Ignite Creation Date:
2024-05-06 @ 11:03 AM
Last Modification Date:
2024-10-26 @ 12:39 PM
Study NCT ID:
NCT03425201
Status:
COMPLETED
Last Update Posted:
2023-12-28
First Post:
2018-02-01
Brief Title:
Niraparib in Combination With Cabozantinib XL184 in Patients With Advanced Urothelial Cancer NICARAGUA
Sponsor:
Fundacion CRIS de Investigación para Vencer el Cáncer
Organization:
Fundacion CRIS de Investigación para Vencer el Cáncer
Study Overview
Official Title:
A Phase I-II Study to Evaluate the Efficacy and Safety of Niraparib in Combination With Cabozantinib XL184 in Patients With Advanced Urothelial Cancer After Failure to First-line Platinum-based Chemotherapy
Status:
COMPLETED
Status Verified Date:
2024-08
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:
NICARAGUA
Brief Summary:
Cabozantinib is an oral small-molecule tyrosine kinase inhibitor Its primary targets are Hepatocyte growth factor receptor protein MET vascular endothelial growth factor receptor 1-3 VEGFR1-3 RET AXL FLT3 and KIT Cabozantinib has been approved by the FDA for clinical treatment of progressive metastatic medullary thyroid cancer Recently published trials have demonstrated activity for cabozantinib in patients with advanced renal cell carcinoma and metastatic castration-resistant prostate cancer mCRPC Furthermore in preclinical models of urothelial carcinoma UC of the bladder cabozantinib has demonstrated the ability to inhibit tumor xenograft growth It has been suggested that levels of soluble Met ectodomain sMet can be measured in the urine as a useful biomarker to monitor the efficacy of c-Met therapy in bladder cancer patients Moreover cabozantinib has demonstrated activity in heavily pretreated advanced bladder cancer patients with a response rate of 195 and manageable toxicities
In the phase I of this study it is proposed to evaluate DLTs of niraparib and cabozantinib combination and determine maximum tolerated dose MTD in patients with advanced urothelial or renal cell carcinoma In the phase II it is proposed to make a preliminary evaluation of the efficacy of this combination in patients with urothelial cell carcinoma Efficacy results will be correlated with genomic alterations related to c-Met and Poly ADP-ribose polymerase PARP inhibitor activity
In the phase I of this study it is proposed to evaluate DLTs of niraparib and cabozantinib combination and determine maximum tolerated dose MTD in patients with advanced urothelial or renal cell carcinoma In the phase II it is proposed to make a preliminary evaluation of the efficacy of this combination in patients with urothelial cell carcinoma Efficacy results will be correlated with genomic alterations related to c-Met and Poly ADP-ribose polymerase PARP inhibitor activity
Detailed Description:
Bladder cancer is the 9th most common cancer worldwide with around 429800 new cases diagnosed in 2012 and the 5th most common cancer in Europe with more than 151000 new cases diagnosed in 2012 Relating mortality figures bladder cancer is the 13th most common cause of cancer death worldwide with around 165100 deaths from bladder cancer in 2012 and the 9th in Europe with around 52400
Cisplatin-based chemotherapy remains the standard treatment in patients with metastatic urothelial carcinoma UCThis regimen has been associated with a median survival of 14-15 months The prognosis of patients who progress after a platinum-based regimen is dismal Several chemotherapy drugs tested in the second-line setting such as taxanes vinflunine and pemetrexed have demonstrated limited activity with response rates of 5-20 median progression-free survival PFS of 2-4 months and median survival of 6-8 months Thus there are significant unmet medical needs in the second-line setting New therapeutic targets should be tested in urothelial carcinoma to improve these results
Therapies targeting DNA repair pathways can exploit DNA repair defects in cancer cells to generate synthetic lethality Alterations in DNA repair pathways have been associated with response to DNA-damaging agents For example defective homologous recombination HR plays a crucial role in tumors where platinum agents are involved in therapeutic management as well as in those treated with PARP inhibitors which have synthetic lethal effects when applied to cells with defective HR Targeted mutational profiling of HR genes using next-generation sequencing has been used to identify mutations of key HR genes Furthermore HR-defective tumors exhibit genomic instability including loss of heterozygosity LOH telomeric allelic imbalance TAI and large-scale state transitions LST A combined HR deficiency score myChoice homologous recombination deficiency HRD test from Myriad Genetics defined as the sum of LOH TAI and LST has been developed This score has been associated with response to platinum-based chemotherapy and in ovarian cancer with the efficacy of niraparib in patients without germline breast cancer gene gBRCA mutations
