Primary objective:To observe an increase in Overall Response Rate (ORR) from 20% in the pembrolizumab alone arm to 50% in the pembrolizumab after SBRT arm at 12 weeks. Secondary Objective: - Disease Control Rate, defined as the percentage of…
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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
Primary outcome: ORR (Overall Response Rate) at 12 weeks
Secondary outcome
Secondary outcome: DCR (Disease Control Rate), PFS (Progression Free Survival),
OS (Overall Survival) and toxicity
Exploratory outcome: biomarkers
Background summary
Despite the availability of accepted second line chemotherapy agents, patients
with recurrent NSCLC will still progress quickly; have significant side effects
and die of the disease. Therefore new treatment options should be considered.
Recently, immune checkpoint inhibitors have attracted attention and have shown
to have both effectiveness and a very good toxicity profile. One of these
classes of drugs is the anti-PD1 monoclonal antibodies and these are currently
tested in different tumor types including NSCLC.
Radiation therapy (Stereotactic body radiation therapy (SBRT) or high
fractionated standard radiation) can be given successfully to small tumors.
SBRT has shown to be a successful treatment for tumors of the lung with sizes
of < 5 cm. SBRT can be given in doses varying up to 3x18 Gy. Toxicity is very
limited, but the treatment is until now restricted to early stages of lung
cancer or oligometastatic disease. Other organ sites suitable for SBRT are
primary tumors and/or metastases e.g. brain, liver, adrenal gland and bone
(spine) tumors.
The traditional, palliative role of radiotherapy in metastatic disease is now
evolving into that of a powerful initiator for immunotherapy. From different
preclinical studies the expression of tumor antigens has shown to be
up-regulated directly after radiotherapy and might therefore lead to changes in
the immune response of the body. At this stage little is known about the impact
of different total dose and fractionation regimens on the anti-tumor immune
response. Both SBRT and standard palliative treatment regimens such as 5x4 Gy
have shown to be successful. Therefore it is of great interest to investigate
the effect of a treatment with radiotherapy, directly followed by the
administration of pembrolizumab and to compare these results to treatment with
pembrolizumab alone.
Since PD-L1 expression is not yet validated to be the best marker for immune
modulation it is imperative that this study will be accompanied by a
translational research focusing on factors involved in the immune response.
Study objective
Primary objective:
To observe an increase in Overall Response Rate (ORR) from 20% in the
pembrolizumab alone arm to 50% in the pembrolizumab after SBRT arm at 12 weeks.
Secondary Objective:
- Disease Control Rate, defined as the percentage of patients having a complete
response, partial response or stable disease at 12 weeks
- PFS, defined as time from randomization to disease progression or death,
- OS, defined as time from randomization to death (of any cause).
- Toxicity
Exploratory Objective:
Paired tumor material and blood samples will be used to identify possible new
biomarkers for selection of patients who might benefit from immunotherapy.
Tumor tissue will be examined for at least the expression of the following:
PD-L1 expression (DAKO kit); PD1 expression; Tregs; NK infiltration; CD3+, CD8+
CD45RO T cells, and M2 macrophages.
Fluid Phase Biopsies (peripheral blood) will be collected for further analysis
and comparative studies.
Study design
This is an open label, three center randomized 2-arm phase 2 study comparing
pembrolizumab treatment alone with pembrolizumab after SBRT.
Intervention
Patients will be randomized into two arms.
Arm 1: High dose radiation (SBRT) followed by pembrolizumab treatment within 7
days after completion.
Arm 2: pembrolizumab treatment
There is a stratification for never/hardly smokers vs ongoing/recent smokers
planned in this study.
The treatment duration of pembrolizumab (after 1 year) may be extended to 2
years, when no severe toxicity has occurred and it is in the best interest of
the patient.
Study burden and risks
- Blood samples: drawing blood from your arm may cause pain, bruising,
lightheadedness, and rarely, infection.
- IV line: may cause discomfort, irritation, mild bruising, bleeding, leakage
of drug solution, and rarely, infection, nausea, and lightheadedness. Because
Pembrolizumab is an antibody, there is the possibility that an acute infusion
reaction takes place. These are side effects that occur during or immediately
after administration of Pembrolizumab. Possible signs and symptoms may include:
change in blood pressure; coughing; dizziness; fast heart rate; the cold; the
feeling that the tongue becomes swollen or that the airways are closed and have
trouble breathing; fever; headache; joint pain; muscle pain; nausea; skin rash,
hives or itching; shortness of breath; sweating; fatigue; vomiting.
- ECG: the procedure may cause minimal discomfort during the attachment and
removal of the ECG leads to and from the skin.
