We aim to establish proof-of-concept for use of pembrolizumab as novel neo-adjuvant therapy in dMMR and POLE-EDM UC. When ICB proves to be feasible as defined in the primary endpoint (see 2.1), we will follow-up with larger studies to determine…
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Source
Brief title
Condition
- Reproductive neoplasms female malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary objective is to assess pathological response will be determined on
tumor tissue collected during standard of care hysterectomy. Which is planned
approximately 3 weeks after the second cycle of pembrolizumab..
Secondary outcome
The secundary endpoint is to assess the radiograpic response is measured by MRI
using RECIST 1.1 criteria. Baseline MRI will be scheduled before start therapy.
The follow-up MRI scan is scheduled as close to the hysterectomy as possible
(approximatly 3 weeks after the second cycle of pembroluzimab.)
Background summary
Uterine cancer (UC) is the most common gynecological malignancy in the Western
world. Standard treatment comprises surgery with or without chemo/radiotherapy.
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 hysterectomy. 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 therapies that i) spare the uterus and
ii) reduce risk of relapse. Herein, we believe a strong case can be made for
the use of checkpoint inhibition.
Approximately 30% of all uterine cancers are characterized by a high mutational
load which are results of MisMatch Repair deficiency (dMMR) or mutations in the
exonuclease (proofreading) domain of DNA polymerase epsilon (POLE-EDM).
DMMR and POLE-EDM occur in 20% and 12% of all uterine cancers (UCs),
respectively. Both tumors types are characterized by a high number of
mutation-associated neo-antigens (MANAs) and are therefore prime targets for
immunotherapy. In line with this, objective tumor response rates to immune
checkpoint blockade (ICB) in recurrent dMMR endometrial cancer were 53%, with
20% complete responses. ICB in POLE-EDM has only been reported in case studies,
but has so far been promising. In addition two recent studies show that
neo-adjuvant administration of ICB is effective and safe as described in
*nature and extent of the burden and risks* later in this section.
If these numbers translate well to the primary setting, ICB could have a place
as neo-adjuvant therapy in primary dMMR/POLE-EDM UC. ICB as a neo-adjuvant
therapy can potentially reduce relapse rates especially in dMMR UC, replace
adjuvant therapy with chemo/radiotherapy and thereby reduce toxicity and may
even be used as a uterus-sparing intervention in woman of childbearing
potential.
However, an essential question that first needs to be addressed is whether ICB
as neo-adjuvant treatment is feasible in primary dMMR/POLE-EDM UC.
Study objective
We aim to establish proof-of-concept for use of pembrolizumab as novel
neo-adjuvant therapy in dMMR and POLE-EDM UC. When ICB proves to be feasible as
defined in the primary endpoint (see 2.1), we will follow-up with larger
studies to determine clinical efficacy, such as postponing standard-of-care
surgery or randomized studies to standard-of-care.
Study design
We propose a window-of-opportunity study of pembrolizumab in 20 primary dMMR UC
and primary POLE-EDM UC patients. Pembrolizumab (anti-PD1) will be administered
in two cycles of 3 weeks between diagnosis and standard-of-care hysterectomy.
Tumor responses to pembrolizumab will be assessed 3 weeks after the second
cycle of pembrolizumab by MRI. In case of progressive or stable disease the
hysterectomy will take place (standard-of care).
Peripheral blood and tumor samples will be used to evaluate immune responses.
Intervention
Pembrolizumab, 200mg IV Q3W for a total of 2 administrations per patient
integrated into standard-of-care protocol prior to surgery.
Study burden and risks
Neo-adjuvant administration of ICB has already been performed in at least three
published clinical trials using similar dosing scheme as proposed here; in
melanoma, early-stage colon cancer and resectable non-small-cell-lung cancer. A
randomized phase IB trial in 20 melanoma patients compared 4 courses adjuvant
ICB treatment with 2 courses neoadjuvant and 2 courses adjuvant ICB treatment.
The neo-adjuvant treatment was feasible, all patients underwent surgery at the
preplanned time point and no surgery-related adverse events were attributed to
the prior immunotherapy. Furthermore, the trial demonstrated possible
superiority of neo-adjuvant therapy and high clinical activity, 6 out of 9
evaluable patients achieving near complete (<10% viable tumor cells) or
complete pathological responses. A subsequent phase II randomized trial
comparing different neo-adjuvant dosage regimes resulted in a complete
pathological response in 17/30 patients (57%) in the best performing study-arm.
Neo-adjuvant administration of ICB in early-stage colon cancer resulted in
major pathologic response in all 7 dMMR colon tumors, including 4 complete
responses. In lung cancer, neo-adjuvant ICB induced a major pathological
response in 9 out of 20 (45%) of the resected tumors, of which three complete
responses in the primary tumor. Importantly, no treatment-related surgical
delays occurred in either studies and adverse events are highly consistent with
those reported across clinical trials for anti-PD1 ICB.
We expect grade 1-2 adverse events in 2-4 of our 20 patients with no
treatment-related surgical delays. Nevertheless, ~3% of patients treated with
pembrolizumab are at risk of developing thyroiditis or colitis. Theoretically,
this may result in postponement of surgery for 1-3 weeks. Nevertheless, we
expect that after management using corticosteroids, surgical intervention can
still be successfully achieved in these women. Based on available literature,
postponing the surgery for this time-period will not negatively affect
survival.
Based on the response rates to ICB in recurrent dMMR UC women included in the
trial can potentially 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
dMMR/POLE-EDM uterine cancer who are intended to be treated with hysterectomy
will be enrolled in this study.
- 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 the contraceptive guidance in section 5.2 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 woman who has a positive urine pregnancy test within 72 hours prior to
allocation.
- 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
- Has received prior systemic anti-cancer therapy including investigational
agents within 4 weeks prior to allocation.
- Has received prior radiotherapy within 2 weeks of start of study treatment.
- Has received a live vaccine within 30 days prior to the first dose of study
drug.
- Is currently participating in or has participated in a study of an
investigational agent or has used an investigational device within 4 weeks
prior to the first dose of study treatment.
- 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.
- Has known active CNS metastases and/or carcinomatous meningitis.
- 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
- 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).
- Hepatitis B of C
- 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 |
|---|---|
| EudraCT | EUCTR2018-001816-31-NL |
| CCMO | NL67996.042.19 |