Ignite Creation Date:
2024-05-06 @ 4:05 PM
Last Modification Date:
2024-10-26 @ 2:03 PM
Study NCT ID:
NCT04869475
Status:
UNKNOWN
Last Update Posted:
2021-05-13
First Post:
2021-04-28
Brief Title:
Arsenic Trioxide in Refractory Solid Tumors With Rescuable p53 Mutation
Sponsor:
Ruijin Hospital
Organization:
Ruijin Hospital
Study Overview
Official Title:
Arsenic Trioxide in Refractory Solid Tumors With Rescuable p53 Mutation
Status:
UNKNOWN
Status Verified Date:
2021-05
Last Known Status:
RECRUITING
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:
None
Brief Summary:
This study is an open prospective single arm multi center exploratory basket clinical study 20 refractory solid tumors patients with rescuable p53 mutation will be enrolled and the efficacy and safety of arsenic trioxide in those patients will be evaluated
Detailed Description:
p53 is the most frequently mutated protein in cancer It is mutated in about half of all cancers and losses tumor-suppressive function Yet there is no approved p53-targeted therapy being one of the most unmet clinical needs At least 45 approachesagents were identified to kill cancer cells via p53 mutations by 2017 with at least 17 agents reported to function by restoring mutant p53 with wild-type p53 activity yet these compounds are far from being able to achieve the desired outcome of converting all mutant p53 molecules to become fullywild-type-like
In 2020 investigators reported the FDA-approved arsenic trioxide ATO as a mutant p53 rescue drug Investigators firstly based on the knowledge that the hundreds of p53 mutations inactivate p53 via heterogeneous mechanisms proposed that there may be no single agent that is able to recue all of therainbowp53 mutants Investigators next proposed a rational mutant p53 rescue strategy wherein the unfolded p53 mutants termed as structural mutants were precisely selected as rescue objects and in addition a thermostabilizing compounds were rationally used to promote the folding of structural mutants Thirdly investigators aimed at a cryptical completely-buried pocket inside p53 in conventional targeted therapy the targeted pockets are on the protein surface and thus exposed By above investigators identified ATO as a mutant p53 rescue compound mechanistically mimicking the formation of disulfide bonds in C124-C135-C141 triad to promote the folding of structural mutants in the solved co-crystal structures disulfide bond is one of the main forces to promote protein folding upon protein translation in classic biological chemistry textbook
ATO differentiates itself from previously reported broad-spectrum mutant p53 rescue compounds in i ATO is superior to the reported compounds by at least 100-time rescue efficiencies in promoting structural p53 mutantsthermostability protein folding specific DNA-binding ability transcriptional activity and other p53 activities in laboratories ii the rescue is accompanied with a structural mechanism revealing how broad-spectrum p53 mutants note not all p53 mutants can be rescued by a single small molecule iii ATO is the compound that can only rescue a part of structural p53 mutations it can not rescue all p53 mutations it can not rescue all structural p53 mutations neither and also a compound that has been experimentally applied and confirmed on dozens of p53 mutations
ATO is the most effective APL leukemia treatment drug When combined with ATRA ATO cures APL leukemia 5-year survival from 30 to over 90 ATO was also reported to be efficacious in treating patients with non-APL hematological malignance and solid tumors yet the response rate is low Investigators thus proposed that it is p53 mutation conferring the treatment efficacy
The hundreds of p53 mutations have wide-spectrum cancer distribution and in addition have highly diverse rescue efficiencies by ATO Thus cancer type selection and mutation selection are the two challenges in the current clinical trial Note These two challenges do not exist for the other targeted drugs such as the widely used EGFR inhibitors and the recent ground-breaking KRAS-G12C inhibitors since according to the TCGA PanCancer Altas Studies their applicable mutations predominately occur in one cancer type both in lung adenocarcinoma and clustered in one or few codons of their encoding genes For these two challenges
1 The current trial will focus on the cancer types predicted to highly dependent on p53 mutations in other words the p53 mutation should be a key driver in this cancer type and the cancer cells depend on the p53 mutation to survive andor grow Previous clinical trials have confirmed the importance of selecting appropriate cancer types for a targeted drug For example BRAFV600E inhibitors exhibit relatively high efficacy in treating BRAF-mutated melanoma but not colorectal cancers
2 The current trial will further precisely select p53 mutations that can be effectively and ideally highly efficiently rescued by ATO Since ATO can only rescues a part of structural mutations investigators thus initialized a large-scale project-PANDA P53 AND Arsenic cancer project since 2016 wherein investigators cloned the most frequent 800 p53 mutations individually covering 95 p53 missense mutation cases in IARC and quantified their rescue efficiencies by ATO for their transcriptional activities the mutations were quantified individually anti-proliferation ability in cancer cells anti-tumor growth in xenograft mouse model et al In the PANDA cancer project there is an apparent trend that ATO is most efficient in rescuing large-to-small amino acid mutations mutations near the arsenic-binding pocket temperature-sensitive mutations as well as the mutations occurring on hydrophobic residues and in the LSH motif Based on the rescue efficiencies by ATO p53 mutations were stratified in several classes in the PANDA project the open-access website for PANDA project is estimated to be completed in end of 2021 The patients harboring the class of p53 mutations that can be relatively efficiently and most efficiently rescued by ATO will be precisely recruited in the current trial
