Trial Title:
Pembrolizumab Plus Enfortumab Vedotin in Collecting Duct and Renal Medullary Carcinoma
NCT ID:
NCT06302569
Condition:
Bellini Carcinoma
Collecting Duct Carcinoma
Renal Medullary Carcinoma
Conditions: Official terms:
Carcinoma
Carcinoma, Medullary
Thyroid Neoplasms
Carcinoma, Neuroendocrine
Carcinoma, Ductal
Carcinoma, Renal Cell
Pembrolizumab
Conditions: Keywords:
Pembrolizumab
Enfortumab Vedotin
Non-clear cell renal cell carcinoma
Collecting Duct Carcinoma
Renal Medullary Carcinoma
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Not yet recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Pembrolizumab + Enfortumab Vedotin
Description:
- Pembrolizumab will be given for a maximum of 2 years i.e. a total of 35 cycles of
pembrolizumab with the q3 week dosing. Participants who complete study intervention
after 2 years of pembrolizumab are eligible for up to 1 year of additional
pembrolizumab (second course) upon experiencing disease progression.
- Enfortumab Vedotin will be given for a maximum of 3 cycles on day 1 and day 3 each 3
weeks. EV treatment could be re-started in case of Progressive Disease RECIST v1.1
during pembrolizumab monotherapy treatment.
Arm group label:
Pembrolizumab + Enfortumab Vedotin
Other name:
KEYTRUDA + PADCEV
Summary:
This is a single-arm, monocentric, phase II trial, enrolling patients with histological
diagnosis of collecting duct carcinoma and renal medullary carcinoma with locally
advanced or metastatic disease who will be treated with Pembrolizumab plus Enfortumab
Vedotin.
Approximately, 23 patients will be enrolled. At screening, pre-existing archival primary
and metastatic FFPE tumor specimen will be collected and submitted for central pathology
review and translational analysis. All participants will undergo baseline screening
imaging for clinical staging. Patients will be treated with Pembrolizumab q21 plus
Enfortumab Vedotin 1,8q21 for 3 cycles (3 infusion of Pembrolizumab and 6 infusion of
Enfortumab Vedotin) then radiological imaging will be repeated and patients with SD, PR
or CR will continue pembrolizumab until disease progression, unacceptable toxicities or
completion of treatment (17 cycles). Patients with progressive disease after 3 cycles of
study intervention will be treated as per clinical practice.
Patients who will experience progressive disease during pembrolizumab monotherapy
treatment could restart Enfortumab Vedotin.
The study will also involve collection of a blood sample taken at the commencement of
treatment, at the first cycle, after cycle 3 and at the end of treatment or progression
of disease, to be used for research purposes.
Detailed description:
BACKGROUND Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal
antibody (mAb) with high specificity of binding to the programmed cell death 1 (PD 1)
receptor, thus inhibiting its interaction with programmed cell death ligand 1 (PD-L1) and
programmed cell death ligand 2 (PD-L2). Based on preclinical in vitro data, pembrolizumab
has high affinity and potent receptor blocking activity for PD 1. Pembrolizumab has an
acceptable preclinical safety profile and is in clinical development as an intravenous
(IV) immunotherapy for advanced malignancies. Keytruda® (pembrolizumab) is indicated for
the treatment of patients across a number of indications because of its mechanism of
action to bind the PD-1 receptor on the T cell. For more details on specific indications
refer to the Investigator brochure (IB).
Enfortumab Vedotin (EV) is an ADC comprised of a fully human anti-Nectin-4 IgG1 kappa mAb
conjugated to the small molecule microtubule disrupting agent, MMAE, via a protease
cleavable maleimidocaproyl vc linker. Conjugation takes place on cysteine residues that
comprise the interchain disulfide bonds of the antibody to yield a product with a drug to
antibody ratio of approximately 3:8.
EV binds to the V domain of Nectin-4 protein. In the presumed mechanism of action, the
drug binds to the Nectin-4 protein on the cell surface and is internalized, causing
proteolytic cleavage of the vc linker and intracellular release of MMAE. Free MMAE
subsequently disrupts tubulin polymerization and leads to mitotic arrest.
