RC88 in Platinum-Resistant Recurrent Epithelial Ovarian Cancer, Fallopian Tube Cancer, and Primary Peritoneal Cancer

Study Overview
=================
Brief Summary
-----------------
This study is designed to evaluate the efficacy, safety, and pharmacokinetics of RC88 monotherapy in subjects with Platinum-Resistant Recurrent Epithelial Ovarian, Fallopian Tube and Primary Peritoneal Cancer (PROC).

Detailed Description
-----------------
This study is designed to evaluate the efficacy, safety, and pharmacokinetics of RC88 monotherapy in subjects with Platinum-Resistant Recurrent Epithelial Ovarian, Fallopian Tube and Primary Peritoneal Cancer (PROC). Approximately 88 eligible patients will be enrolled，and all patients will receive single-agent RC88 at 2.0 mg/kg administered on Day 1 of every 3-week cycle (Q3W). Patients will continue to receive RC88 until disease progression, unacceptable toxicity, withdrawal of consent, death, or until the Sponsor terminates the study (whichever comes first). Tumor assessments, including radiological assessments by CT/MRI scans will be performed at Screening and subsequently every 6 weeks (± 1 week) from Cycle 1 Day 1 (C1D1) for the first 48 weeks then every 12 weeks (± 1 week) until disease progression, death, the start of new anticancer therapy, or patient's withdrawal of consent (whichever occurs first). All patients who discontinue RC88 will be followed for survival every 3 months (± 2 weeks) until death, lost to follow-up, withdrawal of consent for survival follow-up, or end of study (whichever comes first).

Official Title
-----------------
A Multicenter, Single-arm, Phase 2 Study to Evaluate the Efficacy, Safety and Pharmacokenetics of RC88 Monotherapy in Platinum-resistant Reccurent Epithelial Ovarian, Fallopian Tube and Primary Peritoneal Cancer

Conditions
-----------------
Primary Peritoneal Cancer, Fallopian Tube, Epithelial Ovarian

