AK112 +/− AK117 for Colorectal Cancer

Not currently recruiting at 4 trial locations

Overseen By Xufang Yu, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Akeso

Must not be taking: Immunotherapy

Disqualifiers: Autoimmune disease, HIV, Hepatitis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests new treatments for individuals with metastatic colorectal cancer, which has spread beyond the colon and rectum. Researchers aim to evaluate the effectiveness and safety of the experimental drug AK112, both alone and in combination with another experimental drug, AK117, alongside various chemotherapy options. The trial targets individuals who cannot undergo surgery and have either not responded to other cancer treatments or cannot tolerate them. Eligible participants must have a confirmed diagnosis of colorectal cancer and have experienced recurrence or spread of the disease after previous treatments. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to advancements in cancer therapy.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that AK112 and AK117 are generally safe. AK112, also known as ivonescimab, was tested at various doses and proved safe for patients up to 20 mg/kg every two weeks. Some patients experienced side effects, but these were usually manageable. When combined with AK117, the safety profile remained similar.

For AK112 alone, studies found it could be administered safely, even at higher doses. Patients experienced some side effects, but they were typically mild or manageable with care.

Overall, these early findings suggest that both AK112 and AK117 are well-tolerated, though individual experiences may vary. Participants should discuss any concerns with their healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the treatments involving AK112 and AK117 for colorectal cancer because they introduce innovative mechanisms that differ from standard options like FOLFOX or FOLFIRI regimens. AK112 and AK117 are novel antibodies designed to target specific pathways that may enhance the immune system's ability to fight cancer cells more effectively. These treatments are unique because they combine these antibodies with existing chemotherapy regimens, potentially boosting the overall effectiveness and offering a new approach to tackling this cancer. This combination strategy aims to improve patient outcomes by potentially reducing cancer progression and increasing survival rates beyond what current therapies offer.

What evidence suggests that this trial's treatments could be effective for colorectal cancer?

Research has shown that using AK112 and AK117 together holds promise for treating advanced colorectal cancer. In this trial, some participants will receive the combination of AK112 and AK117. Studies have shown that after about 9.6 months, 86.2% of patients did not experience cancer progression, indicating the treatment helped control the cancer for most during that period. AK112 targets proteins that aid cancer growth and has shown positive results in other studies, with 25.5% of patients experiencing significant tumor shrinkage. Adding AK117, which also targets the immune system, might enhance these effects. These findings suggest that AK112, with or without AK117, could effectively slow cancer progression. ^{1 3 6 7 8}

Are You a Good Fit for This Trial?

This trial is for adults with metastatic colorectal cancer that can't be removed by surgery. Participants must have a specific type of tumor, not had systemic therapy for metastasis, and should have received 2-4 prior lines of anticancer therapy. They need to be relatively active (good performance status) and have tumors measurable by certain medical criteria.

Inclusion Criteria

My diagnosis is colorectal cancer confirmed by tissue analysis.

I am fully active or restricted in physically strenuous activity but can do light work.

My cancer returned or spread 12 months after my last cancer treatment.

Exclusion Criteria

Pregnancy or lactation

My cancer is MSI-H or has dMMR.

History of autoimmune disease

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Chemotherapy Regimen Selection

Participants receive AK112 with or without AK117 in combination with XELOX or FOLFOXIRI to determine the optimal chemotherapy regimen

3-6 weeks

Biweekly visits for chemotherapy administration

Maintenance Treatment

Participants receive maintenance therapy with capecitabine plus AK112 plus AK117 or 5-FU/LV plus AK112 plus AK117 until disease progression or unacceptable toxicity

Until disease progression or unacceptable toxicity

Biweekly visits for maintenance therapy

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to approximately 2 years

What Are the Treatments Tested in This Trial?

