Botensilimab + Balstilimab for Rectal Cancer

Recruiting at 6 trial locations

Overseen By Paul Romesser, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: Anticancer, Experimental, Immunosuppressive, others

Disqualifiers: Recurrent cancer, Active infection, HIV, 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

40 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot take other experimental therapies or systemic corticosteroids (a type of medication that reduces inflammation) one week before starting the study drug. It's best to discuss your specific medications with the trial team.

Is the combination of Botensilimab and Balstilimab generally safe for humans?

The safety of Botensilimab and Balstilimab, which are types of immunotherapy, may involve immune-related side effects. These treatments can cause a range of adverse events (unwanted effects) due to immune system activation, similar to other immunotherapy drugs, but specific safety data for this combination in humans is not detailed in the provided research. ^{1 2 3 4 5}

How is the drug Botensilimab + Balstilimab unique for treating rectal cancer?

Botensilimab + Balstilimab is unique because it combines two types of immunotherapy drugs, an anti-CTLA-4 antibody and an anti-PD-1 antibody, to enhance the body's immune response against rectal cancer. This combination has shown exceptional responses in patients with a specific type of rectal cancer (mismatch repair proficient/microsatellite stable) that typically does not respond well to immunotherapy, potentially sparing patients from chemotherapy. ^{6 7 8 9 10}

What is the purpose of this trial?

The purpose of this study is to find out whether the combination of botensilimab and balstilimab (BOT/BAL) is a safe and effective treatment that causes few or mild side effects for people with mismatch repair proficient (MMRp)/microsatellite stable (MSS) locally advanced rectal adenocarcinoma. The investigators will also find out whether BOT/BAL is an effective treatment when given in combination with standard chemotherapy.

Research Team

Andrea Cercek, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

This trial is for individuals with locally advanced rectal adenocarcinoma that's mismatch repair proficient (MMRp)/microsatellite stable (MSS). Participants must meet certain health criteria to join, but specific inclusion and exclusion details are not provided.

Inclusion Criteria

Radiologically measurable or clinically evaluable disease per Protocol Section 13.0.

My cancer has not spread to distant parts of my body.

I can give or my representative can give consent for me to join the trial.

Exclusion Criteria

Known active hepatitis B (e.g., HbsAg reactive) or hepatitis C (e.g., HCV RNA [qualitative] is detected).

My rectal cancer has come back.

My tumor is blocking my intestines but I have a temporary bypass.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Neoadjuvant Treatment

Participants receive neoadjuvant combination of botensilimab and balstilimab

12 weeks

Chemotherapy

Participants receive standard chemotherapy in combination with BOT/BAL

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

Treatment Details

Interventions

• Balstilimab
• Botensilimab

Trial Overview The study tests the safety and effectiveness of combining two drugs, Botensilimab and Balstilimab (BOT/BAL), with standard chemotherapy in treating rectal adenocarcinoma. It aims to determine if this combination leads to few or mild side effects.

Participant Groups

Group I: Participants with locally advanced rectal cancer Experimental Treatment 2 Interventions

Up to 40 patients with mismatch repair proficient (MMRp)/microsatellite stable (MSS) locally advanced (stage II or III) rectal cancer

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Agenus Inc.

Industry Sponsor

Trials

58

Recruited

4,900+

Findings from Research

A total of 3120 adverse event cases related to avapritinib were reported to the FDA, with 44% occurring within the first 30 days of treatment, highlighting the importance of monitoring patients closely during this period.

The study found that elderly male patients are at a higher risk for serious adverse events, indicating that clinicians should exercise caution when prescribing avapritinib to this demographic.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A post-marketing pharmacovigilance study of avapritinib: Adverse event data mining and analysis based on the United States Food and Drug Administration Adverse Event Reporting System database. Rong, L., Xie, M., Jiang, M., et al.[2023]

In the BEACON CRC study involving 216 patients with BRAFV600E-mutated metastatic colorectal cancer, the combination of encorafenib and cetuximab was generally well tolerated, with most adverse events being mild to moderate in severity and resolving quickly, typically within 1-2 weeks.

The most common adverse events included dermatological toxicity (75.5%), arthralgia/myalgia (56.0%), and fatigue/asthenia (56.0%), with notable survival benefits observed in patients experiencing these side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Events Associated with Encorafenib Plus Cetuximab in Patients with BRAFV600E-mutant Metastatic Colorectal Cancer: An in-depth Analysis of the BEACON CRC Study. Taieb, J., Lonardi, S., Desai, J., et al.[2023]

A disproportionality analysis of 33,327 reports identified 687 cases of adverse reactions associated with alpelisib, with hyperglycaemia being the most significant adverse event, indicating a strong association with this medication.

The most frequently reported adverse events included hyperglycaemia, rash, and diarrhoea, highlighting the need for monitoring these effects in patients receiving alpelisib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events of alpelisib: A postmarketing study of the World Health Organization pharmacovigilance database. Chen, X., Wei, L., Chi, L., et al.[2022]

Immunotherapy, particularly with checkpoint inhibitors like anti-PD1 and anti-CTLA-4 agents, has shown high response rates in cancer treatment, but it can lead to a variety of immune-related adverse events that are not selective.

