MCLA-128 With Trastuzumab/Chemotherapy in HER2+ and With Endocrine Therapy in ER+ and Low HER2 Breast Cancer

Inclusion Criteria:

1. Signed informed consent before initiation of any study procedures.

2. Women with histologically or cytologically confirmed breast cancer with evidence of
metastatic or locally advanced disease not amenable to any local therapy with curative
intent.

3. Measurable disease as defined by RECIST version 1.1 by radiologic methods on or after
the most recent line of therapy. For Cohort 2, imaging must be available for central
review.

4. Eastern Cooperative Oncology Group performance status of 0 or 1.

5. Life expectancy of ≥ 12 weeks, as per investigator.

6. Left ventricular ejection fraction ≥ 50% by echocardiogram or multiple gated
acquisition scan.

7. Patients must have adequate organ function

Exclusion Criteria:

1. Central nervous system metastases that are untreated or symptomatic, or require
radiation, surgery, or continued steroid therapy to control symptoms within 14 days of
study entry.

2. Known leptomeningeal involvement.

3. Advanced/metastatic, symptomatic, visceral spread, with a risk of life-threatening
complications in the short term.

4. Participation in another interventional clinical trial or treatment with any
investigational drug within 4 weeks prior to study entry.

5. Any systemic anticancer therapy within 3 weeks of the first dose of study treatment.
For cytotoxic agents that have major delayed toxicity, e.g. mitomycin C and
nitrosoureas, or anticancer immunotherapies, a washout period of 6 weeks is required.
For patients in Cohort 2, this does not apply to the most recently received hormone
therapy.

6. Major surgery or radiotherapy within 3 weeks of the first dose of study treatment.
Patients who received prior radiotherapy to ≥ 25% of bone marrow are not eligible,
irrespective of when it was received.

7. Persistent grade > 1 clinically significant toxicities related to prior antineoplastic
therapies (except for alopecia); stable sensory neuropathy ≤ grade 1 NCI-CTCAE v. 4.0
is allowed.

8. History of prior ≥ grade 3 hypersensitivity reaction or any toxicity attributed to
trastuzumab or murine proteins that warranted permanent cessation of these agents
(applicable for Cohort 1 only).

9. Previous exposure to vinorelbine (applicable for Cohort 1 triplet combination only)

10. Chronic use of high-dose oral corticosteroid therapy .

11. Uncontrolled hypertension or unstable angina.

12. History of congestive heart failure of Class II-IV New York Heart Association (NYHA)
criteria, or serious cardiac arrhythmia requiring treatment (except atrial
fibrillation, paroxysmal supraventricular tachycardia).

13. History of myocardial infarction within 6 months of study entry.

14. History of prior or concomitant malignancies (other than excised non-melanoma skin
cancer or cured in situ cervical carcinoma) within 3 years of study entry.

15. Current dyspnea at rest of any origin, or other diseases requiring continuous oxygen
therapy.

16. Current serious illness or medical conditions including, but not limited to
uncontrolled active infection, clinically significant pulmonary, metabolic or
psychiatric disorders.

17. Known HIV, HBV, or HCV infection.

18. Pregnant or lactating women; women of childbearing potential must use effective
contraception methods prior to study entry, for the duration of study participation,
and for 6 months after the last dose of MCLA-128.