This study has been transitioned to CTIS with ID 2024-516736-10-00 check the CTIS register for the current data. Based on the success of the pilot feasibility study, we propose a follow-up efficacy study to explore neo-adjuvant ICB therapy as…
ID
Source
Brief title
Condition
- Reproductive neoplasms female malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is the fraction of patients that achieve a major
pathologic response (MPR) after 9 cycles of pembrolizumab. MPR was chosen in
line with neo-adjuvant vs adjuvant ICB trials in other cancer types (e.g. the
NADINA trial; NCT04949113 for melanoma patients) and will be used to inform
the design of a randomized follow-up trial. The trial is considered positive if
a >=74% MPR rate is observed (see also sample size calculation).
Secondary outcome
Secondary endpoints are the radiologic response rates, recurrence-free survival
(RFS) at 2 years from disease diagnosis, and the safety and tolerability of 9
cycles of pembrolizumab. Exploratory endpoints relate to the nature of the
immune responses in peripheral blood and tumor, the involvement of Tumor
Draining Lymph Nodes (TDLN), and changes in circulating tumor DNA (ctDNA)
during treatment.
Background summary
Uterine cancer (UC) is the most common gynecological malignancy in the Western
world. Standard-of-care (SoC) treatment comprises surgery with or without
radio(chemo)therapy. Despite an overall favorable prognosis, many women relapse
and succumb to the disease. In addition, patients experience a reduction in
quality of life as a result of the adjuvant therapy. This is particularly true
for younger women and especially for women of childbearing age. A significant
improvement for UC patients could therefore be achieved by novel approaches
that can replace
radio(chemo)therapy and reduce risk of relapse. Herein, we believe a strong
case can be made for the use of immune checkpoint inhibition.
In brief, approximately 20% of all uterine cancers (UCs) are characterized by a
high tumor mutational burden (TMB) which are results of MisMatch Repair
deficiency (MMRd). MMRd UCs are characterized by a high number of
mutation-associated neo-antigens (MANAs) and are therefore prime targets for
immunotherapy. In line with this, a high response rate to ICB in recurrent MMRd
UC has been demonstrated for PD-1 inhibitors pembrolizumab (57%) and
dostarlimab (49%), and for PD-L1 inhibitors avelumab (27%) and durvalumab (43%).
Interestingly, recent work in colorectal cancer (CRC) has suggested
neo-adjuvant treatment with ICB in MMRd tumors is equally, if not more,
effective. Indeed, a pilot study of 2 cycles neo-adjuvant anti-PD1+anti-CTLA4
in colorectal cancer (NICHE trial) was associated with pathological responses
in 20/20 MMRd tumors (100%; 95% exact confidence interval (CI): 86-100%), with
12/20 pathological complete responses (pCRs) (38). Data from the NICHE-II trial
presented at ESMO this year has confirmed these striking responses with pCRs in
72/107 patients (67%). With respect to single-agent ICB therapy, a study of
anti-PD1 monotherapy in MMRd rectal cancer reported clinical complete responses
(cCRs) in 100% of patients (12/12).
Based on these successes of ICB in MMRd CRC tumors, we initiated and recently
completed a pilot feasibility study of neo-adjuvant anti-PD1 ICB in MMRd UC
(NCT04262089). As described in detail below, we observed significant
pathological and radiological responses with up to 90.9% tumor reduction in
patients at high-risk of recurrence (grade 3 or clear cell histology).
Study objective
This study has been transitioned to CTIS with ID 2024-516736-10-00 check the CTIS register for the current data.
Based on the success of the pilot feasibility study, we propose a follow-up
efficacy study to explore neo-adjuvant ICB therapy as potential alternative for
SoC adjuvant radio(chemo)therapy in MMRd UC.
Study design
Patients will be treated with neo-adjuvant pembrolizumab (200mg IV Q3W, for a
total of 9 administrations), followed by SoC surgery and adjuvant therapy where
indicated. Tumor responses to pembrolizumab will be assessed by a pathologist
(primary endpoint) using material from the SoC surgery. In addition, tumor
response will be evaluated by MRI (secondary endpoint) after the second,
fourth, sixth, and last cycle of pembrolizumab. In case of progressive disease,
the hysterectomy will immediately take place. Peripheral blood and tumor
samples will be used to explore dynamics of tumor and immune responses during
therapy.
Intervention
Pembrolizumab, 200mg IV Q3W for a total of 9 administrations per patient, prior
to SoC therapy.
Study burden and risks
In MMRd rectal cancer, neo-adjuvant administration of anti-PD1 ICB using an
identical treatment scheme as proposed here (9 cycles;Q3W over 6-months) was
associated with clinical complete responses (cCRs) in 100% of patients (12/12).
