The overall aim of this study is to demonstrate increase of tumor-infiltrating CD8+ T cells in non-small cell lung cancer during neo-adjuvant treatment with durvalumab (MEDI4736).
ID
Source
Brief title
Condition
- Respiratory and mediastinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
he primary endpoint of this study will be to demonstrate 1) feasibility and 2)
safety of two courses durvalumab (MEDI4736) 750 mg Q2W in neo-adjuvant setting
in resectable NSCLC.
Study parameter 1): no delayed surgical procedures, all surgery should be
performed within 42 days after the first therapeutic dose of durvalumab
(MEDI4736).
Study parameter 2): number of grade 3 or higher adverse events related to
durvalumab (MEDI4736).
Secondary outcome
1. Correlative studies across different imaging modalities.
2. Validation of in vivo imaging findings with other potential biomarkers
derived from quantitative immune histochemistry and peripheral blood immune
profiling.
3. Assessment of neo-adjuvant durvalumab (MEDI4736) on outcome measures related
to clinical care.
Background summary
The approved indications of immunotherapy for non-small cell lung cancer
(NSCLC) patients are expanding. High recurrence rates in early stage resectable
NSCLC patients require novel treatment strategies to reduce micrometastatic
disease. Adjuvant therapy has recently demonstrated to improve
time-to-recurrence which has elicited the application of immune therapy in
neo-adjuvant setting.
Study objective
The overall aim of this study is to demonstrate increase of tumor-infiltrating
CD8+ T cells in non-small cell lung cancer during neo-adjuvant treatment with
durvalumab (MEDI4736).
Study design
This is an interventional study, to assess feasibility and safety of durvalumab
(MEDI4736) in neo-adjuvant setting in patients with resectable NSCLC.
Additional analyses of potential imaging biomarkers, e.g. Zr-89 labelled
durvalumab (MEDI4736), ex vivo In-111-oxine labelled CD8+ T-cells and
high-resolution immune cell imaging, in relation to immunotherapy induced
immune responses on quantitative immune histochemical analysis of the resected
tumor specimen, will be performed.
Intervention
Patients will receive two courses of durvalumab (MEDI4736)at a fixed dose of
750mg Q2W intravenously, prior to scheduled resection of NSCLC. Patients are
amendable to adjuvant chemo and/or radiation treatment, per standard-of-care.
Additionally, patients will undergo a Zr-89 labelled durvalumab (MEDI4736)
PET/CT and dedicated perfusion-CT prior to treatment with durvalumab (MEDI4736)
and ex vivo In-111-oxine labelled CD8+ T-cells after two courses of treatment,
prior to surgery.
Study burden and risks
1. Related to neo-adjuvant durvalumab (MEDI4736):
In monotherapy clinical studies, AEs (all grades) were reported commonly (>= 10%
of patients) mostly fatigue, nausea, decreased appetite, dyspnea, cough.
Approximately 3.5% of patients experienced a SAE related to durvalumab
(MEDI4736) (See IB version 12, Appendix 1)].
The majority of treatment-related AEs were manageable using established
treatment guidelines for immune-mediated toxicity. The only published study to
date demonstrated safety and feasibility PD-1/PD-L1 axis directed immune
therapy in neo-adjuvant setting without compromising current standard-of-care:
curative resection.
2. Related to Zr-89 durvalumab (MEDI4736) PET/CT scan:
Patients will undergo a PET/CT with acquisition time of 45 minutes, for which
no extra preparation is needed. PET/CT will be scheduled at the same visit as
first injection with therapeutic dose durvalumab (MEDI4736). The committed
effective dose for the study population related to 37 MBq Zr-89-labelled
durvalumab (MEDI4736) and low-dose CT is 5,7 mSv [18].
3. Related to In-111-oxine labelled CD8+ T-cell scan:
Three days prior to surgery, an aphaeresis will be performed to isolate
autologous CD8+ T-cells. At 4 hrs and 48 hrs after intravenous injection of
In-111-oxine labelled CD8+ T-cells, during hospital admission, a planar
scintigraphy and SPECT/CT, acquisition in total 60 min, will be performed.
There will be no extra preparation necessary.
The committed effective dose of In-111-labelled autologous cells for the study
population is, based on dosimetry data from the guideline EANM on In-111-oxine
labelled leukocytes, maximum 4.8 mSv (excluding low-dose CT).
