Symptoms and General Pathology

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Diseases and Abnormalities at or Before Birth

Nutritional and Metabolic Diseases

Rare Diseases

Syndrome

Li-Fraumeni Syndrome

Neoplastic Syndromes, Hereditary

Genetic Diseases, Inborn

DNA Repair-Deficiency Disorders

Metabolic Diseases

Antineoplastic Agents

All Drugs and Chemicals

Antirheumatic Agents

Etoposide

Cyclophosphamide

Topotecan

Vincristine

Cisplatin

Etoposide phosphate

Arsenic Trioxide

Patients with p53-mutated pediatric cancer should initially undergo the corresponding first-line chemotherapy regimen. If the patient is evaluated as PD/SD, arsenic trioxide (ATO) will be administered in conjunction with previous conventional chemotherapy on the third day of each treatment cycle.

Patients should be treated with the corresponding first-line chemotherapy regimen first, for example: Neuroblastoma: CAV (cyclophosphamide, pinarubicin, vincristine), PVP (cisplatin, etoposide) ,CT (cyclophosphamide, topotecan).If patients was evaluted as PD/SD after treatments, arsenic trioxide (ATO) will be administered 0.18mg/kg per day over six hours IV daily for ten days in combination with previous chemotherapy regimen on the third day of each treatment cycle. Other pediatric tumors with TP53 mutations not mentioned above will have similar treatment regimens. If the efficacy of the conventional standard chemotherapy regimen is evaluated as PD/SD, then the next course of treatment will be combined with ATO on the basis of the standard chemotherapy regimen.

Arsenic trioxide

Yang Li, Professor

This prospective, single-arm, multi-center clinical trial aims to explore and evaluate the efficacy and safety of arsenic trioxide combined with chemotherapy for pediatric cancer with p53 mutation.

Germline mutation on tumor suppressor p53 can result in Li-Fraumeni syndrome (LFS), a hereditary condition characterized by the development of multiple cancer types, often at a young or middle age. LFS individuals face a lifetime cancer risk of up to 80-90%, with approximately half of them developing cancer by the age of 30 years. Despite the significantly increased risk of cancer-related morbidity and mortality, clinical management for LFS families is mainly the cancer screenings such as annual whole-body MRIs and the prevention measures such as avoiding exposure to DNA-damaging agents and radiation. Treatment options for LFS patients remain limited. The common LFS treatment regimens involve DNA-damaging chemotherapies and radiotherapies, which often lead to subsequent primary tumors in LFS patients. The susceptibility to second primary tumors is expected since TP53 functions as a haploinsufficient genome guardian. Mutant p53 rescue drugs, which restore tumor-suppressive function to mutant p53 without causing DNA damage, are attractive alternatives, yet no such drugs have been approved for clinical use to date. Unfortunately, the development of LFS-specific treatment drugs has received limited attention from the pharmaceutical industry possibly due to the low prevalence of LFS (occurring in 1 in 5,000 to 1 in 20,000 people worldwide, as evidenced by the lack of clinical trials for LFS treatment.

Different from cancers harboring germline p53 mutation, cancers harboring somatic p53 mutation are being extensively studied in the laboratories and clinics. Somatic p53 mutations can be detected in up to 10 million new cancer incidences per year, making p53 rescue small molecule being one of the most desirable targeted drug in oncology. Many standard treatments (partly) rely on functional wild-type p53 to achieve full treatment efficacy, as supported by the frequently observed higher p53 mutational prevalence in relapsed/refractory cancer patients. Thus, rescue of mutant p53 may (re)sensitize p53-mutant patients to various standard treatments. By 2023, about 25 clinical trials for mutant p53 rescue small molecules, involving over 2000 cancer patients with somatic p53 mutation, are registered on ClinicalTrials.gov.

