Clinical trial NCT04489706: Arsenic Trioxide in Recurrent and Metastatic Ovarian Cancer and Endometrial Cancer With P53 Mutation
Official title: A Clinical Trial to Evaluate the Efficacy, Safety, and Tolerability of Arsenic Trioxide for Injection in Patients With Recurrent and Metastatic Ovarian Cancer and Endometrial Cancer With P53 Mutation
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Ovarian Cancer
Endometrial Cancer
Keywords: Arsenic Trioxide for injection
P53 mutation
Recurrent and Metastatic Cancer
Lead sponsor: Ruijin Hospital
Sponsor class: OTHER
First posted: 2020-07-28
Enrollment: 20
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Histologically confirmed ovarian cancer and endometrial cancer patients with P53 mutation who had relapsed or metastasized after at least one line of standard system therapy. 20 subjects will be enrolled in this study.
Primary purpose: TREATMENT

Brief summary: This study is a Single-center, open, single-arm and non-randomized clinical trial in China. The aim of this study is to evaluate the efficacy, safety, and tolerability of Arsenic trioxide for injection in patients with recurrent and metastatic ovarian cancer and endometrial cancer with P53 mutation A group of 20 women with histologically confirmed ovarian cancer and endometrial cancer who had previously received at least one line of standard system therapy and had relapsed or metastasized had a P53 mutation.

The subjects of this study are histologically confirmed ovarian cancer and endometrial cancer patients with P53 mutation who had relapsed or metastasized after at least one line of standard system therapy. 20 subjects will be enrolled in this study.

Main objectives of the study are Independent imaging and tumor markers assess ORR (objective response rate) in patients with recurrent and metastatic ovarian cancer and endometrial cancer with P53 mutation treated with Arsenic trioxide for injection, based on RECIST v1.1 （Response evaluation criteria in solid tumors） Secondary objectives including DCR (Disease control rate), CBR (Clinical benefit rate), PFS (Progression free survival), OS (Overall survival), DoR (Duration of response), safety and tolerability of Arsenic trioxide for injection, based on NCI CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events), evaluated by researchers and life quality.

The study will be conducted in the department of obstetrics and gynecology in Shanghai Jiaotong University School of Medicine affiliated Ruijin Hospital.

Research intervention: injection Arsenic trioxide, 0.16mg/kg (maximum single dose is 10 mg), daily IV drip, d1 to d14, once every 28 days, for six cycles of treatment or until one of the following events occurs: Initiation of new anti-tumor therapy, disease progression, withdrawal of Informed consent form (ICF) and/or death.

The duration of this study will be 2.5 years; the admission period will be 1.5 years and the follow-up period will be 1 year.

Detailed description: The P53 mutation plays an important role in the development of ovarian cancer and endometrial cancer, which has been found to occur in more than 95% of high grade serous ovarian cancers, 25% of the endometrial cancer, with serous endometrial cancer having a P53 mutation rate of 88%.

In Acute promyelocytic leukemia treatment, a combination of retinoic acid (ATRA) and Arsenic trioxide (ATO) has an extremely high cure rate, with an overall five-year survival rate of 88% , the therapeutic effect of ATO on some hematologic malignancies has been widely recognized. What's more, it is also found that arsenic has potential therapeutic effects on a variety of solid tumors, including Esophageal, liver and lymphoma.

Preciously research modified H1299 cells with structural mutant P53 (p53-R175H) and treated them with doxcycline to knock down p53-R175H. The system was able to determine whether the observed antitumor effects were dependent on the structural mutant p53. In the transplanted tumor model of this cell line in mice, ATO significantly inhibited the tumor growth rate. In mice fed with doxcycline, cancer cells expressed almost no P53-R175H, and the ATO had limited inhibitory effect on the transplanted tumor model. These results suggest that ATO inhibits tumor cell proliferation mainly by targeting structural mutant p53.

Researchers tested the antineoplastic effects of ATO on various solid tumor PDX models on a small scale. the results showed than the antineoplastic effect of ATO on the PDX (Patient-Derived tumor Xenograft) model was observed in several solid tumor models with structural mutant P53, including liver, Lung, and Pancreatic Cancer. This suggests that the antineoplastic effects of ATO are not limited to the types of cancer. Its anti-tumor effect is only related to the structural mutant p53 in cancer cells.