Intervention / Treatment
-----------------
* Drug: RC88


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects must meet all of the following inclusion criteria to be eligible for enrollment in the study: Signed Informed Consent Form and ability to comply with the study protocol Age ≥ 18 years at the time of signing Informed Consent Form; Histology confirmed high grade serous ovarian, fallopian tube or primary peritoneal cancer; Platinum-resistant disease defined as: If patients have received only 1 line of platinum-based therapy, they must have received at least 4 cycles of a platinum agent, must have experienced a CR/PR, and must have progressed >3 months but ≤6 months after the last dose Patients who have received 2-3 lines of platinum-based therapy must have progressed on or within 6 months after the date of the last dose of platinum. (Patients with platinum-refractory disease during front-line treatment are excluded). Received at least 1 but no more than 3 prior systemic lines of therapy, including at least 1 type of platinum-based therapy，Nnotes： (Neo)adjuvant treatment is considered a single line of treatment； Maintenance therapy （eg:Bevacizumab 、PARP Inhibitors）is considered part of the preceding line of treatment (not a separate line of treatment); If patients switch therapies due to toxicity without progression of disease (PD), both therapies will be considered as the same line of treatment; Hormonal therapy will be counted as a separate line of therapy unless it was given as maintenance treatment； Patients must have progressed radiographically on or after their most recent line of anticancer therapy. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1; Life expectancy of at least 12 weeks; Patients must provide adequate archival tumor tissue samples for MSLN IHC test. If adequate archival tumor samples are not available, a fresh biopsy may be performed; Patients must have at least 1 lesion that meets the definition of measurable disease by RECIST v1.1 (radiologically measured by the Investigator) Patients must have completed prior therapy within the specified times below: Systemic antineoplastic therapy within 5 half-lives or 4 weeks (whichever is shorter) prior to first dose of RC88 Focal radiation completed at least 2 weeks prior to first dose of RC88 Patients must have adequate hematological, liver, cardiac and kidney function(assessed at least 2 weeks after transfusion with blood products, TPO, EPO and/or G-CSF、GM-CSF、Meg-CSF): Absolute neutrophil count (ANC)≥1.5×109/L; Platelet count≥100×109/L; Hemoglobin≥9.0 g/dL; Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 times the upper limit of normal (ULN) (if liver metastases are present, then≤5×ULN is allowed); Bilirubin≤1.5×ULN, except in patients diagnosed with Gilbert's syndrome, direct bilirubin≤3×ULN; Acceptable renal function: creatinine clearance CrCl ≥50 mL/min, as calculated using the Cockcroft-Gault formula; International normalized ratio (INR)、Prothrombin time (PT) time、Activated partial thromboplastin time (aPTT)≤1.25 ULN for patients not on anti-coagulation therapy，if Patients on anti-coagulants that require laboratory within the expected range . Patients of childbearing potential (a woman is considered of childbearing potential i.e. fertile, following menarche and until becoming post-menopausal for within 2 years unless permanently ster-ilized. Permanent sterilization methods include hysterectomy, bi-lateral salpingectomy and bilateral oophorectomy) must have a negative pregnancy test within 7 days from day 1 of cycle 1 and agree to use a highly effective method of contraception while sign the informed consent form and for at least 1 months after end of treatment； Exclusion Criteria: Primary platinum-refractory disease defined as disease that did not respond to or progressed within 3 months of the last dose of first-line platinum-containing chemotherapy Subjects with effusion in the third space , that cannot be controlled by drainage or other methods;eg:significant pleural effusion, pericardial effusion, or ascites requiring symptomatic treatment; Patients with untreated or symptomatic central nervous system (CNS) metastases (new or progressiving) and/or leptomeningeal metastasis Patients with clinical symptoms or signs of gastrointestinal obstruction and who require parental hydration and/or nutrition； History of cirrhotic liver disease (Child-Pugh Class B or C); Patients with immunodeficiency diseases,or Currently on high dose steroid (>10 mg prednisone or equivalent per day or other immune suppressant) or immune suppressant therapy within 7 days prior to the first dose of study intervention； Patients with ongoing clinically significant toxicity associated with prior treatment that has not resolved to ≤ Grade 1 or returned to baseline (except for alopecia,pigmentation and other conditions with no safety risk according to investigators' assessment)by NCI CTCAE 5.0; Major surgery within 4 weeks and no fully recovered prior to the first dose of study intervention. Patients who have planned major surgery during the treatment period must be excluded from the trial; Patients with a history of another invasive malignancy within 3 years before the first dose of study intervention , except for thyroid papillary carcinoma,basal cell or non-melanoma skin cancer which has shown no evidence of recurrence/progression, and carcinoma in situ adequately controlled (including carcinoma in situ of the cervix or breast)； Patients with known active infection, or reactivation of a latent infection,within 14 days of dosing.eg.active pulmonary tuberculosis； Serological virological tests (based on the normal range of research center): Subjects with positive for HBV surface antigen and HBV DNA>2000IU/ml or>104copies/ml. If subjects who have been curatively treated for hepatitis B virus then HBV DNA ≤2000IU/ml or≤104copies/ml are permitted; Subjects with known active hepatitis C virus (HCV) infection and HCV RNA >103 copies/ml；If subjects who have been curatively treated for hepatitis C infection with HCV RNA ≤103 