Herewith, we present a research protocol for a phase II trial that allows us to examine the efficacy (histopathological response rate) of ICI in the form of nivolumab or nivolumab plus ipilimumab prior to SOC in patients with resectable stage III-…
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Brief title
Condition
- Skin neoplasms malignant and unspecified
- Skin neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint will be histopathological tumor response after
neo-adjuvant ICI, defined as the proportion of viable tumor cells left in the
resected specimen. Responses will be divided into histopathological complete
response (pCR, no viable tumor cells), histopathological near complete response
(near-pCR, <=10% viable tumor cells) and histopathological partial response
(pPR, <=50% viable tumor cells).
Secondary outcome
Secondary endpoints:
- Histopathological tumor response to neo-adjuvant immunotherapy as measured in
the tumor resection specimen (primary endpoint) will be compared to the tumor
response as measured via serial tumor biopsies, the tumor biopsy at time of
surgery and imaging (clinical photography, FDG-PET and (f)MRI).
Histopathologic response in the tumor biopsies will be defined similarly as
histopathologic response in the resected specimen. Response at imaging studies
will be measured as follows: Clinical photography via specific clinical
observation criteria (paragraph 8.3), FDG-PET via EORTC criteria and % change
in TLG or MTV (paragraph 8.3), and (f)MRI via RECIST 1.1. and experimental
measures (paragraph 8.3).
- Rate and type of AE (NCI CTCAE v 5.0) prior to standard of care, and no
significant delay (>1 week) or cancelation of SOC surgery due to immune-related
toxicity.
- RFS at 2 years FU of responders versus non-responders to neo-adjuvant ICI
- OS at 2 years FU of responders versus non-responders to neo-adjuvant ICI
- Rate and type of AE (NCI CTCAE v 5.0) up to 2 years FU after SOC
- Clinical and histopathalogical response of potentially additional AK surface
areas after ICI identified by digital clini-cal photography on day 0, day 28
and during FU. In order to investigate TME of AK's biopsies will be taken at
day 0 and day 28.
- Quality of life as measured by EORTC QLQ-C30, H&N 35, EQ5D, CWS, IT
questionnaire and the sexuality questionnaire
- Cost-effectiveness of nivolumab and nivolumab plus ipilimumab at time of SOC,
with a health-technology assessment.
Exploratory endpoints:
The MATISSE trial will offer exploratory translational research by collecting
clinical data, tumor specimens, and blood samples at multiple time-points*
short and longer term after start of immunotherapy. The translational research
we aim for will provide insights in the (very) early kinetics of the tumor
microenvironment (TME) and the systemic immune system. Consequently, it may
identify novel parameters for antitumor immunity and/or novel immune evasion
mechanisms present in CSCC patients with early stage disease, and it may
provide a rationale for the optimized timing of neo-adjuvant ICI with respect
to surgery to be tested in future treatment regimens.
Exploring the TME (early) upon ICI:
- IHC and Bulk DNA & RNA sequencing of local tumor (when feasible also lymph
node metas-tases) specimens at the aforementioned time points before and after
start of ICI*, and its corre-lation to clinical outcome.
- The development of an ex vivo functional assay for CSCC (Daniela Thommen
platform) to predict individual ICI response.
- The development of an ex vivo functional assay to challenge tumor specimens
(and when feasible lymph node specimens) with ICI drugs at aforementioned
time-points before and after start of neoadjuvant ICI*.
- Single cell sequencing of tumor specimens before and after start of ICI*.
- Hyperion Mass Cytometry of tumor specimens (and when feasible lymph node
specimens) before and after start of ICI*.
- Residual tumor-digest supernatant and blood plasma or serum will be taken to
third parties for metabolomics and lipid omics, and for cytokine and chemokines
assays
Endpoints for exploring systemic immunotherapy-related alterations:
- Fresh blood flow cytometry (with a focus on suppressive cells as monocytes,
neutrophils) will be performed pre-, on and post-treatment* on all blood
samples.
- Heparin peripheral blood mononuclear cells (PBMCs) will be analysed pre-, on
and post-treatment* on all blood samples for a quantitative and qualitative
assessment of circulating adaptive immune cells.
- Serum blood will be analysed for chemokines and cytokines, pre-, on and
post-treatment* on all blood samples.
- EDTA blood will be analysed complement factors, pre-, on and post-treatment*
on all blood samples.
- T-cell receptor sequencing of baseline TILs and their potential expansion in
the peripheral blood compartment on-treatment (*immunoSeq*.).
- EDTA blood will be analysed for ctDNA (kinetics) before treatment, on
treatment, and long-term after neo-adjuvant ICI*.
