A Study of AK104 With Chemotherapy as First-line Treatment in Patients With Advanced Pancreatic Cancer

Study Overview
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Brief Summary
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This study is a multicenter, open-label, phase II study to evaluate the safety, tolerability, pharmacokinetics (PK), immunogenicity, pharmacodynamics (PD) and anti-tumor activities of AK104，a PD-1/CTLA-4 bispecific antibody, in combination with gemcitabine and nab-paclitaxel as first-line therapy in subjects with advanced unresectable or metastatic pancreatic ductal adenocarcinoma.

Official Title
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A Multicenter, Open-label, Phase II Study of AK104, a PD-1/CTLA-4 Bispecific Antibody, in Combination With Chemotherapy as First-line Treatment in Patients With Locally Advanced Unresectable or Metastatic Pancreatic Cancer

Conditions
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Pancreatic Cancer

Intervention / Treatment
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* Drug: AK104
* Drug: AK104
* Drug: Gemcitabine
* Drug: Nab-Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to understand and voluntarily sign a written informed consent form (ICF), which must be signed before the specified study procedures required for the study are performed. Males or females aged ≥ 18 years and ≤ 75 years at the time of signing the ICF. Histologically or cytologically confirmed pancreatic ductal adenocarcinoma (PDAC). Patients have not received prior systemic therapy for locally advanced or metastatic pancreatic cancer; for patients who have received prior induction chemotherapy, concurrent chemoradiotherapy, or adjuvant/neoadjuvant chemotherapy for curative intent, the time between disease progression and last treatment should be at least 6 months. Patients have at least one measurable tumor lesion per RECIST v1.1; lesions that received radiotherapy are not selected as target lesions, unless the lesion is the only measurable lesion and has unequivocal progression as judged by imaging, it can be considered as a target lesion. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Expected survival ≥ 3 months. Patients who have adequate organ function. Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to the first dose and agree to take effective contraception measures during the study drug administration and within 120 days after the last dose. Male patients with female partners of childbearing potential must agree to take effective contraception measures during the study drug administration and within 120 days after the last dose. Exclusion Criteria: Histologically or cytologically confirmed other pathological types, such as acinar cell carcinoma, pancreatic neuroendocrine neoplasms or pancreatoblastoma. Known active or untreated brain metastases, meningeal metastases, spinal cord compression, or leptomeningeal disease. However, patients who meet the following requirements and have measurable lesions outside the central nervous system are allowed to be enrolled: asymptomatic after treatment and radiographically stable for at least 4 weeks prior to the start of study treatment (e.g., no new or enlarged brain metastases), and the systemic glucocorticoids and anticonvulsant medications have been discontinued for at least 2 weeks. Patients with known germ line BRAC1/2 mutation. Presence of clinically symptomatic pleural effusion, pericardial effusion, or ascites requiring frequent drainage (≥ 1/month). Patients who, in the opinion of the investigator, have symptoms or signs suggestive of clinically unacceptable deterioration of the primary disease at the time of screening. Medical history of gastrointestinal perforation or gastrointestinal fistula within 6 months prior to the first dose. If the perforation or fistula has been treated with resection or repair and the disease has recovered or resolved as judged by the Investigator, enrollment may be allowed. Clinically significant gastrointestinal disorder including gastrointestinal obstruction (including partial bowel obstruction), can not swallowing or malabsorption syndrome, uncontrolled nausea, vomiting, diarrhea, or other gastrointestinal disorders that severely affect nutrition absorption. History of clinically significant hemorrhage symptom or clear hemorrhagic diathesis within 1 month prior to the first dose, such as digestive tract hemorrhage, gastirc ulcer hemorrhage or vasculitis. Active malignancies within the past 3 years, with the exception of tumors in this study and cured local tumors, such as basal cell carcinoma of skin, squamous cell carcinoma of skin, superficial bladder cancer, carcinoma in situ of cervix, carcinoma in situ of breast, localized prostate cancer, papillary thyroid microcarcinoma, etc. Major surgery other than the diagnosis of pancreatic cancer within 28 days prior to the first dose or major surgery is expected during the study. Presence of cardiovascular and cerebrovascular diseases or cardiovascular and cerebrovascular risk factors. Presence of ≥ Grade 2 peripheral neuropathy as defined by NCI CTCAE v5.0. Presence of clinically active hemoptysis or active diverticulitis. Patients with serious neurological or psychiatric disorders, including dementia and epileptic seizure. Pregnant or lactating women. Patients who received any prior treatments targeting the mechanism of tumor immunity, such as immune checkpoint blockades (e.g., anti-PD-1 antibody, anti-PD-L1 antibody, anti-CTLA-4 antibody, etc.), immune checkpoint agonists (e.g., antibodies against ICOS, CD40, CD137, GITR, OX40 targets, etc.), immune cell therapy (e.g., CAR-T), etc. Patients who received palliative local therapy for any tumor lesion within 2 weeks prior to the first dose; systemic nonspecific immunomodulatory therapy (e.g., interleukin, interferon, thymosin, etc.) within 2 weeks prior to the first dose; and Chinese herbal medicine or traditional Chinese medicinal products with anti-tumor indications within 2 weeks prior to the first dose. Patients who require systemic treatment with glucocorticoids (> 10 mg/day prednisone or equivalent) or other immunosuppressive drugs within 14 days prior to the first dose. Unresolved toxicities during prior anti-tumor therapy are defined as the toxicities that do not resolved to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (NCI CTCAE v5.0) Grade 0 or 1, or to the levels specified in the inclusion/exclusion criteria, with the exception of alopecia/pigmentation. patients with irreversible toxicity that are not expected to worsen after study drug administration (e.g., hearing loss) may be included in the study after consultation with the medical monitor. patients with long-term toxicity due to radiotherapy that cannot be recovered at the discretion of the Investigator may be included in the study after consultation with the medical monitor. Patients with known contraindications to NP and Gem chemotherapy (see instructions for NP and Gem). Patients with known medical history of severe hypersensitivity reactions to other monoclonal antibodies or intravenous gamma globulin; patients with a known history of allergy or hypersensitivity to AK104, nab-paclitaxel or other albumin products, gemcitabine, or any component thereof. Active autoimmune disease requiring systemic treatment within 2 years prior to the start of study treatment, or autoimmune diseases that may relapse or require scheduled treatment as judged by the Investigator, including, but not limited to, inflammatory bowel disease, celiac disease, Wegener syndrome, Hashimoto's thyroiditis, systemic lupus erythematosus, scleroderma, sarcoidosis, or autoimmune hepatitis. Known active pulmonary tuberculosis. patients with suspected active pulmonary tuberculosis should be examined through chest imaging, sputum, and clinical symptoms and signs. Patients with active hepatitis B or active hepatitis C. Known medical history of immunodeficiency or positive HIV test. Known presence of interstitial lung disease or noninfectious pneumonitis that is currently symptomatic or requires prior systemic glucocorticoid therapy that, in the judgment of the Investigator, may affect the assessment or management of toxicity related to study treatment. Patients with active infection, including those requiring intravenous antibiotics or antifungal therapy for 2 weeks prior to first dose, and unexplained fever during screening (CTCAE≥1, except those determined by the investigator to be neoplasmic). Known history of allogeneic organ transplantation and allogeneic hematopoietic stem cell transplantation. Patients must not have received a live vaccine within 28 days before the first dose, and patients, if enrolled, should not receive live vaccines during the study or for 120 days after the last dose of AK104. Concurrent participation in another clinical study, unless it is an observational, non-interventional clinical study or the follow-up period of an interventional study. Any condition that, in the opinion of the Investigator, may result in a risk when receiving the study drug, or would interfere with the evaluation of the study drug or the safety of patients, or the interpretation of the study results.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

