Camrelizumab Plus Fluzoparib for TP-53 Mutated Endometrial Cancer

Efficacy and Safety of Camrelizumab Plus Albumin-bound Paclitaxel/Carboplatin Followed by Camrelizumab With or Without Fluzoparib Maintenance Therapy for TP-53 Mutated Recurrent or Metastatic Endometrial Cancer: A Phase II Trial

This study is an open-label Phase II randomized controlled trial designed to evaluate the safety and efficacy of camrelizumab plus fluzoparib maintenance therapy in patients with recurrent or metastatic TP-53 mutated Endometrial Cancer. The study will also explore the prevalence of homologous recombination reficiency in Chinese patients with TP-53 mutated endometrial cancer and its therapeutic significance.

Study Overview

• Status: Recruiting
• Conditions: Endometrial Carcinoma; Recurrent or Metastatic; TP53 Mutation
• Intervention / Treatment: Drug: Fluzoparib; Drug: Camrelizumab; Drug: paclitaxel (albumin bound); Drug: Carboplatin injection; Drug: Carboplatin; Radiation: External irradiation

Detailed Description

The treatment of recurrent or metastatic endometrial carcinoma (R/M-EC) has entered the era of molecular marker oriented precision therapy. Meanwhile, several large multicenter Phase III RCT studies have been conducted, such as NRG-GY018, RUBY, DUO-E and AtTEnd, and suggested that chemotherapy combined with immunotherapy could significantly improve the prognosis of R/M-EC. Unfortunately, the efficacy of ICBs in Asian R/M-EC population is not obvious, with small size.

On the other hand, up to 63% of patients with R/M-EC have TP-53 gene mutations (TP53mut). And the efficacy of chemotherapy combined with immunotherapy in thse patients is controversial. In the RUBY study, TC combined with Dostarlimab reduced the risk of death in patients with TP53mut-R/M-EC by 59 percent. However, in the DUO-E study, chemotherapy combined with Durvalumab failed to improve serous -EC in 154 patients (approximately 92% TP53mut). Therefore, how to optimize the strategy of chemotherapy combined with immunotherapy in TP53mut-R/M-EC is urgently needed.

Considering TP53mut-EC patients with tumor local T-lymph Cell infiltration and PD-L1 expression were significantly higher than those of TP-53 gene wild type (TP53wt) patients. It was also suggested that ICB and PARPi had a good synergistic effect. The DUO-E study revealed the combination of Durvalumab and Olaparib maintenance therapy significantly improves the prognosis of serous EC.

Therefore, as an investigator-initiated open-label Phase II randomized controlled study, the study will include 117 patients with TP53mut-R/M-EC, and randomly divided 2:1 into experimental group and control group to evaluate the safety and efficacy of camrelizumab plus fluzoparib maintenance therapy in patients with recurrent or metastatic TP-53 mutated Endometrial Cancer. The study will also explore the prevalence of homologous recombination reficiency in Chinese patients with TP-53 mutated endometrial cancer and its therapeutic significance.

• Study Type: Interventional
• Enrollment (Estimated): 117
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Shuangzheng Jia, Ph D; Phone Number: 00-86-010-87788276; Email: jiashuangzheng@cicams.ac.cn

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100021
      • Recruiting
      • Cancer Hospital, Chinese Academy of Medical Sciences
      • Contact: SHUANGZHENG JIA

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥18
• Eastern Cooperative Oncology Group (ECOG) Performance Status (ECOG): 0-2. Expected survival ≥ 6 months.
• Patients with newly diagnosed International Federation of Gynecology and Obstetrics (FIGO) 2009 stage III-IV endometrial cancer or recurrent endometrial cancer after ≤ 1 line of platinum-based chemotherapy (including neoadjuvant, adjuvant, and concurrent chemotherapy). For patients who have failed platinum-based chemotherapy, a platinum-free interval of ≥ 12 months is required.
• No restriction on pathological type, abnormal p53 expression indicated by immunohistochemistry, and confirmation of TP53 gene mutation by Sanger sequencing or next-generation sequencing (NGS).
• No prior treatment with immune checkpoint blockade (ICB) or poly (ADP-ribose) polymerase inhibitor (PARPi).
• Discontinuation of previous radiation therapy, chemotherapy, or hormone therapy for at least 4 weeks.
• Adequate organ function as follows (no use of drugs containing blood components or corrective treatment with hematopoietic growth factors in the 7 days prior to randomization): Aspartate Aminotransferase (AST) and Alanine Transaminase (ALT) ≤ 2.5 times the upper limit of normal (≤ 5 times for patients with liver metastasis) and total bilirubin ≤ 1.5 times the upper limit of normal; serum creatinine ≤ 1.5 times the upper limit of normal; platelets ≥ 90,000 cells/mm3, hemoglobin ≥ 90 g/L, and neutrophils ≥ 1,500/mm3.
• Thyroid function prior to randomization: Thyroid-stimulating hormone (TSH) level ≤ 1 times the upper limit of normal, or if TSH is not within the normal range, free T4 ≤ 1 times the upper limit of normal.
• Peripheral neuropathy grade < 2 (Common Terminology Criteria for Adverse Events, CTCAE 5.0) before treatment.
• Signed informed consent and ability to provide tumor tissue samples from initial diagnosis/recurrence for homologous recombination deficiency (HRD) testing.
• Willingness to comply with clinic visits and follow-up.