- Residual tumor digest supernatant and blood plasma or serum will be taken to
third parties for metabolomics: Semi-targeted biochemical profiling assay (LUMC
depart-ment of Prof Martin Giera and Jacques Neefjes) HydroRP:TripleTOF6600
uses liquid chromatographic separation able to operate on one hundred percent
water condition, allowing separation of small polar metabolites in a
reproducible fashion, overcoming problem of mass resolution and ionization
suppression. Using a unique In-house li-brary, including accurate precursor
mass, accurate retention time and fragmentation spectra, we are able to fully
identify over four hundred small polar molecules (amino acids, nucleotides,
sugars, alpha-cheto acids, etc).
- Residual tumor digest supernatant and blood plasma or serum will be taken to
third parties for lipid omics. DMS shotgun Lipidomics assay (LUMC department of
Prof Martin Giera and Jacques Neefjes) Lipidyzer:SelexIon uses differential
mobility spec-trometry (DMS) which is a gas phase separation technique based on
ion mobility. We use it to separate lipid classes, thereby overcome isobar
overlap, which renders the accurate MS/MS based quantification of many lipid
species impossible. In addition, us-ing the Shotgun Lipidomics Assistant (SLA)
software the platform is able to quantita-tively measure over 1450 lipid
species across 17 lipid (sub)classes.
- Residual tumor digest supernatant and blood plasma or serum will be taken to
third parties for cytokine and chemokines assays.
*= before treatment, and one week (either day 2-3, or day 4-6 or day 7-9, at
least 6 people per treatment arm), two weeks (right before 2nd infusion of
immunotherapy), 4 weeks (at time of surgery) and long-term after start of ICI,
see figure 1 and 2, and table 1, pages (23, 24 and 47).
Background summary
Cutaneous squamous cell carcinoma (CSCC) is the most common skin cancer after
basal cell carcinoma and has an increasing incidence of currently 15,000
patients per year in the Netherlands. Although most patients with CSCC present
with localized disease, about 4% of the patients develops metastases. 87% of
these metastases are lymph nodal. CSCC-related mortality is in 85% a
consequence of uncontrolled loco-regional disease. Lymph nodal positive
patients (stage III-IV) have a poor prognosis with a 3-year overall survival of
29-46%. Standard of care (SOC) in patients with stage III-IV CSCC currently
comprises (major) surgery, sometimes followed by adjuvant radiotherapy (RT).
Systemic chemotherapy, such as cisplatin, has been administered to patients
with locally incurable or metastatic CSCC, though its efficacy is limited and
not well-established. In a recent randomized trial the addition of carboplatin
to postoperative RT in high-risk CSCC did not improve loco-regional control,
disease-free or overall survival. Therefore, there is a need to improve SOC and
increase cure rates in patients with resectable stage III-IV disease.
T cell checkpoint blockade by anti-cytotoxic T-lymphocyte associated protein 4
(CTLA4) and/or anti-programmed cell death protein 1 (PD1) is currently a
promising treatment modality for patients with broad diversity of cancers. Most
patients with CSCC have a history of excessive sun exposure and CSCCs are thus
characterized by ultraviolet radiation (UVR) associated DNA damage with
corresponding high mutational load, rendering them potentially highly
immunogenic and responsive to immunotherapy. In 2018 a phase I and II study
supported this hypothesis, demonstrating the effect of immune checkpoint
inhibition (ICI) with anti-PD1 monoclonal antibody cemiplimab in patients with
locally incurable or metastatic CSCC, leading to its FDA approval. Cemiplimab,
given at a dose of 3 mg per kg every two weeks, was generally well tolerated
(42% of the patients had CTCAE grade >=3 adverse events (AE), which led to
discontinuation of treatment in 5% of the patients) and induced an objective
response (RECIST version 1.1) in approximately 50% and controlled disease in
approximately 70% of patients with distant metastases and/or locally incurable
CSCC .
To date, the efficacy of anti-PD1 ICI with nivolumab in CSCC has not been
systematically investigated. More importantly, it is unclear whether CSCC
patients benefit from adding anti-CTLA4 to anti-PD1 ICI.
Study objective
Herewith, we present a research protocol for a phase II trial that allows us to
examine the efficacy (histopathological response rate) of ICI in the form of
nivolumab or nivolumab plus ipilimumab prior to SOC in patients with resectable
stage III-IVa CSCC. In addition, we aim to investigate the (ex vivo) kinetics
of immune cell activity early upon nivolumab or nivolumab plus ipilimumab and
to correlate our findings with clinical outcome.
Study design
An investigator-initiated randomized non-comparative phase II trial consisting
of 40 patients with resectable stage III-IVa CSCC randomized 1:1 to ARM A: 2
courses of nivolumab 3 mg/kg in week 0 and 2, or ARM B: 2 courses of nivolumab
3 mg/kg in week 0 and 2 plus 1 course of ipilimumab 1mg/kg in week 0. Both
treatment arms are neo-adjuvant and applied prior to SOC at week 4.