copies/ml are permitted ； Human immunodeficiency virus (HIV) infection； Subjects with prior solid organ or bone marrow transplantation Uncontrolled cardiac disease including: History within 6 months prior to the first dose of study drug of ：NYHA Class III or IV congestive heart failure、myocardial infarction or cerebral infarction、Pulmonary embolism,unstable angina,etc;or Cardiac arrhythmia with requiring treatment during screening; Primary myocardial diseases (eg: dilated cardiomyopathy, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, restrictive cardiomyopathy, unclassified cardiomyopathy). Clinically significant prolongation of QTc interval, including atrioventricular II or III block; QTcF interval >470 msec; Atrial fibrillation (EHRA grade ≥ 2b); uncontrolled hypertension of the investigator would preclude the participants participation in the clinical study； History with interstitial lung disease requiring treatment or currently having a severe pulmonary disease, including active pulmonary tuberculosis, interstitial lung disease, etc. In the opinion of the investigator ,any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that would contraindicate the use of an investigational drug, or affecting the results of the study. Patients with active ocular surface disease patients with fundus examination and other ophthalmological examinations , judged ineligible by an ophthalmologist; Patients with known allergies, hypersensitivity, or intolerance to RC88 or its excipients. History of severe allergic or anaphylactic reactions to monoclonal antibodies or chemotherapies; Chemotherapy, targeted therapy, biological therapy, hormone therapy, or traditional Chinese medicine for tumor control within 28 days or 5*half-life (whichever is shorter) prior to the first dose of study intervention； Subjects who have received a live or live-attenuated vaccine within 4 weeks prior to the first dose of study intervention； Subjects participated in another clinical study within 4 weeks from date of signed ICF; Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial； Pregnant and/or breast-feeding women； Subjects with unable to comply with all aspects of the protocol,or any other condition which, in the opinion of the investigator would preclude the participants participation in the clinical study； Any prior treatment with antibody-drug conjugates, or other MSLN-targeting agents.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RC88 for Injection<br>RC88 for Injection Arm all patients will receive single-agent RC88 at 2.0 mg/kg administered on Day 1 of every 3-week cycle (Q3W). | Drug: RC88<br>* 2.0mg/kg Q3W IV<br>* Other names: RC88 for Injection;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) by Independent Review Committee (IRC) | Objective Response Rate was defined as the percentage of participants with a complete response (CR) or partial response (PR) .The objective response rate will be mainly analyzed by the Independent Review Committee (IRC) by according to the RECIST 1.1 standard tumor evaluation. | Up to approximately 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) by investigator | Objective Response Rate was defined as the percentage of participants with a complete response (CR) or partial response (PR) . ORR by the investigator will be analyzed. | Up to approximately 2 years | 
| Duration of response (DOR) by Independent Review Committee (IRC) | Duration of response was defined as the time interval between confirmed initial remission (CR or PR) disease progression (PD) or death, whichever is earlier. Evaluation by the Independent Review Committee (IRC) will be performed. | Up to approximately 2 years | 
| Duration of response (DOR) by investigator | Duration of response was defined as the time interval between confirmed initial remission (CR or PR) as assessed by the investigator and investigator-assessed disease progression (PD) or death, whichever is earlier. | Up to approximately 2 years | 
| Progression-free survival (PFS) by Independent Review Committee (IRC) | Progression-free survival (PFS) by Independent Review Committee (IRC) was defined as the time interval between the first administration of RC88 and IRC-assessed imaging disease progression (PD) or death, whichever is earlier | Up to approximately 2 years | 
| Progression-free survival (PFS) by investigator | Progression-free survival (PFS) by investigator was defined as the time interval between the first administration of RC88 and investigator-assessed imaging disease progression (PD) or death, whichever is earlier | Up to approximately 2 years | 
| Overall survival(OS) | Overall survival(OS) was defined as the time interval between the first administration of RC88 and death. | Up to approximately 2 years | 
| Changes of serum CA125 by GCIG criteria | Serum CA125 Assessment | Up to approximately 2 years | 
| Maximum Concentration (Cmax) of RC88 | Cmax will be derived from the PK blood samples collected. | 15 days cycle，Cycle 1 and Cycle 3：Pro-dose ,0.5hr,72hrs,168hrsafter start of infusion. Cycle 2:Pro-dose,0.5hr after start of infusion.Cycle 5 and thereafter (only odd number of doses)：Pro-dpse,0.5hr.Up to approximately 2 years | 
| Incidence of anti-drug antibodies to RC88 | ADA Assessment | Up to approximately 2 years | 
| Patient-Reported Health Related Quality of Life (HRQoL)-EORTC-QLQ-C30 | Change from baseline in the physical functioning subscale of the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) scores. Scale scores range from 0-100. For functioning and global health status/ QoL scales, higher scores indicate better functioning or global health status/QoL. For symptom scales, higher scores indicate greater symptom burden. | Up to approximately 2 years | 
| Expression of MSLN using IHC | Immunohistochemistry was used to detect the expression of MSLN in tissue sections, and the results were used for later retrospective analysis | Up to approximately 2 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Primary Peritoneal Cancer, Fallopian Tube, Epithelial Ovarian, Platinum-Resistant Recurrent