mRNA-4106 + Checkpoint Inhibitors for Cancer

Recruiting at 2 trial locations

Overseen By Moderna WeCare Team

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: ModernaTX, Inc.

Must not be taking: Chemotherapy, Hormonal therapy

Disqualifiers: CNS tumors, Unstable illness, others

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

Compensation: Varies

Number of Visits: Unknown

57 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to assess the safety and tolerability of mRNA-4106 administered alone and in combination with checkpoint inhibitor (CPI) therapy in participants with solid tumors.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot receive certain anticancer therapies or investigational agents within 14 days before starting the study treatment. It's best to discuss your current medications with the study team.

What data supports the effectiveness of the drug mRNA-4106 + Nivolumab/Relatlimab for cancer?

Research shows that combining immune checkpoint inhibitors like Nivolumab with other treatments can enhance the immune system's ability to fight cancer. For example, combining CD40 activation with checkpoint inhibitors has led to complete tumor regression in some cancer models, suggesting that similar combinations could be effective in treating cancer. ^{1 2 3 4 5}

What safety data exists for mRNA-4106 and checkpoint inhibitors like Nivolumab/Relatlimab in humans?

Immune checkpoint inhibitors, including Nivolumab, can cause immune-related side effects like skin rashes, fatigue, and in rare cases, bone fractures. In a study of Chinese patients, 84.1% experienced some side effects, with 20.9% having severe ones, and 0.8% had treatment-related deaths. Close monitoring is recommended due to these potential risks. ^{6 7 8 9 10}

What makes the mRNA-4106 treatment unique for cancer?

The mRNA-4106 treatment is unique because it combines mRNA technology with checkpoint inhibitors to enhance the immune system's ability to fight cancer. This approach may offer a novel way to overcome resistance to traditional checkpoint inhibitor therapies by priming T cells and potentially improving outcomes in 'cold' tumors that are typically less responsive to immunotherapy. ^{2 3 5 11 12}

Eligibility Criteria

This trial is for individuals with solid tumors, including uterine tumors. Participants should be adults who have a tumor that can be measured and are willing to provide tissue samples. They must not have had prior treatment with certain vaccines or gene therapies.

Inclusion Criteria

I am fully active and can carry on all pre-disease activities without restriction.

My blood and organ functions are within normal ranges.

Participants who could become pregnant: negative pregnancy test within 24 hours before the first dose of study treatment.

Exclusion Criteria

Participant has any unstable or clinically significant concurrent medical/psychiatric illness or social situation that would limit compliance with study requirements or compromise the ability of the participant to provide written informed consent, per the discretion of the Investigator.

I have active brain tumors or cancer that has spread to my brain.

I haven't taken any prohibited cancer treatments or investigational drugs recently.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive mRNA-4106 at a test dose as monotherapy

8 weeks

Dose Confirmation

Participants receive mRNA-4106 in combination with nivolumab/relatlimab at a standard dose

8 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• mRNA-4106
• Nivolumab/Relatlimab

Trial Overview The study is testing the safety of mRNA-4106 alone and combined with immune checkpoint inhibitors Nivolumab/Relatlimab in treating solid tumors. It will observe how patients tolerate these treatments and their effects on the cancer.

Participant Groups

Group I: Arm 2 (Dose Confirmation): mRNA-4106 in Combination with Nivolumab/Relatlimab Experimental Treatment 2 Interventions

Participants will receive mRNA-4106 at an applicable dose in combination with nivolumab/relatlimab at a standard dose.

Group II: Arm 1 (Dose Escalation): mRNA-4106 Alone Experimental Treatment 1 Intervention

Participants will receive mRNA-4106 at a test dose as monotherapy.

Who Is Running the Clinical Trial?

ModernaTX, Inc.

Lead Sponsor

Trials

127

Recruited

66,790,000+

Dr. Stephen Hoge

ModernaTX, Inc.

Chief Medical Officer

MD from Harvard Medical School

Stéphane Bancel

ModernaTX, Inc.

Chief Executive Officer since 2011

MBA from Harvard Business School, MSc in Engineering from École Centrale Paris

Findings from Research

In a study of 65 patients with various cancers treated with PD1-targeting antibodies, specific immune-related gene expressions were identified that correlated with better responses to treatment and longer progression-free survival (PFS).

The findings suggest that measuring preexisting immune responses through mRNA expression patterns can reliably predict clinical outcomes in patients receiving PD1 therapy, regardless of cancer type or the specific antibody used.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune-Related Gene Expression Profiling After PD-1 Blockade in Non-Small Cell Lung Carcinoma, Head and Neck Squamous Cell Carcinoma, and Melanoma. Prat, A., Navarro, A., Paré, L., et al.[2022]

In the phase 3 MYSTIC trial involving 1118 patients with metastatic non-small cell lung cancer, durvalumab did not significantly improve overall survival compared to chemotherapy, nor did the combination of durvalumab and tremelimumab show better outcomes than chemotherapy for patients with high PD-L1 expression.