PHARMACEUTICAL AND THERAPEUTIC BACKGROUND
Pembrolizumab. The importance of intact immune surveillance function in controlling
outgrowth of neoplastic transformations has been known for decades. Accumulating evidence
shows a correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable
prognosis in various malignancies. In particular, the presence of CD8+ T-cells and the
ratio of CD8+ effector T cells/FoxP3+ regulatory T-cells (T-regs) correlates with
improved prognosis and long-term survival in solid malignancies, such as ovarian,
colorectal, and pancreatic cancer; hepatocellular carcinoma; malignant melanoma; and
renal cell carcinoma. Tumor-infiltrating lymphocytes can be expanded ex vivo and
reinfused, inducing durable objective tumor responses in cancers such as melanoma.
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress
immune control. The normal function of PD-1, expressed on the cell surface of activated T
cells under healthy conditions, is to down-modulate unwanted or excessive immune
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an
immunoglobulin (Ig) superfamily member related to cluster of differentiation 28 (CD28)
and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) that has been shown to
negatively regulate antigen receptor signaling upon engagement of its ligands (PD L1
and/or PD-L2).
The structure of murine PD-1 has been resolved. PD-1 and its family members are type I
transmembrane glycoproteins containing an Ig-variable-type (IgV type) domain responsible
for ligand binding and a cytoplasmic tail responsible for the binding of signaling
molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an
immunoreceptor tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based
switch motif. Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases,
SHP-1 and SHP-2, to the immunoreceptor tyrosine-based switch motif within its cytoplasmic
tail, leading to the dephosphorylation of effector molecules such as CD3 zeta (CD3ζ),
protein kinase C-theta (PKCθ), and zeta-chain-associated protein kinase (ZAP70), which
are involved in the CD3 T-cell signaling cascade. The mechanism by which PD-1
down-modulates T cell responses is similar to, but distinct from, that of CTLA-4, because
both molecules regulate an overlapping set of signaling proteins. As a consequence, the
PD 1/PD-L1 pathway is an attractive target for therapeutic intervention in Collecting
Duct Carcinoma and Renal Medullary Carcinoma.
Enfortumab Vedotin Nectin-4 is a 66 kDa type I transmembrane protein that belongs to the
Nectin family of adhesion molecules. It is composed of an ECD containing 3 Ig-like
subdomains, a transmembrane helix, and an intracellular region. Nectins are thought to
mediate Ca2+-independent cell-cell adhesion via both homophilic and heterophilic trans-
interactions at adherens junctions where they can recruit cadherins and modulate
cytoskeletal rearrangements. Sequence identity of Nectin-4 to other Nectin family members
is low and ranges from 25% to 30% in the ECD.
The 3 Ig-like subdomains in the ECD of Nectin-4 are designated V, C1, and C2. The C1
domain is responsible for cisplatin-interaction (homodimerization), while V domains of
most Nectin molecules contribute to trans-interaction and cell-cell adhesion.
Nectin-4 was originally identified by bioinformatics and cloned from human trachea. In
humans, Nectin-4 is normally expressed in keratinocytes of the skin, sweat glands, hair
follicles, transitional epithelium of the bladder, salivary gland ducts, esophagus,
breast, and stomach. Nectin-4 was identified as markedly upregulated in urothelial
carcinoma using suppression subtractive hybridization on a pool of urothelial carcinoma
specimens. Immunohistochemical characterization of expression in multiple tumor specimens
demonstrated high levels of Nectin-4 in bladder, breast, pancreatic, lung, ovarian and
other cancers.
Enfortumab Vedotin in Combination with Pembrolizumab. Combining PD-1/PD-L1 inhibitors
with a novel therapy, such as EV, may improve patient outcomes. Data from preclinical
studies of brentuximab vedotin (a CD30-directed ADC comprising the same linker and MMAE
payload as EV), shows potential to induce ICD, antigen presentation, and tumor immune
infiltration. These results suggest that the effects are due to MMAE. Treatment with
brentuximab vedotin in vitro and in preclinical models has been shown to induce hallmarks
of ICD. ICD is characterized by induction of the endoplasmic reticulum stress response
and subsequent surface presentation of DAMPs immune stimulatory molecules. These DAMPs
induce innate immune migration and activation into the tumor microenvironment.
