NSCLC, Stage IPhase 1/2NCT03446911
Combining SBRT and Immunotherapy in Early Stage NSCLC Patients Planned for Surgery
A Phase 1/2 study testing SABR and SABR + pembrolizumab in people with NSCLC, Stage I, run by Amsterdam UMC, location VUmc.
Trial summary
This study aims to evaluate the safety and mechanisms of action of the trimodality treatment (radiotherapy, immunotherapy and surgery) in early-stage non-small cell lung cancer. Half of the patients will receive stereotactic ablative radiotherapy followed by 2 cycles of immunotherapy (pembrolizumab); the other half… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- NSCLC, Stage I
- What is being tested?
- SABR and SABR + pembrolizumab
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 20 participants
- Where
- No sites listed yet
- Study dates
- Mar 2018to May 2020
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Have a histologically or cytologically confirmed diagnosis of early stage (T1bN0 and T2aN0) peripherally located NCSLC, eligible for surgical resection.
- Be willing and able to provide written informed consent/assent for the trial.
- Be 18 years of age or over on day of signing informed 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.
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- Demonstrate adequate organ function, 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 2 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 been free from 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.
Who cannot join
- 1. Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment.
- 2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
- 3. Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
- 4. 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 at baseline) from adverse events due to a previously administered agent.
- Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
- Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
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- 5. 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.
- 6. 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.
- 7. Has a history of (non-infectious) pneumonitis that required steroids, evidence of interstitial lung disease or active, non-infectious pneumonitis.
- 8. Has an active infection requiring systemic therapy. 9. 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.
- 10. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
- 11. Is pregnant or breastfeeding, 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.
- 12. 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).
- 13. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
- 14. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
- 15. Has received a live vaccine within 30 days prior to the first dose of trial treatment.
Trial locations and contacts
No sites are listed yet.
Anna-Larissa N Niemeijer, MD contact
About this study
Official title: Combining SBRT and Immunotherapy in Early Stage NSCLC Patients Planned for Surgery: Exploring Safety and Immunological Proof of Principle.
This study aims to evaluate the safety and mechanisms of action of the trimodality treatment (radiotherapy, immunotherapy and surgery) in early-stage non-small cell lung cancer. Half of the patients will receive stereotactic ablative radiotherapy followed by 2 cycles of immunotherapy (pembrolizumab); the other half will not receive the immunotherapy treatment. After treatment, both groups will continue treatment according to guidelines and will undergo surgery (lobectomy).
Read the detailed description
An open label randomized exploratory study of the safety and mechanisms of action of combined treatment with SBRT and immunotherapy (pembrolizumab, anti-PD1) for early stage NSCLC.
Intervention:
Patients will be randomized between SBRT 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 SBRT +/- pembrolizumab treatment. Translational research to explore the immune mechanism of action will include biological imaging with immuno-PET (positron emission tomography). 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.
Main study parameters/endpoints:
To assess the safety of combined SBRT and pembrolizumab treatment in early stage NSCLC and to identify the immunological mechanism of action.
- Conditions
- NSCLC, Stage I
- Being tested
- SABR, SABR + pembrolizumab
- Keywords
- SABR, Immunotherapy
- Medical subject headings
- Carcinoma, Non-Small-Cell Lung
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
SABRRadiation
Prior to surgery (lobectomy), patients receive stereotactic ablative radiotherapy.
SABR + pembrolizumabCombination product
Prior to surgery (lobectomy), patients receive stereotactic ablative radiotherapy + 2 rounds of pembrolizumab
| Study group | Role | What they receive |
|---|---|---|
| SABR | Active comparator | Patients receive prior to surgery (lobectomy) SABR. Receives: Radiation: SABR |
| SABR + pembrolizumab | Active comparator | Patients receive prior to surgery (lobectomy) SABR + 2 rounds of pembrolizumab Receives: Combination Product: SABR + pembrolizumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Incidence and severity of adverse events in patients treated by combining SBRT and pembrolizumab
Safety of the combination of SBRT and pembrolizumab will be assessed by the percentage of ≥3 pneumonitis. When combined SBRT and pembrolizumab treatment results in NCIC-CTC grade ≥3 pneumonitis in ≤10% of patients, the combination is regarded as safe. Serious adverse events will be recorded to assess both incidence and severity.
Measured: Up to 90 days post-treatment
Secondary outcomes (14)
PD-1 expression
PD-1 expression in tumor tissue, tumordraining lymphnodes and peripheral blood.
Measured: Up to 90 days post-treatment
PD-L1 expression
PD-L1 expression in tumor tissue, tumordraining lymphnodes and peripheral blood.