Intervention
In this trial patients will be treated neo-adjuvantly with 2 courses of
nivolumab 3 mg/kg in week 0 and 2 or with the combination of ipilimumab 1 mg/kg
plus nivolumab 3 mg/kg in week 0 and nivolumab 3 mg/kg in week 2. Surgery will
be planned in week 4. If necessary, adjuvant RT will start 4-6 week after
surgery.
Study burden and risks
In our proposed trial all stadium III-IVa CSCC patients will receive
neo-adjuvant ICI prior to SOC. Based upon the most recent literature, as
described above, participation in this trial may lead to improved clinical
outcome in terms of loco regional control, recurrence free survival (RFS) and
OS.
Participants of this study will be exposed to one or two immunotherapeutic
agents (nivolumab with or without ipilimumab) known to induce immune related
adverse events. In the trial of Midgen et al, grade >=3 AE occurred in 42% of
the patients with metastatic CSCC after administration of Cemiplimab
monotherapy (3 mg/kg) every two weeks during the median follow up of 7.9
months. The most common AE were diarrhea (occurring in 27% of the patients),
fatigue (24%), nausea (17%), constipation (15%), and rash (15%). In another
previous trial containing patients with lung carcinoma receiving the
combination treatment of nivolumab 3 mg/kg (every 2 weeks, median of 8.5 doses
received) and ipilimumab 1 mg/kg (every 6 weeks, median of 3 doses received),
29% of the patients experienced grade >=3 treatment related AE.
The patient characteristics (concerning age, risk factors, comorbidities) of
the two studies described above will be relatively comparable with the future
patients of our study. So it could be, that these two trials reflect the
expected toxicity in our patient population. However, the total treatment time
in the MATISSE trial will be considerably shorter compared to the
above-described trials. The number of infusions and total treatment time in our
proposed trial will be more similar to the trial of Gross et al, of which the
first results have recently been presented. In this trial, wherein 20 patients
with stage III-IVa CSCC received neo-adjuvant anti-PD1 ICI (cemiplimab) prior
to surgery, no surgical delays occurred and only 7 (35%) patients experienced
grade 1 and 2 AE.
In the past years our hospital has gained the expertise to manage the
administration of neo-adjuvant ICI (consisting of the combination nivolumab +
ipilimumab) without delaying time of surgery, in almost all cases. In the
IMCISION trial all 32 patients with advanced head and neck SCC (26 patients
received nivolumab combined with ipilimumab) received surgery as planned with
no unexpected wound healing problems (clinical data analysis done, manuscript
not yet published).In the OPACIN-neo trial surgery was delayed in only 3 out of
86 patients due to immune related AE and in the OPACIN trial all patients in
the neo-adjuvant arm (n=10) underwent surgery at the pre-planned time. Of note,
out of precaution in this elderly CSCC population, our proposed study will
offer the combination of nivolumab (3 mg/kg) with or without ipilimumab (1
mg/kg) only in the first week and nivolumab (3 mg/kg) monotherapy in the third
week, whereas the OPACIN and the OPACIN-neo trial (2 of the 3 treatment arms)
offered the combination of nivolumab and ipilimumab every three weeks (so week
1 and 4). The infusion of ICI in our study will be given 4 (nivolumab with or
without ipilimumab) and 2 (nivolumab) weeks prior to surgery, so patients will
be enabled to recover from possible acute side effects. To conclude, we believe
that in our proposed trial the expected AE will be manageable and will not
delay the planned time of surgery.
For this trial patients will undergo 2 extra primary tumor biopsies and 2 extra
lymph node biopsies under local anaesthesia. It is our experience that patients
may endure slight temporarily discomfort due to taking the extra biopsies with
a very small enlarged risk (< 1%) for bleeding and infection afterwards. Of
note, the lymph node biopsies under local anaesthesia are not mandatory for
inclusion in the trial. In total, 6 extra blood samples will be collected in 2
years* time. The blood samples, tumor biopsies and lymph node biopsies will be
taken at the same days. The radiation burden for an extra FDG PET/CT is
estimated at 5 mSv for 200 MBq FDG + 3 mSv for low dose CT = 8 mSv. These doses
are in the range of normal diagnostic procedures and are in risk category IIIa
(justified research in normal heathy adults for prevention or cure of diseases
in the future) of the Nederlandse commissie voor stralingsdosimetrie.In
addition to the baseline MRI-scan, two extra (f)MRI-scans will be made in week
2 (before ICI and the tumor biopsy) and week 3-4. The (f)MRI in week 2 is
optional and not mandatory for inclusion in the trial. The duration of a (f)MRI
is slightly longer than usual. Quality of life questionnaires will be taken at
baseline, in week 4 (before surgery) and during FU visits. Completing the
questionnaires will take a maximum of 30 minutes. Overall, this is a low risk
trial whereby for participation, two extra visits to the hospital are warranted
plus the 2 extra days at which patients will receive immunotherapy.
