A Study of AK112 Combined With PARP Inhibitor in the Treatment of Recurrent Ovarian Cancer

Study Overview
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Brief Summary
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Phase Ib/II open label, multicenter study to evaluate the efficacy and safety of anti-PD-1 and VEGF bispecific antibody (AK112) combined with PARP inhibitor in patients with recurrent ovarian cancer.

Official Title
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Phase Ib/II Clinical Study of Anti-PD-1 and VEGF Bispecific Antibody (AK112) Combined With PARP Inhibitor in the Treatment of Recurrent Ovarian Cancer

Conditions
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Ovarian Neoplasms, Recurrent Ovarian Carcinoma, Relapsed Ovarian Cancer, Ovarian Cancer

Intervention / Treatment
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* Drug: AK112 low dose
* Drug: AK112 medium dose
* Drug: AK112 high dose


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be able and willing to provide written informed consent. ≥ 18 years old to ≤ 75 years old at study enrollment, female subjects. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Have a life expectancy of at least 3 months. Have histologically or cytologically diagnosis of epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 assessed by investigator. Be able to provide formalin fixed, paraffin-embedded (FFPE) tumor tissue. Has adequate organ function. All subjects of reproductive potential must agree to use an effective method of contraception, as determined by the Investigator, during and for 120 days after the last dose of study treatment. Able to to comply with all requirements of study participation (including all study procedures). Exclusion Criteria: Previous history (within five years) or concurrent malignant neoplasm, except that basal cell carcinoma and/or squamous cell carcinoma of the skin, superficial bladder cancer, cervical cancer in situ or breast cancer in situ that has undergone curative therapy. Participation in a study of an investigational drug or using an investigational device within 4 weeks of first study drug administration. Previous use of PARP inhibitors. Ovarian, fallopian tube or primary peritoneal cancer cancer of non-epithelial origin (such as germ cell carcinoma). Previous targeted therapy using small molecule and/or anti-angiogenic therapy (including but not limited to bevacizumab or its biosimilar). Have a potent or moderate CYP3A inhibitor, or a potent or moderate CYP3A inducer within 1 week prior to first study drug administration (or 5 drug half-lives, whichever is longer). Has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Active or previous history of inflammatory bowel disease such as Crohn's disease, ulcerative colitis or chronic diarrhea. History of immunodeficiency and/or HIV antibody positive subjects. Has severe infection 4 weeks prior to first study drug administration, including but not limited to complications requiring hospitalization, sepsis or severe pneumonia; active infection requiring systemic anti-infective therapy within 2 weeks prior to first study drug administration (excluding antiviral therapy for hepatitis B or C). Has known active Hepatitis B that is untreated and requiring antiviral therapy during study period; or active Hepatitis C subjects (HCV antibody positive with HCV-RNA levels above the detection threshold). Has undergone major surgery or severe trauma within 30 days prior to the first study drug administration. Has known active central nervous system (CNS) metastases. Uncontrolled co-morbidities including but not limited to symptomatic congestive heart failure (NYHA≥2), unstable angina, acute myocardial infarction, poorly controlled arrhythmias, decompensated cirrhosis, nephrotic syndrome, uncontrolled metabolic disorders, severe peptic ulcer disease or gastritis. Uncontrolled hypertension despite optimal medical treatment; history of hypertensive crisis or hypertensive encephalopathy. Any arterial thromboembolism, transient ischemic attack, cerebrovascular accident occurred within 6 months prior to the first study drug administration. History of abdominal fistula or gastrointestinal perforation associated with anti-VEGF therapy; imaging results revealed invasion of the intestinal wall by tumor during screening. Imaging or clinical findings of gastrointestinal obstruction, including incomplete obstruction. Unable to swallow tablets or has had gastrointestinal abnormalities that may affect drug absorption as determined by the investigator. Has had live vaccine within 30 days prior to first study drug administration or plan to receive live vaccine during the study period. Has known psychiatric or substance abuse disorders, including alcohol or drug abuse. Pregnant or lactating female subject. Any prior or concurrent disease, treatment, or laboratory test abnormality that may confuse study results, affect subjects' full participation in the study, or may not be in their best interest to participate.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AK112<br>AK112 injection | Drug: AK112 low dose<br>* AK112 injection low dose+ olaparib (Lynparza®) PARP inhibitor<br>Drug: AK112 medium dose<br>* AK112 injection medium dose+ olaparib (Lynparza®) PARP inhibitor<br>Drug: AK112 high dose<br>* AK112 injection high dose+ olaparib (Lynparza®) PARP inhibitor<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety endpoint: number of subjects with adverse events (AE) | An AE is any untoward medical occurrence in a subject, temporally associated with the use of study treatment, whether or not considered related to the study treatment. | Up to approximately 2 years | 
| Primary efficacy endpoint: objective response rate (ORR) | ORR is the proportion of subjects with complete response(CR) or partial response(PR) assessed according to RECIST v1.1 | Up to approximately 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy Endpoint assessed according to RECIST v1.1 : disease control rate (DCR) | DCR based on RECIST v1.1. DCR is defined as the proportion of subjects with CR, PR, or SD. | Up to approximately 2 years | 
| Efficacy Endpoint assessed according to RECIST v1.1 : progression-free survival (PFS) | PFS based on RECIST v1.1. PFS is defined as the time from the date of randomization till the first documentation of disease progression assessed by the investigator or death due to any cause (whichever occurs first) | Up to approximately 2 years | 
| Efficacy Endpoint assessed according to RECIST v1.1 : Overall survival (OS) | OS based on RECIST v1.1. OS is defined as the time from the date of randomization or first dosing date to death due to any cause | Up to approximately 2 years | 
| Serum PK concentrations of AK112 | Serum PK concentrations of AK112 in individual subjects at different time points after AK112 administration | Up to approximately 2 years | 
| To evaluate the immunogenicity of AK112: Number of subjects with anti-drug antibodies (ADA) | Immunogenicity of AK112: Number of subjects with detectable anti-drug antibodies (ADA) | Up to approximately 2 years | 
| To evaluate the immunogenicity of AK112: Percentage of subjects with anti-drug antibodies (ADA) | Immunogenicity of AK112: Percentage of subjects with detectable anti-drug antibodies (ADA) | Up to approximately 2 years | 
| To evaluate the correlation between the expression of PD-L1 and the antitumor activity of AK112 in tumor tissues | Correlation between PD-L1 and AK112 in tumor tissues | Up to approximately 2 years | 
| To evaluate the association between gBRCA1/2 mutation in peripheral blood and the antitumor activity of AK112 in subjects with recurrent ovarian cancer | Association between gBRCA1/2 mutation in peripheral blood and antitumor activity of AK112 | Up to approximately 2 years |