Previous studies have shown that Arsenic trioxide can bind to the structural mutant P53 and partially restore its function, so the goal of this study is to observe the efficacy, safety, and tolerability of Arsenic trioxide for injection in patients with recurrent and metastatic ovarian cancer and endometrial cancer combined with P53 mutation.

Eligibility criteria: Inclusion Criteria:

* Participants (or their legal Representatives/guardians) are required to sign an informed consent form, indicating that they understand the objectives of the study, necessary procedures and are willing to participate in the study.
* Women over 18 years of age with histologically confirmed recurrence or metastasis of ovarian cancer or endometrial cancer.
* Laboratory confirmed P53 Gene Mutation.
* Previously received no less than 1-line treatment in the past with disease recurrence or progression.
* Disease Recurrence or progression (based on clinical, tumor markers, or imaging findings) occurs less than 6 months after the last treatment.
* At least one measurable lesion was confirmed by independent central imaging, according to RECIST V1.1, or elevation of tumor markers.
* ECOG PS (Eastern Cooperative Oncology Group Performance Status) score 0-1
* Estimated survival time ≥12 weeks.
* Sexually active, fertile subjects and their spouses have to agree to contraception throughout the study and within 90 days of the last study drug being given.

Exclusion Criteria:

* Hematopoiesis or organ dysfunction (blood products, such as blood transfusions, should not be used until less than 14 days before the first dose of the drug is studied) .
* ANC (Absolute neutrophil count）\<1.5×10\^9/L.
* HGB（Hemoglobin）\< 8 g/dL.
* PLT (Platelet）\<100×10\^9/L.
* TBIL (Total bilirubin）\>1.5 × ULN（Upper limit of normal)
* AST（Aspartate transferase）and/or ALT（Alanine aminotransferase）\>3 × ULN，\>5 × ULN in subjects with liver metastases.
* Cr (Creatine) \>1.5 × ULN.
* INR (International normalized ratio)\>1.5 × ULN，aPTT (activated Partial thromboplastin time) \>1.5 × ULN, (INR is only applicable to subjects who have not received anticoagulation therapy).
* Radiation therapy less than 4 weeks before the first dose of study drug, or chemotherapy, biotherapy, endocrine therapy or small molecule targeted therapy before the first dose of study drug (elution ≥5 half-lives can be grouped).
* Toxic response to previous antitumor therapy has not yet recovered to 1 grade, according to NCI CTCAE V5.0, except for alopecia.
* Clinically significant active infection.
* Clinically significant active bleeding.
* Alcoholism or drug addiction.
* A history of clinically significant liver disease, including active viral or other hepatitis, alcohol abuse, or cirrhosis, except in subjects with a prior hepatitis which is inactive, confirmed by PCR (Polymerase chain reaction).
* HIV (Human immunodeficiency virus) infection.
* NYHA (The New York Heart Association) Class II or above Heart failure; History of myocardial infarction or unstable Angina within 6 months before treatment; History of myocardial infarction or unstable angina within 6 months before treatment.
* Pregnancy, breastfeeding or planning to become pregnant during the study period.
* Bowel obstruction within 12 weeks before the first dose of the drug.
* Received major surgery within 4 weeks before the first dose of the study drug.
* Received oral or intravenous Glutathione within 3 weeks before the start of treatment.
* Known to be allergic or hypersensitive to any ingredient of Arsenic trioxide.
* Subjects with poor adherence, or with any unsuitability to participate in this trial; Subjects with any clinical or laboratory abnormalities were not eligible to participate in this clinical study.

Primary outcomes:
measure: the diameter of the measurable lesion
timeFrame: From the date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, through study completion, an average of 1 year.
measure: the level of tumor markers in serum.
timeFrame: From the date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, through study completion, an average of 1 year.
Secondary outcomes:
Other outcomes:
Locations:
city: Shanghai
country: China
facility: Shanghai JiaoTong University School of Medicine affliated Ruijin Hospital
state: Shanghai
Study officials:
affiliation: Ruijin Hospital
name: Weiwei Feng, PhD
role: STUDY_CHAIR
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