Botensilimab + Balstilimab for Colorectal Cancer

(BBOpCo Trial)

Overseen By Emily Bolch

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Nicholas DeVito, MD

Must not be taking: Corticosteroids, Immunosuppressants, Live vaccines, others

Disqualifiers: Liver metastases, Autoimmune disease, 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: 4

Duration: Up to 2 years

15 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a single-arm, interventional, pilot clinical trial. Fifteen evaluable patients will have tumor-informed ctDNA testing at baseline and start botensilimab and balstilimab treatment. They will receive botensilimab and balstilimab in 6-week cycles until progression, after which mFOLFOX6 and bevacizumab or panitumumab will be added to the regimen. Subjects will have safety testing at baseline and every two weeks while on study drug. Study treatment with botensilimab and balstilimab, mFOLFOX6, and bevacizumab or panitumumab will be continued until radiographic or clinical progression, toxicity, or patient withdrawal. Subjects will have one safety follow up visit 30 days after the last treatment and will be followed for survival every 12 weeks for up to 2 years.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, if you are using medications that are prohibited in combination with the study drug, you may need to stop those. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

What data supports the idea that Botensilimab + Balstilimab for Colorectal Cancer is an effective treatment?

The available research does not provide specific data on the effectiveness of Botensilimab + Balstilimab for Colorectal Cancer. Instead, it focuses on other treatments and their outcomes for this condition. Without direct evidence from studies on Botensilimab + Balstilimab, we cannot conclude its effectiveness compared to other treatments. ^{1 2 3 4 5}

What safety data exists for Botensilimab and Balstilimab in humans?

Immune checkpoint inhibitors like Balstilimab (anti-PD-1) and Botensilimab (anti-CTLA-4) can cause side effects such as diarrhea and colitis (inflammation of the colon). These side effects are more common with CTLA-4 inhibitors, and combination therapies may increase the risk of these issues. ^{6 7 8 9 10}

What makes the drug Botensilimab + Balstilimab unique for colorectal cancer?

The combination of Botensilimab and Balstilimab is unique because it involves two immune checkpoint inhibitors that may work together to enhance the body's immune response against colorectal cancer, offering a novel approach compared to traditional chemotherapy or targeted therapies. ^{3 11 12 13 14}

Eligibility Criteria

This trial is for patients with colorectal cancer. Participants must have tumor-informed ctDNA testing at baseline to start treatment. The study excludes certain individuals, but specific exclusion criteria are not provided.

Inclusion Criteria

The participant (or legally acceptable representative if applicable) provides written informed consent for the trial

I have not had any drug treatments for colon cancer.

I may have had chemotherapy before or after surgery with the study leader's approval.

Exclusion Criteria

I have had a blockage in my intestines in the last 3 months.

A WOCBP who is pregnant or breastfeeding or has a positive pregnancy test within 72 hours prior to receiving study treatment

I haven't had any cancer except for certain treated types in the past 2 years.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

4 weeks

1 visit (in-person)

Treatment

Participants receive botensilimab and balstilimab in 6-week cycles until progression, with mFOLFOX6 and bevacizumab or panitumumab added upon progression.

Up to 2 years

Visits every 2 weeks (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, with a safety follow-up visit 30 days after the last treatment and survival follow-up every 12 weeks for up to 2 years.

Up to 2 years

1 visit (in-person) at 30 days, then phone calls every 12 weeks

Treatment Details

Interventions

• Balstilimab
• Botensilimab

Trial Overview The BBOpCo trial tests botensilimab and balstilimab treatments in cycles until the disease progresses. If progression occurs, mFOLFOX6 chemotherapy with bevacizumab or panitumumab is added. Safety is monitored every two weeks during treatment.

Participant Groups

Group I: Treatment Experimental Treatment 7 Interventions

botensilimab + balstilimab until disease progression, then botensilimab + balstilimab + mFOLFOX6 (leucovorin, fluorouracil, oxaliplatin) + {bevacizumab or panitumumab}

Who Is Running the Clinical Trial?