Measured: Up to 90 days post-treatment
CD4 expression
CD4 expression in tumor tissue, tumordraining lymphnodes and peripheral blood.
Measured: Up to 90 days post-treatment
CD8 expression
CD8 expression in tumor tissue, TDLN's and peripheral blood.
Measured: Up to 90 days post-treatment
FoxP3 expression
FoxP3 expression in tumor tissue, tumordraining lymphnodes and peripheral blood.
Measured: Up to 90 days post-treatment
Ki67 expression
Ki67 expression in tumor tissue, tumordraining lymphnodes and peripheral blood.
Measured: Up to 90 days post-treatment
Immune cell count
Cell count of the individual immune cells in tumordraining lymphnodes and non-tumordraining lymphnodes
Measured: Up to 90 days post-treatment
Analysis of PET data - SUVmax (standardized uptake value)
SUVmax will be measured in all tumor lesions, enlarged lymph nodes and liver, kidneys, lungs, spleen and left ventricle of the heart.
Measured: Up to 90 days post-treatment
Analysis of PET data - SUVpeak (standardized uptake value)
SUVpeak will be measured in all tumor lesions, enlarged lymph nodes and liver, kidneys, lungs, spleen and left ventricle of the heart.
Measured: Up to 90 days post-treatment
Analysis of PET data -SUVmean (standardized uptake value)
SUVmean will be measured in all tumor lesions, enlarged lymph nodes and liver, kidneys, lungs, spleen and left ventricle of the heart.
Measured: Up to 90 days post-treatment
Analysis of CT data - Hounsfield Unit density
The pre- and post SBRT +/- pembrolizumab CT scans will be assessed for HU density and f-air values
Measured: Up to 90 days post-treatment
Analysis of CT data - f-air values
The pre- and post SBRT +/- pembrolizumab CT scans will be assessed for and f-air values
Measured: Up to 90 days post-treatment
Correlation between PET data and Blood + Tissue markers
The data of the PET-scan will be analyzed and compared to the blood and tissue samples to find a correlation between findings.
Measured: Up to 90 days post-treatment
Correlation between tumor uptake of Zr89-pembrolizumab and irAEs
SUV are values used to describe PET-data. irAE's are specific adverse events. This outcome aims to correlate the (possible) irAE's with the PET-data.
Measured: Up to 90 days post-treatment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Feb 2018
- Study startMar 2018 (estimated)
- Primary completionMay 2020 (estimated)
- Study completionMay 2020 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for NSCLC, Stage IStudies of the same condition, open and under way.
- More trials run by Amsterdam UMC, location VUmcThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 20 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Amsterdam UMC, location VUmc
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, A.J. de Langen, Amsterdam UMC, location VUmc
- Investigators
- E.F. Smit, MD, PhD, Principal investigator, The Netherlands Cancer InstituteA.J. de Langen, MD, PhD, Study chair, The Netherlands Cancer Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03446911
- Sponsor's protocol ID
- MK3475-586
- Status last verified
- Feb 2018
- First submitted
- 8 Nov 2017
- Last updated
- 27 Feb 2018
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Borm FJ, Smit J, Bakker J, Wondergem M, Smit EF, de Langen AJ, de Gruijl TD. Early response evaluation of PD-1 blockade in NSCLC patients through FDG-PET-CT and T cell profiling of tumor-draining lymph nodes. Oncoimmunology. 2023 Apr 26;12(1):2204745. doi: 10.1080/2162402X.2023.2204745. eCollection 2023.
PubMed 37123045
Study at a glance
From the registry record, last updated by the sponsor on 27 Feb 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Combining SBRT and Immunotherapy in Early Stage NSCLC Patients Planned for Surgery: Exploring Safety and Immunological Proof of Principle.
- ClinicalTrials.gov ID
- NCT03446911
- Acronym / sponsor ID
- MK3475-586
- Conditions
- NSCLC, Stage I
- Keywords
- SABR, Immunotherapy
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 20 participants (estimated)
- Lead sponsor
- Amsterdam UMC, location VUmcUniversity, hospital or other
- Study start
- Mar 2018 (estimated)
- Primary completion
- May 2020 (estimated)
- Study completion
- May 2020 (estimated)
- First posted
- 27 Feb 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This study aims to evaluate the safety and mechanisms of action of the trimodality treatment (radiotherapy, immunotherapy and surgery) in early-stage non-small cell lung cancer. Half of the patients will receive stereotactic ablative radiotherapy followed by 2 cycles of immunotherapy (pembrolizumab); the other half will not receive the immunotherapy treatment. After treatment, both groups will continue treatment according to guidelines and will undergo surgery (lobectomy).