Exclusion Criteria:

• Currently participating in another clinical trial or within 4 weeks since completing another clinical trial.
• Known allergy to any components of the investigational drug.
• Previous treatment with immune checkpoint inhibitors, including but not limited to other anti-PD-1 and anti-PD-L1 antibodies.
• Patients requiring the use of immunosuppressive medications.
• Previous treatment with poly (ADP-ribose) polymerase inhibitors (PARPi).
• Patients requiring systemic or absorbable topical corticosteroids at an immunosuppressive dose, or patients who have used prednisone or equivalent drugs at a dose >10 mg/day in the two weeks prior to taking the study drug.
• Patients with any active autoimmune disease or a history of autoimmune diseases, including but not limited to active hepatitis, pneumonia, uveitis, colitis (inflammatory bowel disease), pituitary inflammation, vasculitis, nephritis, hyperthyroidism, and hypothyroidism, excluding resolved childhood asthma/atopic diseases and vitiligo. Patients with intermittent use of bronchodilators or other medical interventions for asthma should also be excluded.
• Patients in the active infectious phase requiring antimicrobial treatment (e.g., antibiotics, antiviral drugs, antifungal drugs).
• History of immunodeficiency, including human immunodeficiency virus (HIV) seropositivity or other acquired or congenital immunodeficiency diseases.
• Uncontrolled clinically significant cardiac symptoms or diseases within the past year, including but not limited to New York Heart Association (NYHA) class II or higher heart failure, unstable angina, myocardial infarction within the past year, atrial fibrillation, clinically significant supraventricular or ventricular arrhythmias requiring treatment or intervention, PR interval >250 ms, or QTc ≥470 ms.
• Arterial or venous thrombosis within the past 6 months.
• Poorly controlled hypertension (systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg) despite antihypertensive medication, proteinuria ≥(++) and 24-hour total urinary protein >1.0 g.
• Coagulation abnormalities (international normalized ratio [INR] >2.0, prothrombin time [PT] >16s), bleeding tendency, or receiving thrombolytic or anticoagulant therapy.
• Patients with other malignant tumors within the past 5 years, excluding basal cell carcinoma of the skin and squamous cell carcinoma of the skin.
• Vaccination with live vaccines within 4 weeks prior to the first administration of the investigational drug. Note: Administration of inactivated seasonal influenza vaccines is allowed.
• History of substance abuse with psychotropic drugs and unable to quit, or patients with psychiatric disorders.
• The investigator believes that any other medical, psychiatric, or social factors may affect the rights, safety, ability to sign informed consent, patient's completion of the study, or interpretation of study results.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Camrelizumab with Fluzoparib as maintainance therapy; The treatment period mainly includes: Injection of Paclitaxel (Albumin-bound) at a dose of 260mg/m^2 administered intravenously every 3 weeks as one treatment cycle, for 6 cycles.; Injection of Carboplatin (AUC=5) administered intravenously every 3 weeks as one treatment cycle, for 6 cycles.; Injection of Camrelizumab at a dose of 200mg administered intravenously every 3 weeks as one treatment cycle, for 6 cycles.; Radiation therapy: Not mandatory. Maintainance therapy period mainly includes: Injection of Camrelizumab at a dose of 200mg administered intravenously every 3 weeks as one treatment cycle until disease progression, intolerable toxicity, death, or up to a maximum of 2 years.; Oral administration of Fluzoparib capsules at a dose of 150mg, once in the morning and once in the evening until disease progression, intolerable toxicity, death, or up to a maximum of 2 years.	