Study of AK119 and AK 112 With or Without Chemotherapy for Colorectal Cancer Patients

Study Overview
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Brief Summary
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This is a phase Ib/II clinical study on AK119 and AK112 combined with or without chemotherapy in advanced microsatellite stabilized (pMMR/MSS) colorectal cancer

Detailed Description
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The study included the screening period (no more than 28 days after the subject signed the informed consent form to the first medication), the treatment period (until the investigator assessed that there was no clinical benefit, intolerable toxicity or withdrew the informed consent, whichever occurred first) and the follow-up period (including safety follow-up, disease progress follow-up and survival follow-up). Subjects will be screened and evaluated within 28 days before the first medication to determine whether they meet the study conditions. During the screening period, tumor samples of the subjects need to be collected. Subjects who meet the study conditions will be treated according to the study medication plan until the following conditions occur: the investigator judges that the subject cannot continue to benefit, there is intolerable toxicity, there is a concomitant disease that affects further treatment, the investigator decides, the subject withdraws his informed consent or the treatment needs to be terminated for other reasons specified in the plan (whichever occurs first). The investigator regularly evaluated the tumor response of all subjects according to RECIST 1.1 standard. Subjects were evaluated once every 6 weeks (± 7 days) within 54 weeks after enrollment, and then once every 9 weeks (± 7 days). For subjects undergoing treatment, their clinical decisions are based on the tumor response evaluated by the researchers

Official Title
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A Phase Ib/II Study of AK112 and AK119 in Combination With or Without Chemotherapy in the Treatment of Patients With Advanced Microsatellite Stabilized (pMMR/MSS) Colorectal Cancer

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Drug: AK119
* Drug: AK112
* Drug: Oxaliplatin
* Drug: Irinotecan
* Drug: Calcium folinate
* Drug: Fluorouracil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be able to understand and voluntarily sign the written informed consent, which must be signed before the specified research procedure required by the research is implemented. Age ≥ 18 when signing the informed consent form (ICF), both male and female。 Microsatellite stable colorectal cancer confirmed by histopathology; Microsatellite stability was defined as the expression of four common MMR proteins (MLH1, MSH2, MSH6 and PMS2) detected by immunohistochemistry, and all four proteins were positive for pMMR. Or PCR method was used to detect sites (BAT25, BAT26, D5S346, D2S123 and D17S250), and the detection results showed that the stability was microsatellite stability or microsatellite low degree instability. The first and second cohorts: recurrent or metastatic colorectal cancer that has failed to undergo at least the second-line standard treatment in the past; The chemotherapy of at least one of the treatment lines is the combination chemotherapy of at least two cytotoxic drugs based on platinum or irinotecan; Definition of treatment failure: disease progression occurs during or after treatment. All patients who change the treatment plan due to drug intolerance are not considered as treatment failure; For subjects who have received induction chemotherapy, concurrent radiotherapy and chemotherapy or adjuvant chemotherapy in the past, if relapse/metastasis occurs within 6 months after the last treatment, the original treatment plan is defined as the first-line treatment plan for the subject. The third and fourth cohorts: for patients with advanced colorectal cancer who have not undergone systematic treatment, the recurrence time should be at least 6 months from the end of the last treatment for those who have previously received induction chemotherapy, concurrent radiotherapy and chemotherapy or adjuvant/neoadjuvant chemotherapy. Agree to provide archived or freshly obtained tumor tissue samples within 2 years before the first administration (preferably newly obtained tumor tissue samples) About 20 unstained FFPE pathological sections (if the sample size is not enough, only 10 unstained FFPE pathological sections can be provided with the approval of medical inspectors FFPE pathological section). According to RECIST v1.1 standard, subjects have at least one measurable target lesion; The focus that has received radiotherapy is not selected as the target lesion, unless the radiotherapy focus is the only measurable focus and the progress is determined according to the imaging, it can be considered as the target lesion. The Eastern Cancer Cooperation Organization (ECOG) physical state score is 0 or 1. The expected survival period is ≥ 3 months. Exclusion Criteria: Pathological examination confirmed other pathological types, such as squamous cell carcinoma, sarcoma or undifferentiated carcinoma, gastrointestinal stromal tumor, etc. Palliative local treatment for non-target lesions within 2 weeks before the first administration; Have received systemic non-specific immunomodulation therapy (such as interleukin, interferon, thymosin, etc.) within 2 weeks before the first administration; Received Chinese herbal medicine or traditional Chinese patent medicines and simple preparations with anti-tumor indications within 2 weeks before the first administration。 Had been treated with anti-CD73 inhibitors, immune checkpoint inhibitors (such as anti-PD-1 antibody, anti-PD-L1 antibody, anti-CTLA-4 antibody, etc.), immune checkpoint agonists (such as antibodies against ICOS, CD40, CD137, GITR, OX40 targets, etc.), immune cell therapy (such as CAR-T) and other therapies aimed at tumor immune mechanism. There is a history of gastrointestinal perforation and fistula within 6 months before the first administration. If the perforation or fistula has been removed or repaired, and the researcher judges that the disease has recovered or alleviated, it can be admitted into the group. Active or inactive Inflammatory bowel disease (such as Crohn's disease or ulcerative colitis) previously recorded. Inability to swallow, malabsorption syndrome, or uncontrollable nausea, vomiting, diarrhea or other gastrointestinal diseases that seriously affect the use and absorption of drugs. Except for the tumor that the subject had at the time of enrollment, there was active malignant tumor in the previous five years. However, the tumors participating in the study and cured local tumors are excluded, such as skin basal cell carcinoma, skin squamous cell carcinoma, superficial bladder cancer, cervical carcinoma in situ, breast carcinoma in situ, localized prostate cancer, etc. At the same time, another interventional clinical study was enrolled. Receive the last systemic anti-tumor treatment within 3 weeks before the first administration; Received small molecular TKI treatment within 2 weeks before the first administration

