TU2218 + Checkpoint Inhibitors for Solid Tumors

Recruiting in Palo Alto (17 mi)

+2 other locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: TiumBio Co., Ltd.

Must not be taking: Anticoagulants, NSAIDs, Steroids, others

Disqualifiers: Heart disease, Infections, Autoimmune, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial tests a new drug, TU2218, to see if it can safely help treat patients with advanced solid tumors by reducing tumor size. Sunitinib malate has shown promising clinical activity in the treatment of advanced solid tumors.

Will I have to stop taking my current medications?

The trial requires a washout period of 4 weeks for any biologic material and a minimum of 5 half-lives for any chemotherapy before starting treatment. You must also stop using certain medications like strong inhibitors of specific enzymes and gastric pH elevating agents at least 8 days before the study. If you are on chronic systemic steroids or other immunosuppressive medications, you may need to stop them as well.

What data supports the effectiveness of the drug TU2218 + Checkpoint Inhibitors for Solid Tumors?

Research shows that immune checkpoint inhibitors, like Pembrolizumab (Keytruda), are effective in treating certain types of cancers, such as non-small cell lung cancer and colorectal cancer with specific genetic features. Combining these inhibitors with other treatments has shown promise in improving outcomes for patients with solid tumors. ^{1 2 3 4 5}

What safety information is available for TU2218 and checkpoint inhibitors like Pembrolizumab?

Immune checkpoint inhibitors, including Pembrolizumab, can cause side effects like skin inflammation and issues with the endocrine (hormone) and gastrointestinal (stomach and intestines) systems. Skin reactions are common and usually appear early in treatment. These side effects are due to the way these drugs work with the immune system. ^{6 7 8 9 10}

How is the drug TU2218 + Checkpoint Inhibitors unique for treating solid tumors?

The drug TU2218 combined with checkpoint inhibitors is unique because it targets immune checkpoints, which are proteins that can suppress the immune system's ability to attack cancer cells. This combination aims to enhance the immune response against tumors, potentially leading to better outcomes compared to using checkpoint inhibitors alone. ^{11 12 13 14 15}

Research Team

TU2218

Principal Investigator

TiumBio Co., Ltd.

Eligibility Criteria

Adults with advanced solid tumors where standard therapy has failed or no effective standard exists. Participants must have adequate organ function, not be pregnant, and agree to use contraception. Exclusions include serious medical conditions, brain metastases, heart issues within the last 6 months, active infections including hepatitis B/C and HIV, history of severe bleeding or autoimmune diseases (with some exceptions), and inability to stop certain medications.

Inclusion Criteria

Life expectancy ≥12 weeks as judged by the Investigator

I have waited long enough after my last cancer treatment and any side effects are mild.

My liver and kidney functions meet the required levels.

Exclusion Criteria

I do not have any serious infections, including active hepatitis B or C, or HIV/AIDS.

I had heart or aortic surgery less than 6 months ago.

I haven't taken high-dose aspirin or certain blood thinners in the last 10 days.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Treatment

Escalating doses of TU2218 administered alone and in combination with anti-PD-1 antibody for up to 21-day cycles to determine the Maximum Tolerated Dose (MTD)

6 weeks

Multiple visits per cycle

Phase 2 Treatment

TU2218 administered at the recommended Phase 2 dose (RP2D) alone and in combination with anti-PD-1 antibody to evaluate antitumor activity

24 weeks

Multiple visits per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 weeks

Treatment Details

Interventions

• Anti-PD-1 antibody (Checkpoint Inhibitor)
• TU2218 (Virus Therapy)

Trial Overview The trial is testing TU2218 alone (Part A) and in combination with an Anti-PD-1 antibody (Part B). It aims to find a safe dose for TU2218 (Phase 1) and assess its effectiveness against tumors at that dose (Phase 2). Patients are monitored for how their bodies handle the drug(s) and any signs of tumor shrinkage.

