An Open-label, Phase I/II Study of the Pan-immunotherapy in Patients With Relapsed/Refractory Ovarian Cancer

Study Overview
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Brief Summary
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Ovarian cancer is the most lethal gynecological cancer and the 5th leading cause of cancer death in women. Platinum chemotherapy has been widely adopted as a standard treatment for advanced ovarian cancer, the response rates in patients with relapsed/refractory ovarian cancer is unacceptably low. PD-1 blockade has been developed to a new class of cancer immunotherapy that could restore an adequate immunosurveillance against the neoplasm and enhance T-cell-mediated anticancer immune responses. Manganese has been confirmed to activate antigen-presenting cells and function as mucosal immunoadjuvants in pre-clinical studies. This two-arm, phase I/II study is designed to assess the safety and efficacy of combined therapy of anti-PD-1 antibody and chemotherapy with or without Manganese priming.

Official Title
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A Phase I/II, Open-label, Two-arm, Single-center Study to Evaluate the Safety and Efficacy of the Pan-immunotherapy in Subjects With Relapsed/Refractory Ovarian Cancer

Conditions
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Ovarian Cancer

Intervention / Treatment
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* Drug: Manganese Chloride
* Drug: nab-paclitaxel
* Drug: Platinum chemotherapy
* Drug: Sintilimab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must have histologically proven relapsed or refractory ovarian cancer (Refractory was defined as a lack of response to or progression during the frontline treatment; relapsed was defined as progression after the frontline treatment), including patients diagnosed with primary carcinoma of fallopian tube or peritoneum carcinoma. Female. ≥ 18 years old. Life expectancy of at least 6 months. Eastern Cooperative Oncology Group performance status 0-2. Radiographic imaging (CT/MRI/PET-CT) indicated recurrence or metastasis; or cancer cells in ascites are positive; or CA125 concentration in the peripheral blood is more than 2 times the upper limit of normal value. Subjects must have received at least two frontline therapies, at least one of which is platinum-containing. Subjects with Anti-PD-1 antibody treatment history are eligible which must be resistance. Adequate organ function. Female participants of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of study drug. Exclusion Criteria: Subjects with any autoimmune disease or history of syndrome that requires corticosteroids or immunosuppressive medications. Serious uncontrolled medical disorders or active infections, pulmonary infection especially. Prior organ allograft. Women who are pregnant or breastfeeding. Women with a positive pregnancy test on enrollment or prior to investigational product administration. Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness. Subjects with previous or concurrent other malignancies.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Manganese primed Sintilimab plus nPP chemotherapy<br>Subject received Manganese primed Sintilimab, nab-paclitaxel and platinum chemotherapy every 3 weeks until achieving a second assessable complete response or progressive disease, development of unacceptable toxicity, or withdrawal of consent. | Drug: Manganese Chloride<br>* Administered by inhalation at 0.4mg/kg twice per week in the first 3-week cycle, and then inhaled 0.4mg/kg twice in the first week of each 3-week cycle thereafter<br>Drug: nab-paclitaxel<br>* Administered intravenously, 180-220mg/m2 on day 2 in a 3-week cycle (day 1 without Manganese priming)<br>* Other names: Paclitaxel For Injection (Albumin Bound);Drug: Platinum chemotherapy<br>* Administered intravenously, Cisplatin (60-80mg/m2) or Carboplatin (area under the curve [AUC] 4-6 mg/mL per min) on day 2 in a 3-week cycle (day 1 without Manganese priming)<br>Drug: Sintilimab<br>* Administered intravenously, 200mg on day 3 in a 3-week cycle (day 2 without Manganese priming)<br>* Other names: anti-PD-1 antibody; PD-1 inhibitor;|
| Active Comparator: Sintilimab plus nPP chemotherapy<br>Subject received Sintilimab, nab-paclitaxel and platinum chemotherapy every 3 weeks until achieving a second assessable complete response or progressive disease, development of unacceptable toxicity, or withdrawal of consent. | Drug: nab-paclitaxel<br>* Administered intravenously, 180-220mg/m2 on day 2 in a 3-week cycle (day 1 without Manganese priming)<br>* Other names: Paclitaxel For Injection (Albumin Bound);Drug: Platinum chemotherapy<br>* Administered intravenously, Cisplatin (60-80mg/m2) or Carboplatin (area under the curve [AUC] 4-6 mg/mL per min) on day 2 in a 3-week cycle (day 1 without Manganese priming)<br>Drug: Sintilimab<br>* Administered intravenously, 200mg on day 3 in a 3-week cycle (day 2 without Manganese priming)<br>* Other names: anti-PD-1 antibody; PD-1 inhibitor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Object response rate (ORR) | ORR is defined as the proportion of subjects who achieved a partial response (PR) or complete response (CR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 | 24 months | 
| Number of Subjects with treatment-related adverse events (AEs) | Incidence, nature, and severity of adverse events graded according to the NCI CTCAE v5.0. AEs were considered to be treatment-related if they had started or worsened within the interval from first study drug administration until the follow-up visit. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease control rate (DCR) | DCR is defined as the proportion of subjects who achieved a stable disease (SD), partial response (PR) or complete response (CR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. | 12 months | 
| Progression-free survival (PFS) | PFS time was measured from study entry to the first documentation of disease progression or death. Disease progression was determined per the RECIST V1.1. | 12 months | 
| Overall survival (OS) | OS time was measured from the study entry to the date of death. | 24 months | 
| Number of participants with laboratory test abnormalities | The laboratory tests of serum cytokines and chemokines will be performed on day 1 and 3 of each cycle, and the abnormality will be determined by the investigator. | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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relapsed, refractory, anti-PD-1 antibody, Manganese, chemotherapy