4. Related to contrast-enhanced CT perfusion scan:
Prior to start of immunotherapy and prior to surgery, patients will receive an
CT perfusion scan. This dedicated acquisition protocol consists of several
ultra-low dose CT scans following the standard bolus injection of iodine-based
contrast. There is no need for additional administration of iodine-based
contrast agent and the scans will be acquired during the standard venous phase
contrast-enhanced CT of the chest during routine clinical care. The committed
effective dose for this study population related to the perfusion CT protocol
is 0.64 mSv.
5. Related to translational and biomarker investigations:
Extra peripheral blood will be drawn via a venous canula at three time points;
prior to start of immunotherapy, after neo-adjuvant immunotherapy/prior to
surgery and during follow-up at 3 months after surgery. Per procedure 41 ml
peripheral blood is required (10ml EDTA, 27ml heparin and 4ml serum tubes). A
complete overview of study related procedures is provided in Figure 1, Table 2
and Section 9.4.
Geert Grooteplein Zuid 10
Nijmegen 6525 GA
NL
Geert Grooteplein Zuid 10
Nijmegen 6525 GA
NL
Listed location countries
Age
Inclusion criteria
All patients must meet all of the following criteria:;1. Male or female subjects aged >50 years at time of study entry
2. Histopathological proven primary non-small cell lung cancer, with fully evaluable histological biopsies available
3. ECOG performance status of 0 or 1
4. AJCC stage I, II or IIIa as determined by contrast-enhanced CT chest-abdomen and F-18-FDG PET/CT: cT1cN0-1M0, cT2aN0-1M0 en cT3N0-1M0 (T3 separate nodule)
5. Solid appearance of the tumor on contrast-enhanced CT
6. Scheduled for resection with curative intent
7. Patients should be medically operable defined by:
8. Sufficient cardiopulmonary function
9. Major contra-indications for surgery.
10. No underlying immune disease (neutro- or lymphopenia, coagulation disorders) that could interfere with T-cell isolation
11. Life expectancy at least 6 months
12. Written informed consent and comply with study protocol for the duration of the study and follow-up
13. Adequate laboratory values (refer to study protocol)
Exclusion criteria
A patient will be excluded from participation in the trial if one or more of the following criteria are met:;1. Inability to lie supine for more than 30 minutes
2. Documented previous severe allergic reaction to iodine-based contrast media, despite adequate pre-medication.
3. Indication for cervical mediastinoscopy
4. Participation in another clinical study with an investigational product during the past 6 months
5. Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study
6. Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumour embolization, monoclonal antibodies) <6 months prior to the first dose of study drug
7. Any unresolved toxicity NCI CTCAE Grade >=2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria
8. Patients with Grade >=2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician.
9. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab (MEDI4736) may be included only after consultation with the Study Physician.
10. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.
11. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 6 months of the first dose of study drug
12. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP.
13. History of allogenic organ transplantation.
14. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]).
15. History of another primary malignancy except for: Malignancy treated with curative intent and with no known active disease >=5 years before the first dose of IP and of low potential risk for recurrence, Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease, Adequately treated carcinoma in situ without evidence of disease
16. History of active primary immunodeficiency
17. Active infection including: tuberculosis, hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, human immunodeficiency virus (positive HIV 1/2 antibodies), Epstein Barr Virus (EBV, positive IgM antibodies), cytomegalo virus (CMV, positive IgM antibodies)
18. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab (MEDI4736); exceptions apply.
19. Receipt of live attenuated vaccine within 30 days prior to the first dose of durvalumab (MEDI4736). Note: Patients, if enrolled, should not receive live vaccine whilst receiving durvalumab (MEDI4736) and up to 30 days after the last dose of durvalumab (MEDI4736).
20. Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab (MEDI4736) monotherapy.
21. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
22. Prior randomisation or treatment in a previous durvalumab (MEDI4736) and/or tremelimumab clinical study regardless of treatment arm assignment.
23. Patients who have received prior anti-PD-1, anti PD-L1 or anti CTLA-4.
24. Judgment by the investigator that the patient is unsuitable to participate in the study and the patient is unlikely to comply with study procedures, restrictions and requirements.
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 | EUCTR2019-000670-37-NL |
| ClinicalTrials.gov | NCT(nognietbekend) |
| CCMO | NL68987.091.19 |