The current exploratory trial was termed as PANDA-bascket1
In 2020 investigators reported the FDA-approved arsenic trioxide ATO as a mutant p53 rescue drug Investigators firstly based on the knowledge that the hundreds of p53 mutations inactivate p53 via heterogeneous mechanisms proposed that there may be no single agent that is able to recue all of therainbowp53 mutants Investigators next proposed a rational mutant p53 rescue strategy wherein the unfolded p53 mutants termed as structural mutants were precisely selected as rescue objects and in addition a thermostabilizing compounds were rationally used to promote the folding of structural mutants Thirdly investigators aimed at a cryptical completely-buried pocket inside p53 in conventional targeted therapy the targeted pockets are on the protein surface and thus exposed By above investigators identified ATO as a mutant p53 rescue compound mechanistically mimicking the formation of disulfide bonds in C124-C135-C141 triad to promote the folding of structural mutants in the solved co-crystal structures disulfide bond is one of the main forces to promote protein folding upon protein translation in classic biological chemistry textbook
ATO differentiates itself from previously reported broad-spectrum mutant p53 rescue compounds in i ATO is superior to the reported compounds by at least 100-time rescue efficiencies in promoting structural p53 mutantsthermostability protein folding specific DNA-binding ability transcriptional activity and other p53 activities in laboratories ii the rescue is accompanied with a structural mechanism revealing how broad-spectrum p53 mutants note not all p53 mutants can be rescued by a single small molecule iii ATO is the compound that can only rescue a part of structural p53 mutations it can not rescue all p53 mutations it can not rescue all structural p53 mutations neither and also a compound that has been experimentally applied and confirmed on dozens of p53 mutations
ATO is the most effective APL leukemia treatment drug When combined with ATRA ATO cures APL leukemia 5-year survival from 30 to over 90 ATO was also reported to be efficacious in treating patients with non-APL hematological malignance and solid tumors yet the response rate is low Investigators thus proposed that it is p53 mutation conferring the treatment efficacy
The hundreds of p53 mutations have wide-spectrum cancer distribution and in addition have highly diverse rescue efficiencies by ATO Thus cancer type selection and mutation selection are the two challenges in the current clinical trial Note These two challenges do not exist for the other targeted drugs such as the widely used EGFR inhibitors and the recent ground-breaking KRAS-G12C inhibitors since according to the TCGA PanCancer Altas Studies their applicable mutations predominately occur in one cancer type both in lung adenocarcinoma and clustered in one or few codons of their encoding genes For these two challenges
1 The current trial will focus on the cancer types predicted to highly dependent on p53 mutations in other words the p53 mutation should be a key driver in this cancer type and the cancer cells depend on the p53 mutation to survive andor grow Previous clinical trials have confirmed the importance of selecting appropriate cancer types for a targeted drug For example BRAFV600E inhibitors exhibit relatively high efficacy in treating BRAF-mutated melanoma but not colorectal cancers
2 The current trial will further precisely select p53 mutations that can be effectively and ideally highly efficiently rescued by ATO Since ATO can only rescues a part of structural mutations investigators thus initialized a large-scale project-PANDA P53 AND Arsenic cancer project since 2016 wherein investigators cloned the most frequent 800 p53 mutations individually covering 95 p53 missense mutation cases in IARC and quantified their rescue efficiencies by ATO for their transcriptional activities the mutations were quantified individually anti-proliferation ability in cancer cells anti-tumor growth in xenograft mouse model et al In the PANDA cancer project there is an apparent trend that ATO is most efficient in rescuing large-to-small amino acid mutations mutations near the arsenic-binding pocket temperature-sensitive mutations as well as the mutations occurring on hydrophobic residues and in the LSH motif Based on the rescue efficiencies by ATO p53 mutations were stratified in several classes in the PANDA project the open-access website for PANDA project is estimated to be completed in end of 2021 The patients harboring the class of p53 mutations that can be relatively efficiently and most efficiently rescued by ATO will be precisely recruited in the current trial
The current exploratory trial was termed as PANDA-bascket1
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