1) To assess uptake of [18F]BMS-986192 in tumor lesions before and after treatment with nivolumab, in relation to [18F]-FDG uptake as potential whole body biomarker for response. 2) To evaluate safety and tolerability of neoadjuvant nivolumab 3) To…
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
1. To investigate heterogeneity in tumor uptake of [18F]BMS-986192 between
patients and within tumor lesions of the same patient (primary tumor and
TDLN/lymph node metastases) before treatment, in relation to changes in
[18F]-FDG uptake before and on treatment.
2. To investigate the feasibility and safety of neoadjuvant nivolumab
immunotherapy prior to surgery for locally advanced oral cancer.
Secondary outcome
3. To investigate effects of nivolumab treatment on PD-L1 expression and
availability for tracer binding in the patient and the relation to (changes in)
[18F]-FDG uptake.
4. To investigate the relationship between [18F]BMS-986192 tumor uptake and
tumor cell and tumor infiltrating lymphocyte (TIL) PD-1 and PD-L1 expression as
well as other immune parameters.
5. To investigate changes in [18F]-FDG uptake during treatment.
6. To investigate the genomic profile of the tumor (neoantigens, mutational
load, copy number changes and splice variants), in relation to [18F]BMS-986192
uptake, immune activation parameters and clinical response.
7. To investigate blood based analyses of the immuneprofile and plasma vesicle
miRNAs on treatment and after treatment, in relation to immune activation
parameters and clinical outcome.
Background summary
Intensive treatment regimens with surgical resection and adjuvant
(chemo)radiotherapy of patients with locally advanced oral cancer still result
in only 50-60% cure rate, leaving a substantial group of patients who will
develop a local recurrence or distant metastases with minimal curative salvage
treatment options. Treatment with anti-PD1 monoclonal antibodies (mAbs) has
shown promise in patients with recurrent/metastatic head and neck squamous cell
carcinoma (r/m HNSCC). This supports the hypothesis that including treatment
with anti PD-1 mAb nivolumab could improve the outcome for patients with
locally advanced oral cancer resulting in a higher cure rate. Response rate
with nivolumab was below 20% in unselected patients with r/m HNSCC. Therefore,
biomarkers for response are urgently needed. Tumor PD-L1 immunohistochemistry
(IHC) was shown to be
related to nivolumab response but cannot be reliably used for patient
selection. Temporal and spatial heterogeneity of tumor PD-L1 expression (within
and between tumor lesions) might be responsible for its suboptimal predictive
value as biomarker of response. Therefore there is a need to further evaluate
tumor PD-L1 expression as predictive biomarker, as well as exploring
alternatives. Serial PET imaging with [18F]BMS-986192 (anti-PD-L1 tracer) and
[18F]-FDG has the potential to provide whole body information of the patient
over time, at baseline as well as on treatment and represents a biomarker for
toxicity and efficacy. In addition, we will investigate the immunophenotype of
the patient and tumor, as well as the presence of neoantigens and other
potential other biomarkers such as plasma vesicle miRNAs.
Study objective
1) To assess uptake of [18F]BMS-986192 in tumor lesions before and after
treatment with nivolumab, in relation to [18F]-FDG uptake as potential whole
body biomarker for response.
2) To evaluate safety and tolerability of neoadjuvant nivolumab
3) To evaluate tumor and blood immunoprofiling, presence of neoantigens, and
other potential biomarkers of response such as plasma vesicle miRNAs.
Study design
This pilot study is a single arm, open label, mono-center study. It is designed
to asses the safety and feasibility of neoadjuvant nivolumab and serve as a
pilot study to asses possible biomarkers for response.
Intervention
After screening, eligible subjects will undergo a standard [18F]-FDG PET scan
and an experimental [18F]BMS-986192 PET scan. Patients will be treated with a
single dose of 480 mg of nivolumab followed by an experimental [18F]BMS-986192
and [18F]-FDG PET scan 14 days later to monitor changes in biodistribution and
early therapeutic effects. Patients are planned to undergo surgery within 30
days after diagnosis. Tissue samples will
be collected at diagnostic panendoscopy and at surgery. Blood samples will be
collected at multiple time points. Up to two additional biopsies can be
performed depending on the baseline imaging results and whether the location
can be reached safely. Treatment and follow-up (12 months) after surgery will
be according to standard procedures.