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: AK104 6mg/kg and chemotherapy<br> | Drug: AK104<br>* AK104 (6mg/kg) on day 1, IV, Q2W<br>Drug: Gemcitabine<br>* Gemcitabine (1000mg/m2) on days 1, 8 and 15, IV, Q4W<br>Drug: Nab-Paclitaxel<br>* Nab-Paclitaxel (125mg/m2) on days 1, 8 and 15, IV, Q4W<br>|
| Experimental: AK104 10mg/kg and chemotherapy<br> | Drug: AK104<br>* AK104 (10mg/kg) on day 1, IV, Q2W<br>Drug: Gemcitabine<br>* Gemcitabine (1000mg/m2) on days 1, 8 and 15, IV, Q4W<br>Drug: Nab-Paclitaxel<br>* Nab-Paclitaxel (125mg/m2) on days 1, 8 and 15, IV, Q4W<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) | ORR is the proportion of subjects with CR or PR based on RECIST v1.1 | Up to 2 years | 
| The number of subjects experiencing adverse events (AEs) | Incidence and severity of adverse events (AEs) and serious adverse events (SAEs), and clinically significant abnormal laboratory results. | From the subject signs the ICF to 90 days after the last dose of study treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum observed concentration (Cmax) of AK104 | The endpoints for assessment of PK of AK104 include serum concentrations of AK104 at different timepoints after AK104 administration. | From first dose of study drug until the 8th cycle (each cycle is 28 days) of study drug administration. | 
| Minimum observed concentration (Cmin) of AK104 at steady state | The endpoints for assessment of PK of AK104 include serum concentrations of AK104 at different timepoints after AK104 administration. | From first dose of study drug until the 8th cycle (each cycle is 28 days) of study drug administration. | 
| Area under the curve (AUC) of AK104 | The endpoints for assessment of PK of AK104 include serum concentrations of AK104 at different timepoints after AK104 administration. | From first dose of study drug until the 8th cycle (each cycle is 28 days) of study drug administration. | 
| Number of subjects who develop detectable anti-drug antibodies (ADAs) | The immunogenicity of AK104 will be assessed by summarizing the number of subjects who develop detectable antidrug antibodies (ADAs). | From first dose of study drug until the 8th cycle (each cycle is 28 days) of study drug administration. |