Primary objective:• To investigate the efficacy, defined as clinical benefit (stable disease (SD), partial response (PR), complete response (CR)) at 12 weeks, confirmed on a second scan after 4 weeks, of an FMT-intervention with responder and non-…
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Source
Brief title
Condition
- Skin neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
For the efficacy analysis the primary endpoint will be clinical benefit (SD,
PR, CR) at 12 weeks, confirmed on a second scan after 4 weeks.
Secondary outcome
For the safety analysis the endpoint will be occurrence of toxicity of grade 3
or higher (secondary endpoint).
Background summary
For patients with advanced stage melanoma, treatment possibilities have changed
considerably in the past 10 years. Both targeted therapies for BRAF V600
mutated melanomas, blocking intracellular signaling proteins (mutated BRAF and
downstream MEK) in the MAPK pathway, and immunotherapy, blocking inhibitory
receptors on activated T cells (CTLA-4 and PD-1), have improved outcomes for
these patients with at best five year overall survival rates of 50%. Despite
these impressive results, the majority of patients with metastatic melanoma
still succumbs to the disease.
For non-melanoma skin cancers, immunotherapy has also become a standard of care
treatment in recent years.For patients with locally incurable of metastatic
cutaneous squamous cell carcinoma (cSCC) anti-PD-1 checkpoint inhibition with
cemiplimab induces objective responses in approximately 50% of patients, with a
duration of response exceeding six months in 57% of these patients.5,6 For
patients with Merkel cell carcinoma (MCC), a rare and highly aggressive
neuroendocrine skin malignancy, response rates of up to 68% have been observed
with anti-PD-(L)1 checkpoint inhibitors (avelumab, pembrolizumab or nivolumab).
Nevertheless, for both cSCC and MCC, a significant number of patients either do
not respond to ICI therapy or experience a relapse after an initial response.
Further approved treatment options, such as targeted therapies, are lacking for
these patients.
Ample research of the tumor microenvironment has revealed several escape
mechanisms to both targeted therapy and immunotherapy, but so far, novel drugs
or novel combination of drugs to overcome these resistance mechanisms, have not
been approved and some are in clinical development. However, major
breakthroughs are still lacking. Therefore, other mechanisms to improve the
anti-tumor immune responses should be explored. One such a mechanism may be
incorporated in the gut microbiome. Preclinical data showed that the presence
or absence of certain microbial taxa in the gut plays an important role in
immune responses, including antitumor immunity.
In a recently published study, investigators analyzed the microbiota taxa in
stool samples from metastatic melanoma patients either responding or
progressing on anti-PD-1 treatment. The presence of certain taxa was strongly
correlated with better outcome (Firmicutes) whereas the presence of Bacteroides
species was correlated with worse outcome. Stool transplantation of anti-PD-1
responders and progressors to germ-free mice followed by melanoma transplant
and treatment with anti-PD-1 showed that only mice having received FMT from
anti-PD-1 responder patients had an anti-PD-1 antitumor response. These data
corroborate that the capacity of the murine immune system to response to
anti-PD-1 may be influenced by the gut microbiome.
FMT is in itself not a new treatment. FMT has been successfully used to treat
patients with multiple recurrent Clostridium difficile infection (rCDIs) of the
colon, with cure rates over of 85%. Also in severely immunocompromised
patients, FMT appears safe and effective for the treatment of rCDI though extra
screening tests are included to prevent transmission of low-pathogenic
microorganisms.
In conclusion, manipulation of the gut microbiome by donor fecal microbiota
transplantation may influence the immune response in both autoimmune disease
and cancer, inducing remission in autoimmune bowel disease or severe and
refractory immune-related colitis, whereas augmenting an anticancer immune
response in the context of immune checkpoint blockade. Preclinical studies
illustrate that both CD4 and CD8 T cell responses are affected by FMT, probably
by improving antigen-presentation by dendritic cells. These finding are further
supported by several observational (pre)clinical studies, in which feces from
R/NR patients was transferred into mice. They found that a favorable gut
microbiome was associated with reduced tumor growth, higher density of CD8+ T
cell infiltrate, increased number of CD8+ T cells in the gut, higher systemic
levels of effector CD4+ and CD8+ T cells, and lower levels of Tregs and
myeloid-derived suppressor cells (MDSCs). Furthermore, in clinical studies
using FMT to treat ICI-unresponsive patients, complete responses, partial
responses and durable stable disease have been observed, with prolonged overall
survival. The exact underlying mechanism determining which patients will or
will not respond, and what the optimal FMT composition is, are not completely
understood.
