In this phase II clinical trial with an explorative nature, the efficacy of the combination
of monalizumab and trastuzumab is assessed in patients with metastatic or locally incurable
HER2-positive breast cancer. Clinical efficacy will be assessed in patients with high stromal
tumor-infiltrating lymphocytes (sTILs) or low sTILs in two separate cohorts (higher or equal
to 5% versus lower than 5%). Since the combination of monalizumab and trastuzumab has not
been administered before, dose limiting toxicities (DLTs) will be monitored throughout the
trial using the Pocock-type boundary rules for continuous monitoring of toxicity in phase II
trials.
In the first stage, 11 patients will be accrued per cohort. If there are 1 or fewer responses
in these 11 patients, the study will be stopped. Otherwise, 8 additional patients will be
accrued for a total of 19 patients.
The study will start with two cohorts (sTILs high and sTILs low), a total of 22 (2x11)
patients will be included in the first stage. Dependent on the interim analysis (continuation
of no cohorts, 1 or 2 cohorts), a maximum of 38 patients will be included.
Inclusion Criteria:
without SISH amplification) breast cancer. HER2-positivity must have been assessed on a
metastatic lesion.
- Histological or cytological confirmed locally incurable or metastatic disease
- Accessible lesion for study biopsies.
- Administration of at least one line of palliative treatment with documented
progression and a maximum of three lines of palliative chemotherapy in combination
with HER2 targeting agents (TDM-1 is considered one line of palliative treatment).
Trastuzumab in combination with endocrine treatment is not defined as one line of
treatment.
- Documented progression during previous trastuzumab-based therapy
- Measurable disease according to RECIST1.1 (at least one target lesion)
- Left ventricular ejection fraction of 50% or higher
- WHO performance status of 0 or 1
- No signs of a visceral crisis
- Signed written informed consent - Subjects with brain metastases are eligible if they
have been treated, asymptomatic and there is no magnetic resonance imaging (MRI)
evidence of progression for at least 4 weeks prior to study registration. There must
also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10
mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration
Exclusion Criteria:
- uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris
- known leptomeningeal disease localization
- history of having received other anticancer therapies within 2 weeks of start of the
study drug
- history of immunodeficiency, autoimmune disease, conditions requiring
innmunosuppression (>10 mg daily prednisone equivalents) or chronic infections.
Subjects with vitiligo, diabetes mellitus type I on a stable insulin regimen,
psoriasis not requiring systemic treatment or resolved childhood asthma/atopy would be
an exception to this rule. Subjects that require intermittent use of bronchodilators,
inhaled steroids, or local steroid injections will not be excluded from the study.
Subjects with hypothyroidism stable on hormone replacement, Sjogren's syndrome or
conditions not expected to recur in the absence of an external trigger will not be
excluded from the study. Adrenal replacement doses >10 mg daily prednisone equivalents
are permitted in the absence of active autoinnmune disease
- prior treatment with immune checkpoint blockade or other forms of imnnunotherapy, such
as but not limited to: anti-PD-(L)1, anti-PD-L2, anti-CTLA-4, anti-GITR or CD137/0X40
agonists
- prior treatment with HER2-based vaccines
- live vaccine within two weeks prior to start of the study, at any time during the
study or within 5 months following the last dose of monalizumab. Inactivated vaccines,
such as the seasonal flu vaccination, are allowed
- history of clinically significant or uncontrolled cardiac disease, including
congestive heart failure (New York Heart Association functional classification .3),
angina, myocardial infarction within 12 months prior to study treatment or ventricular
arrhythmia.
- active other cancer
- positive test for hepatitis B surface virus surface antigen (HBsAg) or hepatitis C
virus ribonucleic acid (HCV antibody) indicating acute or chronic infection.
- allogeneic stem cell or organ transplantation, HIV or active tuberculosis
- history of uncontrolled serious medical or psychiatric illness
- Presence of any psychological, familial, sociological or geographical condition
potentially hampering compliance with the study protocol and follow-up schedule
- current pregnancy or breastfeeding. Women of childbearing potential (WOCBP) must use
adequate contraceptive protection. WOCBP must have a negative serum or urine pregnancy
test
