AK112 +/− AK117 for Colorectal Cancer

Recruiting at 2 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

254 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

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.

What data supports the effectiveness of the drug combination AK112 +/− AK117 for colorectal cancer?

Research shows that drugs like 5-fluorouracil (5-FU), leucovorin, oxaliplatin, and irinotecan, which are part of the treatment, have improved survival rates in colorectal cancer patients. Additionally, capecitabine, a drug that turns into 5-FU in the body, is effective and well-tolerated, especially when combined with other drugs like oxaliplatin and irinotecan. ^{1 2 3 4 5}

Is the treatment AK112 +/− AK117 for colorectal cancer generally safe in humans?

The safety of treatments like capecitabine (Xeloda) and 5-fluorouracil (5-FU), often used in colorectal cancer, has been well-studied. Capecitabine is known for its favorable safety profile compared to 5-FU, and both are commonly used in combination with other drugs like oxaliplatin and irinotecan, showing good tolerability in patients. ^{1 6 7 8 9}

What makes the AK112 +/− AK117 drug for colorectal cancer unique?

The AK112 +/− AK117 drug for colorectal cancer is unique because it combines traditional chemotherapy agents like 5-FU, capecitabine, and oxaliplatin with targeted therapies such as bevacizumab, potentially enhancing effectiveness by attacking cancer cells in multiple ways. This combination aims to improve survival rates and manage side effects better than standard treatments. ^{2 10 11 12 13}

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Oral capecitabine: bridging the Atlantic divide in colon cancer treatment. [2018]

2. England pubmed.ncbi.nlm.nih.gov

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

3. United States pubmed.ncbi.nlm.nih.gov

FOLFOX alternated with FOLFIRI as first-line chemotherapy for metastatic colorectal cancer. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

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

5. United States pubmed.ncbi.nlm.nih.gov

Adjuvant therapy of colon cancer. [2019]

6. United States pubmed.ncbi.nlm.nih.gov

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

7. United States 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. [2022]

8. Germany 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. [2018]

9. England pubmed.ncbi.nlm.nih.gov

Oxaliplatin combined with irinotecan and 5-fluorouracil/leucovorin (OCFL) in metastatic colorectal cancer: a phase I-II study. [2020]

10. United States pubmed.ncbi.nlm.nih.gov

Role of oral chemotherapy in colorectal cancer. [2015]

11. Netherlands pubmed.ncbi.nlm.nih.gov

Treatment of colorectal cancer metastasis: the role of chemotherapy. [2019]

12. United States 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. [2018]

13. United States pubmed.ncbi.nlm.nih.gov

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