Interventions

• 5-fluorouracil
• AK112
• AK117
• Bevacizumab
• Capecitabine
• Irinotecan
• Leucovorin
• Oxaliplatin

Trial Overview The study tests AK112 alone or combined with AK117 in treating metastatic colorectal cancer. It's a Phase II trial focusing on how well these treatments work, their safety, and how the body processes them. Standard chemotherapy drugs may also be used.

How Is the Trial Designed?

Group I: Part 2 cohort 2(AK112+AK117) Experimental Treatment 2 Interventions

Subjects receive AK117 and AK112 until disease progression or unacceptable toxicity AK112 and AK117 ( until disease progression, unacceptable toxicity or patient's refusal)

Group II: Part 2 cohort 1(AK112) Experimental Treatment 1 Intervention

Subjects receive AK112 until disease progression or unacceptable toxicity AK112 (until disease progression, unacceptable toxicity or patient's refusal)

Group III: Part 1_Extension Stage Group G (AK112 DS2+mFOLFOX6) Experimental Treatment 4 Interventions

AK112 (Dose2) +mFOLFOX6 ( Oxaliplatin 85 mg/sqm IV day 1, Leucovorin 400 mg/sqm IV day 1, 5-fluorouracil(5-FU) 2400 mg/sqm 46-48 hours continuous infusion, starting on day 1) If no progression occurs during AK112 plus mFOLFOX6, patients will receive maintenance 5- FU/LV plus AK112 at the same dose used at the last cycle of the induction treatment. 5-FU/LV plus AK112 will be repeated biweekly until disease progression, unacceptable toxicity or patient's refusal.

Group IV: Part 1_Extension Stage Group F (AK112 DS1 + mFOLFOX6) Experimental Treatment 4 Interventions

AK112 (Dose1) +mFOLFOX6 ( Oxaliplatin 85 mg/sqm IV day 1, Leucovorin 400 mg/sqm IV day 1, 5-fluorouracil(5-FU) 2400 mg/sqm 46-48 hours continuous infusion, starting on day 1). If no progression occurs during AK112 plus mFOLFOX6, patients will receive maintenance 5- FU/LV plus AK112 at the same dose used at the last cycle of the induction treatment. 5-FU/LV plus AK112 will be repeated biweekly until disease progression, unacceptable toxicity or patient's refusal.

Group V: Part 1_Expansion Stage Group E (AK112 DS2+AK117 DS1+Chemotherapy) Experimental Treatment 7 Interventions

AK112(Dose2)+AK117(Dose1)+Chemotherapy(Decided by Chemotherapy Regimen Selection Stage) AK112 and AK117 and XELOX or FOLFOXIRI(the same dosage, frequency and duration with Chemotherapy Regimen Selection Stage)

Group VI: Part 1_Expansion Stage Group D (AK112 DS2 +AK117 DS2 +Chemotherapy) Experimental Treatment 7 Interventions

AK112(Dose2) + AK117(Dose2)+Chemotherapy(Decided by Chemotherapy Regimen Selection Stage) AK112 and AK117 and XELOX or FOLFOXIRI(the same dosage, frequency and duration with Chemotherapy Regimen Selection Stage)

Group VII: Part 1_Expansion Stage Group C (AK112 DS2+Chemotherapy) Experimental Treatment 6 Interventions

AK112 (Dose2)+Chemotherapy(Decided by Chemotherapy Regimen Selection Stage). AK112 and XELOX or FOLFOXIRI(the same dosage, frequency and duration with Chemotherapy Regimen Selection Stage).