Detailed description
An open label randomized exploratory study of the safety and mechanisms of action of combined treatment with SBRT and immunotherapy (pembrolizumab, anti-PD1) for early stage NSCLC.
Intervention:
Patients will be randomized between SBRT 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 SBRT +/- pembrolizumab treatment. Translational research to explore the immune mechanism of action will include biological imaging with immuno-PET (positron emission tomography). 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.
Main study parameters/endpoints:
To assess the safety of combined SBRT and pembrolizumab treatment in early stage NSCLC and to identify the immunological mechanism of action.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| SABR | Active comparator | Radiation: SABRPatients receive prior to surgery (lobectomy) SABR. |
| SABR + pembrolizumab | Active comparator | Combination Product: SABR + pembrolizumabPatients receive prior to surgery (lobectomy) SABR + 2 rounds of pembrolizumab |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- Have a histologically or cytologically confirmed diagnosis of early stage (T1bN0 and T2aN0) peripherally located NCSLC, eligible for surgical resection.
- Be willing and able to provide written informed consent/assent for the trial.
- Be 18 years of age or over on day of signing informed consent.
- Have measurable disease based on RECIST 1.1.
- Must provide tissue from a core or excisional biopsy of the primary tumor lesion.
Key exclusion criteria (16 listed)
- 1. Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment.
- 2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
- 3. Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
- 4. 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 at baseline) from adverse events due to a previously administered agent.
- Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| SABRPrior to surgery (lobectomy), patients receive stereotactic ablative radiotherapy. | Radiation | SABR |
| SABR + pembrolizumabPrior to surgery (lobectomy), patients receive stereotactic ablative radiotherapy + 2 rounds of pembrolizumab | Combination product | SABR + pembrolizumab |
Primary outcome
Incidence and severity of adverse events in patients treated by combining SBRT and pembrolizumab
Time frame: Up to 90 days post-treatment
Safety of the combination of SBRT and pembrolizumab will be assessed by the percentage of ≥3 pneumonitis. When combined SBRT and pembrolizumab treatment results in NCIC-CTC grade ≥3 pneumonitis in ≤10% of patients, the combination is regarded as safe. Serious adverse events will be recorded to assess both incidence and severity.
14 secondary outcomes
PD-1 expression
Time frame: Up to 90 days post-treatment
PD-L1 expression
Time frame: Up to 90 days post-treatment
CD4 expression
Time frame: Up to 90 days post-treatment
CD8 expression
Time frame: Up to 90 days post-treatment
FoxP3 expression
Time frame: Up to 90 days post-treatment
Ki67 expression
Time frame: Up to 90 days post-treatment
Immune cell count
Time frame: Up to 90 days post-treatment
Analysis of PET data - SUVmax (standardized uptake value)
Time frame: Up to 90 days post-treatment
Analysis of PET data - SUVpeak (standardized uptake value)
Time frame: Up to 90 days post-treatment
Analysis of PET data -SUVmean (standardized uptake value)
Time frame: Up to 90 days post-treatment
Analysis of CT data - Hounsfield Unit density
Time frame: Up to 90 days post-treatment
Analysis of CT data - f-air values
Time frame: Up to 90 days post-treatment
Correlation between PET data and Blood + Tissue markers
Time frame: Up to 90 days post-treatment
Correlation between tumor uptake of Zr89-pembrolizumab and irAEs
Time frame: Up to 90 days post-treatment
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Feb 2018.
- Derived from this study: PubMed 37123045Borm FJ, Smit J, Bakker J, Wondergem M, Smit EF, de Langen AJ, de Gruijl TD. Early response evaluation of PD-1 blockade in NSCLC patients through FDG-PET-CT and T cell profiling of tumor-draining lymph nodes. Oncoimmunology. 2023 Apr 26;12(1):2204745. doi: 10.1080/2162402X.2023.2204745. eCollection 2023.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Anna-Larissa N Niemeijer, MD contact
E.F. Smit, MD, PhD principal investigator
The Netherlands Cancer Institute
A.J. de Langen, MD, PhD study chair
The Netherlands Cancer Institute
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing SABR and SABR + pembrolizumab in people with NSCLC, Stage I, run by Amsterdam UMC, location VUmc.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 27 Feb 2018. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Eveline A van de Stadt, MD (+31204445242, e.vandestadt@vumc.nl), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Incidence and severity of adverse events in patients treated by combining SBRT and pembrolizumab (time frame: Up to 90 days post-treatment). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03446911, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Feb 2018.