Isunakinra + Pembrolizumab for Colorectal Cancer

Recruiting at 1 trial location

Overseen By Hans Olivecrona, MD PhD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Buzzard Pharmaceuticals

Must be taking: PD-1 inhibitors

Must not be taking: Systemic steroids

Disqualifiers: Pregnancy, Autoimmune diseases, 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

Duration: 6 months

20 Participants Needed

Trial Summary

What is the purpose of this trial?

This study will enroll patients with colorectal cancer that is locally advanced or metastatic. The tumor must be microsatellite stable (MSS), have a tumor mutational burden that is high (TMB-H) and be kras mutated. Patients must have been treated with available approved treatments already. In this study the investigators are testing a new type of immunotherapy, the potent IL-1 inhibitor isunakinra to be added to already approved immunotherapy (PD-1/PD-L1 inhibitor) in an attempt to get this treatment to work in this treatment resistant type of tumor.

Will I have to stop taking my current medications?

The trial requires a minimum of 2 weeks without chemotherapy or radiation therapy and 4 weeks without immunotherapy before starting. Other medications are not specifically mentioned, so it's best to discuss with the trial team.

What data supports the effectiveness of the drug Isunakinra + Pembrolizumab for colorectal cancer?

Research shows that pembrolizumab, one of the drugs in the treatment, is effective for certain types of colorectal cancer, particularly those with specific genetic features (microsatellite instability-high or mismatch repair-deficient). It has been shown to improve survival and quality of life compared to standard chemotherapy. ^{1 2 3 4 5}

Is the combination of Isunakinra and Pembrolizumab safe for treating colorectal cancer?

Pembrolizumab has been shown to have manageable safety in treating advanced colorectal cancer, with common side effects including diarrhea, fatigue, and nausea. The European Medicines Agency and the FDA have both approved its use, indicating a positive benefit-risk balance. ^{1 2 3 6 7}

What makes the drug Isunakinra + Pembrolizumab unique for colorectal cancer?

Isunakinra + Pembrolizumab is unique because it combines a novel drug, Isunakinra, with Pembrolizumab, an established immunotherapy that blocks a protein called PD-1, helping the immune system attack cancer cells. This combination may offer a new approach for treating colorectal cancer, especially in cases where the cancer has specific genetic features like microsatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR). ^{1 2 3 8 9}

Eligibility Criteria

This trial is for individuals with advanced or metastatic colorectal cancer that's microsatellite stable (MSS), has a high tumor mutational burden (TMB-H), and KRAS mutation. Participants must have tried all approved treatments already.

Inclusion Criteria

Patients must have measurable disease by radiographic criteria

Patients must meet specific washout periods from prior therapies

I can carry out all my self-care activities without assistance.

Exclusion Criteria

I do not have any major health issues that could affect my treatment.

Pregnant women or women presently breast-feeding their children

Dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive isunakinra in combination with pembrolizumab for colorectal cancer

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Treatment Details

Interventions

• Isunakinra

Trial Overview The study tests isunakinra, a new immunotherapy, alone and combined with Pembrolizumab, an existing immunotherapy. The goal is to see if adding isunakinra can make resistant tumors respond to treatment.

Participant Groups

Group I: combination immunotherapy Experimental Treatment 1 Intervention

Who Is Running the Clinical Trial?

Buzzard Pharmaceuticals

Lead Sponsor

Trials

2

Recruited

40+

Findings from Research

In a phase II study involving 124 patients with metastatic MSI-H/dMMR colorectal cancer, pembrolizumab demonstrated an objective response rate of 33% in both treatment cohorts, indicating its efficacy in this difficult-to-treat population.

The treatment showed a manageable safety profile, with 16% of patients in cohort A and 13% in cohort B experiencing grade 3-4 adverse events, suggesting that pembrolizumab can be safely administered to patients with prior treatment failures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Open-Label Study of Pembrolizumab in Treatment-Refractory, Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: KEYNOTE-164. Le, DT., Kim, TW., Van Cutsem, E., et al.[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]

The KEYNOTE-177 study demonstrated that pembrolizumab significantly improves progression-free survival compared to the current standard of care for patients with metastatic colorectal cancer that has DNA mismatch repair or microsatellite instability-high.