In patients with muscle-invasive bladder cancer MIBC the Cancer Genome Atlas project found 31 of alterations in BRCA1-2 genes mainly related to copy number and overexpression In addition a high percentage of tumors had alterations in other DNA repair genes Recently in platinum-treated UC patients 47 of mutations in DNA repair genes have been found including 50 of mutations in HR Fanconi anemia and DNA-damage-response checkpoint pathways The presence of these mutations has been associated with survival These results suggest a potential role for PARP inhibitors in UC Niraparib is a highly selective inhibitor of poly adenosine diphosphate ADP-ribose polymerase PARP12 nuclear protein PARP enzymes are involved in DNA repair through activation of the base excision repair BER pathway and alternative end-joining pathways and inhibition of non-homologous end-joining PARP inhibition in cells with HR deficiency causes accumulation of unrepaired DNA double-strand breaks leading to cell death For these reasons PARP inhibitors are selectively lethal in tumor cells with defective HR Niraparib at the recommended oral dose of 300 mg daily has demonstrated efficacy in platinum- sensitive recurrent ovarian cancer with defective HR The most significant toxicity was hematologic thrombocytopenia neutropenia and anemia Among non-hematologic toxicities hypertension was detected in 8 of patients
c-Met receptor tyrosine kinase RTK is activated by its ligand hepatocyte growth factor HGF and induces increased proliferation migration motility and invasion of bladder cancer cells c-Met is overexpressed in more than 60 of metastatic bladder cancer patients and is linked to poor outcome Furthermore in bladder cancer c-Met is co-expressed with other RTKs such as AXL and PDGFR Some evidence suggests a relationship between c-Met and AXL expression with DNA damage response and resistance to chemotherapy For example Balaji et al have demonstrated that AXL inhibition leads to a defect in the HR pathway sensitizing cells to PARP inhibition In a recently published study a significant interaction between c-Met and Poly ADP-ribose polymerase 1 PARP1 was detected in breast cancer cell lines c-Met activity can decrease response to PARP inhibitors whereas treatment with c-Met inhibitors renders cells more sensitive to PARP inhibition Likewise in in vivo models with xenograft tumors the combination of c-Met and PARP inhibitors showed a significant reduction in tumor growth compared to either inhibitor alone This interaction can be explained because c-Met mediates PARP1 function through phosphorylation of PARP1 at Y907 These results raise the possibility that bladder cancer patients with tumors overexpressing c-Met can benefit from the combination of c-Met inhibitors and PARP inhibitors
Cabozantinib is an oral small-molecule tyrosine kinase inhibitor Its primary targets are MET VEGFR1-3 RET AXL FLT3 and KIT Cabozantinib has been approved by the FDA for clinical treatment of progressive metastatic medullary thyroid cancer The recommended dose of cabozantinib has been established in phase I trials at 60 mgday in 28-day cycles Recently published trials have demonstrated activity for cabozantinib in patients with advanced renal cell carcinoma and metastatic castration-resistant prostate cancer mCRPC Furthermore in preclinical models of UC of the bladder cabozantinib has demonstrated the ability to inhibit tumor xenograft growth It has been suggested that levels of soluble Met ectodomain sMet can be measured in the urine as a useful biomarker to monitor the efficacy of c-Met therapy in bladder cancer patients Moreover cabozantinib has demonstrated activity in heavily pretreated advanced bladder cancer patients with a response rate of 195 and manageable toxicities
In the phase I of this study it is proposed to evaluate DLTs of niraparib and cabozantinib combination and determine MTD in patients with advanced urothelial or renal cell carcinoma In the phase II it is proposed to make a preliminary evaluation of the efficacy of this combination in patients with urothelial cell carcinoma Efficacy results will be correlated with genomic alterations related to c-Met and PARP inhibitor activity
Cisplatin-based chemotherapy remains the standard treatment in patients with metastatic urothelial carcinoma UCThis regimen has been associated with a median survival of 14-15 months The prognosis of patients who progress after a platinum-based regimen is dismal Several chemotherapy drugs tested in the second-line setting such as taxanes vinflunine and pemetrexed have demonstrated limited activity with response rates of 5-20 median progression-free survival PFS of 2-4 months and median survival of 6-8 months Thus there are significant unmet medical needs in the second-line setting New therapeutic targets should be tested in urothelial carcinoma to improve these results
