Ignite Creation Date:
2024-05-06 @ 8:13 PM
Last Modification Date:
2024-10-26 @ 3:23 PM
Study NCT ID:
NCT06302569
Status:
NOT_YET_RECRUITING
Last Update Posted:
2024-03-08
First Post:
2024-02-16
Brief Title:
Pembrolizumab Plus Enfortumab Vedotin in Collecting Duct and Renal Medullary Carcinoma
Sponsor:
Giuseppe Procopio
Organization:
Fondazione IRCCS Istituto Nazionale dei Tumori Milano
Study Overview
Official Title:
Activity of Pembrolizumab Plus Enfortumab Vedotin in Collecting Duct and Renal Medullary Carcinoma
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-07
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
REPRINT
Brief 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 18q21 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
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 18q21 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 38
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 cellsFoxP3 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 andor 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 1PD-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-1PD-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 05 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-103KEYNOTE-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
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 38
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 cellsFoxP3 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 andor 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 1PD-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-1PD-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 05 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-103KEYNOTE-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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None