Therefore, based on these findings in inflammatory bowel disease and in cancer,
we propose to initiate a randomized phase Ib/IIa study investigating the effect
(safety and efficacy) of donor FMT on unresponsiveness of metastatic melanoma
and non-melanoma skin cancer patients while on immune checkpoint blockade.
Study objective
Primary objective:
• To investigate the efficacy, defined as clinical benefit (stable disease
(SD), partial response (PR), complete response (CR)) at 12 weeks, confirmed on
a second scan after 4 weeks, of an FMT-intervention with responder and
non-responder patients as donors in ICI-refractory metastatic melanoma and
non-melanoma skin cancer patients while on immune checkpoint blockade.
Secondary objective:
• To study the safety of FMT with responder and non-responder patients as donor
in metastatic melanoma and non-melanoma skin cancer patients.
Study design
This is a randomized double-blind intervention phase Ib/IIa trial in ICI
refractory metastatic melanoma and non-melanoma skin cancer patients receiving
either FMT of an ICI responding or FMT from an ICI non-responding donor, in
combination with ICI.
Intervention
Following randomization, patients will receive vancomycin 250 mg, four times
daily for 4 days (day -5 up until day -2), and undergo bowel clearance on day
-1 (in total 1L MoviPrep). The FMT, either derived from donor group R or donor
group NR, will be performed by a gastroenterologist using
esophagogastroduodenoscopy. A total amount of 198mL (containing a total of 60
gram feces) will be used for transplantation. Anti-PD-(L)1 treatment will be
continued according to the patient*s regular treatment schedule. Evaluation of
safety and response to treatment will be performed.
Intervention tested: FMT, while continuing anti-PD-(L)1 treatment.
Lab testing: baseline, +2 weeks, +6 weeks and +12 weeks after FMT.
Feces sample: baseline, pre-FMT, +2 weeks, +6 weeks, +12 and +16w weeks after
FMT.
Tumor biopsies: baseline and +12 weeks after FMT.
CT scans: baseline, +12 and +16 weeks after FMT.
Study burden and risks
Metastatic melanoma patients with disease progression while on first line or
adjuvant immunotherapy (IT), especially those without an activating mutation in
the BRAF V600 gene, have a dismal prognosis. Currently, there are no approved
treatment options, other than single agent ipilimumab in case of progressive
disease (PD) on single agent anti-PD-1. For patients with metastatic MCC or
cSCC developing progressive disease during ICI treatment, further approved
treatment options are lacking at all. Clinical trials are a preferred choice
for these patients, of which most are phase I clinical trials.
Here, we propose to initiate a phase Ib/IIa clinical trial combining the
transfer of fecal microbiota originating from responder or non-responder
metastatic melanoma patients via FMT with immunotherapy (anti-PD-1) in order to
revert the IT unresponsive state of the tumor microenvironment during immune
checkpoint blockade. Patients that become feces donors will be screened for
comorbidities, and assessments of serum and stool samples will be performed for
presence of potential pathogens.
Patients with refractory metastatic melanoma or non-melanoma skin cancer while
on anti-PD-(L)1 treatment will be informed and asked to participate in this
randomized phase Ib/IIa trial. Both reversion of unresponsiveness and safety
will be measured. Considering the poor life expectancy, we consider the bowel
clearance, treatment with antibiotics, and FMT via oesophagogastroduodenoscopy
an acceptable burden. Based on the results from two recently published studies
by Baruch et al. and Davar et al. who did not observe any significant side
effects, direct toxicity from FMT or the combination with anti-PD-1 seems
unlikely. Likewise, serious adverse events are rare in FMT treated patients
with multiple, recurrent Clostridium difficile infection (rCDI). Nonetheless,
FMT in healthy volunteers may result in systemic inflammatory response
syndrome. Apart from FMT, patients will undergo stool sampling, blood sampling
and, if feasible, tumor biopsies to measure the changes during this combined
treatment. As this is a phase Ib/IIa study we consider this patient population
with anti-PD-(L)1 treatment-refractory disease the optimal population to
perform this study.