Group VIII: Part 1_Expansion Stage Group B(AK112 DS1+AK117 DS1+Chemotherapy) Experimental Treatment 7 Interventions

AK112 (Dose1) +AK117 (Dose1) +Chemotherapy(Decided by Chemotherapy Regimen Selection Stage) AK112 and AK117 and XELOX or FOLFOXIRI(the same dosage, frequency and duration with Chemotherapy Regimen Selection Stage)

Group IX: Part 1_Expansion Stage Group A(AK112 DS1+Chemotherapy) Experimental Treatment 6 Interventions

AK112 (Dose1) +Chemotherapy(Decided by Chemotherapy Regimen Selection Stage) AK112 and XELOX or FOLFOXIRI(the same dosage, frequency and duration with Chemotherapy Regimen Selection Stage)

Group X: Part 1_Chemotherapy Regimen Selection Stage Group B(AK112+AK117+FOLFOXIRI) Experimental Treatment 6 Interventions

AK112+AK117+FOLFOXIRI AK112 and AK117 and 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 46-48 hours continuous infusion, starting on day 1) If no progression occurs during AK112 plus AK117 plus FOLFOXIRI, patients will receive maintenance 5-FU/LV plus AK112 plus AK117 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.

Group XI: Part 1_Chemotherapy Regimen Selection Stage Group A(AK112+AK117+XELOX) Experimental Treatment 4 Interventions

AK112+AK117+XELOX AK112 and AK117 and XELOX(Oxaliplatin 130 mg/sqm iv day 1, Capecitabine via oral, the total daily dose was 2000mg/sqm, day1-14) If no progression occurs during AK112 plus AK117 plus XELOX, patients will receive maintenance capecitabine plus AK112 plus AK117 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.

5-fluorouracil is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as 5-FU for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer
• Esophageal cancer
• Anal cancer

Approved in European Union as 5-FU for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer
• Esophageal cancer
• Anal cancer

Approved in Canada as 5-FU for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer
• Esophageal cancer
• Anal cancer

Approved in Japan as 5-FU for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer
• Esophageal cancer
• Anal cancer

Who Is Running the Clinical Trial?

Akeso

Lead Sponsor

Trials

122

Recruited

23,400+

Dr. Simon Williams

Akeso

Chief Executive Officer since 2022

PhD in Organic Chemistry from Cambridge University

Dr. Baiyong Li

Akeso

Chief Medical Officer

MD from an unspecified institution

Summit Therapeutics

Industry Sponsor

Trials

18

Recruited

4,500+

Published Research Related to This Trial

In a study of 187 patients with metastatic colorectal cancer, the combination of S-1 and irinotecan (with or without bevacizumab) showed similar overall response rates and survival outcomes compared to the standard FOLFOX regimen, indicating comparable efficacy.

S-1 and irinotecan were well tolerated, with gastrointestinal side effects being the most common, while FOLFOX was associated with neutropenia and sensory neuropathy, suggesting a different safety profile for the two treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

S-1 and irinotecan with or without bevacizumab versus 5-fluorouracil and leucovorin plus oxaliplatin with or without bevacizumab in metastatic colorectal cancer: a pooled analysis of four phase II studies. Iwasa, S., Nagashima, K., Yamaguchi, T., et al.[2018]

Adjuvant therapy using 5-fluorouracil/leucovorin (5-FU/LV) regimens and capecitabine has significantly improved 3-year disease-free survival rates in stage III colorectal cancer patients, indicating its efficacy in early disease stages.

The addition of oxaliplatin to 5-FU-based regimens has been confirmed to enhance disease-free survival, establishing it as a standard treatment alongside other chemotherapy options for colorectal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapid evolution in colorectal cancer: therapy now and over the next five years. de Gramont, A.[2007]

The X-ACT trial, involving 1987 patients, demonstrated that capecitabine is at least as effective as the traditional 5-FU/leucovorin regimen for treating stage III colon cancer, with significant evidence supporting its noninferiority.

Capecitabine resulted in fewer severe side effects and hospital admissions compared to 5-FU/LV, making it a safer and more convenient oral treatment option that also reduces overall healthcare costs for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Xeloda in Adjuvant Colon Cancer Therapy (X-ACT) trial: overview of efficacy, safety, and cost-effectiveness. Twelves, CJ.[2022]

5-Fluorouracil (5-FU) has been the standard treatment for colorectal cancer for 40 years, but its overall survival benefit remains limited to about 12 months, even with enhancements like leucovorin.