In addition, almost all neo-adjuvant studies with anti-PD1 monotherapy in
non-MMRd TMB-high indications (lung cancer, melanoma, etc.) have opted for the
same 6-month dosing regimen. Adverse events of any grade with this dosing
regimen occurred in 75% of MMRd rectal cancer patients (95% CI, 48 to 92). No
adverse events of grade 3 or higher were reported. The most common adverse
events (AEs) of grade 1 or 2 included rash or dermatitis (in 31% of the
patients), pruritus (in 25%), fatigue (in 25%), and nausea (in 19%).
Thyroid-function abnormalities occurred in 1 patient (6%).Nevertheless, while
we expect only grade 1 or 2 AEs in the current study, larger cohort studies
have indicated ~3% of patients treated with pembrolizumab are at risk of
developing thyroiditis or colitis. Nevertheless, we expect that these can be
effectively managed using replacement therapy and corticosteroids respectively
as applied in daily clinically practice for pembrolizumab-associated AEs. Based
on the response rates to ICB in our pilot study and in MMRd rectal cancer, we
expect women included in the trial will benefit from the ICB prior to
standard-of-care therapy. We expect that risk of recurrence will be reduced in
responding participants.
Hanzeplein 1
Groningen 9713 GZ
NL
Hanzeplein 1
Groningen 9713 GZ
NL
Listed location countries
Age
Inclusion criteria
- Female participants who are at least 18 years of age on the day of signing
informed consent with histologically confirmed primary diagnosis of G3/CC
MMRd uterine cancer who are intended to be treated with hysterectomy.
- A female participant is eligible to participate if she is not pregnant, not
breastfeeding, is not a woman of childbearing potential (WOCBP) or agrees to
follow contraceptive guidance during the treatment period and at least
until standard-of-care hysterectomy.
- The participant (or legally acceptable representative if applicable) provides
written informed consent for the trial.
Exclusion criteria
- A WOCBP who has a positive serum pregnancy test at screening.
- Has received 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, CD137).
- Has received prior systemic anti-cancer therapy including investigational
agents within 4 weeks [could consider shorter interval for kinase inhibitors or
other short half-life drugs] prior to allocation.
- Has received prior radiotherapy within 2 weeks of start of study treatment or
radition-related toxicities requiring corticosteroids. Note: Two weeks or fewer
of palliative radiotherapy for non-CNS disease with a 1-week washout is
permitted.
- Has received a live vaccine or live-attenuated vaccine within 30 days before
to the first dose of study intervention. Administration of killed vaccines and
Covid vaccines is allowed.
- Has received an investigational agent or has used an investigational device
within 4 weeks prior to study intervention administration.
- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid
therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other
form of immunosuppressive therapy within 7 days prior to the first dose of
study drug.
- Has a known additional malignancy that is progressing or has required active
treatment within the past 3 years. Note: Participants with basal cell
carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in
situ (e.g. breast carcinoma, cervical cancer in situ) that have undergone
potentially curative therapy are not excluded.
- Has known active CNS metastases and/or carcinomatous meningitis. Participants
with previously treated brain metastases may participate provided they are
radiologically stable, i.e. without evidence of progression for at least 4
weeks by repeat imaging (note that the repeat imaging should be performed
during study screening), clinically stable and without requirement of steroid
treatment for at least 14 days prior to first dose of study treatment.
- Has severe hypersensitivity (>=Grade 3) to pembrolizumab and/or any of its
excipients.
- Has active autoimmune disease that has required systemic treatment in the
past 2 years except replacement therapy (eg., thyroxine, insulin, or
physiologic corticosteroid).
- Has a history of (non-infectious) pneumonitis that required steroids or has
current pneumonitis.
- Has an active infection requiring systemic therapy.
- Has a known history of Human Immunodeficiency Virus (HIV). Note: No HIV
testing is required unless mandated by local health authority.
- Has a known history of Hepatitis B (defined as Hepatitis B surface antigen
[HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA
[qualitative] is detected) infection. Note: no testing for Hepatitis B and
Hepatitis C is required unless mandated by local health authority.
- Has not adequately recovered from major surgery or has ongoing surgical
complications.
- Has a history or current evidence of any condition, therapy, or laboratory
abnormality that might confound the results of the study, interfere with the
subject*s participation for the full duration of the study, 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 within the projected
duration of the study, starting with the screening visit through 120 days after
the last dose of trial treatment.
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 |
|---|---|
| EU-CTR | CTIS2024-516736-10-00 |
| EudraCT | EUCTR2022-003922-27-NL |
| CCMO | NL83379.042.22 |