Study burden and risks
* PET scans
No toxicity is expected from PET scans with tracer microdoses. The amount of
[18F]BMS986192 will be in the pico to nano molar quantity, far below the dose
for a pharmacological effect. Patients do not derive benefit from the PET scan
results. Since there is a lack of a well performing predictive biomarker of
response, the results of this imaging biomarker study can be of high interest
for HNSCC patients that are eligible for anti-PD-(L)1 treatment in the future.
* Tumor biopsy
Additional tumor biopsies obtained at panendoscopy are considered safe with a
low complication rate as during this procedure already standard biopsies are
taken. Besides, additional biopsies are allowed in this study (after the
baseline PET scans) in case the [18F]BMS-986192 or the [18F]-FDG PET scan show
heterogeneous or discrepant uptake in individual patients. Although this is
demanding for patients, tumor biopsies in cancer patients are considered safe
with a low and manageable complication rate. These biopsies will be used to
explain heterogeneous tracer uptake and relate the imaging results to that of
the tissue biomarkers PD-1 IHC (locally) and PD-L1 IHC (BMS Dako assay), as
well as immune monitoring outcomes.
* Blood withdrawal
By performing immunophenotyping on PBMC*s at the indicated time points unique
insight will be gained in the kinetics of T cell activation following PD-1
blockade and pre- and ontreatment immune effector/suppressor subset profiles
that may serve as biomarkers for clinical response and/or outcome, as we
previously showed in a trial of combined ipilimumab and Prostate GVAX
immunotherapy [Santegoets, 2012].
* Nivolumab treatment
The overall cure rate for locally advanced oral cancer is 50-60% with surgery
and if indicated adjuvant (chemo)radiotherapy. Preliminary data have shown
promising responses with neoadjuvant treatment with nivolumab or pembrolizumab.
It is therefore not unlikely that patients derive benefit from this study. As
can be found in the Investigator Brochure, the toxicity is manageable and the
safety profile acceptable.
De Boelelaan 1117
Amsterdam 1081HV
NL
De Boelelaan 1117
Amsterdam 1081HV
NL
Listed location countries
Age
Inclusion criteria
- Histologically confirmed diagnosis of locally advanced oral cancer (stage
III/IV) which is planned for treatment with curative intent includiing surgical
resection.
- Must provide tissue from fresh tumor biopsy pretreatment and from the
surgical resection material to determine actual PD-L1 status and perform
immunomonitoring and DNA/RNA profiling.
- Willing to allow up to two additional biopsies when baseline [18F]BMS-986192
PET /[18F]-FDG PET scans show heterogeneous and/or discrepant uptake.
- ECOG performance scale 0-1
- Have adequate organ function (hematological, renal and hepatic) as
demonstrated by screening laboratory test.
- Women of childbearing potential must use appropriate method(s) of
contraception during the study and for 23 week after the last dose of nivolumab
- Men who are sexually active with women of childbearing potential must use any
contraceptive method with a failure rate of less than 1% per year.
Exclusion criteria
- Is currently participating in or has participated in a study of an
investigational agent within 4 weeks of the first dose of treatment or has not
recovered (i.e., * Grade 1 or at baseline) from adverse events due to agents
administered more than 4 weeks earlier.
- Has a known current 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 or synchronous head and neck squamous cell
carcinoma.
- If subject received major surgery for any other reason, they must have
recovered adequately from the toxicity and/or complications from the
intervention prior to starting therapy.
- Subjects with a condition requiring systemic treatment with either
corticosteroids (> 10 mg daily prednisone equivalent) or other
immunosuppressive medications within 14 days of day -5. Inhaled or topical
steroids, and adrenal replacement steroid > 10 mg daily prednisone equivalent,
are permitted in the absence of active autoimmune disease.
- Has an active autoimmune disease requiring systemic steroid treatment within
the past 3 months or a documented history of clinically severe autoimmune
disease, or a syndrome that requires systemic steroids.
- Has evidence of interstitial lung disease or active, non-infectious
pneumonitis.
- Has an active infection requiring systemic therapy.
- 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.
- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
- 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 23 weeks after the last dose of trial treatment.
- Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2,
anti-CTLA-4 antibody, or any other antibody or drug specifically targeting
T-cell costimulation or immune checkpoint pathways.
-Has a known history of Human Immunodeficiency Virus infection with a
detectable viral load. Patients with an undetectable load (<50 copies/ml)
receiving adequate anti-retroviral therapy, are allowed to participate.
- Has known active Hepatitis B or C.
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 | EUCTR201800264328-NL |
| CCMO | NL66823.029.18 |