Immunotherapy with TLR Agonist for Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Antiretrovirals, Immunosuppressants, Corticosteroids, others

Disqualifiers: Autoimmune disease, HIV, Hepatitis, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 30

Duration: 12 weeks

28 Participants Needed

Trial Summary

What is the purpose of this trial?

The goal of this clinical research study is to find the highest tolerable dose of MGN1703 that can be given in combination with ipilimumab to patients with advanced tumors. The safety of this drug combination will also be studied. This is an investigational study. MGN1703 is not FDA approved or commercially available. It is currently being used for research purposes only. Ipilimumab is FDA approved and commercially available for the treatment of unresectable (cannot be removed with surgery) or metastatic (has spread) melanoma. Up to 60 participants will be enrolled in this study. All will take part at MD Anderson.

Will I have to stop taking my current medications?

Participants must stop taking prior chemotherapy, hormonal therapy, or biological therapy for at least 4 weeks before joining the trial, except for prostate cancer patients who can continue LHRH agonist treatment. The protocol does not specify other medications, so it's best to discuss with the study team.

What data supports the effectiveness of the drug combination Ipilimumab, Yervoy, and MGN1703 for cancer treatment?

Research shows that Ipilimumab, also known as Yervoy, has been effective in improving survival in patients with advanced melanoma by boosting the immune system's response to tumors. Additionally, Toll-like receptor (TLR) agonists, like MGN1703, have shown promise in enhancing immune responses against cancer, especially when combined with other therapies. ^{1 2 3 4 5}

What is the safety profile of Ipilimumab (Yervoy) in humans?

Ipilimumab, used for treating advanced melanoma, can cause immune-related side effects like diarrhea, colitis, and hepatitis. While most side effects are mild and manageable, about 15% of patients may experience severe reactions that need careful monitoring and treatment with steroids. ^{3 6 7 8 9}

How is the drug Ipilimumab with MGN1703 different from other cancer treatments?

This drug combination is unique because it uses a TLR agonist, which helps activate the immune system to recognize and fight cancer cells more effectively. TLR agonists are being explored for their ability to enhance immune responses specifically within the tumor environment, making them a novel approach in cancer therapy. ^{1 10 11 12 13}

Research Team

David Hong, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

Adults with advanced solid tumors that standard therapy has failed to cure or for which no standard treatment exists can join this trial. They must have been off other treatments for at least 4 weeks, have a stable health status, and agree to use contraception. People with severe allergies to the study drugs, recent vaccines, certain infections or diseases like severe autoimmune disorders cannot participate.

Inclusion Criteria

Patients must be willing and able to review, understand, and provide written consent before study enrollment

You have a disease that can be measured using specific criteria.

My cancer is advanced or has spread, and standard treatments haven't worked or aren't available.

Exclusion Criteria

I have not had radiation therapy in the last 4 weeks.

I don't have any health issues that could make the study drug dangerous for me or affect the study results.

I am HIV-positive on HAART or have Hepatitis B/C and am receiving treatment.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive MGN1703 and ipilimumab over 4 cycles, each cycle lasting 21 days. MGN1703 is administered subcutaneously on Days 1, 8, and 15, and ipilimumab is administered intravenously on Day 8 of each cycle.

12 weeks

Weekly visits for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment. Follow-up includes phone calls every 30 days for 90 days after the last dose to check on new anticancer drugs and overall health.

12 weeks

Phone calls every 30 days

Extension

Participants may continue receiving MGN1703 alone if deemed beneficial by the doctor, until disease progression or intolerable side effects occur.

Treatment Details

Interventions

• Ipilimumab
• MGN1703

Trial Overview The trial is testing the highest dose of MGN1703 (not FDA approved) that's safe when given with ipilimumab (FDA approved for melanoma) in patients with advanced tumors. Researchers want to see how well these two drugs work together and what side effects they might cause.

Participant Groups

Group I: MTD Post XRT Group: MGN1703 (subcutaneously) + Ipilimumab Experimental Treatment 2 Interventions

Dose expansion group consists of participants with advanced malignancy treated with radiation (XRT) within the past 2 weeks. MGN1703 given subcutaneously at MTD from the Dose Escalation Group. Ipilimumab dosed at 3 mg/kg once per cycle on Day 8 following MGN1703 administration. Each cycle is 21 days long.

Group II: MTD Group: MGN1703 (subcutaneously) + Ipilimumab Experimental Treatment 2 Interventions

Dose expansion group consists of participants with advanced malignancy and cutaneous or subcutaneous manifestations. MGN1703 given subcutaneously at MTD from the Dose Escalation Group. Ipilimumab dosed at 3 mg/kg once per cycle on Day 8 following MGN1703 administration. Each cycle is 21 days long.