Based on the potential enhancement of immune response, it is hypothesized that combining
EV with pembrolizumab will result in improved response leading to prolonged PFS and OS in
patients with Collecting Duct Carcinoma and Renal Medullary Carcinoma with minimal
overlapping toxicities between the 2 agents.
RATIONALE FOR THE TRIAL AND SELECTED POPULATION Non-clear cell renal cell carcinomas
(nccRCC) comprise several rare and poorly described diseases. Among them, Renal medullary
carcinoma (RMNC) represents less than 0,5% and Collecting Duct Carcinoma (CDC) represents
1% of all renal cell carcinomas. Both are characterized by an aggressive clinical
behaviour and a particular poor prognosis. Both tumors are under-represented in
prospective randomized trials predominantly including clear-cell histotype. Thus, a
standard of treatment for these rare and aggressive histologies has not been defined yet.
Based on the data of a small phase II study with responses of 23%, the more used first
line therapy in both cases is a platinum-based cytotoxic chemotherapy that has the
ability to control the disease but only for a limited time. More recently, the
prospective BONSAI trial met its primary endpoint showing encouraging efficacy of
cabozantinib in first line with an objective response (ORR) of 35% in 25 patients with
metastatic CDC (mCDC). Immune-checkpoint inhibitors (ICI) such as Pembrolizumab in
combination with Tyrosine Kinase Inhibitors are now recommended as standard-of-care
options for clear-cell renal cell carcinoma due to the relevant results in term of
antitumor activity and Overall Survival (OS). Cases of excellent response to ICI are
reported in literature also in previously treated mCDC patients. Enfortumab Vedotin
showed encouraging activity in different tumour types and when combined with
pembrolizumab showed relevant results in term of ORR and PFS. More recently, the
combination of EV and pembrolizumab in the EV-103/KEYNOTE-869 (NCT03288545) study has
demonstrated dramatic improvement in ORR in cisplatin- ineligible patients with locally
advanced and metastatic urothelial carcinoma, with a preliminary ORR of 73% (95% CI: 58,
85) regardless of PD-L1 expression level.
Due to the mechanism of action of Enfortumab Vedotin, the expression of NECTIN-4 in CDC
is under analysis in the CICERONE trial (NCT05372302). Unpublished results from this
trial, state that NECTIN-4 is expressed in 30% of CDC tissue. Furthermore, biology of CDC
and of Urothelial Carcinoma is similar, and this support the expression of NECTIN-4 in
this orphan disease and the activity of EV.
Based on the encouraging data regarding the use of ICI in clear cell renal cell
carcinoma, the investigators hypothesize that in these histotypes it may be useful to
evaluate in more depth the action of drugs that act on the immune system in combination
with Antibody-Drug Conjugate (ADC).
PLANNED EXPLORATORY BIOMARKER RESEARCH Analysis on biomarkers is exploratory by nature
and will be performed retrospectively after the main study analysis is completed. Tissue
assessments will include the identification of somatic mutations in CDC and the
assessment of the mutational load by focused exome analysis, as well as the
identification of transcript fusions by RNA sequencing.
Plasma and viable peripheral blood mononuclear cell (PBMC) will be isolated and stored
frozen for subsequent analysis. PBMC will be studied for immune cell profile by
multicolor cytofluorimetry (including frequency and activation state of antitumor and
immunosuppressive cell subsets of both innate and adaptive immunity), associated with
gene-expression profiling and Cibersort analysis for assessing the activation state of
the immune cell subsets.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Male/female participants who are at least 18 years of age on the day of signing
informed consent with histologically confirmed diagnosis of metastatic or advanced
Collecting Duct Carcinoma or Medullary Renal Cell Carcinoma will be enrolled in this
study.