Plesmanlaan 121
Amsterdam 1066 CX
NL
Plesmanlaan 121
Amsterdam 1066 CX
NL
Listed location countries
Age
Inclusion criteria
- Patients should be 18 years or older
- Patients have pathologically confirmed advanced stage cutaneous melanoma
cutaneous squamous cell carcinoma or Merkel cell carcinoma (stage III or IV)
requiring systemic treatment with anti-PD-(L)1
- In case of melanoma patients with stage IV disease, only patients
with limited disease progression without immediate clinical risks of delaying
other treatment options, based on the judgment of the treating physician, are
eligible.
- Patients have confirmed disease progression (>=20% increase according to
RECIST 1.1 or measurable recurrence under adjuvant treatment) on two
consecutive scans with a four week interval while on anti-PD-1 treatment, of
which the second scan has to be performed within 3 weeks prior to signing
informed consent.
- Patients must have measurable disease per RECIST 1.1 criteria
- Patients have an ECOG performance status of 0-1
- Patients have a life expectancy of >3 months
- Patients have adequate organ function as determined by standard-of-care
pre-checkpoint inhibitor infusion lab (including serum ALAT/ASAT less than
three times the upper limit of normal (ULN); serum creatinine clearance
50ml/min or higher; total bilirubin less than or equal to 20 micromol/L, except
in patients with Gilbert*s Syndrome who must have a total bilirubin less than
50 micromol/L)
- Patients have an LDH level of <2x times ULN
- Patients of both genders must be willing to use a highly effective method of
birth control during treatment
- Patients must be able to understand and sign the Informed Consent document
Exclusion criteria
- Patients with acral, uveal or mucosal melanoma.
- Patients with non-cutaneous squamous cell carcinoma
- Patients who have received systemic treatment for their melanoma or
non-melanoma skin cancer other than anti-PD-(L)1 treatment.
- Stage IV melanoma patients with rapid or invasive disease progression
necessitating an immediate switch to a proven effective treatment, as judged by
the treating physician.
- Patients with autoimmune diseases: patients with a history of inflammatory
bowel disease, including ulcerative colitis and Crohn*s disease, are excluded
from this study (except Hashimoto thyroiditis, vitiligo, history of psoriasis,
but no active disease)
- Patients with any grade 3 or 4 immune-related adverse events still requiring
active immunosuppressive medication (prednisone <=10mg/day or equivalent are
permitted), apart from endocrinopathies that are stable under hormone
replacement therapy. Patients who had developed grade 3-4 immune related
toxicity, which has reverted to grade I with immunosuppressive drugs and who
are off immunosuppression at least two weeks prior to enrollment are eligible
(prednisone <=10mg/day or equivalent are permitted.
- Patients with active or symptomatic brain metastasis or LM metastasis (brain
metastases treated with radiotherapy, that are inactive and asymptomatic are
allowed).
- Patients with an elevated LDH level.
- Patients that have undergone major gastric/esophageal/bowel surgery (like
Wipple, subtotal colectomy)
- Severe food allergy (e.g. nuts, shellfish)
- Patients with a swallowing disorder or expected bowel passage problems
(ileus, fistulas, perforation).
- Severe dysphagia with incapability of swallowing 1 liter of bowel lavage.
- Patients with a life expectancy of less than three months
- Patients with severe cardiac or pulmonary comorbidities (per judgement of the
investigator)
- Women who are pregnant or breastfeeding
- Patients with any active systemic infections, coagulation disorders or other
active major medical illnesses
- Patients with other malignancies, except adequately treated and a
cancer-related life-expectancy of more than 5 years.
- Patients who received treatment with antibiotics in the three months prior to
study enrolment, or patients we are expected to receive systemic antibiotics
during the course of this study
Design
Recruitment
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 |
|---|---|
| ClinicalTrials.gov | NCT05251389 |
| CCMO | NL78423.031.21 |