Capecitabine has been shown to be as effective as 5-FU and is now a first-line treatment, especially when combined with other agents like CPT-11 or oxaliplatin, which improve response rates and overall survival in patients with advanced colorectal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of colorectal cancer metastasis: the role of chemotherapy. Xiong, HQ., Ajani, JA.[2019]

The OCFL regimen, combining oxaliplatin, irinotecan, and 5-fluorouracil/leucovorin, was found to be well tolerated with a recommended dose established, showing a high overall response rate of 78% in patients with metastatic colorectal cancer.

Patients experienced a median overall survival of 25.4 months and a median time to progression of 9.5 months, indicating significant efficacy, especially as a pre-surgical treatment option for tumor control.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oxaliplatin combined with irinotecan and 5-fluorouracil/leucovorin (OCFL) in metastatic colorectal cancer: a phase I-II study. Seium, Y., Stupp, R., Ruhstaller, T., et al.[2020]

Capecitabine, an oral medication, showed at least equivalent efficacy to intravenous 5-FU plus leucovorin in treating metastatic colorectal cancer, with an overall response rate of 18.9% compared to 15.0% for 5-FU/LV among 602 patients.

Capecitabine had a more favorable safety profile, resulting in significantly lower rates of stomatitis and neutropenia, while being associated with a higher incidence of hand-foot syndrome, making it a convenient and effective alternative to traditional IV treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. Van Cutsem, E., Twelves, C., Cassidy, J., et al.[2022]

Recent trials indicate that oral fluoropyrimidine agents like capecitabine (Xeloda) and UFT/leucovorin are as effective as standard intravenous 5-FU in treating advanced colorectal cancer, showing similar response rates and survival outcomes.

These oral agents also have the added benefit of reducing side effects such as neutropenia and stomatitis, making them a promising option for patients undergoing treatment for colorectal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of oral chemotherapy in colorectal cancer. Donehower, RC.[2015]

In a study of 62 advanced colorectal cancer patients resistant to fluorouracil, the oxaliplatin/irinotecan (OC) combination showed promising safety and efficacy, with median overall survival of 12.3 months.

The tritherapy regimen (5-FU/folinic acid combined with irinotecan and oxaliplatin) resulted in lower activity, possibly due to reduced dose intensities of the drugs, despite both regimens being generally safe with no treatment-related deaths.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized multicenter phase II study comparing a combination of fluorouracil and folinic acid and alternating irinotecan and oxaliplatin with oxaliplatin and irinotecan in fluorouracil-pretreated metastatic colorectal cancer patients. Bécouarn, Y., Gamelin, E., Coudert, B., et al.[2018]

The evolution of chemotherapy for colorectal cancer has shifted from the single-agent use of 5-fluorouracil (5-FU) to more effective combination regimens that include irinotecan, oxaliplatin, and targeted agents like bevacizumab, significantly improving patient survival rates.

Combination therapies utilizing 5-FU as a base have been shown to enhance treatment outcomes, highlighting the importance of integrating newer drugs into established regimens for better management of colorectal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current approaches to first-line treatment of advanced colorectal cancer. Goldberg, RM.[2019]

Capecitabine, an oral fluoropyrimidine, has been shown to achieve superior response rates and equivalent overall survival compared to traditional intravenous 5-FU plus leucovorin in metastatic colorectal cancer, making it a preferred treatment option.

Recent trials, including the Xeloda Adjuvant Chemotherapy Trial (X-ACT), confirm that capecitabine is at least as effective and safer than IV 5-FU/LV for adjuvant treatment in patients with resected stage III colon cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral capecitabine: bridging the Atlantic divide in colon cancer treatment. Van Cutsem, E., Verslype, C., Tejpar, S.[2018]

In a study of 79 patients with advanced colorectal cancer, an alternating treatment schedule of 5-fluorouracil with leucovorin, oxaliplatin, and irinotecan achieved a 54% objective response rate, indicating significant efficacy in managing the disease.