Participant Groups

Group I: TU2218 Phase 2a Experimental Treatment 1 Intervention

TU2218 at a RP2D orally administered daily for two weeks followed by on week of rest for up to 21-day cycles

Group II: TU2218 Phase 1a Experimental Treatment 1 Intervention

Escalating doses of TU2218 orally administered daily for two weeks followed by one week of rest for up to 21-day cycles

Group III: TU2218 Food Effect Experimental Treatment 1 Intervention

TU2218 orally administered at a one dose level below MTD under fasting condition on -Day 2, followed by the same dose orally administered with meals on -Day 1 and then continued under fasted condition for two weeks followed by one week of rest for up to 21-day cycles

Group IV: TU2218 + Anti-PD-1 antibody Phase 2b Experimental Treatment 2 Interventions

TU2218 at a RP2DC in combination with anti-PD-1 antibody up to 21-day cycles

Group V: TU2218 + Anti-PD-1 antibody Phase 1b Experimental Treatment 2 Interventions

Escalating doses of TU2218 in combination with anti-PD-1 antibody up to 21-day cycles

Who Is Running the Clinical Trial?

TiumBio Co., Ltd.

Lead Sponsor

Trials

4

Recruited

510+

Findings from Research

In a review of 19 trials involving 5404 participants, it was found that 4-10% of patients treated with PD-(L)1 inhibitors showed responses even after being classified as having disease progression, highlighting the unique efficacy of these immune checkpoint inhibitors.

The study suggests that traditional RECIST criteria are inadequate for evaluating responses to PD-(L)1 inhibitors, recommending the use of immune-related response criteria and advising that treatment should continue beyond initial progression until confirmed by a second evaluation at least 4 weeks later.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nonconventional patterns of benefit of solid tumors treated with PD-(L)1 inhibitors: a systematic review. Abdel-Rahman, O.[2018]

Combination immunotherapies, such as PD-1 and CTLA-4 blockade, show promising results in treating non-small cell lung cancer (NSCLC), potentially improving outcomes compared to single-agent therapies.

Early clinical trials indicate that these combination therapies can be administered safely without significantly increasing toxicity, but further research is necessary to assess long-term safety, efficacy, and optimal patient selection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination Immunotherapy in Non-small Cell Lung Cancer. Marmarelis, ME., Aggarwal, C.[2022]

In a large study of 48,782 cancer cases, PD-L1 expression was more commonly found in immune cells than in tumor cells, and there was a strong correlation between PD-L1 expression and other biomarkers like CD274 gene amplification, microsatellite instability (MSI), and tumor mutational burden (TMB).

Over half of the cases (50.3%) tested positive for at least one biomarker related to immunotherapy response, highlighting the potential for personalized treatment strategies, particularly for the PD-L1+/TMB+ subset, which may respond best to immunotherapy, though further clinical trials are needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A pan-cancer analysis of PD-L1 immunohistochemistry and gene amplification, tumor mutation burden and microsatellite instability in 48,782 cases. Huang, RSP., Haberberger, J., Severson, E., et al.[2023]

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]

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]

Older adults with solid tumors generally benefit from immune checkpoint inhibitors just as much as younger patients, and they tolerate these treatments well.

However, when older patients receive combination therapies that may increase toxicity, the benefits can be diminished, highlighting the need for careful patient selection and geriatric assessments to optimize treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunotherapy for older patients with cancer. Araujo Vargas, TP., Al-Humiqani, A., Giffoni De Mello Morais Mata, D., et al.[2023]

Three patients developed uveal effusion, a condition affecting the eye, after starting anti-PD-1 and anti-PD-L1 monoclonal antibody therapy for cancer, highlighting a potential adverse effect of these immunotherapies.

The uveal effusion resolved in most cases after stopping the therapy, suggesting that while these treatments can be effective for cancer, they may also cause significant inflammatory side effects that need to be monitored.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Uveal Effusion After Immune Checkpoint Inhibitor Therapy. Thomas, M., Armenti, ST., Ayres, MB., et al.[2022]

Immune checkpoint inhibitors like ipilimumab, nivolumab, and pembrolizumab commonly cause skin-related side effects, which are often the first adverse events to appear during treatment, highlighting the need for prompt recognition and management.

This review provides practical guidance for healthcare professionals on identifying and treating these skin adverse events, based on data from clinical trials and real patient case studies, aiming to improve patient care and treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of skin adverse events associated with immune checkpoint inhibitors in patients with melanoma: A nursing perspective. Thebeau, M., Rubin, K., Hofmann, M., et al.[2018]

Immune checkpoint inhibitors, such as pembrolizumab and nivolumab, can lead to immune-related adverse events (irAEs) due to their mechanism of enhancing the immune response against cancer, which can sometimes mistakenly target healthy tissues.