Plesmanlaan 121
Amsterdam 1066 CX
NL
Plesmanlaan 121
Amsterdam 1066 CX
NL
Listed location countries
Age
Inclusion criteria
1. Age 18 years or older.
2. Patient is able to understand and comply with the protocol requirements and
has signed the informed consent form.
3. World Health Organization (WHO) Performance Status 0 or 1 (Appendix B).
4. Patients with histologically or cytologically confirmed, de novo/primary or
recurrent stage III-IVA CSCC (T3-4 N0-3 M0 or T0-2/x N1-3 M0) of all body
sites.
• Primary tumor sites Head and Neck:
o Vermillion border lip: C00.0, C00.1, C00.2
o Skin of lip NOS: C44.0
o External ear: C44.2
o Skin face unspecified (ao: external lip and nasal vestibulum): C44.3
o Skin scalp and neck: C44.4
o Overlapping lesion of skin: C44.8
o Primary site eyelid: C44.1
• CSCC outside head and neck area, but not vulva, anus and penis
OR
Patients with histologically or cytologically proven stage I-II CSCC (T1-2 N0
M0), only in the case of:
• Presence of multifocal disease for which extensive and/or mutilating surgery
is necessary (e.g. near-total scalp resection).
• Situated in an anatomical localization that necessitates extensive and/or
mutilating surgery (e.g. orbital exenteration, (partial) nose amputation or
(partial) ear amputation).
5. Eligible for standard-of-care, curatively intended surgery with or without
adjuvant radiotherapy.
6. Screening laboratory values must meet the following criteria: WBC >= 2.0x109
/L, Neutrophils >=1.5x109 /L, Platelets >=100 x109 /L, Hemoglobin >=5.5 mmol/L,
Creatinine <=1.5x ULN, AST <= 1.5 x ULN, ALT <= 1.5 x ULN, Bilirubin <=1.5 X ULN
(except subjects with Gilbert Syndrome, who are eligible when total bilirubin <
3.0 mg/dL).
7. Women of childbearing potential (WOCBP) must use appropriate method(s) of
contraception. They should use an adequate method to avoid pregnancy for 23
weeks (30 days plus the time required for nivolumab to undergo five half-lives)
after the last dose of the investigational drug.
8. WOCBP must have a negative serum or urine pregnancy test (minimum
sensitivity 25IU/L or equivalent units of HCG) prior to the start of nivolumab
or nivolumab + ipilimumab.
9. Men who are sexually active with WOCBP must use a contraceptive method with
a failure rate of less than 1% per year and will be instructed to adhere to
contraception for a period of 31 weeks after the last dose of investigational
product. Surgically sterile or azoospermic men do not require aforementioned
contraception.
Exclusion criteria
A potential subject who meets any of the following criteria will be excluded
from participation in this study:
1. Distantly metastasized (stadium IVb) CSCC.
2. SCC localized in a mucosal surface (i.e. anus, vulva, penis or mucosal
portion of lip).
3. Patients for whom SOC consists of definitive (brachy)radiotherapy.
4. Primary or recurrent CSCC appearing in an area that has been previously
irradiated.
5. Prior anti-CTLA4 or anti-PD1 immunotherapy.
6. Active human immunodeficiency virus (HIV) or known acquired immunodeficiency
syndrome (AIDS).
7. A positive test for hepatitis B virus surface antigen (HBsAg) or hepatitis C
antibody (HCV Ab).
8. Subjects with any active autoimmune disease or a documented history of
autoimmune disease, except for:
• Subjects with vitiligo
• Resolved childhood asthma/atopy
• Residual hypothyroidism due to an autoimmune condition requiring only hormone
replacement
• Psoriasis not requiring systemic treatment
• Any condition not expected to recur in the absence of an external trigger.
9. Underlying medical conditions that, in the investigator's opinion, will make
the administration of study drug hazardous or obscure the interpretation of
toxicity or AE.
10. A concurrent medical condition requiring the use of immunosuppressive
medications, or immunosuppressive doses of systemic or absorbable topical
corticosteroids;
11. Pregnant or nursing.
12. A history of allergy to study drug components and/or a history of severe
hypersensitivity to any monoclonal antibody.
13. Use of other investigational drugs 30 days before study drug administration
and 5 half times before study inclusion.
14. Use of prohibited medication at start of study period (see paragraph 5.2).
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 | EUCTR2020-001074-30-NL |
| CCMO | NL73483.031.20 |