TTX-080 +/− Cetuximab/Pembrolizumab for Cancer

Recruiting at 18 trial locations

Overseen By Tizona Therapeutics, Inc.

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Tizona Therapeutics, Inc

Must not be taking: Immunosuppressants, Steroids

Disqualifiers: Severe autoimmune, Active malignancy, others

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

Compensation: Varies

Number of Visits: Unknown

240 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests TTX-080, a new drug, alone and with other cancer drugs in patients with hard-to-treat cancers. It works by helping the immune system find and attack cancer cells.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot be on high-dose steroid therapy or other immunosuppressive treatments. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug TTX-080 combined with Cetuximab and Pembrolizumab for cancer?

Research suggests that Pembrolizumab, when used alone, has shown effectiveness in shrinking tumors and improving survival in non-small cell lung cancer and head and neck squamous cell carcinoma. Additionally, the combination of Pembrolizumab and Cetuximab may be beneficial for certain head and neck cancers, especially in cases resistant to other treatments. ^{1 2 3 4 5}

What safety data exists for the treatment TTX-080 +/− Cetuximab/Pembrolizumab for Cancer?

Pembrolizumab is generally well tolerated, with common side effects including itching, tiredness, and loss of appetite. However, it can cause rare but serious heart-related side effects and other inflammatory conditions. In nonhuman primate studies, pembrolizumab showed no significant toxic effects, supporting its safety profile in humans. ^{1 6 7 8 9}

What makes the drug TTX-080 unique in cancer treatment?

TTX-080 is unique because it targets HLA-G, a protein that helps cancer cells evade the immune system, making it different from other treatments like pembrolizumab and cetuximab, which target PD-1 and EGFR, respectively. This novel approach may offer a new way to enhance the immune system's ability to fight cancer. ^{1 2 3 10 11}

Eligibility Criteria

This trial is for adults with advanced or metastatic cancer who are in fairly good health (able to perform daily activities without significant assistance) and have a life expectancy of at least 12 weeks. They must be able to consent to the study, not have severe allergies to treatment components, no recent use of other investigational drugs, no high-dose steroids or immunosuppressants, and no uncontrolled illnesses.

Inclusion Criteria

I'm sorry, I don't understand what you mean by "Abbreviated." Could you please provide more context or information?

I am 18 or older and can agree to participate.

I am mostly active and my doctor expects me to live at least 12 more weeks.

Exclusion Criteria

History of allergy or hypersensitivity to study treatment components

History of severe autoimmune disease

Subjects with a history of severe hypersensitivity reaction to any monoclonal antibody

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1a Dose Escalation

Dose escalation to determine the safety, tolerability, MTD or OBD, and the RP2D of TTX-080 as a single agent

8-12 weeks

Phase 1b Dose Expansion

Dose expansion of TTX-080 monotherapy and in combination with pembrolizumab, cetuximab, or FOLFIRI plus cetuximab to evaluate pharmacokinetics, immunogenicity, and anti-tumor activity

16-24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

Treatment Details

Interventions

• Cetuximab
• Pembrolizumab
• TTX-080

Trial Overview The TTX-080 clinical trial is testing the safety and optimal dosing of a new drug called TTX-080 alone or combined with pembrolizumab or cetuximab in patients with resistant cancers. It's an early-phase study where researchers gradually increase doses to find what's safe and potentially effective.

Participant Groups

Group I: TTX-080 in combination with FOLFIRI plus cetuximab Experimental Treatment 3 Interventions

Arm 9: TTX-080 in combination with FOLFIRI plus cetuximab Randomized Arms in subjects with metastatic RAS, BRAF and HER2 wild type colorectal cancer (CRC) who have been received oxaliplatin and 5-FU based chemotherapy in the first line or adjuvant (relapse within 6 months) setting. Prior bevacizumab allowed. No prior EGFR inhibitor.

Group II: Phase 1b, Dose Expansion: TTX-080 monotherapy (NSCLC) Experimental Treatment 1 Intervention

Arm 6 will enroll subjects with advanced/metastatic non-small cell lung cancer (NSCLC)

Group III: Phase 1b, Dose Expansion: TTX-080 monotherapy (CRC) Experimental Treatment 1 Intervention

Arm 3 will enroll subjects with advanced/metastatic colorectal cancer (CRC)

Group IV: Phase 1b, Dose Expansion: TTX-080 in combination with pembrolizumab (NSCLC) Experimental Treatment 2 Interventions

Arm 7 will enroll subjects with advanced/metastatic prior checkpoint inhibitor treated non-small cell lung cancer (NSCLC)

Group V: Phase 1b, Dose Expansion: TTX-080 in combination with pembrolizumab (HNSCC) Experimental Treatment 2 Interventions

Arm 1 will enroll subjects with advanced/metastatic, prior checkpoint inhibitor treated Head and Neck Squamous Cell Carcinoma (HNSCC)

Group VI: Phase 1b, Dose Expansion: TTX-080 in combination with cetuximab (HNSCC) Experimental Treatment 2 Interventions

Arm 2 will enroll subjects with advanced/metastatic Head and Neck Squamous Cell Carcinoma (HNSCC)

Group VII: Phase 1b, Dose Expansion: TTX-080 in combination with cetuximab (CRC), prior anti-EGFR therapy Experimental Treatment 2 Interventions

Arm 4 will enroll subjects with advanced/metastatic MSI-L/MSS, KRAS wild-type colorectal cancer (CRC) who have progressed on a prior anti-EGFR therapy

Group VIII: Phase 1b, Dose Expansion: TTX-080 in combination with cetuximab (CRC), no prior anti-EGFR therapy Experimental Treatment 2 Interventions