This finding suggests that pembrolizumab could be a more effective first-line treatment option for this specific type of colorectal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PD-1 Inhibitor Bests Chemo for Colorectal Cancer. [2021]

In a study of 44 women with advanced or recurrent MMRd/MSI-H endometrial adenocarcinomas treated with pembrolizumab, obesity (BMI≥30) was linked to a higher disease control rate (85.2%) compared to those with a BMI<30 (59.8%).

Patients with obesity also experienced significantly longer progression-free survival (PFS) while overall survival (OS) rates remained similar regardless of BMI, suggesting that body weight may influence treatment outcomes with pembrolizumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Obesity is associated with improved progression-free survival in Microsatellite-Instability-High endometrial cancer treated with pembrolizumab. Bernard, L., How, JA., Patel, S., et al.[2023]

In the KEYNOTE-177 study involving 307 patients with metastatic colorectal cancer, pembrolizumab significantly improved health-related quality of life (HRQOL) compared to chemotherapy, with a clinically meaningful difference in global health status scores.

Patients receiving pembrolizumab experienced a longer time to deterioration in quality of life measures, including physical and social functioning, indicating that pembrolizumab not only extends progression-free survival but also enhances overall well-being.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Health-related quality of life in patients with microsatellite instability-high or mismatch repair deficient metastatic colorectal cancer treated with first-line pembrolizumab versus chemotherapy (KEYNOTE-177): an open-label, randomised, phase 3 trial. Andre, T., Amonkar, M., Norquist, JM., et al.[2021]

Pembrolizumab has been approved as a first-line treatment for adults with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) metastatic colorectal cancer, showing a significant improvement in progression-free survival (PFS) compared to standard of care, with a median PFS of 16.5 months versus 8.2 months.

The treatment was associated with manageable adverse events, including diarrhea and fatigue, and the European Medicines Agency deemed the benefit-risk balance positive, marking a significant advancement in targeted cancer therapy based on DNA repair deficiency biomarkers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The EMA assessment of pembrolizumab as monotherapy for the first-line treatment of adult patients with metastatic microsatellite instability-high or mismatch repair deficient colorectal cancer. Trullas, A., Delgado, J., Genazzani, A., et al.[2021]

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 phase I/II trial involving 55 patients with metastatic colorectal cancer, the combination of napabucasin and pembrolizumab showed promising antitumor activity, particularly in patients with microsatellite instability high (MSI-H) tumors, achieving an immune-related objective response rate (irORR) of 50%.

The treatment was generally well-tolerated, with no dose-limiting toxicities observed at the recommended phase 2 dose of napabucasin (480 mg), although the overall efficacy did not meet the primary endpoint, highlighting the need for further investigation into biomarkers that may influence treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicenter Phase I/II Trial of Napabucasin and Pembrolizumab in Patients with Metastatic Colorectal Cancer (EPOC1503/SCOOP Trial). Kawazoe, A., Kuboki, Y., Shinozaki, E., et al.[2021]

In a study of 107 patients with advanced well-differentiated neuroendocrine tumors (NETs), pembrolizumab showed limited efficacy, with an objective response rate of only 3.7%, indicating that it may not be a highly effective treatment for this specific cancer type.

Despite the low response rate, pembrolizumab was associated with manageable safety, as 75.7% of patients experienced treatment-related adverse events, with only 21.5% classified as severe (grade 3-5).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Neuroendocrine Tumors: Results From the Phase II KEYNOTE-158 Study. Strosberg, J., Mizuno, N., Doi, T., et al.[2021]

References

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

Phase II Open-Label Study of Pembrolizumab in Treatment-Refractory, Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: KEYNOTE-164. [2021]

2. 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]

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

PD-1 Inhibitor Bests Chemo for Colorectal Cancer. [2021]

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

Obesity is associated with improved progression-free survival in Microsatellite-Instability-High endometrial cancer treated with pembrolizumab. [2023]

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

Health-related quality of life in patients with microsatellite instability-high or mismatch repair deficient metastatic colorectal cancer treated with first-line pembrolizumab versus chemotherapy (KEYNOTE-177): an open-label, randomised, phase 3 trial. [2021]

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

The EMA assessment of pembrolizumab as monotherapy for the first-line treatment of adult patients with metastatic microsatellite instability-high or mismatch repair deficient colorectal cancer. [2021]

7. 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]

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

Multicenter Phase I/II Trial of Napabucasin and Pembrolizumab in Patients with Metastatic Colorectal Cancer (EPOC1503/SCOOP Trial). [2021]

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

Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Neuroendocrine Tumors: Results From the Phase II KEYNOTE-158 Study. [2021]