However, patients with a blood tumor mutational burden (bTMB) of 20 or more mutations per megabase experienced significantly improved overall survival with durvalumab plus tremelimumab, suggesting that bTMB may be a useful biomarker for treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab With or Without Tremelimumab vs Standard Chemotherapy in First-line Treatment of Metastatic Non-Small Cell Lung Cancer: The MYSTIC Phase 3 Randomized Clinical Trial. Rizvi, NA., Cho, BC., Reinmuth, N., et al.[2021]

In a study of 581 cancer patients treated with PD-1/PD-L1 inhibitors, 20% experienced endocrine adverse events (AEs), with pembrolizumab showing a significantly higher incidence of 38.5%.

Patients who developed endocrine AEs had better overall response rates (33.3% vs. 23.1%) and disease control rates (91.1% vs. 79.1%), suggesting that these AEs may be associated with a more favorable treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A real-world retrospective study of incidence and associated factors of endocrine adverse events related to PD-1/PD-L1 inhibitors. Wang, Z., Hu, C., Zhang, A., et al.[2023]

Cancer immunotherapies, particularly anti-CTLA4 and anti-PD1/PD-L1, are becoming more common in treatment regimens, leading to increased exposure of patients to immune-related adverse events (irAEs).

These immunotherapies can activate the immune system to fight tumors effectively, but they also have a unique toxicity profile that can cause autoimmune reactions, necessitating changes in clinical management practices to address these side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Management of adverse events associated with cancer immunotherapy]. Laparra, A., Champiat, S., Michot, JM., et al.[2021]

In a study of 93 Chinese patients with advanced melanoma treated with PD-1 inhibitors, those who developed immune-related adverse events (irAEs) had significantly higher overall response rates (ORR) and disease control rates (DCR) compared to those without irAEs.

Patients experiencing three or more irAEs showed even better clinical outcomes, including longer progression-free survival and overall survival, suggesting that the presence of irAEs may indicate a more effective immune response to PD-1 therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association between immune-related adverse events and efficacy of PD-1 inhibitors in Chinese patients with advanced melanoma. Zhao, JJ., Wen, XZ., Ding, Y., et al.[2021]

In a study of 144 breast cancer patients, PD-L1 expression was found more frequently in triple negative breast cancer (TNBC) patients, suggesting that these patients may benefit from PD-L1 inhibition therapy due to their resistance to standard chemotherapy.

The study found no significant difference in soluble PD-L1 serum levels between breast cancer patients and healthy women, indicating that low serum levels of sPD-L1 are unlikely to interfere with PD-L1 inhibition therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PD-L1 expression in tumor lesions and soluble PD-L1 serum levels in patients with breast cancer: TNBC versus TPBC. Yazdanpanah, P., Alavianmehr, A., Ghaderi, A., et al.[2021]

References

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

Immune-Related Gene Expression Profiling After PD-1 Blockade in Non-Small Cell Lung Carcinoma, Head and Neck Squamous Cell Carcinoma, and Melanoma. [2022]

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

Sufficiency of CD40 activation and immune checkpoint blockade for T cell priming and tumor immunity. [2020]

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

In situ vaccination with defined factors overcomes T cell exhaustion in distant tumors. [2021]

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

Durvalumab With or Without Tremelimumab vs Standard Chemotherapy in First-line Treatment of Metastatic Non-Small Cell Lung Cancer: The MYSTIC Phase 3 Randomized Clinical Trial. [2021]

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

IL10 Release upon PD-1 Blockade Sustains Immunosuppression in Ovarian Cancer. [2022]

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

Landscape of immune checkpoint inhibitor-related adverse events in Chinese population. [2021]

7. China pubmed.ncbi.nlm.nih.gov

A real-world retrospective study of incidence and associated factors of endocrine adverse events related to PD-1/PD-L1 inhibitors. [2023]

8. France pubmed.ncbi.nlm.nih.gov

[Management of adverse events associated with cancer immunotherapy]. [2021]

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

Association between immune-related adverse events and efficacy of PD-1 inhibitors in Chinese patients with advanced melanoma. [2021]

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

Bone fracture as a novel immune-related adverse event with immune checkpoint inhibitors: Case series and large-scale pharmacovigilance analysis. [2021]

11. England pubmed.ncbi.nlm.nih.gov

Role of PCIF1-mediated 5'-cap N6-methyladeonsine mRNA methylation in colorectal cancer and anti-PD-1 immunotherapy. [2023]

12. Netherlands pubmed.ncbi.nlm.nih.gov

PD-L1 expression in tumor lesions and soluble PD-L1 serum levels in patients with breast cancer: TNBC versus TPBC. [2021]