To identify the immunological response to combined SABR and pembrolizumab treatment in early stage NSCLC. Expression rates andactivation states of immune effector subsets will be assessed in tumor core biopsy specimens, peripheral blood and tumor…
ID
Source
Brief title
Condition
- Respiratory and mediastinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Examination of tumor core biopsies and resection material. FACS analysis on
EBUS-FNA of tumor draining lymphnodes (TDLNs) and peripheral blood to detect
immunomodulation.
Secondary outcome
The correlations of in-vivo PD-1 expression, quantified by immune-PET, with
tissue and blood based immune-parameters.
Assessment of clinical signs of radiation pneumonitis
Background summary
The current standard treatment for early stage NSCLC is an anatomical surgical
resection, with SABR being reserved for patients not fit to undergo resection.
Despite the early stage of disease, a substantial number of patients with early
stage non-small-cell lung cancer (NSCLC) relapse within five years of
treatment. A pooled analysis of the ROSEL and STARS trials showed that
stereotactic ablative radiotherapy (SABR) may provide an alternative to
surgical treatment for patients with early stage disease. One of the reasons
for the favorable effects of SABR may be due to an immunological response
against tumor cells, elicited by radiotherapy. In this protocol we will explore
the addition of immunotherapy to SABR to augment the antitumor T cell response,
associated with radiotherapy. Because surgical resection is still the current
standard of care for patients who are fit to undergo surgery, the subjects will
undergo a lobectomy with hilar and mediastinal lymph node dissection after
pembrolizumab or SABR +/- pembrolizumab treatment. This is a key feature of
this study and an unique opportunity to perform histological examination of the
entire lung tumor, its associated lymph nodes and normal lung tissue after
immunotherapy, allowing the study of immune response heterogeneity and
correlating this with non-invasive imaging and blood results. In the
surrounding normal lung tissue, radiation and immunotherapy induced toxicity
can be evaluated.
Study objective
To identify the immunological response to combined SABR and pembrolizumab
treatment in early stage NSCLC. Expression rates and
activation states of immune effector subsets will be assessed in tumor core
biopsy specimens, peripheral blood and tumor draining lymph
nodes (TDLNs) by means of EBUS derived fine needle aspirates. Samples will be
taken before and after treatment with SABR, pembrolizumab or SABR +
pembrolizumab combined, and at surgery.
Study design
An open label randomized exploratory study of the mechanisms of action of
combined treatment with SABR and immunotherapy (pembrolizumab, anti-PD1) for
early stage NSCLC.
Intervention
Patients will be randomized between pembrolizumab or SABR with or without 2
cycles of pembrolizumab treatment (starting on the first day of radiotherapy).
The patients will undergo a lobectomy with hilar and mediastinal lymph node
dissection after pembrolizumab or SABR +/- pembrolizumab treatment.
Translational research to explore the immune mechanism of action will include
biological imaging with immuno-PET. This immuno-PET can be stressfull for
patients and therefore, this immuno-PET is not obligated for participating in
this study. Expression rates and activation states of immune effector subsets
will be assessed in tumor core biopsy specimens, peripheral blood and tumor
draining lymph nodes (TDLNs) by means of fine needle aspirates of TDLNs.
Samples will be taken before and after pembrolizumab or SABR +/- pembrolizumab
treatment and at surgery.
Study burden and risks
Combining SABR with surgery appears safe, according to previously performed
studies. The addition of pembrolizumab to SABR might lead to a higher rate of
pneumonitis. However, the incidence of pneumonitis depends on the target volume
and is rarely seen with treatment of early stage lung cancer. Because only
patients with peripheral tumors are eligible for this trial and patients
receive a lobectomy according to national guidelines on the treatment for
NSCLC, the irradiated lung lobe will be resected and resection margins (i.e.
central bronchial and vascular structures) are not involved in the radiation
target volume.
Radiotherapy is a widely used therapy for lungcancer. Given the precise
targeting of SABR, we expect no to little toxicity. Symptoms of fatigue,
dysphagia and irritated skin could occur. With radiotherapy targeted at or in
the area of a rib, it is possible that pain symptoms may occur months after
therapy. This will be treated with pain medication and is self-limiting. Pain
symptoms may also be prevented by the use of radiotherapy. Other toxicity is
dependent of the target location.
