A Phase II Study of Utidelone With Toripalimab in Advanced Cervical Cancer

NCT07363330NOT_YET_RECRUITINGPHASE2INTERVENTIONAL

Summary

This is a Phase II clinical trial to evaluate the safety and efficacy of Utidelone, a genetically engineered epothilone derivative, combined with Toripalimab, a PD-1 inhibitor, in patients with recurrent or metastatic cervical cancer who have progressed after standard treatments. The study will also assess the safety profile of this combination therapy. The primary objectives of this study include: (1) to determine the objective response rate (ORR), meaning whether the treatment can reduce the size of tumors or make them disappear, according to the RECIST 1.1 criteria; (2) to evaluate the safety of the treatment and document the side effects experienced by participants. This study is for individuals who: (1) are between 18 and 75 years old; (2) have a confirmed diagnosis of recurrent or metastatic cervical cancer; (3) have previously received at least one standard chemotherapy regimen that is no longer controlling the cancer; (4) are in generally good health, as determined by the study investigators. In this single-arm study, all participants will receive the same treatment: Utidelone will be administered by intravenous (IV) infusion over 1.5 hours, once a day for 5 consecutive days, in each 21-day treatment cycle; Toripalimab will be administered by IV infusion over 1.5 hours, once on Day 6 of each 21-day cycle. Participants may continue receiving the study drugs as long as they are benefiting from the treatment and side effects are manageable. Doctors will assess tumor size using imaging scans (like CT or MRI) every 6 weeks to monitor how the cancer responds to treatment. The study will take place at Zhongnan Hospital of Wuhan University and plans to include approximately 32 participants.

Key Facts

Lead Sponsor

Zhongnan Hospital

Enrollment

32

Start Date

2026-02-01

Completion Date

2027-12-31

Study Type

INTERVENTIONAL

Official Title

Utidelone Combined With Toripalimab in Patients With Pretreated Recurrent or Metastatic Cervical Cancers: a Single-Arm, Phase II Study

Interventions

Utidelone plus Toripalimab

Conditions

Cervical CancerRecurrentMetastatic

Eligibility

Age Range

18 Years – 75 Years

Sex

FEMALE

Inclusion Criteria:

1. Informed Consent: Patients must voluntarily sign an informed consent form prior to any study-related procedures.
2. Age: Aged ≥18 years and ≤75 years.
3. Diagnosis: Histologically or cytologically confirmed recurrent or metastatic cervical carcinoma.
4. Performance Status: With an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
5. Measurable Disease: With at least one measurable lesion as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
6. Prior Therapy:

   * Patients must have received at least one line of standard systemic chemotherapy for recurrent/metastatic disease, OR
   * Patients with rapid disease progression (occurring within 6 months) during or after prior neoadjuvant or concurrent chemoradiotherapy.
7. Treatment-Related Toxicity: Recovery from all toxicities related to prior anti-cancer therapies to ≤ Grade 1 (according to CTCAE v5.0). Patients with alopecia of any grade are eligible.
8. Adequate Hematological Function (within 1 week prior to enrollment, per local laboratory reference ranges):

   * White blood cell count (WBC) ≥ 2.5 × 10⁹/L.
   * Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L.
   * Platelet count (PLT) ≥ 100 × 10⁹/L.
   * Hemoglobin (Hb) ≥ 9.0 g/dL (transfusion or erythropoietin use is permitted to meet this criterion).
9. Adequate Liver and Kidney Functions (within 1 week prior to enrollment, per local laboratory reference ranges):

   * Total bilirubin (TBIL) ≤ 1.5 × the upper limit of normal (ULN).
   * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN (≤ 5 × ULN for patients with liver metastases).
   * Calculated creatinine clearance (Ccr) ≥ 60 mL/min.
10. Contraception: Patients of childbearing potential must agree to use highly effective contraception during the study and for at least 90 days after the last dose of study treatment. A negative serum or urine pregnancy test is required for female patients of childbearing potential within 7 days prior to enrollment.
11. Life Expectancy: Anticipated life expectancy of at least 12 weeks.
12. Compliance: Patients must be able and willing to comply with the study protocol for treatment and follow-up.

