Clinical Trial Details
— Status: Active, not recruiting
Administrative data
NCT number |
NCT03425201 |
Other study ID # |
NICARAGUA |
Secondary ID |
2017-004367-12 |
Status |
Active, not recruiting |
Phase |
Phase 1/Phase 2
|
First received |
|
Last updated |
|
Start date |
October 14, 2019 |
Est. completion date |
April 2024 |
Study information
Verified date |
December 2023 |
Source |
Fundacion CRIS de Investigación para Vencer el Cáncer |
Contact |
n/a |
Is FDA regulated |
No |
Health authority |
|
Study type |
Interventional
|
Clinical Trial 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
19.5% 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.
Description:
Bladder cancer is the 9th most common cancer worldwide, with around 429.800 new cases
diagnosed in 2012 and the 5th most common cancer in Europe, with more than 151.000 new cases
diagnosed in 2012. Relating mortality figures, bladder cancer is the 13th most common cause
of cancer death worldwide, with around 165.100 deaths from bladder cancer in 2012 and the 9th
in Europe, with around 52.400.
Cisplatin-based chemotherapy remains the standard treatment in patients with metastatic
urothelial carcinoma (UC).This 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 (PARP)1/2 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 mg/day 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 19.5% 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.