Group III: MTD Group: MGN1703 (intratumoral injection) + Ipilimumab Experimental Treatment 2 Interventions

Dose expansion group consists of participants with advanced malignancy and cutaneous or or subcutaneous manifestations. MGN1703 given by intratumoral injection at MTD from the Dose Escalation Group. Ipilimumab dosed at 3 mg/kg once per cycle on Day 8 following MGN1703 administration. Each cycle is 21 days long.

Group IV: Dose Escalation Group: MGN1703 + Ipilimumab Experimental Treatment 2 Interventions

Participants receive MGN1703 on Days 1, 8, and 15 of all cycles as an injection under the skin. Ipilimumab dosed at 3 mg/kg once per cycle on Day 8 following MGN1703 administration. Each cycle is 21 days long. Participants receive a total of 4 treatment cycles for a total of 12 weeks on treatment.

Ipilimumab is already approved in United States, European Union for the following indications:

Approved in United States as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Approved in European Union as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Mologen AG

Industry Sponsor

Trials

7

Recruited

770+

Findings from Research

Ipilimumab is a monoclonal antibody that blocks CTLA-4, enhancing T-cell activation and leading to significant antitumor immune responses, which has been shown to improve survival in patients with advanced melanoma in two global phase 3 clinical studies involving over 13,000 patients.

Approved in over 40 countries, including the U.S. and EU, ipilimumab is the first treatment to demonstrate an overall survival benefit for advanced melanoma, with ongoing trials exploring its efficacy in other cancers like lung and gastric cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Ipilimumab]. Tokudome, T.[2017]

Ipilimumab, an anti-CTLA-4 antibody, has been shown to improve survival in patients with unresectable or metastatic melanoma, with a standard dosing of 3 mg/kg every 3 weeks for a total of 4 doses.

While ipilimumab can cause immune-related adverse events in 15% of patients, most are mild and manageable; however, high-grade events can be serious and require careful monitoring and treatment with corticosteroids.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab for advanced melanoma: a pharmacologic perspective. Trinh, VA., Hagen, B.[2021]

In a review of 129 oncology patients treated with immune checkpoint inhibitors, 51.9% experienced at least one immune-related adverse event (irAE), highlighting the common occurrence of these side effects.

Nearly half of the irAEs were managed according to established guidelines, but there was significant variability in documentation and management practices, indicating a need for improved adherence as immunotherapy use increases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-World Adherence to Toxicity Management Guidelines for Immune-Related Adverse Events. Teimouri, A., Minard, LV., Scott, SN., et al.[2022]

Ipilimumab, an antibody that enhances T-cell activation, is effective for treating metastatic melanoma but can cause immune-mediated side effects, including rare cases of ileitis without colitis, as seen in a 54-year-old patient.

The study highlights the need for further research into genetic and epigenetic factors to personalize treatment and minimize adverse effects associated with ipilimumab therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab and immune-mediated adverse events: a case report of anti-CTLA4 induced ileitis. Venditti, O., De Lisi, D., Caricato, M., et al.[2018]

Ipilimumab (Yervoy®) is an approved monoclonal antibody for treating malignant melanoma by blocking the CTLA-4 protein, which enhances T-cell responses against tumor cells, showing its efficacy in cancer immunotherapy.

Currently, ipilimumab is also being tested in phase III trials for prostate cancer and phase II trials for non-small cell lung cancer, indicating its potential for broader applications in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab: first global approval. Cameron, F., Whiteside, G., Perry, C.[2021]

References

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

Trial watch: Toll-like receptor ligands in cancer therapy. [2023]

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

SD-101 in Combination with Pembrolizumab in Advanced Melanoma: Results of a Phase Ib, Multicenter Study. [2020]

3. Japan pubmed.ncbi.nlm.nih.gov

[Ipilimumab]. [2017]

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

Intratumoral immunotherapy using a TLR2/3 agonist, L-pampo, induces robust antitumor immune responses and enhances immune checkpoint blockade. [2022]

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

Safety, Pharmacokinetics, and Pharmacodynamics of the TLR4 Agonist GSK1795091 in Healthy Individuals: Results from a Randomized, Double-blind, Placebo-controlled, Ascending Dose Study. [2021]

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

Ipilimumab for advanced melanoma: a pharmacologic perspective. [2021]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Real-World Adherence to Toxicity Management Guidelines for Immune-Related Adverse Events. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Ipilimumab and immune-mediated adverse events: a case report of anti-CTLA4 induced ileitis. [2018]

9. New Zealand pubmed.ncbi.nlm.nih.gov

Ipilimumab: first global approval. [2021]

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

Small-Molecule Modulators Targeting Toll-like Receptors for Potential Anticancer Therapeutics. [2023]

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

Toll-like receptor agonists in cancer therapy. [2021]

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

Trial Watch: Toll-like receptor agonists in cancer immunotherapy. [2021]

13. England pubmed.ncbi.nlm.nih.gov

TLR ligand suppression or enhancement of Treg cells? A double-edged sword in immunity to tumours. [2020]