Exclusion Criteria:

1. Concurrent Malignancy: History of other active malignancies within the past 5 years, except for adequately treated basal cell carcinoma of the skin.
2. Recent Anti-cancer Therapy: Any anti-cancer therapy (including chemotherapy, radical radiotherapy, hormonal therapy, biological therapy, or anti-cancer Chinese herbal medicine) within 4 weeks prior to the initiation of study treatment.
3. Recent Major Surgery/Trauma: Major surgical procedure (excluding diagnostic biopsy) or significant traumatic injury within 4 weeks prior to the first dose of study drug, or anticipation of the need for major surgery during the study period.
4. Prior Neurotoxicity: History of ≥ Grade 3 neurological adverse reactions attributed to prior anti-microtubule therapy.
5. Symptomatic CNS Metastases: Patients with symptomatic central nervous system (CNS) metastases.
6. Pregnancy/Lactation: Women who are pregnant or breastfeeding.
7. Hypersensitivity: Known or suspected hypersensitivity to any component of the study drugs or their excipients.
8. Severe Comorbidities: Any uncontrolled or severe concurrent medical condition that, in the investigator's judgment, would preclude participation, including but not limited to:

   * Severe cardiovascular or cerebrovascular disease.
   * Uncontrolled diabetes mellitus or hypertension.
   * Active severe infection.
   * Active peptic ulcer disease.
   * Uncontrolled psychiatric illness/disorder.
9. General Exclusion: Any other condition or circumstance that, in the opinion of the investigator, would compromise the patient's safety or compliance, or make the patient unsuitable for study participation.
10. Contraindication to Steroids: Conditions for which corticosteroid use is contraindicated.

Outcome Measures

Primary Outcomes

Objective response rate (ORR)

Time frame: Tumor assessments are performed at baseline and every 6 weeks (± 3 days) until progression or start of new therapy. ORR is analyzed after all patients have completed at least 18 weeks of follow-up or experienced a study endpoint event.

Secondary Outcomes

Progression-Free Survival (PFS)

Time frame: From the date of enrollment until first documented disease progression (per RECIST 1.1) or death from any cause, whichever occurs first, assessed up to approximately 24 months.

Time to Response (TTR)

Time frame: From the date of enrollment to the first documented objective response (Complete or Partial Response per RECIST 1.1), assessed up to approximately 24 months.

Duration of Response (DoR)

Time frame: From the date of first documented objective response (CR or PR) until documented disease progression or death due to underlying cervical cancer, assessed up to approximately 36 months.

Overall Survival (OS)

Time frame: From the date of enrollment until death from any cause, assessed up to approximately 36 months.

Incidence of Treatment-Emergent Adverse Events (TEAEs)

Time frame: From the first dose of study drug until 30 days after the last dose, assessed throughout the treatment period (up to approximately 24 months).

Incidence of Serious Adverse Events (SAEs)

Time frame: From the first dose of study drug until 90 days after the last dose, assessed throughout the treatment and extended safety follow-up period (up to approximately 27 months).

Number of Participants With Clinically Significant Laboratory Abnormalities

Time frame: Laboratory parameters are monitored at each 21-day treatment cycle from first dose until 30 days after the last dose (up to approximately 24 months).

Locations

Zhongnan Hospital of Wuhan University, Wuhan, China

Linked Papers

2023-12-01

Atezolizumab plus bevacizumab and chemotherapy for metastatic, persistent, or recurrent cervical cancer (BEATcc): a randomised, open-label, phase 3 trial

