This study has been transitioned to CTIS with ID 2024-512862-32-00 check the CTIS register for the current data. The primary objectives of this trial are to study clinical efficacy and immune activation of neoadjuvant PD-1 blockade in VSCC.
ID
Source
Brief title
Condition
- Skin neoplasms malignant and unspecified
- Obstetric and gynaecological therapeutic procedures
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
1. To study the clinical efficacy of neoadjuvant PD-1 blockade in VSCC, as
measured by an objective change in tumor size (according to RECIST 1.1) and
documented by calipers using standardized digital photography with reference
ruler) at the time of surgery (approximately 6 weeks after first administration
Pembrolizumab).
2. To study the activation, proliferation and migration of CD4+CD39+PD-1+
effector T cell population upon PD-1 blockade.
Secondary outcome
1. To study pathological complete responses (pCR) at time of surgery
2. To study feasibility(defined as delay in planned surgery and surgical
outcome), safety according to NCI-CTC version 5.0
3. To study the activation, proliferation and migration of the
CD8+CD103+CD39+PD-1+ intratumoral T-cell population upon PD-1 blockade.
Background summary
Vulvar squamous cell carcinoma (VSCC) is a rare cancer with a rising incidence.
Standard treatment comprises wide local excision of the primary tumour and
inguinal lymph nodes and sometimes (chemo) radiotherapy. Treatment is
associated with impressive and long-lasting morbidity, sexual and psychological
dysfunction and wound healing disorders. Recurrent disease develops in up to
40% of all treated patients. The unmet need, therefore, is a less radical and
more effective treatment for VSCC. Based on the local immune profile in a large
fraction of patients with primary VSCC we hypothesize that neoadjuvant PD-1
checkpoint inhibition may reinvigorate tumor-specific T cells resulting in a
reduced tumor load, potentially leading to less radical surgery and reduces the
recurrence rate.
Study objective
This study has been transitioned to CTIS with ID 2024-512862-32-00 check the CTIS register for the current data.
The primary objectives of this trial are to study clinical efficacy and immune
activation of neoadjuvant PD-1 blockade in VSCC.
Study design
This is a prospective, multicenter phase II non-controlled clinical trial in 40
VSCC patients.
Intervention
Anti-PD1 antibody pembrolizumab, 200 mg IV Q3W for a total of 2 administrations
per patient over a period of 6 weeks prior to surgery.
Extension phase: Responders have the option to participate in an extension
cohort with adjuvant pembrolizumab (400 mg IV, Q6W, 7 times) from week 16 to
week 58, to monitor long-term (safety/immune monitoring) effects.
Non-responders and responders who do not receive extended pembrolizumab will
visit the hospital at weeks 13 and 16 to monitor potential long-term effects of
pembrolizumab, including blood draws for safety values and for oncology
follow-up in accordance with standard of care guidelines
Study burden and risks
The extra burden for the patient consists of one extra examination and biopsy
at the start of study, a pregnancy test, standardized tumor measurement by
caliper (clinical exam), and 6 time points in which blood samples are
collected. Moreover, patients will be asked to fill out a quality of life
questionnaires at baseline, and at week 13, and for objective clinical
responders continuing treatment in week 61.
Furthermore, standard of care treatment is delayed for at least 4 weeks. The
use of pembrolizumab requires 2 extra visits to the clinic and is associated
with possible side effects as reported in the registered use of Keytruda®
(pembrolizumab) for the treatment of patients across a number of indications
(https://www.ema.europa.eu/en/medicines/human/EPAR/keytruda;
https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125514s096lbl.pdf).
See the Investigator brochure (IB) for more details on specific indications.
The most common adverse reactions are fatigue (24%), rash (19%), itchiness
(pruritus) (17%), diarrhea (12%), nausea (11%) and joint pain (arthralgia)
(10%). Other adverse effects occurring in between 1% and 10% of patients
include anemia, decreased appetite, headache, dizziness, distortion of the
sense of taste, dry eye, high blood pressure, abdominal pain, constipation, dry
mouth, severe skin reactions, vitiligo, various kinds of acne, dry skin,
eczema, muscle pain, pain in a limb, arthritis, weakness, edema, fever, chills,
myasthenia gravis, and flu-like symptoms. This may theoretically result in
postponement of surgery for 1-3 weeks. We expect that after management using
corticosteroids surgical treatment can still be successfully achieved in these
patients. Based on current guidelines, postponing surgery for this time-period
will not negatively affect prognosis.
