To determine the activity (as measured by objective response rate by RECIST1.1) of monalizumab and trastuzumab in patients with metastatic HER2-positive breast cancer.
ID
Source
Brief title
Condition
- Breast neoplasms malignant and unspecified (incl nipple)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Objective:
To determine the activity (as measured by objective response rate by RECIST1.1)
of monalizumab and trastuzumab in patients with metastatic HER2-positive breast
cancer.
Secondary outcome
Secondary Objectives:
• To evaluate activity (as measured by objective response rate by RECIST1.1) in
all included patients
• To evaluate progression-free survival according to RECIST1.1
• To evaluate overall survival
• To evaluate the safety of monalizumab and trastuzumab as the percentage of
patients with toxicity and immune-related adverse events
Background summary
The cornerstone of the treatment of HER2-positive breast cancer is targeting
HER2 with trastuzumab. The mechanism of action of trastuzumab is partly based
on the lysis of tumor cells via ADCC, a cell-mediated immune mechanism
requiring NK cells. Monalizumab is an antibody targeting the inhibitory
receptor NKG2A on NK cells and CD8 T cells and has demonstrated clinical
activity when combined with cetuximab (anti-EGFR antibody) in head and neck
cancer. We hypothesize that the combination of trastuzumab and monalizumab can
promote anti-tumor immunity by unleashing NK cells and CD8 T cells in
HER2-positive breast cancer and thereby induce clinical responses.
Study objective
To determine the activity (as measured by objective response rate by RECIST1.1)
of monalizumab and trastuzumab in patients with metastatic HER2-positive breast
cancer.
Study design
To get an impression of the pre-existing immunity, levels of tumor-infiltrating
lymphocytes will be determined at baseline. Clinical efficacy will be assessed
independently of tumor infiltrating-lymphocyte levels.
An optimal Simon*s two-stage design will be used. The null hypothesis that the
true response rate is 10% will be tested against a one-sided alternative. In
the first stage, 11 patients will be accrued per cohort. If there are 1 or
fewer responses in these 11 patients, the cohort will be stopped. Otherwise, 8
additional patients will be accrued for a total of 19 patients. The null
hypothesis of a response rate of 10% will be rejected if 4 or more responses
are observed in 19 patients. This design yields a type I error rate of 0.1 and
power of 0.9 when the true response rate is 35%. Dependent on the interim
analysis, a maximum of 19 patients will be included.
Intervention
Patients will be treated with monalizumab (750 mg) and trastuzumab (4 mg/kg)
every two weeks until progressive disease or intolerable toxicity.
Study burden and risks
The most important risk associated with the use of monalizumab are
infusion-related reactions, as described in the investigator*s brochure
(version 10.1, dated on 09 Nov 2021). Activation of NK cells and subset T cells
through blockade of inhibitory receptors may potentially lead to immune-related
adverse events (AEs). Furthermore, trastuzumab might induce cardiac toxicity
with a decrease in left ventricular ejection fraction. This will be carefully
monitored throughout the trial. The potential of monalizumab (and trastuzumab)
to induce durable responses through reactivation of T cells and NK cells can be
of benefit for patients.
Plesmanlaan 121
Amsterdam 1066CX
NL
Plesmanlaan 121
Amsterdam 1066CX
NL
Listed location countries
Age
Inclusion criteria
• Histologically confirmed HER2-positive (immunohistochemistry 2+ with SISH
amplification or 3+ reagrdless of SISH amplification) breast cancer.
HER2-positivity must have been assessed on a baseline study biopsy of 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
immunosuppression (>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, Sjøgren*s syndrome or conditions not expected to recur in the
absence of an external trigger will not be excluded from the study. In
addition, subjects with Graves* disease stable on hormone replacement will also
not be excluded from the study. Adrenal replacement doses >10 mg daily
prednisone equivalents are permitted in the absence of active autoimmune disease
• prior treatment with immune checkpoint blockade or other forms of
immunotherapy, such as but not limited to: anti-PD-(L)1, anti-PD-L2,
anti-CTLA-4, anti-GITR or CD137/OX40 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
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2020-000849-14-NL |
| ClinicalTrials.gov | NCT04307329 |
| CCMO | NL73029.031.20 |