The treatment was associated with manageable toxicity, with no grade 3/4 neurotoxicity and no toxic deaths reported, suggesting a safer profile compared to traditional sequential therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FOLFOX alternated with FOLFIRI as first-line chemotherapy for metastatic colorectal cancer. Aparicio, J., Fernandez-Martos, C., Vincent, JM., et al.[2022]

Oxaliplatin, a new platinum analog, shows high effectiveness in treating metastatic colorectal cancer, particularly when used in combination with 5-FU and leucovorin, which has led to its approval in Europe for first- and second-line treatments.

This ongoing compassionate-use study aims to provide oxaliplatin to patients in the United States who have no adequate second- or third-line therapy options available, highlighting the urgent need for safety data and FDA approval for this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oxaliplatin with 5-FU or as a single agent in advanced/metastatic colorectal cancer. Mitchell, EP.[2018]

Postoperative adjuvant chemotherapy with fluorouracil (5-FU) and leucovorin significantly improves disease-free and overall survival in patients with node-positive (stage III) colorectal cancer, based on clinical trials involving over 5,000 cases.

Current clinical trials are exploring the effectiveness of combining 5-FU/leucovorin with other agents like irinotecan and oxaliplatin, which have shown superior results compared to 5-FU/leucovorin alone in advanced colorectal cancer, aiming to refine the standard of care for resected cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant therapy of colon cancer. Macdonald, JS., Astrow, AB.[2019]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05382442

NCT05382442 | A Study of AK112 With or Without AK117 ... The purpose of this study is to evaluate the efficacy, safety, and pharmacokinetics of AK112 with or without AK117 in participants with metastatic colorectal ...

2. withpower.com withpower.com/trial/phase-2-colorectal-neoplasms-5-2022-5caeb

AK112 +/− AK117 for Colorectal Cancer Adjuvant therapy using 5-fluorouracil/leucovorin (5-FU/LV) regimens and capecitabine has significantly improved 3-year disease-free survival rates in stage III ...

3. clin.larvol.com clin.larvol.com/trial-detail/NCT05382442

AK112-206 / NCT05382442 At a median follow-up of 9.6 months, the median progression-free survival (mPFS) has not yet been reached, with a 9-month PFS rate of 86.2%. In the first-line ...

4. centerwatch.com centerwatch.com/clinical-trials/listings/NCT05382442/a-study-of-ak112-with-or-without-ak117-in-metastatic-colorectal-cancer

A Study of AK112 With or Without AK117 in Metastatic ... The purpose of this study is to evaluate the efficacy, safety, and pharmacokinetics of AK112 with or without AK117 in participants with ...

5. fightcolorectalcancer.org fightcolorectalcancer.org/clinical-trial/nct05382442/

A Study of AK112 With or Without AK117 in Metastatic ... Trial in China, for patients with metastatic MSS only CRC. First part for patients receiving first line therapy for metastatic disease.

6. smmttx.com smmttx.com/pressrelease/promising-anti-tumor-activity-and-safety-of-ivonescimab-in-combination-therapies-in-crc-tnbc-and-hnscc-featured-at-esmo-2024-2/

Promising Anti-Tumor Activity and Safety of Ivonescimab in ... Data for the novel, potential first-in-class investigational bispecific antibody, ivonescimab, was presented at the 2024 European Society for Medical Oncology ...

7. ctv.veeva.com ctv.veeva.com/study/a-study-of-ak112-with-or-without-ak117-in-metastatic-colorectal-cancer

A Study of AK112 With or Without AK117 in Metastatic ... The purpose of this study is to evaluate the efficacy, safety, and pharmacokinetics of AK112 with or without AK117 in participants with metastatic colorectal ...

8. akesobio.com akesobio.com/media/2300/ak112-crc.pdf

ak112-crc.pdf We report preliminary results from a phase 2 trial of ivonescimab and ligufalimab plus chemotherapy in patients with previously untreated mCRC.