Ages Eligible for Study
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Minimum Age: 18 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: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AK119 20mg/kg+ AK112 20mg/kg<br>Subjects will receive AK119 plus AK112 via intravenously (IV) Q2W, up to 2 years | Drug: AK119<br>* AK119 IV every 2 weeks.intravenous infusion<br>Drug: AK112<br>* AK112 IV every 2 weeks.intravenous infusion<br>|
| Experimental: AK119 40mg/kg+ AK112 20mg/kg<br>Subjects will receive AK119 plus AK112 via intravenously (IV) Q2W, up to 2 years | Drug: AK119<br>* AK119 IV every 2 weeks.intravenous infusion<br>Drug: AK112<br>* AK112 IV every 2 weeks.intravenous infusion<br>|
| Experimental: AK119 + AK112 20mg/kg +mFOLFOX6<br>Subjects will receive AK119 and AK112 plus mFOLFOX6 via intravenously (IV)Q2W, up to 12 cycles. Afterward, AK119 and AK112 will continue to be treated up to 2 years. | Drug: AK119<br>* AK119 IV every 2 weeks.intravenous infusion<br>Drug: AK112<br>* AK112 IV every 2 weeks.intravenous infusion<br>Drug: Oxaliplatin<br>* Oxaliplatin: 85mg/m2, intravenous infusion<br>Drug: Calcium folinate<br>* Calcium folinate: 400mg/m2, intravenous infusion<br>Drug: Fluorouracil<br>* Fluorouracil 400mg/m2, intravenous injection<br>|
| Experimental: AK119 + AK112 20mg/kg +FOLFIRI<br>Subjects will receive AK119 and AK112 plus FOLFIRI via intravenously (IV)Q2W, up to 12 cycles. Afterward, AK119 and AK112 will continue to be treated up to 2 years. | Drug: AK119<br>* AK119 IV every 2 weeks.intravenous infusion<br>Drug: AK112<br>* AK112 IV every 2 weeks.intravenous infusion<br>Drug: Irinotecan<br>* Irinotecan 180mg/m2, intravenous infusion<br>Drug: Calcium folinate<br>* Calcium folinate: 400mg/m2, intravenous infusion<br>Drug: Fluorouracil<br>* Fluorouracil 400mg/m2, intravenous injection<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 defined as the proportion of subjects with confirmed CR or confirmed PR | Up to 2 years | 
| Number of subjects with adverse events (AEs) | AE refers to any untoward medical occurrence or deterioration of existing medical event after the subject signed the ICF, whether or not considered related to the study treatment. | From the time of informed consent signed through 90 days after the last dose of study drug | 
| recommended phaseII dose | Phase II clinical study recommended dose (RP2D) of AK119 and AK112 combined with or without chemotherapy | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | PFS is defined as the time from the start of treatment until the first documentation of disease progression or death due to any cause, whichever occurs first (based on RECIST Version 1.1) | Up to 2 years | 
| Disease control rate (DCR) | DCR is defined as the proportion of subjects with CR, PR, or SD (based on RECIST Version 1.1). | Up to 2 years | 
| Duration of response (DoR) | DoR is defined as the duration from the first documentation of objective response to the first documented disease progression (based on RECIST Version 1.1) or death due to any cause, whichever occurs first | Up to 2 years | 
| Time to response (TTR) | TTR is defined as the time from the start of the treatment to the first objective tumor response observed for patients who achieved CR or PR (based on RECIST Version 1.1) | Up to 2 years | 
| Total survival time (OS) and 12-month OS rate | OS defined as the time from the first dose to death from any cause | Up to 2 years | 
| Maximum observed concentration (Cmax) of AK119 and AK112 | The PK parameters include serum concentrations of AK119 and AK112 at different timepoints after study drug administration. | From first dose of study drug through last dose up to 100 weeks | 
| Number of subjects who develop detectable anti-drug antibodies (ADAs) | The immunogenicity of AK119 and AK112 will be assessed by summarizing the number of subjects who develop detectable antidrug antibodies (ADAs). | From first dose of study drug through last dose up to 100 weeks | 
| Correlation between biomarkers and efficacy | Correlation between the expression level of PD-L1 and CD73 biomarkers and efficacy ORR, PFS and OS | Up to 2 years |