- CT-scan: A CT-scan uses radiation. CT-scans may be done with or without oral
or intravenous contrast. The scan may take between 30-90 minutes to complete
depending on the areas of the body being scanned and the type of scanner.
- Tumor biopsy: having biopsies performed may cause pain, bruising, bleeding,
redness, low blood pressure, swelling, and/or infection at the site of the
biopsy. An allergic reaction to the anesthetic may occur. A scar may form at
the biopsy site. If a tumor in the lung is punctured a pneumothorax can occur.
- The CBCT that is created during each radiation treatment adds a tiny bit of
extra radiation that is negligible compared to the radiation treatment. The
radiation treatment itself can cause fatigue, dysphagia and light skin
irritations. If patient will be irradiated on and around the rib, pain can
arise after radiation. This pain can respond well to treatment with painkillers
and then also usually go away.
Plesmanlaan 121
Amsterdam 1066 CX
NL
Plesmanlaan 121
Amsterdam 1066 CX
NL
Listed location countries
Age
Inclusion criteria
1. Be willing and able to provide written informed consent/assent for the trial.
2. Be >= 18 years of age on day of signing informed consent.
3. Have measurable disease based on RECIST 1.1.
4. Must provide newly obtained tissue from a core or excisional biopsy of a
tumor lesion and are willing to have a second biopsy performed form any
non-irradiated lesion after the radiation and immune-modulating treatment.
5. Have a performance status of 0 or 1 on the ECOG Performance Scale.
6. Stage IV NSCLC; treated with at least 1 regimen of chemotherapy.
7. Have at least 2 separate (metastatic) lesions of which one is amenable for
irradiation with a size of < 5 cm.
8. Demonstrate adequate organ function:
Absolute neutrophil count (ANC) >=1,500 /mcL; Platelets >=100,000 / mcL;
Hemoglobin >=9 g/dL or >=5.6 mmol/L; Serum creatinine <=1.5 X upper limit of
normal (ULN) OR measured or calculated creatinine clearance (GFR can also be
used in place of creatinine or CrCl) >=50 mL/min for subject with creatinine
levels > 1.5 X institutional ULN; Serum total bilirubin <= 1.5 X ULN OR Direct
bilirubin <= ULN for subjects with total bilirubin levels > 1.5 ULN; AST (SGOT)
and ALT (SGPT) <= 2.5 X ULN OR <= 5 X ULN for subjects with liver metastases;
International Normalized Ratio (INR) or Prothrombin Time (PT) and Activated
Partial Thromboplastin Time (aPTT) <=1.5 X ULN unless subject is receiving
anticoagulant therapy as long as PT or PTT is within therapeutic range of
intended use of anticoagulants.
All screening labs should be performed within 10 days of treatment initiation.
9. 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.
10. 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 (Reference Section 5.7.2). Subjects of childbearing potential
are those who have not been surgically sterilized or have not been free from
menses for > 1 year.
11. 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
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 or targeted small molecule therapy 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 a previously administered agent.
- Note: Subjects with <= Grade 2 neuropathy are an exception to this criterion
and may qualify for the study.
- Note: If subjects received major surgery, they must have recovered adequately
from the toxicity and/or complications from the intervention prior to starting
therapy.
5. Have had previous radical radiation to any tumor site within 6 months prior
to study Day 1.
6. Have known but untreated driver mutations of the EGFR gene or ALK
translocation.
7. 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.
8. Has known active central nervous system (CNS) metastases and/or
carcinomatous meningitis. Subjects with previously treated brain metastases may
participate provided they are stable (without evidence of progression by
imaging for at least six weeks prior to the first dose of trial treatment and
any neurologic symptoms have returned to baseline), have no evidence of new or
enlarging brain metastases, and are not using steroids for at least 14 days
prior to trial treatment.
9. 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 Sjögren*s syndrome will not be
excluded from the study.
10. Has evidence of symptomatic interstitial lung disease or a history of
(non-infectious) pneumonitis that required steroids or current pneumonitis.
11. Has an active infection requiring systemic therapy.
12. 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.
13. Has known psychiatric or substance abuse disorders that would interfere
with cooperation with the requirements of the trial.
14. 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.
15. 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).
16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2
antibodies).
17. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g.,
HCV RNA [qualitative] is detected).
18. Has received a live vaccine within 30 days prior to the first dose of trial
treatment.
19. Has had major surgery or major blood transfusions (>3 packed cells) in the
past 3 months.
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 | EUCTR2014-005118-49-NL |
CCMO | NL51468.031.14 |