The GOG240 trial established bevacizumab with chemotherapy as standard first-line therapy for metastatic or recurrent cervical cancer. In the BEATcc trial (ENGOT-Cx10-GEICO 68-C-JGOG1084-GOG-3030), we aimed to evaluate the addition of an immune checkpoint inhibitor to this standard backbone. In this investigator-initiated, randomised, open-label, phase 3 trial, patients from 92 sites in Europe, Japan, and the USA with metastatic (stage IVB), persistent, or recurrent cervical cancer that was measurable, previously untreated, and not amenable to curative surgery or radiation were randomly assigned 1:1 to receive standard therapy (cisplatin 50 mg/m Between Oct 8, 2018, and Aug 20, 2021, 410 of 519 patients assessed for eligibility were enrolled. Median progression-free survival was 13·7 months (95% CI 12·3-16·6) with atezolizumab and 10·4 months (9·7-11·7) with standard therapy (hazard ratio [HR]=0·62 [95% CI 0·49-0·78]; p<0·0001); at the interim overall survival analysis, median overall survival was 32·1 months (95% CI 25·3-36·8) versus 22·8 months (20·3-28·0), respectively (HR 0·68 [95% CI 0·52-0·88]; p=0·0046). Grade 3 or worse adverse events occurred in 79% of patients in the experimental group and in 75% of patients in the standard group. Grade 1-2 diarrhoea, arthralgia, pyrexia, and rash were increased with atezolizumab. Adding atezolizumab to a standard bevacizumab plus platinum regimen for metastatic, persistent, or recurrent cervical cancer significantly improves progression-free and overall survival and should be considered as a new first-line therapy option. F Hoffmann-La Roche.

2022-09-13

Recurrent or primary metastatic cervical cancer: current and future treatments

Despite screening programs for early detection and the approval of human papillomavirus vaccines, around 6% of women with cervical cancer (CC) are discovered with primary metastatic disease. Moreover, one-third of the patients receiving chemoradiation followed by brachytherapy for locally advanced disease will have a recurrence. At the end, the vast majority of recurrent or metastatic CC not amenable to locoregional treatments are considered incurable disease with very poor prognosis. Historically, cisplatin monotherapy, then a combination of cisplatin and paclitaxel were considered the standard of care. Ten years ago, the addition of bevacizumab to chemotherapy demonstrated favorable data in terms of response rate and overall survival. Even with this improvement, novel therapies are needed for the treatment of recurrent CC in first as well as later lines. In the last decades, a better understanding of the interactions between human papillomavirus infection and the host immune system response has focused interest on the use of immunotherapeutic drugs in CC patients. Indeed, immune checkpoint inhibitors (pembrolizumab, cemiplimab, and others) have recently emerged as novel therapeutic pillars that could provide durable responses with impact on overall survival in patients in the primary (in addition to chemotherapy) or recurrent (monotherapy) settings. Tisotumab vedotin, an antibody-drug conjugate targeting the tissue factor, is another emerging drug. Several trials in monotherapy or in combination with immunotherapy, chemotherapy, or bevacizumab showed very promising results. There is a high need for more potent biomarkers to better accurately determine which patients would receive the greatest benefit from all these aforementioned drugs, but also to identify patients with specific molecular characteristics that could benefit from other targeted therapies. The Cancer Genome Atlas Research Network identified several genes significantly mutated, potentially targetable. These molecular data have highlighted the molecular heterogeneity of CC.

