A Study of AK112 With or Without AK117 in Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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This trial is a Phase II study. The purpose of this study is to evaluate the efficacy, safety, and pharmacokinetics of AK112 with or without AK117 in participants with metastatic colorectal cancer who are not suitable for surgery.

Official Title
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A Phase II Study of AK112 With or Without AK117 for Patients With Metastatic Colorectal Cancer

Conditions
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Metastatic Colorectal Cancer

Intervention / Treatment
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* Drug: AK112
* Drug: AK117
* Drug: Oxaliplatin
* Drug: Capecitabine
* Drug: Irinotecan
* Drug: Leucovorin
* Drug: 5-fluorouracil
* Drug: Bevacizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically proven diagnosis of colorectal adenocarcinoma Part1: Initially unresectable metastatic colorectal cancer(metastasis detected at diagnosis) not previously systemic antitumor therapy for metastatic disease. Part2: Prior radiation therapy for lesions which were primary or metastatic from colorectal cancer.Patient must have received at least 2 prior line and no more than 4 prior lines of systemic anticancer therapy. Eastern Cooperative Oncology Group performance status of 0 or 1 Measurable disease as defined by RECIST v1.1 Adequate hematologic and end-organ function Exclusion Criteria: Known MSI-H(Microsatellite-Instability-High) or dMMR(Mismatch Repair-Deficient) Prior treatment with immunotherapy, including immune checkpoint inhibitors , immune checkpoint agonists, immune cell therapy and any treatment targeting tumor immune pathway History of autoimmune disease Prior allogeneic stem cell or solid organ transplantation Positive test for human immunodeficiency virus,Active hepatitis B or hepatitis C Receipt of a live, attenuated vaccine within 30 days prior to randomization, during treatment Pregnancy or lactation Dysphagia