Nicholas DeVito, MD

Lead Sponsor

Trials

1

Recruited

20+

Gateway for Cancer Research

Collaborator

Trials

47

Recruited

2,500+

Agenus Inc.

Industry Sponsor

Trials

58

Recruited

4,900+

Findings from Research

In the FIRE-3 trial involving 592 patients with KRAS wild-type metastatic colorectal cancer, those who received first-line treatment with FOLFIRI plus cetuximab (arm A) had significantly longer progression-free survival (6.5 months) and overall survival (16.3 months) compared to those treated with FOLFIRI plus bevacizumab (arm B).

The study found that the choice of subsequent therapy was influenced by the initial treatment, with a higher percentage of patients from arm A receiving bevacizumab and those from arm B receiving cetuximab or panitumumab, suggesting that the sequence of drug administration may be crucial for optimizing treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of Subsequent Therapies on Outcome of the FIRE-3/AIO KRK0306 Trial: First-Line Therapy With FOLFIRI Plus Cetuximab or Bevacizumab in Patients With KRAS Wild-Type Tumors in Metastatic Colorectal Cancer. Modest, DP., Stintzing, S., von Weikersthal, LF., et al.[2022]

In a study of 63 patients with KRAS wild-type metastatic colorectal cancer, the combination of irinotecan, bevacizumab, and cetuximab/panitumumab as a 4th-line treatment was found to be safe and well tolerated, with a toxicity profile consistent with the individual drugs.

The treatment resulted in a median progression-free survival of 6.1 months and a median overall survival of 11.9 months, indicating a significant level of disease control in patients who had already undergone multiple lines of therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dual Inhibition of EGFR and VEGF in Heavily Pretreated Patients with Metastatic Colorectal Cancer. Larsen, FO., Markussen, A., Nielsen, D., et al.[2018]

In a study of 40 frail elderly patients (aged ≥ 75 years) with metastatic RAS-BRAF wild-type colorectal cancer, single-agent panitumumab demonstrated an objective response rate of 32.5% and a disease control rate of 72.5%, indicating its efficacy as a treatment option for this population.

Panitumumab was found to be well-tolerated, with a median progression-free survival of 6.4 months and overall survival of 14.3 months, while only 23% of patients experienced dose reductions due to adverse events, primarily skin rash, suggesting a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-Agent Panitumumab in Frail Elderly Patients With Advanced RAS and BRAF Wild-Type Colorectal Cancer: Challenging Drug Label to Light Up New Hope. Pietrantonio, F., Cremolini, C., Aprile, G., et al.[2022]

Older adults (70 years and older) were less likely to receive second-line therapy for metastatic colorectal cancer compared to younger adults, with a decrease in odds of receiving treatment by 11% for each additional decade of age.

Despite the lower likelihood of receiving second-line therapy, older and younger adults showed similar median time to progression (TTP) and overall survival (OS) outcomes after treatment, indicating that age alone may not impact the effectiveness of the therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metastatic Colorectal Cancer Outcomes by Age Among ARCAD First- and Second-Line Clinical Trials. McCleary, NJ., Harmsen, WS., Haakenstad, E., et al.[2022]

In a phase II trial involving 35 patients with untreated metastatic colorectal cancer, the combination of gefitinib, capecitabine, and oxaliplatin resulted in an 80% disease control rate, with 8.6% achieving a complete response and 40% a partial response.

The treatment led to a median overall survival of 21.9 months, which is promising compared to previous regimens, and the side effects were manageable, primarily consisting of diarrhea and vomiting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II trial of gefitinib in combination with capecitabine and oxaliplatin as first-line chemotherapy in patients with advanced colorectal cancer. Gelibter, AJ., Gamucci, T., Pollera, CF., et al.[2018]

The PI3K pathway is crucial in cancer progression and immune response, and several PI3K inhibitors, including idelalisib, copanlisib, duvelisib, and umbralisib, have been approved for treating hematological malignancies.