Therapies targeting DNA repair pathways can exploit DNA repair defects in cancer cells to generate synthetic lethality Alterations in DNA repair pathways have been associated with response to DNA-damaging agents For example defective homologous recombination HR plays a crucial role in tumors where platinum agents are involved in therapeutic management as well as in those treated with PARP inhibitors which have synthetic lethal effects when applied to cells with defective HR Targeted mutational profiling of HR genes using next-generation sequencing has been used to identify mutations of key HR genes Furthermore HR-defective tumors exhibit genomic instability including loss of heterozygosity LOH telomeric allelic imbalance TAI and large-scale state transitions LST A combined HR deficiency score myChoice homologous recombination deficiency HRD test from Myriad Genetics defined as the sum of LOH TAI and LST has been developed This score has been associated with response to platinum-based chemotherapy and in ovarian cancer with the efficacy of niraparib in patients without germline breast cancer gene gBRCA mutations
In patients with muscle-invasive bladder cancer MIBC the Cancer Genome Atlas project found 31 of alterations in BRCA1-2 genes mainly related to copy number and overexpression In addition a high percentage of tumors had alterations in other DNA repair genes Recently in platinum-treated UC patients 47 of mutations in DNA repair genes have been found including 50 of mutations in HR Fanconi anemia and DNA-damage-response checkpoint pathways The presence of these mutations has been associated with survival These results suggest a potential role for PARP inhibitors in UC Niraparib is a highly selective inhibitor of poly adenosine diphosphate ADP-ribose polymerase PARP12 nuclear protein PARP enzymes are involved in DNA repair through activation of the base excision repair BER pathway and alternative end-joining pathways and inhibition of non-homologous end-joining PARP inhibition in cells with HR deficiency causes accumulation of unrepaired DNA double-strand breaks leading to cell death For these reasons PARP inhibitors are selectively lethal in tumor cells with defective HR Niraparib at the recommended oral dose of 300 mg daily has demonstrated efficacy in platinum- sensitive recurrent ovarian cancer with defective HR The most significant toxicity was hematologic thrombocytopenia neutropenia and anemia Among non-hematologic toxicities hypertension was detected in 8 of patients
c-Met receptor tyrosine kinase RTK is activated by its ligand hepatocyte growth factor HGF and induces increased proliferation migration motility and invasion of bladder cancer cells c-Met is overexpressed in more than 60 of metastatic bladder cancer patients and is linked to poor outcome Furthermore in bladder cancer c-Met is co-expressed with other RTKs such as AXL and PDGFR Some evidence suggests a relationship between c-Met and AXL expression with DNA damage response and resistance to chemotherapy For example Balaji et al have demonstrated that AXL inhibition leads to a defect in the HR pathway sensitizing cells to PARP inhibition In a recently published study a significant interaction between c-Met and Poly ADP-ribose polymerase 1 PARP1 was detected in breast cancer cell lines c-Met activity can decrease response to PARP inhibitors whereas treatment with c-Met inhibitors renders cells more sensitive to PARP inhibition Likewise in in vivo models with xenograft tumors the combination of c-Met and PARP inhibitors showed a significant reduction in tumor growth compared to either inhibitor alone This interaction can be explained because c-Met mediates PARP1 function through phosphorylation of PARP1 at Y907 These results raise the possibility that bladder cancer patients with tumors overexpressing c-Met can benefit from the combination of c-Met inhibitors and PARP inhibitors
Cabozantinib is an oral small-molecule tyrosine kinase inhibitor Its primary targets are MET VEGFR1-3 RET AXL FLT3 and KIT Cabozantinib has been approved by the FDA for clinical treatment of progressive metastatic medullary thyroid cancer The recommended dose of cabozantinib has been established in phase I trials at 60 mgday in 28-day cycles Recently published trials have demonstrated activity for cabozantinib in patients with advanced renal cell carcinoma and metastatic castration-resistant prostate cancer mCRPC Furthermore in preclinical models of UC of the bladder cabozantinib has demonstrated the ability to inhibit tumor xenograft growth It has been suggested that levels of soluble Met ectodomain sMet can be measured in the urine as a useful biomarker to monitor the efficacy of c-Met therapy in bladder cancer patients Moreover cabozantinib has demonstrated activity in heavily pretreated advanced bladder cancer patients with a response rate of 195 and manageable toxicities
In the phase I of this study it is proposed to evaluate DLTs of niraparib and cabozantinib combination and determine MTD in patients with advanced urothelial or renal cell carcinoma In the phase II it is proposed to make a preliminary evaluation of the efficacy of this combination in patients with urothelial cell carcinoma Efficacy results will be correlated with genomic alterations related to c-Met and PARP inhibitor activity
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
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 2017-004367-12 | EUDRACT_NUMBER | None | None |