To date, there have been reports of over twenty generic mutant p53 rescue compounds, with six entering clinical trials, including ATO, APR-246, PAT, COTI-2, PEITC, and Kevetrin. ATO stabilizes the p53 structure by simultaneously binding to the three spatially closed cysteines of the buried ABP pocket, thus strikingly potently stabilizing \[16\] and rescuing 390 structural p53 mutants, with a preference for the temperature-sensitive (TS) subtype of structural p53 mutants. APR-246 binds to all five exposed cysteines of p53 individually, and the rationale behind stabilizing the p53 structure through the binding of a single exposed cysteine remains inexplicable up to date. PAT shares a similar rescue mechanism to ATO as it also targets the ABP pocket but rescues only the 65 strongest TS p53 mutants due to its weaker stabilization of p53 compared to ATO. The structural rescue mechanisms of COTI-2, PEITC, and Kevetrin are currently unknown. While ATO and PAT are being used to rescue the ATO/PAT-rescuable structural p53 mutations based on their mechanisms and experimental validations, to our knowledge APR-246, COTI-2, PEITC, and Kevetrin are being tested for rescuing all of the p53 mutations in laboratory and clinical settings. However, based on the diversities of the p53 inactivation mechanisms and functional consequences made on p53 mutants, a one-size-fits-all compound that can restore wild-type function to all p53 mutants should not exist. Therefore, p53-rescue treatments in clinical trials is suggested to differentiate p53 mutations and, ideally, experimentally test the rescue effectiveness on the interested mutations before patient treatment.

In this clinical trial, we aim to evaluate the safety and efficacy of ATO in treating cancer patients harboring either germline or somatic p53 mutations. First, we will perform experiments in laboratory to assess the effectiveness of ATO in rescuing the p53 mutations detected in patients. Next, If ATO is effective in rescue a p53 mutation, the patient harboring this mutation (after failures in standard treatments) will be enrolled for clinical trials, using combination treatment of ATO and the standard treatments.

Arsenic Trioxide Combined With Chemotherapy for the Treatment of p53-mutated Pediatric Cancer

Clinical Research on Efficacy and Safety of Arsenic Trioxide Combined With Chemotherapy in p53-mutated Pediatric Cancer Patients：A Prospective，Single-arm, Multi-center Study

Ruijin Hospital

Yang Li

Professor

Blood and Lymph Conditions

Preleukemia

Myelodysplastic Syndromes

Bone Marrow Diseases

Hematologic Diseases

Precancerous Conditions

Decitabine

Antimetabolites

Enzyme Inhibitors

MDS patients of the experimental group will be treated with decitabine and arsenic trioxide.

MDS patients of the controlled group will be treated with decitabine alone.

20mg/m\^2,d1-5,ivgtt,28days as a duration

0.16mg/kg,d1-5,ivgtt,28days as a duration

Zhang Sujiang

Lu Min

This is a prospective,controlled and multi-institution trial.The aim is to identify if using decitabine and Arsenic Trioxide(ATO) as the therapy of Myelodysplastic Syndrome(MDS) has better relapse free survival and complete response than using decitabine alone.

TP53 mutation is commonly associated with poor cancer patient prognosis yet no mutant p53 (mp53)-targeting regimen was clinically established. Particularly, p53 mutation is associated with extremely poor prognosis in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) patients.

Decitabine (DAC) is a FDA approved drug for MDS treatment. In two independent clinical trials reported recently, DNA demethylating drug DAC treatment yielded a surprisingly high rate of complete remission (CR) in mp53-harboring AML/MDS patients (Welch, NEJM, 2016; Chang, BJH, 2017). Notably, all of the mp53-expressing patients in the two clinical studies relapsed quickly.