This review highlights a lack of real-world data on the incidence and gastrointestinal toxicity, specifically colitis, associated with PI3K inhibitors, emphasizing the need for better understanding and management of these adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of Gastro-Intestinal Toxicity of the Pi3 Kinase Inhibitor: Optimizing Future Dosing Strategies. Breal, C., Beuvon, F., de Witasse-Thezy, T., et al.[2023]

A study involving 448 patients with advanced cancers showed that immune checkpoint inhibitors, like anti-PD-1 and anti-CTLA4 therapies, are safe and well tolerated across different age groups, including those aged 75 and older.

Older patients (≥75 years) experienced fewer endocrine toxicities compared to younger patients, while they had a higher incidence of dermatological toxicities, indicating that age does not significantly increase the risk of severe adverse effects from these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of age on the toxicity of immune checkpoint inhibition. Samani, A., Zhang, S., Spiers, L., et al.[2023]

In a review of 18 studies involving 4,653 patients, anti-CTLA-4 inhibitors were associated with a significantly higher incidence of diarrhea (35.4%) and colitis (8.8%) compared to anti-PD-1 inhibitors, which had incidences of 13.7% and 1.6%, respectively.

The study found that patients receiving anti-PD-1 therapy had a lower relative risk of developing diarrhea (0.58) and colitis (0.16) compared to those on anti-CTLA-4 therapy, indicating that PD-1 inhibitors may be a safer option regarding these gastrointestinal toxicities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Risk of Diarrhea and Colitis in Patients With Advanced Melanoma Undergoing Immune Checkpoint Inhibitor Therapy: A Systematic Review and Meta-Analysis. Tandon, P., Bourassa-Blanchette, S., Bishay, K., et al.[2019]

Pembrolizumab significantly improved progression-free survival (PFS) in patients with unresectable or metastatic microsatellite instability-high (MSI-H) colorectal cancer, with a median PFS of 16.5 months compared to 8.2 months for standard chemotherapy, indicating its efficacy as a first-line treatment.

The FDA found no safety concerns during the approval process, and while both pembrolizumab and standard of care had similar adverse reactions, the duration of treatment with pembrolizumab was nearly double that of standard care, suggesting a potentially more favorable treatment profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for the First-line Treatment of Patients with MSI-H/dMMR Advanced Unresectable or Metastatic Colorectal Carcinoma. Casak, SJ., Marcus, L., Fashoyin-Aje, L., et al.[2022]

In a study of 274 elderly patients with advanced melanoma, the risk of developing colitis was similar for those treated with anti-CTLA4 (ipilimumab) and anti-PD1 (nivolumab or pembrolizumab) therapies.

However, when considering patients across all stages of melanoma, anti-PD1 treatment was associated with a significantly lower risk of colitis compared to anti-CTLA4, suggesting a safer profile for anti-PD1 in this broader patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of immune-checkpoint inhibitors and the risk of immune-related colitis among elderly patients with advanced melanoma: real-world evidence from the SEER-Medicare database. Almutairi, AR., Slack, M., Erstad, BL., et al.[2022]

T138067, a novel microtubule targeting agent, was well tolerated in patients with metastatic colorectal cancer, showing only moderate hematologic and gastrointestinal toxicity, while neurotoxicity was minimal.

Despite being well tolerated, T138067 did not demonstrate any clinical activity in patients who had previously been treated with irinotecan and 5-fluorouracil, with a median time to tumor progression of only 1.4 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of T138067, a novel microtubule inhibitor, in patients with metastatic, refractory colorectal carcinoma. Berlin, JD., Venook, A., Bergsland, E., et al.[2018]

In a phase II study involving 99 patients with wild-type KRAS colorectal cancer, the biweekly combination of cetuximab and FOLFOX-4 achieved an overall response rate (ORR) of 60.6%, indicating significant efficacy as a first-line treatment.

