- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04869475
Arsenic Trioxide in Refractory Solid Tumors With Rescuable p53 Mutation
Study Overview
Status
Conditions
Intervention / Treatment
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 approaches/agents 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 fully'wild-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 the'rainbow'p53 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 mutants'thermostability, 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:
- 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 and/or 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.
- 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 Type
Enrollment (Anticipated)
Phase
- Phase 2
Contacts and Locations
Study Contact
- Name: Min Shi, MD & Ph. D
- Phone Number: +86-21-64370045
- Email: sm11998@rjh.com.cn
Study Locations
-
-
-
Shanghai, China, 200025
- Recruiting
- Department of Oncology, Ruijin Hospital
-
Contact:
- Min Shi, MD & Ph. D
- Phone Number: +86-21-64370045
- Email: sm11998@rjh.com.cn
-
Principal Investigator:
- Min Lu, Ph. D
-
Sub-Investigator:
- Min Shi, MD & Ph. D
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Male/female patients aged≥18 years.
- Patients with refractory solid tumors were confirmed by histopathology and structural p53 mutations were confirmed by sanger sequence.
- ECOG performance status 0 or 2, expected lifetime≥3 months.
- Adequate organ function: Absolute neutrophil count (ANC) ≥1.5x109/L, White blood count ≥3.5x109/L, Platelets ≥75x109/L, Hemoglobin (Hb) ≥70g/L, ALT/AST ≤2.5x ULN (for patient with liver metastasis ALT/AST ≤5x ULN), Serum bilirubin ≤1.5x ULN, Serum creatinine ≤1.5x ULN.
- HBV infected patients (inactive/asymptomatic carrier, chronic or active) with HBV DNA<500IU/ml (or 2500 copies/ml).
- Pregnancy test of female patients with fertile activity should be negative within 7 days before enrollment. Patients should keep contraception during treatment.
- Willingness and ability to comply with the protocol for the duration of the study including scheduled visits, examinations, investigations and treatment plans with informed consent form.
Exclusion Criteria:
- Pregnancy or children bearing potential.
- brain or meningeal metastasis.
- With second primary malignant diseases.
- With uncontrolled auto-immune diseases, interstitial pneumonia, ulcerative colitis, or patients who should receive long-term glucocorticoid treatment (>10mg/d prednisone).
- With uncontrollable complications
- Inadequate organ function
- Conditions which impact on pill taking (dysphagia, chronic diarrhea, bowel obstruction).
- known hypersensitivity reaction to any of the study drugs or components.
- Other unsuitable conditions determined by investigators.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Experimental
arsenic trioxide 7mg/m2 ivgtt d1-14, q3w
|
This is a single-arm study with all patients receiving arsenci trioxide.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Disease control rate (DCR)
Time Frame: 12 months
|
12 months
|
Secondary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Progression free survival (PFS)
Time Frame: 12 months
|
12 months
|
Overall response rate (ORR)
Time Frame: 12 months
|
12 months
|
Duration of response (DOR)
Time Frame: 12 months
|
12 months
|
Safety: adverse events as assessed by CTCAE v5.0
Time Frame: 36 months
|
36 months
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Min Lu, Ph. D, Ruijin Hospital
- Principal Investigator: Jun Zhang, MD & PhD, Ruijin Hospital
Publications and helpful links
General Publications
- Tang Y, Song H, Wang Z, Xiao S, Xiang X, Zhan H, Wu L, Wu J, Xing Y, Tan Y, Liang Y, Yan N, Li Y, Li J, Wu J, Zheng D, Jia Y, Chen Z, Li Y, Zhang Q, Zhang J, Zeng H, Tao W, Liu F, Wu Y, Lu M. Repurposing antiparasitic antimonials to noncovalently rescue temperature-sensitive p53 mutations. Cell Rep. 2022 Apr 12;39(2):110622. doi: 10.1016/j.celrep.2022.110622.
- Canon J, Rex K, Saiki AY, Mohr C, Cooke K, Bagal D, Gaida K, Holt T, Knutson CG, Koppada N, Lanman BA, Werner J, Rapaport AS, San Miguel T, Ortiz R, Osgood T, Sun JR, Zhu X, McCarter JD, Volak LP, Houk BE, Fakih MG, O'Neil BH, Price TJ, Falchook GS, Desai J, Kuo J, Govindan R, Hong DS, Ouyang W, Henary H, Arvedson T, Cee VJ, Lipford JR. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature. 2019 Nov;575(7781):217-223. doi: 10.1038/s41586-019-1694-1. Epub 2019 Oct 30.