Arsenic trioxide (ATO) is a FDA approved drug for M3-AML treatment. Despite of the observed efficacy in treating non-APL patients, ATO is not yet approved for non-APL cancer treatment. ATO plays key role in regulating both wild-type p53 (wtp53) and mp53. Our published and unpublished data suggest ATO potentially hijacks nuclear iASPP-mediated STRaND pathway via exposing iASPP's RaDAR nuclear import code (Lu, Cancer Cell, 2013; Lu, Cell, 2014; Lu, Nat Rev Mol Cell Biol, 2016; Lu, unpublished). Our unpublished data also suggests a key role of ATO in regulating mp53 (Lu, The 17th International p53 Workshop, 2017). ATO is widely reported to be able to degrade and thus inhibit mp53's oncogenic function (Hamadeh, BBRC, 1999)(Liu, Blood, 2003). ATO suppressed cancer cell growth by targeting mp53 for degradation by Pirh2 degradation pathway (Yang, JBC, 2011; Yan, PLOS one, 2014);

Here we explore the potential of combination of DAC and ATO in improving the mp53-harboring AML/MDS patients' relapse free survival (RFS) and the ability to thoroughly eliminate mp53 subclone. Basic researches aiming to explore the mechanisms how mp53 cells responds to DAC and/or ATO treatment and how mp53 cells develop resistance to DAC and/or ATO will be coupled. We designate trials aiming for a better treatment regimen for mp53 patients as 'PANDA-Trials'.

300 MDS patients will be recruited for trial. They will be randomly administrated with ATO + decitabine (n=200) or decitabine alone (n=100). The RSF, CR ratio, overall survival will be compared between the two arms. Importantly, TP53 status will be sequenced and its correlation with RSF, CR ratio, overall survival within the two arms will be investigated.

Decitabine and Arsenic Trioxide for Myelodysplastic Syndrome(MDS)

Decitabine and Arsenic Trioxide(ATO) in the Treatment of Myelodysplasic Syndrome

since a patient first being determined as complete release until relapse

the percent of patients with complete release in all patients enrolled

from first diagnosed to death whichever the cause is

Li Junmin

director of the hematology department

Arsenic Trioxide (0.16mg/kg,d1-5,ivgtt,28days as a duration) for injection

Refractory cancer patients without standard-of-care harboring TP53 mutation received Arsenic Trioxide Injection (0.16mg/kg,d1-5,ivgtt,28days as a duration)

Xiaodong Jiao

Yuan-Sheng Zang

TP53 is the most frequently mutated gene in cancer, but these mutations remain therapeutically non-actionable. Previous study reported arsenic trioxide could rescue structural p53 mutations, endowing p53 mutations with thermostability and transcriptional activity. Under Vivo and Vitro experiments, arsenic trioxide could reactivate mutated p53 to inhibit tumor. This trial aimed to explore the efficacy and safety of arsenic trioxide in refractory cancer patients with structural p53 mutations.

Arsenic Trioxide for Structural p53 Mutations

Targeting Structural p53 Mutations With Arsenic Trioxide for Intractable Cancer

Proportion of patients with reduction in tumor burden of a predefined amount, including complete remission and partial remission

Time from treatment beginning until disease progression

Time from treatment beginning until death from any cause

Incidence of Treatment-related adverse Events

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Arsenic Trioxide Combined With Chemotherapy for the Treatment of p53-mutated Pediatric Cancer	NCT06088030	Pediatric Cance... Li-Fraumeni Syn... p53 Mutations	Arsenic trioxid...	- 18 Years	Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
Decitabine and Arsenic Trioxide for Myelodysplastic Syndrome(MDS)	NCT03377725	Myelodysplastic... P53 Mutation	Decitabine Arsenic Trioxid...	18 Years - 75 Years	Ruijin Hospital
Decitabine and Arsenic Trioxide for Myelodysplastic Syndrome(MDS)	NCT03377725	Myelodysplastic... P53 Mutation	Decitabine Arsenic Trioxid...	18 Years - 75 Years	Ruijin Hospital
Arsenic Trioxide for Structural p53 Mutations	NCT04695223	Arsenic Trioxid... p53 Mutations Refractory Canc... Intractable Can...	Arsenic Trioxid...	18 Years - 80 Years	Shanghai Changzheng Hospital
Decitabine and Arsenic Trioxide for Myelodysplastic Syndrome(MDS)	NCT03377725	Myelodysplastic... P53 Mutation	Decitabine Arsenic Trioxid...	18 Years - 75 Years	Ruijin Hospital

Spots Global Cancer Trial Database for p53 mutations