Objective: To identify immunological responses elicited by different schedules of SABR in ES-NSCLC. Expression rates and activation states of immune effector subsets will be assessed in peripheral blood and liquid biopsies (plasma/serum).Hypothesis…
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Brief title
Condition
- Respiratory and mediastinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoints of this study are the immunological responses in the
peripheral blood. The endpoints will be assessed by examination of the liquid
biopsies and peripheral blood to detect immunomodulation.
Secondary outcome
No secundary parameters
Background summary
SABR is a form of hypofractionated radiotherapy where a biologically effective
dose (BED) of >=100 Gy is delivered in 1-8 fractions. SABR is currently standard
of care in early stage non-small cell lung cancer (ES-NSCLC) for patients who
are not fit for surgery or decline surgery, with a local-regional tumor control
of 85-90% in five years. Analysis of nearly 1600 patients from both the VU
University medical center and MD Anderson showed that the risk of distant
metastases within 5 years of SABR treatment is twice as high as that of
loco-regional recurrences, warranting further research on combinations of
therapy to improve the systemic efficacy of treatment. SABR has proved to be
superior to conventional radiotherapy, with less toxicity. Radiotherapy is a
rational modality to combine with immunological therapies (e.g.
checkpoint-inhibitors), due to its limited toxicity and durable responses of
combined treatment in preclinical studies. SABR can induce tumor-directed
immune responses, as was shown both preclinical and clinical by the systemic
T-cell activation accompanied by an increase in PD-1 expression identified in a
major fraction of ES-NSCLC patients. Interestingly, enhanced immune activation
was not induced by surgery, indicating that the immune modulatory effect of
SABR was not merely a result of reduced tumor load and associated immune
suppression. The abscopal effects was first described by Mole in 1953, and
describes the regression of tumor lesions outside the radiation field following
local radiotherapy. Abscopal effects are rarely seen after radiotherapy alone,
probably due to the suppressive effects of the TME. The combination of immune
checkpoint inhibitors (ICI) can overcome this suppressive milieu and induce
abscopal effects in combination with radiotherapy, supporting the rationale for
combined modality treatment. Adjuvant Durvalumab (PD-L1 antibody) in addition
to chemo-radiotherapy, improves progression-free survival in patients with
locally advanced, unresectable stage III lung cancer, according to the results
from the phase III PACIFIC trial. Furthermore, local objective response
enhanced from 16% to 28.4% with Durvalumab, suggesting that a local immune
response was initiated. These results support the concept of SABR as an in-situ
vaccination therapy, which can be potentiated by concurrent treatment with ICI.
Yet, much remains unknown concerning radiotherapy-induced immunological
responses in vivo, especially with regards to SABR. Different SABR schedules
may have comparable outcomes concerning local control, but may be quite
different in immunological outcomes (e.g. MHC expression, activation of
effector T cells, T cell infiltration), as demonstrated in preclinical studies.
Many clinical trials are exploring the efficacy of these combination therapies
in NSCLC. Nevertheless, the optimal schedule of immunotherapy, as well as
optimal SABR dose and fractionation schedules, remain to be elucidated. It has
been suggested that current cancer immune-radiotherapy trials may not use
optimal schedules for optimizing immunological responses. Preclinical models
show a correlation between fractionation dose and abscopal effects and
biologically effective dose (BED) and abscopal effects, with a 50% chance of
gaining abscopal effects with a BED of 60 Gy. Recent preclinical data show that
a high fractionation dose induces expression of TREX1, an intracellular
nuclease that interferes with signaling through the STING pathway and potently
abrogates type-I interferon (IFN) secretion by irradiated cancer cells,
subsequently preventing the activation of an adaptive immune response. Despite
the large amount of preclinical data available, clinical data on immune effects
of radiotherapy, especially SABR, is limited, justifying the initiation of the
exploratory trial laid out in our proposal. This exploratory trial could also
be an important trial for future studies in oligometastatic disease, since
chemotherapy is being replaced by immune-oncology (I-O) treatment in stage IV
disease. Given the number of positive trials a rising number of different I-O
drugs are approved for treatment of stage IV disease. Since SABR has a
significant effectivity in oligometastatic disease too, integrating both
approaches is logical. Patients with synchronous or metachronous metastases can
experience benefit in terms of disease free survival from systemic therapy in
combination with radial local treatment (SABR), however this occurred with a
huge variety in the fractionation dose of radiotherapy. For optimal
understanding and application of SABR in these cases, it is of major importance
that the immunological effects of SABR are being elucidated. We aim to use the
data from this clean, low tumor volume early stage NSCLC SABR trial, for
developing future trials in oligometastastic disease.
Study objective
Objective: To identify immunological responses elicited by different schedules
of SABR in ES-NSCLC. Expression rates and activation states of immune effector
subsets will be assessed in peripheral blood and liquid biopsies (plasma/serum).
Hypothesis: We anticipate that some SABR schedules may alter the immune
activation status more than other schedules, leading to changes in cellular
composition in blood as a consequence of local and/or systemic switches from a
suppressive immune content to a more activated immune content.
Study design
This is a hypothesis generating trial evaluating immunological and molecular
effects of SABR for ES-NSCLC. Patients with early stage (T1N0-T3N0/Nx)
peripherally and centrally located, pathology confirmed NSCLC or suspicion on
early stage NSCLC, and eligible for SABR, will be enrolled in this study.
Patients will be treated with the appropriate SABR schedule defined in
departmental protocols. Translational research to explore the immune mechanism
of action will include FACS analyses, ctDNA and NanoString analyses to assess
expression rates and activation states of immune effector subsets in peripheral
blood. Blood samples will be taken before, during and several times after SABR.
The primary endpoints of this study are the immunological responses in the
peripheral blood. The endpoints will be assessed by examination of liquid
biopsies and peripheral blood to detect immunomodulation.
Study burden and risks
Burden and riks are limited, since we ask only for peripheral blood samples 5
times during this trial.
De Boelelaan 1117
Amsterdam 1081 HV
NL
De Boelelaan 1117
Amsterdam 1081 HV
NL
Listed location countries
Age
Inclusion criteria
1. Have a diagnosis of cytologically proven or suspicion on early stage
(T1N0-T3N0/Nx) NSCLC, for which SABR has been recommended following discussions
within a multi-disciplinary tumor board.
2. Be willing and able to provide written informed consent for the trial.
3. Be 18 years of age on day of signing informed consent.
Exclusion criteria
1. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy
or any other form of immunosuppressive therapy within 30 days prior to the
planned SABR.
2. Has had prior chemotherapy, targeted small molecule therapy, or radiation
therapy within 30 days prior to SABR.
3. Has a known additional malignancy that is progressing or requires active
treatment. Exceptions include basal cell carcinoma of the skin, squamous cell
carcinoma of the skin, or in situ cervical cancer that has undergone
potentially curative therapy.
4. Has an active autoimmune disease requiring systemic treatment within the
past 3 months or a documented history 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 Sjorgen*s syndrome will not be
excluded from the study.
5. Has a history of (non-infectious) pneumonitis that required steroids,
evidence of interstitial lung disease or active, non-infectious pneumonitis.
6. Has an active infection requiring systemic therapy.
7. Has a history 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
best interest of the subject to participate, in the opinion of the treating
investigator.
8. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2
antibodies) or a known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C
(e.g., HCV RNA [qualitative] is detected).
Design
Recruitment
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 |
|---|---|
| CCMO | NL65585.029.18 |