- The participant (or legally acceptable representative if applicable) provides
written informed consent for the trial.
- Have measurable disease based on RECIST 1.1. Lesions situated in a previously
irradiated area are considered measurable if progression has been demonstrated in
such lesions.
- Have confirmed histology diagnosis of Collecting Duct Carcinoma or Medullary Renal
Cell Carcinoma by central pathology review.
- Archival tumor tissue sample or newly obtained [core, incisional or excisional]
biopsy of a tumor lesion not previously irradiated has been provided.
Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides.
Newly obtained biopsies are preferred to archived tissue.
- Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
Evaluation of ECOG is to be performed within 7 days prior to the first dose of study
intervention.
- Have adequate organ function as defined in the following table (Table 4). Specimens
must be collected within 10 days prior to the start of study intervention.
- Participants who are HBsAg positive are eligible if they have received HBV
anti-viral therapy for at least 4 weeks, and have undetectable HBV viral load prior
to randomization.
Note: Participants should remain on anti-viral therapy throughout study intervention and
follow local guidelines for HBV anti-viral therapy post completion of study intervention.
Hepatitis B screening tests are not required unless:
1. Known history of HBV infection
2. As mandated by local health authority
- Participants with a history of HCV infection are eligible if HCV viral load is
undetectable at screening.
Note: Participants must have completed curative anti-viral therapy at least 4 weeks prior
to randomization.
Hepatitis C screening tests are not required unless:
a) Known history of HCV infection b) As mandated by local health authority
- HIV-infected participants must have well-controlled HIV on ART, defined as:
1. Participants on ART must have a CD4+ T-cell count ≥350 cells/mm3 at the time of
screening
2. Participants on ART must have achieved and maintained virologic suppression
defined as confirmed HIV RNA level below 50 or the LLOQ (below the limit of
detection) using the locally available assay at the time of screening and for
at least 12 weeks before screening
3. It is advised that participants must not have had any AIDS-defining
opportunistic infections within the past 12 months.
4. Participants on ART must have been on a stable regimen, without changes in
drugs or dose modification, for at least 4 weeks before study entry (Day 1) and
agree to continue ART throughout the study
5. The combination ART regimen must not contain any antiretroviral medications
that interact with CYP3A4 inhibitors/inducers/substrates
(https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug
-interactions-table-substrates-inhibitors-and-inducers)
Exclusion Criteria:
- 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 2 weeks prior to treatment allocation.
- Has received prior radiotherapy within 2 weeks of start of study intervention or
radiation-related toxicities requiring corticosteroids. Note: Two weeks or fewer of
palliative radiotherapy for non-CNS diseases permitted. The last radiotherapy
treatment must have been performed at least 7 days before the first dose of study
intervention.
- Has received a live vaccine or live-attenuated vaccine within 30 days before the
first dose of study intervention. Administration of killed 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.
- Known additional malignancy that is progressing or has required active treatment
within the past 2 years. Note: Participants with basal cell carcinoma of the skin,
squamous cell carcinoma of the skin, or carcinoma in situ, excluding carcinoma in
situ of the bladder, that have undergone potentially curative therapy are not
excluded. Participants with low-risk early-stage prostate cancer (T1-T2a, Gleason
score ≤6, and PSA <10 ng/mL) either treated with definitive intent or untreated in
active surveillance with stable disease 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 intervention.
- 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/interstitial lung disease that
required steroids or has current pneumonitis/interstitial lung disease.
- Has an active infection requiring systemic therapy.
- 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 or other circumstance that might confound the results of the study,
interfere with the participant's participation for the full duration of the study,
such that it is not in the best interest of the participant 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 or father children within the
projected duration of the study, starting with the screening visit through 120 days
after the last dose of trial treatment.
- Has had an allogenic tissue/solid organ transplant.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Fondazione Irccs Istituto Dei Tumori Di Milano
Address:
City:
Milan
Zip:
20133
Country:
Italy
Start date:
November 2024
Completion date:
November 2028
Lead sponsor:
Agency:
Giuseppe Procopio
Agency class:
Other
Source:
Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06302569