This study reviewed 128 reports involving 239 cases of toxicities associated with these treatments, highlighting the need for careful management of irAEs, as there is currently no standardized approach based on prospective trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of immune checkpoint inhibitor-related adverse events: A review of case reports. Si, X., Song, P., Ni, J., et al.[2021]

Immune checkpoint blockade, using monoclonal antibodies against CTLA-4 and PD-1/PD-L1, has significantly improved treatment outcomes for patients with advanced solid organ tumors, leading to long-lasting responses.

Despite its effectiveness, only a small percentage of patients experience meaningful benefits from these therapies, highlighting the need for better understanding of tumor characteristics and patient profiles to optimize treatment selection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune checkpoint blockade in solid organ tumours: Choice, dose and predictors of response. Navani, V., Graves, MC., Bowden, NA., et al.[2021]

Immune checkpoint inhibitors are promising immunomodulatory agents that help reactivate immune cells to fight tumors, showing significant effectiveness in treating solid cancers like melanoma and non-small cell lung cancer.

Numerous clinical studies are currently investigating the benefits of these inhibitors across various cancer types, with a particular focus on their application in breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune checkpoint inhibitors: Key trials and an emerging role in breast cancer. Gaynor, N., Crown, J., Collins, DM.[2022]

Cancer immunotherapy, particularly through the use of immune checkpoint inhibitors like ipilimumab, has shown promising survival benefits in melanoma, with early trials indicating good tolerability and meaningful response rates across various cancer types.

Targeting inhibitory receptors on T cells can potentially overcome tumor-induced immune dysfunction, and combining different checkpoint inhibitors or integrating them with other therapies may enhance treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cancer immunology - development of novel anti-cancer therapies. Rothschild, SI., Thommen, DS., Moersig, W., et al.[2022]

Immune checkpoint inhibitors, specifically targeting CTLA-4 and PD-1, have been developed to enhance T-lymphocyte activity against cancer, leading to durable responses in various cancer types.

Pembrolizumab, an anti-PD-1 antibody, has been approved by the FDA and is now a key component of cancer treatment, although further research is needed to optimize its use and identify effective biomarkers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunologic checkpoints in cancer therapy: focus on the programmed death-1 (PD-1) receptor pathway. Momtaz, P., Postow, MA.[2022]

Nivolumab, an anti-PD-1 monoclonal antibody, has significantly improved treatment outcomes for advanced cancers like lung cancer, renal cancer, and melanoma, promoting long-lasting anti-tumor immunity.

Despite its effectiveness, nivolumab monotherapy fails in 60-70% of patients, but combining it with other therapies, such as chemotherapy or CTLA-4 inhibitors, has been shown to enhance its efficacy and overcome resistance in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination therapy with nivolumab (anti-PD-1 monoclonal antibody): A new era in tumor immunotherapy. Abedi Kiasari, B., Abbasi, A., Ghasemi Darestani, N., et al.[2022]

References

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

Prediction of Benefit from Checkpoint Inhibitors in Mismatch Repair Deficient Metastatic Colorectal Cancer: Role of Tumor Infiltrating Lymphocytes. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Nonconventional patterns of benefit of solid tumors treated with PD-(L)1 inhibitors: a systematic review. [2018]

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

Combination Immunotherapy in Non-small Cell Lung Cancer. [2022]

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

A pan-cancer analysis of PD-L1 immunohistochemistry and gene amplification, tumor mutation burden and microsatellite instability in 48,782 cases. [2023]

5. 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]

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

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

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

Immunotherapy for older patients with cancer. [2023]

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

Uveal Effusion After Immune Checkpoint Inhibitor Therapy. [2022]

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

Management of skin adverse events associated with immune checkpoint inhibitors in patients with melanoma: A nursing perspective. [2018]

10. Singapore pubmed.ncbi.nlm.nih.gov

Management of immune checkpoint inhibitor-related adverse events: A review of case reports. [2021]

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

Immune checkpoint blockade in solid organ tumours: Choice, dose and predictors of response. [2021]

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

Immune checkpoint inhibitors: Key trials and an emerging role in breast cancer. [2022]

13. Switzerland pubmed.ncbi.nlm.nih.gov

Cancer immunology - development of novel anti-cancer therapies. [2022]

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

Immunologic checkpoints in cancer therapy: focus on the programmed death-1 (PD-1) receptor pathway. [2022]

15. Netherlands pubmed.ncbi.nlm.nih.gov

Combination therapy with nivolumab (anti-PD-1 monoclonal antibody): A new era in tumor immunotherapy. [2022]