- Chen S, Wu JL, Liang Y, Tang YG, Song HX, Wu LL, Xing YF, Yan N, Li YT, Wang ZY, Xiao SJ, Lu X, Chen SJ, Lu M. Arsenic Trioxide Rescues Structural p53 Mutations through a Cryptic Allosteric Site. Cancer Cell. 2021 Feb 8;39(2):225-239.e8. doi: 10.1016/j.ccell.2020.11.013. Epub 2020 Dec 24.
- Kopetz S, Desai J, Chan E, Hecht JR, O'Dwyer PJ, Maru D, Morris V, Janku F, Dasari A, Chung W, Issa JP, Gibbs P, James B, Powis G, Nolop KB, Bhattacharya S, Saltz L. Phase II Pilot Study of Vemurafenib in Patients With Metastatic BRAF-Mutated Colorectal Cancer. J Clin Oncol. 2015 Dec 1;33(34):4032-8. doi: 10.1200/JCO.2015.63.2497. Epub 2015 Oct 12.
- Sabapathy K, Lane DP. Therapeutic targeting of p53: all mutants are equal, but some mutants are more equal than others. Nat Rev Clin Oncol. 2018 Jan;15(1):13-30. doi: 10.1038/nrclinonc.2017.151. Epub 2017 Sep 26.
- Wang H, Liu Y, Wang X, Liu D, Sun Z, Wang C, Jin G, Zhang B, Yu S. Randomized clinical control study of locoregional therapy combined with arsenic trioxide for the treatment of hepatocellular carcinoma. Cancer. 2015 Sep 1;121(17):2917-25. doi: 10.1002/cncr.29456. Epub 2015 May 29.
- Zhang TD, Chen GQ, Wang ZG, Wang ZY, Chen SJ, Chen Z. Arsenic trioxide, a therapeutic agent for APL. Oncogene. 2001 Oct 29;20(49):7146-53. doi: 10.1038/sj.onc.1204762.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Anticipated)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- PANDA-Basket 1
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Refractory Solid Tumors
-
University of Colorado, DenverUniversity of KentuckyCompletedRefractory Solid Tumors | Relapsed Solid TumorsUnited States
-
Cancer Institute and Hospital, Chinese Academy...RecruitingRefractory Solid Tumors | Relapsed Solid TumorsChina
-
National Cancer Institute (NCI)RecruitingSolid Tumor | Refractory Solid Tumors | Malignant Solid Tumors | Other Neoplasms Solid Tumors | Pediatric Solid TumorUnited States
-
Samsung Medical CenterCompletedRefractory Solid TumorsKorea, Republic of
-
Samsung Medical CenterCompletedRefractory Solid TumorsKorea, Republic of
-
Samsung Medical CenterCompletedRefractory Solid TumorsKorea, Republic of
-
TCRx Therapeutics Co.LtdRecruitingRefractory Solid Tumors | Relapsed Solid Tumors | TCR-T CellsChina
-
M.D. Anderson Cancer CenterRecruitingRefractory Solid TumorsUnited States
-
PharmaEngineCompletedRefractory Solid TumorsTaiwan
-
Samsung Medical CenterCompletedRefractory Solid TumorsKorea, Republic of
Clinical Trials on Arsenic trioxide
-
CTI BioPharmaTerminatedMultiple Myeloma and Plasma Cell NeoplasmUnited States
-
Albert Einstein College of MedicineNational Cancer Institute (NCI)CompletedProstate CancerUnited States
-
National Cancer Institute (NCI)CompletedLymphoma | LeukemiaUnited States, Canada, Australia
-
Memorial Sloan Kettering Cancer CenterNational Cancer Institute (NCI)CompletedLymphoma | Leukemia | Multiple Myeloma and Plasma Cell NeoplasmUnited States
-
Southwest Oncology GroupNational Cancer Institute (NCI)CompletedTesticular Germ Cell Tumor | Extragonadal Germ Cell TumorUnited States
-
Washington University School of MedicineNational Cancer Institute (NCI)Completed
-
M.D. Anderson Cancer CenterNational Cancer Institute (NCI)Withdrawn
-
Northwestern UniversityNational Cancer Institute (NCI)TerminatedLymphomaUnited States
-
Northwestern UniversityNational Cancer Institute (NCI)Completed
-
Memorial Sloan Kettering Cancer CenterNational Cancer Institute (NCI)CompletedLymphomaUnited States