The safety profile was consistent with previous studies, with common grade 3-4 toxicities including neutropenia (32.3%) and acne-like rash (15.2%), suggesting that the biweekly regimen is both effective and manageable for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biweekly cetuximab in combination with FOLFOX-4 in the first-line treatment of wild-type KRAS metastatic colorectal cancer: final results of a phase II, open-label, clinical trial (OPTIMIX-ACROSS Study). Fernandez-Plana, J., Pericay, C., Quintero, G., et al.[2023]

In a study involving 54 patients with BRAF-mutant metastatic colorectal cancer, the combination of the RAF inhibitor encorafenib and the EGFR-targeting antibody cetuximab showed promising clinical activity, with overall response rates of 19% for dual therapy and 18% for triple therapy including a PI3Kα inhibitor.

Both treatment combinations were well-tolerated, with no maximum tolerated dose reached, indicating that these therapies could be viable options for patients with difficult-to-treat BRAF-mutant metastatic colorectal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase Ib Dose-Escalation Study of Encorafenib and Cetuximab with or without Alpelisib in Metastatic BRAF-Mutant Colorectal Cancer. van Geel, RMJM., Tabernero, J., Elez, E., et al.[2022]

In the phase I/II KRYSTAL-1 trial, the KRASG12C inhibitor adagrasib showed a high disease control rate of 87% in patients with metastatic colorectal cancer when used alone, with a progression-free survival of 5.6 months.

When adagrasib was combined with the EGFR inhibitor cetuximab, the disease control rate improved to 100%, indicating a potentially more effective treatment strategy, although progression-free survival data for this combination is still being evaluated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adagrasib Data Create Buzz at ESMO. [2022]

References

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

Impact of Subsequent Therapies on Outcome of the FIRE-3/AIO KRK0306 Trial: First-Line Therapy With FOLFIRI Plus Cetuximab or Bevacizumab in Patients With KRAS Wild-Type Tumors in Metastatic Colorectal Cancer. [2022]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Dual Inhibition of EGFR and VEGF in Heavily Pretreated Patients with Metastatic Colorectal Cancer. [2018]

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

Single-Agent Panitumumab in Frail Elderly Patients With Advanced RAS and BRAF Wild-Type Colorectal Cancer: Challenging Drug Label to Light Up New Hope. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Metastatic Colorectal Cancer Outcomes by Age Among ARCAD First- and Second-Line Clinical Trials. [2022]

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

A phase II trial of gefitinib in combination with capecitabine and oxaliplatin as first-line chemotherapy in patients with advanced colorectal cancer. [2018]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Management of Gastro-Intestinal Toxicity of the Pi3 Kinase Inhibitor: Optimizing Future Dosing Strategies. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Impact of age on the toxicity of immune checkpoint inhibition. [2023]

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

The Risk of Diarrhea and Colitis in Patients With Advanced Melanoma Undergoing Immune Checkpoint Inhibitor Therapy: A Systematic Review and Meta-Analysis. [2019]

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

FDA Approval Summary: Pembrolizumab for the First-line Treatment of Patients with MSI-H/dMMR Advanced Unresectable or Metastatic Colorectal Carcinoma. [2022]

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

Association of immune-checkpoint inhibitors and the risk of immune-related colitis among elderly patients with advanced melanoma: real-world evidence from the SEER-Medicare database. [2022]

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

Phase II trial of T138067, a novel microtubule inhibitor, in patients with metastatic, refractory colorectal carcinoma. [2018]

12. England pubmed.ncbi.nlm.nih.gov

Biweekly cetuximab in combination with FOLFOX-4 in the first-line treatment of wild-type KRAS metastatic colorectal cancer: final results of a phase II, open-label, clinical trial (OPTIMIX-ACROSS Study). [2023]

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

A Phase Ib Dose-Escalation Study of Encorafenib and Cetuximab with or without Alpelisib in Metastatic BRAF-Mutant Colorectal Cancer. [2022]

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

Adagrasib Data Create Buzz at ESMO. [2022]