Drug: Fluzoparib; During the maintenance phase of treatment. Oral administration of Fluzoparib capsules at a dose of 150mg（N=78 participants）, once in the morning and once in the evening until disease progression, intolerable toxicity, death, or up to a maximum of 2 years.; Drug: Camrelizumab; During the maintenance phase of treatment. Camrelizumab, 200 mg administered intravenously every 3 weeks until disease progression, intolerable toxicity, death, or up to 2 years.; Drug: paclitaxel (albumin bound); Paclitaxel (albumin-bound) for injection, 260 mg/m^2 administered intravenously in 3-week cycles for 6 cycles.; Drug: Carboplatin injection; AUC=5 Intravenous dosing is administered every 3 weeks for a total of 6 treatment cycles. Specific dosing cycles may be determined by the investigator; Drug: Carboplatin; AUC=5 Intravenous dosing is administered every 3 weeks for a total of 6 treatment cycles. Specific dosing cycles may be determined by the investigator; Radiation: External irradiation; Non-essential, decision to combine is made by the principal investigator based on the patient's condition.
Active Comparator: Camrelizumab without Fluzoparib as maintainance therapy; Treatment period mainly include: Injection of Paclitaxel (Albumin-bound) at a dose of 260mg/m^2 administered intravenously every 3 weeks as one treatment cycle, for a total of 6 cycles.; Injection of Carboplatin (AUC=5) administered intravenously every 3 weeks as one treatment cycle, for a total of 6 cycles.; Injection of Camrelizumab at a dose of 200mg administered intravenously every 3 weeks as one treatment cycle, for a total of 6 cycles.; Radiation therapy: Not mandatory. Whether to combine radiation therapy is determined by the principal investigator based on the patient's condition. Radiation therapy includes external beam radiation and brachytherapy. Maintainance therapy period mainly includes: a) Injection of Camrelizumab at a dose of 200mg administered intravenously every 3 weeks as one treatment cycle until disease progression, intolerable toxicity, death, or up to a maximum of 2 years.	Drug: Camrelizumab; During the maintenance phase of treatment. Camrelizumab, 200 mg administered intravenously every 3 weeks until disease progression, intolerable toxicity, death, or up to 2 years.; Drug: paclitaxel (albumin bound); Paclitaxel (albumin-bound) for injection, 260 mg/m^2 administered intravenously in 3-week cycles for 6 cycles.; Drug: Carboplatin injection; AUC=5 Intravenous dosing is administered every 3 weeks for a total of 6 treatment cycles. Specific dosing cycles may be determined by the investigator; Drug: Carboplatin; AUC=5 Intravenous dosing is administered every 3 weeks for a total of 6 treatment cycles. Specific dosing cycles may be determined by the investigator; Radiation: External irradiation; Non-essential, decision to combine is made by the principal investigator based on the patient's condition.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Investigator-assessed progression-free survival (PFS)	The time between randomization and tumor progression or death	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of Response（DoR）	The duration of remission or complete disappearance of the patient's disease after treatment	12 months
Overall Survival(OS)	The time between randomization and death.	24 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect of HRD status and HRR-mutated on PFS	PFS in patients with different (Homologous Recombination Deficiency)HRD status and (Homologous Recombination Repair)HRR mutations	12 months

Collaborators and Investigators

• Sponsor: Cancer Institute and Hospital, Chinese Academy of Medical Sciences
• Investigators: Principal Investigator: GUANGWEN YUAN, MD, Cancer Institute and Hospital, Chinese Academy of Medical Sciences

Study record dates

Study Major Dates

• Study Start (Actual): May 10, 2024
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): June 1, 2027

Study Registration Dates

• First Submitted: April 23, 2024
• First Submitted That Met QC Criteria: May 10, 2024
• First Posted (Actual): May 14, 2024

Study Record Updates

• Last Update Posted (Actual): May 14, 2024
• Last Update Submitted That Met QC Criteria: May 10, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: TP53-mutated, Endometrial Carcinoma,Camrelizumab, Fluzoparib
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Uterine Neoplasms; Genital Neoplasms, Female; Uterine Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Endometrial Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Poly(ADP-ribose) Polymerase Inhibitors; Carboplatin; Paclitaxel; Fluzoparib
• Other Study ID Numbers: CAFE

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No