Real-world data suggests that the characteristics and management of these adverse events may differ from clinical trial recommendations, highlighting the need for tailored approaches in using corticosteroids and other treatments for severe cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicities from immunotherapy: From clinical trials to real-world clinical practice. Riveiro-Barciela, M., Trallero-Araguás, E., Martínez-Valle, F.[2021]

In the final analysis of the KEYNOTE-164 study, pembrolizumab demonstrated a 32.8% objective response rate in patients with advanced MSI-H/dMMR colorectal cancer who had received multiple prior treatments, indicating its efficacy in this difficult-to-treat population.

The treatment was associated with a median overall survival of 31.4 months for patients with more prior therapies and 47.0 months for those with fewer, while maintaining a manageable safety profile with no new safety concerns reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for previously treated, microsatellite instability-high/mismatch repair-deficient advanced colorectal cancer: final analysis of KEYNOTE-164. Le, DT., Diaz, LA., Kim, TW., et al.[2023]

In a neoadjuvant setting for patients with locally advanced pMMR/MSS colon and rectal cancer, the combination of botensilimab (an anti-CTLA-4 antibody) and balstilimab (an anti-PD-1 antibody) showed exceptional responses, indicating potential efficacy of this immunotherapy approach.

The unique 'inside-out' tumor regression pattern observed suggests a novel mechanism of action for botensilimab, which may influence future clinical trial designs and offer alternatives to chemotherapy for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant botensilimab plus balstilimab response pattern in locally advanced mismatch repair proficient colorectal cancer. Kasi, PM., Hidalgo, M., Jafari, MD., et al.[2023]

In a study involving 18 patient-derived xenograft models of colorectal cancer, 60% of tumors showed regression when treated with a combination of MEK and CDK4/6 inhibitors, indicating significant therapeutic efficacy for RAS mutant colorectal cancer.

The clinical trial of binimetinib and palbociclib confirmed the safety of this treatment approach and provided preliminary evidence of its effectiveness, while also revealing mechanisms of resistance that could be targeted for improved outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting RAS Mutant Colorectal Cancer with Dual Inhibition of MEK and CDK4/6. Sorokin, AV., Kanikarla Marie, P., Bitner, L., et al.[2023]

In a study of 43 patients with BRAF V600-mutant metastatic colorectal cancer, the combination of dabrafenib and trametinib showed activity, with 12% of patients achieving a partial response and one patient achieving a complete response lasting over 36 months.

All patients evaluated during treatment showed a significant reduction in phosphorylated ERK levels, indicating effective inhibition of the mitogen-activated protein kinase signaling pathway, although the response was less pronounced than in BRAF-mutant melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined BRAF and MEK Inhibition With Dabrafenib and Trametinib in BRAF V600-Mutant Colorectal Cancer. Corcoran, RB., Atreya, CE., Falchook, GS., et al.[2022]

BGB-283, a dual RAF kinase/EGFR inhibitor, shows strong potential in treating BRAF(V600E) colorectal cancer by effectively inhibiting tumor growth and preventing the reactivation of EGFR signaling, which is often a problem with first-generation BRAF inhibitors.

In preclinical studies, BGB-283 demonstrated selective cytotoxicity against cancer cells with BRAF(V600E) mutations and EGFR alterations, leading to significant tumor regressions in animal models, indicating its promising efficacy as a new treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BGB-283, a Novel RAF Kinase and EGFR Inhibitor, Displays Potent Antitumor Activity in BRAF-Mutated Colorectal Cancers. Tang, Z., Yuan, X., Du, R., et al.[2020]

Activated T-cells armed with a bispecific antibody targeting CD3 and EGFR significantly increased tumor infiltrating lymphocytes (TIL) and reduced tumor cell viability, indicating enhanced anti-tumor activity.

Combining this bispecific antibody approach with targeted expression of LIGHT further improved T-cell proliferation and infiltration, leading to observable tumor regressions in a model of microsatellite stable colon cancer, suggesting a promising strategy for combination immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

LIGHT enhanced bispecific antibody armed T-cells to treat immunotherapy resistant colon cancer. Qiao, G., Kone, LB., Phillips, EH., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

A post-marketing pharmacovigilance study of avapritinib: Adverse event data mining and analysis based on the United States Food and Drug Administration Adverse Event Reporting System database. [2023]

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

Adverse Events Associated with Encorafenib Plus Cetuximab in Patients with BRAFV600E-mutant Metastatic Colorectal Cancer: An in-depth Analysis of the BEACON CRC Study. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Adverse events of alpelisib: A postmarketing study of the World Health Organization pharmacovigilance database. [2022]

4. Spain pubmed.ncbi.nlm.nih.gov

Toxicities from immunotherapy: From clinical trials to real-world clinical practice. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab for previously treated, microsatellite instability-high/mismatch repair-deficient advanced colorectal cancer: final analysis of KEYNOTE-164. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Neoadjuvant botensilimab plus balstilimab response pattern in locally advanced mismatch repair proficient colorectal cancer. [2023]

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

Targeting RAS Mutant Colorectal Cancer with Dual Inhibition of MEK and CDK4/6. [2023]

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

Combined BRAF and MEK Inhibition With Dabrafenib and Trametinib in BRAF V600-Mutant Colorectal Cancer. [2022]

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

BGB-283, a Novel RAF Kinase and EGFR Inhibitor, Displays Potent Antitumor Activity in BRAF-Mutated Colorectal Cancers. [2020]

10. England pubmed.ncbi.nlm.nih.gov

LIGHT enhanced bispecific antibody armed T-cells to treat immunotherapy resistant colon cancer. [2022]