2021-09-18

Pembrolizumab for Persistent, Recurrent, or Metastatic Cervical Cancer

Pembrolizumab has efficacy in programmed death ligand 1 (PD-L1)-positive metastatic or unresectable cervical cancer that has progressed during chemotherapy. We assessed the relative benefit of adding pembrolizumab to chemotherapy with or without bevacizumab. In a double-blind, phase 3 trial, we randomly assigned patients with persistent, recurrent, or metastatic cervical cancer in a 1:1 ratio to receive pembrolizumab (200 mg) or placebo every 3 weeks for up to 35 cycles plus platinum-based chemotherapy and, per investigator discretion, bevacizumab. The dual primary end points were progression-free survival and overall survival, each tested sequentially in patients with a PD-L1 combined positive score of 1 or more, in the intention-to-treat population, and in patients with a PD-L1 combined positive score of 10 or more. The combined positive score is defined as the number of PD-L1-staining cells divided by the total number of viable tumor cells, multiplied by 100. All results are from the protocol-specified first interim analysis. In 548 patients with a PD-L1 combined positive score of 1 or more, median progression-free survival was 10.4 months in the pembrolizumab group and 8.2 months in the placebo group (hazard ratio for disease progression or death, 0.62; 95% confidence interval [CI], 0.50 to 0.77; P<0.001). In 617 patients in the intention-to-treat population, progression-free survival was 10.4 months and 8.2 months, respectively (hazard ratio, 0.65; 95% CI, 0.53 to 0.79; P<0.001). In 317 patients with a PD-L1 combined positive score of 10 or more, progression-free survival was 10.4 months and 8.1 months, respectively (hazard ratio, 0.58; 95% CI, 0.44 to 0.77; P<0.001). Overall survival at 24 months was 53.0% in the pembrolizumab group and 41.7% in the placebo group (hazard ratio for death, 0.64; 95% CI, 0.50 to 0.81; P<0.001), 50.4% and 40.4% (hazard ratio, 0.67; 95% CI, 0.54 to 0.84; P<0.001), and 54.4% and 44.6% (hazard ratio, 0.61; 95% CI, 0.44 to 0.84; P = 0.001), respectively. The most common grade 3 to 5 adverse events were anemia (30.3% in the pembrolizumab group and 26.9% in the placebo group) and neutropenia (12.4% and 9.7%, respectively). Progression-free and overall survival were significantly longer with pembrolizumab than with placebo among patients with persistent, recurrent, or metastatic cervical cancer who were also receiving chemotherapy with or without bevacizumab. (Funded by Merck Sharp and Dohme; KEYNOTE-826 ClinicalTrials.gov number, NCT03635567.).

Survival with Cemiplimab in Recurrent Cervical Cancer

Patients with recurrent cervical cancer have a poor prognosis. Cemiplimab, the fully human programmed cell death 1 (PD-1)-blocking antibody approved to treat lung and skin cancers, has been shown to have preliminary clinical activity in this population. In this phase 3 trial, we enrolled patients who had disease progression after first-line platinum-containing chemotherapy, regardless of their programmed cell death ligand 1 (PD-L1) status. Women were randomly assigned (1:1) to receive cemiplimab (350 mg every 3 weeks) or the investigator's choice of single-agent chemotherapy. The primary end point was overall survival. Progression-free survival and safety were also assessed. A total of 608 women were enrolled (304 in each group). In the overall trial population, median overall survival was longer in the cemiplimab group than in the chemotherapy group (12.0 months vs. 8.5 months; hazard ratio for death, 0.69; 95% confidence interval [CI], 0.56 to 0.84; two-sided P<0.001). The overall survival benefit was consistent in both histologic subgroups (squamous-cell carcinoma and adenocarcinoma [including adenosquamous carcinoma]). Progression-free survival was also longer in the cemiplimab group than in the chemotherapy group in the overall population (hazard ratio for disease progression or death, 0.75; 95% CI, 0.63 to 0.89; two-sided P<0.001). In the overall population, an objective response occurred in 16.4% (95% CI, 12.5 to 21.1) of the patients in the cemiplimab group, as compared with 6.3% (95% CI, 3.8 to 9.6) in the chemotherapy group. An objective response occurred in 18% (95% CI, 11 to 28) of the cemiplimab-treated patients with PD-L1 expression greater than or equal to 1% and in 11% (95% CI, 4 to 25) of those with PD-L1 expression of less than 1%. Overall, grade 3 or higher adverse events occurred in 45.0% of the patients who received cemiplimab and in 53.4% of those who received chemotherapy. Survival was significantly longer with cemiplimab than with single-agent chemotherapy among patients with recurrent cervical cancer after first-line platinum-containing chemotherapy. (Funded by Regeneron Pharmaceuticals and Sanofi; EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9 ClinicalTrials.gov number, NCT03257267.).

Linked Investigators

Andreia Cristina de Melo