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: Part 1_Chemotherapy Regimen Selection Stage Group A(AK112+AK117+XELOX)<br>AK112+AK117+XELOX AK112 20 mg/kg iv day 1, AK117 20 mg/kg iv day 1 and day 8 and day15, XELOX(Oxaliplatin 130 mg/sqm iv day 1, Capecitabine via oral, the total daily dose was 2000mg/sqm, day1-14)(to be repeated every 3 weeks for a maximum of 6 cycles) If no progression occurs during AK112 plus AK117 plus XELOX, patients will receive maintenance capecitabine plus AK112 plus AK117(day 1and day 8 and day15) at the same dose used at the last cycle of the induction treatment. Capecitabine plus AK112 plus AK117 will be repeated every 3 weeks until disease progression, unacceptable toxicity or patient's refusal. | Drug: AK112<br>* AK112 via intravenous (IV) infusion until disease progression or unacceptable toxicity<br>Drug: AK117<br>* AK117 via intravenous (IV) infusion until disease progression or unacceptable toxicity<br>Drug: Oxaliplatin<br>* Oxaliplatin via IV infusion<br>Drug: Capecitabine<br>* Capecitabine via oral,The total daily dose was 2000mg/sqm, Each cycle was administered for 2 consecutive weeks, followed by a week of rest, with a treatment cycle every 21 days<br>|
| Experimental: Part 1_Chemotherapy Regimen Selection Stage Group B(AK112+AK117+FOLFOXIRI)<br>AK112+AK117+FOLFOXIRI AK112 20 mg/kg iv day 1, AK117 20 mg/kg iv day 1and day 8, FOLFOXIRI(Irinotecan 150-165 mg/sqm iv day 1, Oxaliplatin 85 mg/sqm iv day 1, Leucovorin(LV) 400 mg/sqm iv day 1, 5-fluorouracil(5-FU) 2400-2800 mg/sqm 48 h-continuous infusion, starting on day 1) (to be repeated every 2 weeks for a maximum of 8 cycles) If no progression occurs during AK112 plus AK117 plus FOLFOXIRI, patients will receive maintenance 5-FU/LV plus AK112 plus AK117(day 1and day 8) at the same dose used at the last cycle of the induction treatment. 5-FU/LV plus AK112 plus AK117 will be repeated biweekly until disease progression, unacceptable toxicity or patient's refusal. | Drug: AK112<br>* AK112 via intravenous (IV) infusion until disease progression or unacceptable toxicity<br>Drug: AK117<br>* AK117 via intravenous (IV) infusion until disease progression or unacceptable toxicity<br>Drug: Oxaliplatin<br>* Oxaliplatin via IV infusion<br>Drug: Irinotecan<br>* Irinotecan via IV infusion<br>Drug: Leucovorin<br>* Leucovorin via IV infusion<br>Drug: 5-fluorouracil<br>* 5-fluorouracil via IV infusion<br>|
| Experimental: Part 1_Expansion Stage Group A(AK112+Chemotherapy)<br>AK112+Chemotherapy(Decided by Chemotherapy Regimen Selection Stage) AK112 20 mg/kg iv day 1, XELOX or FOLFOXIRI(the same dosage, frequency and duration with Chemotherapy Regimen Selection Stage) | Drug: AK112<br>* AK112 via intravenous (IV) infusion until disease progression or unacceptable toxicity<br>Drug: Oxaliplatin<br>* Oxaliplatin via IV infusion<br>Drug: Capecitabine<br>* Capecitabine via oral,The total daily dose was 2000mg/sqm, Each cycle was administered for 2 consecutive weeks, followed by a week of rest, with a treatment cycle every 21 days<br>Drug: Irinotecan<br>* Irinotecan via IV infusion<br>Drug: Leucovorin<br>* Leucovorin via IV infusion<br>Drug: 5-fluorouracil<br>* 5-fluorouracil via IV infusion<br>|
| Experimental: Part 1_Expansion Stage Group B(AK112+AK117+Chemotherapy)<br>AK112+AK117+Chemotherapy(Decided by Chemotherapy Regimen Selection Stage) AK112 20 mg/kg iv day 1, AK117 20 mg/kg iv day 1(qw), XELOX or FOLFOXIRI(the same dosage, frequency and duration with Chemotherapy Regimen Selection Stage) | Drug: AK112<br>* AK112 via intravenous (IV) infusion until disease progression or unacceptable toxicity<br>Drug: AK117<br>* AK117 via intravenous (IV) infusion until disease progression or unacceptable toxicity<br>Drug: Oxaliplatin<br>* Oxaliplatin via IV infusion<br>Drug: Capecitabine<br>* Capecitabine via oral,The total daily dose was 2000mg/sqm, Each cycle was administered for 2 consecutive weeks, followed by a week of rest, with a treatment cycle every 21 days<br>Drug: Irinotecan<br>* Irinotecan via IV infusion<br>Drug: Leucovorin<br>* Leucovorin via IV infusion<br>Drug: 5-fluorouracil<br>* 5-fluorouracil via IV infusion<br>|
| Active Comparator: Part 1_Expansion Stage Group C(Bevacizumab+Chemotherapy)<br>Bevacizumab+Chemotherapy(Decided by Chemotherapy Regimen Selection Stage) Bevacizumab 5 mg/kg iv day 1(q2w) or 7.5 mg/kg iv day 1(q3w), XELOX or FOLFOXIRI(the same dosage, frequency and duration with Chemotherapy Regimen Selection Stage) | Drug: Oxaliplatin<br>* Oxaliplatin via IV infusion<br>Drug: Capecitabine<br>* Capecitabine via oral,The total daily dose was 2000mg/sqm, Each cycle was administered for 2 consecutive weeks, followed by a week of rest, with a treatment cycle every 21 days<br>Drug: Irinotecan<br>* Irinotecan via IV infusion<br>Drug: Leucovorin<br>* Leucovorin via IV infusion<br>Drug: 5-fluorouracil<br>* 5-fluorouracil via IV infusion<br>Drug: Bevacizumab<br>* Bevacizumab via IV infusion<br>|
| Experimental: Part 2 cohort 1(AK112)<br>Subjects receive AK112 until disease progression or unacceptable toxicity AK112 20 mg/kg iv day 1(to be repeated every 3 weeks until disease progression, unacceptable toxicity or patient's refusal) | Drug: AK112<br>* AK112 via intravenous (IV) infusion until disease progression or unacceptable toxicity<br>|
| Experimental: Part 2 cohort 2(AK112+AK117)<br>Subjects receive AK117 and AK112 until disease progression or unacceptable toxicity AK112 20 mg/kg iv day 1, AK117 20 mg/kg iv day 1(qw)(to be repeated every 3 weeks until disease progression, unacceptable toxicity or patient's refusal) | Drug: AK112<br>* AK112 via intravenous (IV) infusion until disease progression or unacceptable toxicity<br>Drug: AK117<br>* AK117 via intravenous (IV) infusion until disease progression or unacceptable toxicity<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rates (ORR) | ORR is the proportion of subjects with complete response(CR) or partial response(PR) , based on RECIST v1.1 | Up to approximately 2 years | 
| Number of participants with adverse events (AEs) | An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. | Up to approximately 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease control rate (DCR) | Disease control rate (DCR) is defined as the proportion of subjects with CR, PR, or stable disease(SD) based on RECIST V1.1 | Up to approximately 2 years | 
| Duration of response (DOR) | DOR is defined for participants who had an objective response as the time from the first occurrence of a documented confirmed response (CR or PR) to the date of disease progression per RECIST v1.1 or death from any cause,whichever occurred first | Up to approximately 2 years | 
| Time to response (TTR) | TTR is defined for participants who had an objective response as the time from the start of treatment to the first occurrence of a documented unconfirmed response (CR or PR) . | Up to approximately 2 years | 
| Progression-free survival (PFS) | PFS is defined as the time from the start of treatment till the first documentation of disease progression (per RECIST v1.1 criteria) assessed by the investigator or death due to any cause (whichever occurs first). | Up to approximately 2 years | 
| Progression-free survival 2 (PFS2) | PFS 2 is defined as the time from the start of treatment till the second documentation of disease progression (per RECIST v1.1 criteria) assessed by the investigator or death due to any cause (whichever occurs first). | Up to approximately 2 years | 
| Overall survival (OS) | Overall survival is defined as the time from the start of treatment until death due to any cause. | Up to approximately 2 years |