The patient will be asked to undergo investigative procedures, in addition to
the procedures that will take place for the (combination)therapy. The
investigative procedures include:
- Physical examination
- Blood sampling
- Urine sampling
- Echocardiography (ECG)
- CT-scans
- MRI scans of the brain
- Endobronchial Ultrasound (EBUS)
- Biopsy of lungtumor
The patient will be exposed to addition ionizing radiation through the use of
positron emitting radionuclides and CT-scanners. The totale radiation exposure
will be around 20 mSv. It is possible that patients experience discomfort
during scanning. To reduce the amount discomfort as much as possible, patients
will be informed about the procedure and staff will be present during scanning.
De Boelelaan 1117
Amsterdam 1081HV
NL
De Boelelaan 1117
Amsterdam 1081HV
NL
Listed location countries
Age
Inclusion criteria
Histologically or cytologically confirmed diagnosis of early stage (T1cN0,
T2aN0 and T2bN0 ) peripherally located NSCLC, eligible for surgical resection.
Highly suspected NSCLC is defined as an a priori change of >85% that the
lesion is malignant, according to the publication of Herder et al. (59)
Be willing and able to provide written informed consent/assent for the trial.
Be 18 years of age or older on day of signing imformed consent.
Have measurable disease based on RECIST 1.1.
Must provide tissue from a core or excisional biopsy of the primary tumor
lesion.
Have a performance status of 0-1 on the ECOG Performance Scale.
Demonstrate adequate organ function as defined in Table 1, all screening labs
should be performed within 10 days of treatment initiation.
Female subject of childbearing potential should have a negative urine or serum
pregnancy within 72 hours prior to receiving the first dose of study
medication. If the urine test is positive or cannot be confirmed as negative, a
serum pregnancy test will be required.
Female subjects of childbearing potential should be willing to use two methods
of birth control or be surgically sterile, or abstain from heterosexual
activity for the course of the study through 120 days after the last dose of
study medication. Subjects of childbearing potential are those who have not
been surgically sterilized or have not ben free form menses for >1 year.
Male subjects should agree to use an adequate method of contraception starting
with the first dose of study therapy through 120 days after the last dose of
study therapy.
Exclusion criteria
Is currently participating in or has participated in a study of an
investigational agent or using investigational device within 4 weeks of the
first dose of treatment.
Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or
any other form of immunosuppressive therapy within 7 days proor to the first
dose of trial treatment.
Has had a prior monoclonal antibody within 4 weeks prior to study day 1 or who
has not recovered (i.e. grade 1 or lower, or at baseling) from adverse events
due to agents administered more than 4 weeks earlier.
Has had prior chemotherapy, targeted small molecule therapy, or radiation
therapy within 2 weeks prior to study day 1 or who has not recovered (i.e.
grade 1 or lower at baseline) from adverse events due to a previously
administered agent.
Has a known additional malignancy that is progressing or requires active
treatment. Exceptions include basal cell carcinoma of the skin, squamous cel
carcinoma of the skin, or in situ cervical cancer that has undergone
potentially curative therapy.
Has an active autoimmune disease requiring systemic treatment within the past 3
months or a documented histroy of clinically severe autoimmune disease, or a
syndrome that requires systemic steroids or immunosuppressive agents. Subjects
with vitiligo or resolved childhood asthma/atopy would be an exception to this
rule. Subjects that require intermittent use of bronchodilators or local
steroid injections would not be excluded from the study. Subjects with
hypothyroidism stable on hormone replacement or Sjogren's syndrome will not be
excluded from the study.
Has a history of (non-infectious) pneumonitis that required steroids, evidence
of interstitial lung disease or active, non-infectious pneumonitis.
Has an active infection requiring systemic therapy.
Has a histroy or current evidence of any condition ,therapy or laboratory
abnormality that might confound the results of the trial, interfere with the
subject's participation for the full duration of the trial, or is not in the
bst interest of the subject to participate, in the opinion of the treating
investigator.
Has known psychiatric or substance abude disorders that would interfere with
cooperation with the requirements of the trial.
Is pregnant or breastfeedig, or expecting to conceive or father children within
the projected duration of the trial, starting with the pre-screening or
screening visit through 120 days after the last dose of trial treatment.
Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2,
anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)
antibody (including ipilimumab or any other antibody or drug specifically
targeting T-cell co-stimulation or checkpoint pathways).
Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
Has known active Hepatitis B (e.g. HBsAg reactive) or Hepatitis C (e.g. HCV RNA
[qualitative] is detected).
Has received a live vaccine within 30 days prior to the first dose of trial
treatment.
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 | EUCTR2016-003819-36-NL |
| CCMO | NL59360.029.17 |