Phase II Study of AK104 (Cadonilimab) for Recurrent Small Cell Neuroendocrine Carcinomas of the Cervix

Primary Objective:

-To estimate progression free survival rate at 6 months (PFS6) in response to AK104 monotherapy in patients with progressive/relapsed high-grade neuroendocrine carcinomas of the cervix.

Secondary Objective:

• To evaluate the efficacy of AK104 monotherapy in terms of DoR and DCR in patients with progressive/relapsed high-grade neuroendocrine carcinomas of the cervix.
• To evaluate the efficacy of AK104 monotherapy in terms of ORR in patients with progressive/relapsed high-grade neuroendocrine carcinomas of the cervix.
• To evaluate the safety and tolerability profile of AK104 monotherapy in patients with progressive/relapsed high-grade neuroendocrine carcinomas of the cervix.
• To determine presence of HPV cell free DNA and if levels of HPV cell free DNA may serve as a surrogate for response to AK104 monotherapy in patients with progressive/relapsed high-grade neuroendocrine carcinomas of the cervix

Inclusion criteria

• Ability to provide written and signed informed consent.
• Age ≥ 18 years at time of study entry
• Histologically or cytologically confirmed recurrent or metastatic high grade neuroendocrine carcinoma of the cervix with disease progression confirmed by radiologic imaging during or following prior platinum-based doublet chemotherapy, with or without bevacizumab for recurrent or metastatic cervical cancer
• Received no more than 2 prior systemic therapies in the recurrent or metastatic setting
• Not eligible for surgery and/or radiation as treatment options for recurrent disease
• Measurable lesions according to RECIST v1.1. (A previously irradiated lesion is not considered measurable and cannot be selected as a target lesion.)
• Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1
• Adequate organ function as determined by:

• Hematological criteria (subjects should not have received either growth factor support or recent transfusions within 7 days prior to starting study treatment):

• Absolute neutrophil count (ANC) ≥1.5 × 109/L (1,500/mm3)
• Platelet count ≥100 × 109/L (100,000/mm3)
• Hemoglobin ≥9.0 g/dL (90 g/L)
• Renal criteria:

• Serum creatinine <1.5 × upper limit of normal (ULN), or estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73 m2 by Cockcroft-Gault formula
• Hepatic criteria:

• AST and ALT ≤2.5 × ULN; for subjects with liver metastasis, AST/ALT can be

≤5 × ULN

• Serum total bilirubin (TBL) ≤1.5 × ULN; for subjects with documented/suspected Gilbert's disease, TBL <3 × ULN
• One of the following conditions applies:

a. Is a woman of childbearing potential (WOCBP) who is sexually active with a nonsterilized male partner must have a negative pregnancy test at the Screening visit (within 3 days prior to the first dose of the investigational product [Cycle 1 Day 1]), should not be lactating, and must agree to use 1 methods of contraception b. Is a woman of nonchildbearing potential

• Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures as specified in the protocol.

Exclusion criteria

• Concurrent enrollment in another clinical study, unless it is an observational (noninterventional) clinical study or the follow-up period of an interventional study
• Histological types of cervical cancer other than high grade neuroendocrine caricnoma (e.g.

squamous carcinoma, adenocaricnoma, adeno-squamous carcinoma, clear cell carcinoma, sarcoma, etc.)

• Prior malignancy active within the previous 2 years except for the tumor for which a subject is enrolled in the study and locally curable cancers that have been apparently cured, such as basal cell skin cancer or carcinoma in situ of the breast
• Brain/central nervous system (CNS) metastases: Subjects with suspected brain metastases should have a computed tomography (CT)/magnetic resonance imaging (MRI) scan of the brain to confirm the absence of brain/CNS metastases prior to enrollment.
• Clinically significant hydronephrosis, as determined by the investigator, not alleviated by nephrostomy or ureteral stent
• Active infections (including tuberculosis) requiring systemic antibacterial, antifungal, or antiviral therapy within 4 weeks prior to the first dose of investigational product.
• Known history of testing positive for human immunodeficiency virus (HIV) or known active acquired immunodeficiency syndrome.
• Known active hepatitis B or C infections (known positive hepatitis B surface antigen [HBsAg] result or positive hepatitis C virus [HCV] antibody with detectable HCV ribonucleic acid [RNA] results).
• Active or prior documented autoimmune disease that may relapse. NOTE: Subjects with controlled type 1 diabetes mellitus, thyroiditis in euthyroid state or hypothyroidism well managed by hormone replacement therapy (HRT), or skin diseases not requiring systemic treatment (e.g., vitiligo, psoriasis) are eligible.
• History of interstitial lung disease or noninfectious pneumonitis, except for those induced by radiation therapies.
• Clinically significant cardio-cerebrovascular disease:

• Myocardial infarction, unstable angina, pulmonary embolism, stroke, or any other significant cardiovascular or cerebrovascular accident within 6 months prior to the first dose of investigational product.
• New York Heart Association Grade III or greater congestive heart failure within 6 months prior to the first dose of investigational product.
• Serious cardiac arrhythmia such as ventricular arrhythmia requiring medication or second- or third-degree atrioventricular block. This does not include asymptomatic atrial fibrillation with controlled ventricular rate.
• Unresolved toxicities from prior anticancer therapy, defined as having not resolved to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0 Grade 0 or 1, or to levels dictated in the eligibility criteria with the exception of toxicities not considered a safety risk (e.g., alopecia, neuropathy, or asymptomatic laboratory abnormalities).
• History of severe hypersensitivity reactions to other mAbs.
• Prior allogeneic stem cell transplantation or organ transplantation.
• Known allergy or reaction to any component of the AK104 formulation.
• Receipt of the following treatments or procedures:

• Anticancer small-molecule targeted agent within 2 weeks prior to the first dose of investigational product.
• Radiation therapy within 2 weeks prior to the first dose of investigational product.
• Other anticancer therapy (e.g., chemotherapy, radiotherapy, anticancer mAbs, etc) within 4 weeks prior to the first dose of investigational product.
• Any major surgery (e.g., laparotomy, thoracotomy, removal of organ[s]) within 4 weeks prior to the first dose of investigational product.
• Any other nonapproved investigational product or procedure within 4 weeks prior to the first dose of investigational product.
• Agents with immunomodulatory effect (e.g., thymosin, IFN, interleukin) within 2 weeks prior to the first dose of investigational product.
• Subjects with a condition requiring systemic treatment with either corticosteroids (>10 mg daily doses of prednisone or equivalent) or other immunosuppressive medications within 14 days prior to the first dose of investigational product. The following are exceptions to this criterion:

• Corticosteroids used as adrenal replacement (<10 mg daily prednisone or equivalent).
• Topical, ocular, intra-articular, intranasal, or inhaled corticosteroids with minimal systemic absorption.
• Corticosteroids used as pretreatment medication for hypersensitivity reactions (e.g., CT scan premedication).
• Receipt of live attenuated vaccines within 30 days prior to the first dose of investigational product. Note: Seasonal vaccines for influenza which are generally inactivated are allowed.
• Prior exposure to any experimental antitumor vaccines, or any agent targeting T-cell costimulation or immune checkpoint pathways (e.g., anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4, anti-CD137 or anti-OX40 antibody, etc).
• Any condition that, in the opinion of the Investigator, would interfere with evaluation of the investigational product or interpretation of subject safety or study results.