Ovary Cancer
Conditions
Keywords
Disitamab vedotin, AK104, bevacizumab
Brief summary
Disitamab vedotin (RC48) in combination with AK104 (PD-1/CTLA-4 bispecific) and bevacizumab for the treatment of recurrent and persistent clear cell ovarian cancer: a single-arm, phase II, multicenter study (DAB OCC study)
Detailed description
Ovarian clear cell carcinoma (OCCC) ranks as the second most common epithelial ovarian malignancy in Asian women, characterized by extremely poor prognosis, with a median overall survival (OS) of 25.3 months. OCCC demonstrates a dismal response rate to conventional chemotherapy, and once in a state of persistence or recurrence, treatments become severely limited, with a mere 5-year survival rate of 13.2%, with over two-thirds of patients succumbing within 1 year. Thus, there is an urgent need to explore new therapeutic approaches for recurrent and persistent OCCC patients. Evidence suggests that anti-angiogenesis therapy is effective against OCCC, which tends to exhibit a "hot tumor" phenotype. Hence, the combination of anti-angiogenesis therapy with immunotherapy holds promise for recurrent and persistent OCCC. Additionally, overexpression of human epidermal growth factor receptor 2 (HER2) plays a pivotal role in OCCC resistance formation. Antibody drug conjugates (ADCs) targeting HER2 have shown increasing efficacy in ovarian cancer treatment, with significant immunomodulatory effects enhancing the efficacy of immunotherapy. Based on this evidence, the investigators hypothesize that the combination of anti-angiogenesis therapy, immunotherapy, and HER2-targeted ADCs may improve the prognosis of OCCC patients. Therefore, the investigators are initiating this clinical study aimed at evaluating the efficacy and safety of disitamab vedotin (HER2-targeted ADC) in combination with AK104 (anti-PD-1 and CTLA4) and bevacizumab (anti-angiogenesis) in HER2 positive recurrent and persistent OCCC patients (disitamab vedotin 2.5 mg/kg + AK104 10 mg/kg + bevacizumab 15 mg/kg, every 3 weeks), with the aim of providing new treatment options for these refractory gynecologic malignancies. During the initial stage of the study, patients with prior exposure to immunotherapy were excluded. Preliminary results from this stage showed antitumor activity and an acceptable safety profile of the combination regimen in patients who met the original eligibility criteria. Subsequently, selected patients with prior immunotherapy exposure and limited effective treatment options received the regimen on a compassionate-use basis after careful clinical assessment, and clinical benefit with manageable safety was observed. Based on these findings, the protocol was amended to remove prior immunotherapy exposure as an exclusion criterion, allowing such patients to be enrolled if they met all other protocol-defined eligibility criteria. The amendment was approved by the ethics committee, and the trial registration information was updated accordingly.
Interventions
DRUGDisitamab vedotin in combination with AK104 and bevacizumab for the treatment of recurrent and persistent clear cell ovarian cancer
Disitamab vedotin (RC48) in combination with AK104 (PD-1/CTLA-4 bispecific) and bevacizumab for the treatment of recurrent and persistent clear cell ovarian cancer
Sponsors
Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
we are initiating this clinical study aimed at evaluating the efficacy and safety of vedolizumab (HER2-targeted ADC) in combination with AK104 (anti-PD-1 and CTLA4) and bevacizumab (anti-angiogenesis) in recurrent and persistent OCCC patients (vedolizumab 2.5 mg/kg + AK104 10 mg/kg + bevacizumab 15 mg/kg, every 3 weeks), with the aim of providing new treatment options for these refractory gynecologic malignancies.
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* The pathological diagnosis confirms ovarian clear cell carcinoma. In cases of mixed carcinoma, a prerequisite is that clear cell carcinoma constitutes at least 70% of the tumor mass. Moreover, adherence to RECIST 1.1 criteria mandates the presence of at least one evaluable lesion. * HER2 IHC ≥1+. * Treatment-naïve individuals encompass those experiencing tumor progression during postoperative chemotherapy and those who, following platinum-containing neoadjuvant chemotherapy, have not undergone surgical intervention yet and subsequently manifested progression during or after platinum-containing chemotherapy, provided that they have received a maximum of 2 prior lines of chemotherapy. * Recurrent patients, whether platinum-sensitive or platinum-resistant, include those lacking a platinum-free interval of ≥6 months and who, post-recurrence, have undergone re-administration of platinum-containing chemotherapy but have demonstrated an inability to tolerate toxic reactions, with a maximum of 2 lines of chemotherapy post-recurrence. * Previous utilization of bevacizumab is permissible. * Adequate bone marrow reserve function necessitates pre-operative blood routine parameters meeting specific criteria: white blood cell count ≥3.0×10\^9/L, neutrophil count ≥1.5×10\^9/L, platelet count ≥100×10\^9/L, and hemoglobin ≥80 g/L. * atisfactory organ function entails biochemical test results within defined limits: AST ≤2.5× upper limit of normal (ULN), ALT ≤2.5× ULN, serum total bilirubin ≤1.5× ULN, and creatinine ≤1.5× ULN. * ECOG performance status score ranging from 0 to 1. * Patient participation is contingent upon voluntary execution of an informed consent form.
Exclusion criteria
* Patients diagnosed with other malignancies within the past five years, excluding skin cancer and thyroid cancer. * Patients with an expected survival of ≤12 weeks. * Patients with a known allergy to taxane-based medications. * Patients who, based on clinical assessment, have contraindications for receiving immunotherapy and/or bevacizumab, such as uncontrolled infections, gastrointestinal fistula, autoimmune diseases, active hepatitis, or active bleeding. Patients currently undergoing treatment with investigational anti-cancer drugs in other clinical trials. * Patients with any unstable condition or situation that may compromise their safety or adherence to the study protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate | 2 years | Objective response rate of advanced or recurrent ovarian clear cell carcinoma |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression free survival | 2 years | Progression free survival of enrolled patients with recurrent or advanced ovarian clear cell |
| Overall survival | 2 years | Overall survival of enrolled patients with recurrent or advanced ovarian clear cell |
| Eastern Cooperative oncology group performance status score | 2 years | ECOG score of enrolled patients |
| Time to progress | 2 years | Time to progress of advanced or recurrent ovarian clear cell carcinoma |
| Adverse event | 2 years | Adverse event rate of treatment with RC48 in combination with AK104 and bevacizumab |
| The time to the first subsequent therapy | 2 years | The time to the first subsequent therapy for enrolled patients |
| Time to response | 2 years | Time to response for enrolled patients |
| Disease control rate | 2 years | Disease control rate of patients with recurrent or advanced ovarian clear cell carcinoma receiving intervention |
| Duration of response | 2 years | Duration of response of advanced or recurrent ovarian clear cell carcinoma |
Countries
China
Contacts
CONTACTJing Li, doctor
CONTACTMiaofang Wu, doctor
Outcome results
None listed