will be
contacted and asked about how you are doing. If you are called, each call should last about 2
minutes. This may also be done in a regular clinic visit.

Inclusion Criteria:

1. Signed Informed Consent Form (ICF) and comply with the requirements of the study
protocol

2. Age >/=18 years

3. ECOG performance status 0-1

4. 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

5. 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.

6. Have at least one metastatic lesion amendable for biopsy (core, punch, or FNA).

7. At least one site of measurable disease (per RECIST 1.1), local or distant

8. Any ER, PR, and HER2 status

9. Adequate hematologic function, defined by the following laboratory results obtained
within 14 days prior to the first study treatment (PD window, Day 1): a. ANC >/= 1500
cells/uL b. WBC counts > 2500/uL c. Lymphocyte count >/= 300/uL d. Platelet count >/=
100,000/uL; e. Hemoglobin >/= 9.0 g/dL

10. Adequate organ function, defined by the following laboratory results obtained within
14 days prior to the first study treatment (Cycle 1, Day 1):f. Total bilirubin x upper limit of normal (ULN) with the following the exception that patients with
known Gilbert disease who have serum bilirubin level AST and ALT and/or ALT patients with documented liver involvement or bone metastases: alkaline phosphatase
/= 50 mL/min on
the basis of the Cockcroft-Gault glomerular filtration rate estimation: (140 - age) x
(weight in kg) x (0.85 if female)/72 x (serum creatinine in mg/dL)

11. 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.

12. INR and aPTT anticoagulation;

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

14. Left Ventricular ejection fraction >/= 50% measured by MUGA scan or echocardiogram

Exclusion Criteria:

1. 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 (SERM, aromatase inhibitor, fulvestrant)
b. Palliative radiotherapy for bone metastases > 1 week prior to study treatment c.
Stable brain metastasis and asymptomatic treated 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

2. AEs from prior anticancer therapy that have not resolved to Grade alopecia and neuropathy (see item below)

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

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

5. Pregnancy, lactation, or breastfeeding

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

7. Inability to comply with study and follow-up procedures

8. 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, Sjögren's syndrome, Guillain-Barré
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.

9. (continuing from #8) 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.

10. 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)

11. 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.

12. 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

13. Known history of 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 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 HBV DNA and referral to virologist
to monitor for HBV reactivation

14. Active tuberculosis based on history, symptoms, physical exam, imaging

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

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

17. 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

18. 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

19. 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.

20. 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)

21. 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

22. Patients will be excluded if they currently have the following risk factors for RVO:
(1) Uncontrolled glaucoma with intra-ocular pressures >/=21mmHg (2) Serum cholesterol
>/= Grade 2 (3) Hypertriglyceridemia >/=Grade 2 (4) Hyperglycemia (fasting) >/= Grade
2

23. Patients with congestive heart failure, congenital long QT syndrome. bradyarrhythmias,
drugs known to prolong the QT interval.

24. 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)

25. 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 (NCI CTCAE Grade 3 and 4)

26. 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

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

28. 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.

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

30. Patients with prior solid organ transplantation on anti-immunosuppressant