Neoadjuvant use of one infusion of pembrolizumab in HPV-unrelated resectable
head and neck cancer and stage III/IV resectable melanoma suggest that
treatment associated grade 1-2 AEs and an occasional grade 3 AE are to be
expected during neoadjuvant treatment. Importantly, in both studies no
unexpected delays in surgery or unexpected surgical complications were found,
while about 40% of the patients showed a pathological response or a
complete/major pathological response. Similar observations were made with 2
infusions of neoadjuvant anti-PD1 antibody nivolumab in stage I-IIIa resectable
lung cancer.
Based on the response rate to ICB in the abovementioned clinical trials women
included in this trial can potentially benefit from ICB prior to
standards-of-care therapy. The potential benefit of study participation is that
neo-adjuvant treatment with pembrolizumab might result in a complete or partial
decrease of tumor size. In addition, the risk of recurrence may be reduced in
these responders.
Participation of responders in the extension phase is optional. Participation
in the extension phase may increase the risk of side effects and may reduce the
risk of disease recurrence.
All patients contribute to our knowledge and understanding how to further
develop new strategies for anti-cancer therapies. In our opinion, the benefits
outweighs the risks of the study. *
Albinusdreef 2
Leiden 2333 ZA
NL
Albinusdreef 2
Leiden 2333 ZA
NL
Listed location countries
Age
Inclusion criteria
1. Signed written informed consent prior to performance of study- specific
procedures or
assessments, and must be willing to comply with treatment and follow- up
assessments.
2. Age >= 18 years old at the day of signing informed consent
3. Histologically confirmed primary vulvar squamous cell carcinoma, with all of
the following characteristics:
- At least 1 lesion that can be measured in at least 1 dimension with >= 10 mm
in largest diameter.
- Clinically stage FIGO I-III.
- Documentation confirming the absence of distant metastasis (M0) as determined
by institutional practice. Routine exams to discard metastases will be
performed according to Investigator judgement but are mandatory in case of
suspicion of metastatic disease.
- Vulvar cancer eligible for primary surgery
- In the case of a multifocal tumor (defined as the presence of two or more
foci of cancer on the vulva), the largest lesion must be >= 10 mm and all
lesions >= 10 mm are designated as "target" lesion(s) for all subsequent tumor
evaluations and biopsies.
Exclusion criteria
1. Locally advanced tumor not amenable to surgical therapy.
2. A woman of child bearing potential who has a positive urine pregnancy test
within 72 hours prior to allocation. If the urine test is positive or cannot be
confirmed as negative, a serum pregnancy test will be required.
3. Prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an
agent directed to another stimulatory or co-inhibitory T-cell receptor (eg,
CTLA-4, OX 40, CD37)
4. Prior systemic anti-cancer therapy including investigational agents within 4
weeks [prior to allocation.
Note: Participants must have recovered from all AEs due to previous therapies
to <=Grade 1 or baseline. Participants with <=Grade 2 neuropathy may be eligible.
Note: If participant received major surgery, they must have recovered
adequately from the toxicity and/or complications from the intervention prior
to starting study treatment.
5. Prior radiotherapy within 2 weeks of start of study treatment. Participants
must have recovered from all radiation-related toxicities, not require
corticosteroids, and not have had radiation pneumonitis.
6. Major surgery within 2 weeks of starting study treatment and patients must
have recovered from any effects of any major surgery.
Design
Recruitment
Medical products/devices used
metc-ldd@lumc.nl
metc-ldd@lumc.nl
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 |
|---|---|
| EU-CTR | CTIS2024-512862-32-00 |
| EudraCT | EUCTR2022-002500-21-NL |
| CCMO | NL82378.058.22 |