Arm 5 will enroll subjects with advanced/metastatic MSI-L/MSS, KRAS wild type colorectal cancer (CRC) who have not received a prior anti-EGFR therapy

Group IX: Phase 1b, Dose Expansion: TTX-080 as monotherapy OR in combination with pembrolizumab Experimental Treatment 2 Interventions

Arm 8: TTX-080 monotherapy: * Advanced/metastatic, prior checkpoint inhibitor treated renal cell carcinoma with predominance of clear cell component * Advanced/metastatic acral melanoma Arm 8: TTX-080 in combination with pembrolizumab: • Advanced/metastatic triple-negative breast cancer (estrogen and progesterone receptor negative and HER2 negative) who has received a prior checkpoint inhibitor

Group X: Phase 1a, Monotherapy Dose Escalation Experimental Treatment 1 Intervention

Group XI: FOLFIRI plus cetuximab Experimental Treatment 2 Interventions

Arm 10: FOLFIRI plus cetuximab Randomized Arms in subjects with metastatic RAS, BRAF and HER2 wild type colorectal cancer (CRC) who have been received oxaliplatin and 5-FU based chemotherapy in the first line or adjuvant (relapse within 6 months) setting. Prior bevacizumab allowed. No prior EGFR inhibitor.

Who Is Running the Clinical Trial?

Tizona Therapeutics, Inc

Lead Sponsor

Trials

1

Recruited

240+

Findings from Research

The study evaluated the effectiveness of pembrolizumab and cetuximab, both alone and in combination, on head and neck squamous cell carcinoma (HNSCC) using the FLAVINO assay, revealing significant variability in patient responses, particularly in those with cisplatin-resistant cases.

An 'IP-10 score' was developed to predict patient outcomes based on their response to treatment, indicating that higher levels of IP-10 release in response to interferon gamma (IFN-γ) stimulation may correlate with better outcomes for certain HNSCC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cytokine Profiles of Head and Neck Squamous Cell Carcinoma Undergoing Dual Immunotherapy With Cetuximab and Pembrolizumab Identify Interferon Gamma-Induced Protein 10 as Novel Biomarker. Berszin, M., Michaelides, I., Siemert, J., et al.[2022]

Pembrolizumab, an immune checkpoint inhibitor, has demonstrated significant efficacy in reducing tumor size and improving survival rates in patients with non-small cell lung carcinoma (NSCLC).

However, the treatment is associated with an increased risk of immune-related adverse effects, including cases of type 1 diabetes mellitus and autoimmune thyroiditis, highlighting the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab: An Immunotherapeutic Agent Causing Endocrinopathies. Chaudry, A., Chaudry, M., Aslam, J.[2020]

In a review of 567 reports of immune-mediated necrotizing myopathy (IMNM), 14 cases were associated with pembrolizumab, indicating a significant link between this treatment and the adverse event, with a reporting odds ratio of 17.59.

The study emphasizes the importance of updated diagnostic criteria for IMNM and suggests that better collaboration between oncologists and neurologists is needed to address these neurological complications related to pembrolizumab treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune-mediated necrotizing myopathy with pembrolizumab: a specific neuromuscular entity. Trenque, T., Lepoix, E., Trenque, A., et al.[2022]

Pembrolizumab is a safe and effective immune checkpoint inhibitor that targets the PD-1 receptor, currently approved for treating advanced melanoma and metastatic non-small cell lung cancer (NSCLC).

Ongoing studies are exploring the potential of pembrolizumab in combination with other treatments for lung cancer and other cancer types, while also investigating biomarkers that may predict patient response to this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of PD-L1 positive advanced or metastatic non-small cell lung cancer. Dang, TO., Ogunniyi, A., Barbee, MS., et al.[2020]

Nivolumab and pembrolizumab are monoclonal antibodies that work by blocking the PD-1 receptor, which helps to enhance the body's immune response against tumors.

Both drugs have been recently approved for treating metastatic melanoma, with nivolumab also approved for non-small cell lung cancer, indicating their efficacy in targeting these specific cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PD-1 Blockers. Wolchok, JD.[2022]

Pembrolizumab, an immune checkpoint inhibitor used for treating non-small cell lung cancer, is generally well tolerated, but can lead to rare immune-mediated adverse effects such as pleuropericarditis, as seen in a case involving a 64-year-old female patient.

The patient was effectively treated with colchicine, furosemide, and methylprednisolone, leading to symptom improvement and a decision to discontinue pembrolizumab, after which she remained asymptomatic for six months, highlighting the importance of recognizing and managing potential side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An unusual case of checkpoint-inhibitor-induced pleuropericarditis. Suarez, ZK., Finke, AC., Hospedales, E., et al.[2023]

Pembrolizumab (Keytruda) effectively blocks the PD-1 pathway, enhancing T-cell activity against tumors, which supports its role in promoting tumor regression and immune rejection.

Preclinical studies in cynomolgus monkeys showed that pembrolizumab has a favorable safety profile with no significant toxicological findings, aligning with its demonstrated safety and efficacy in human clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biophysical and Immunological Characterization and In Vivo Pharmacokinetics and Toxicology in Nonhuman Primates of the Anti-PD-1 Antibody Pembrolizumab. Hutchins, B., Starling, GC., McCoy, MA., et al.[2021]

In a study of 1959 patients treated with PD-1 or PD-L1 inhibitors, 16.31% experienced new-onset cardiac complications, with heart failure being the most common issue (12.57%).

Patients receiving PD-L1 inhibitors had a significantly lower risk of cardiac complications and all-cause mortality compared to those treated with PD-1 inhibitors, indicating that PD-L1 inhibitors may be a safer option for cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Cardiovascular Complications following prescription of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors: a propensity-score matched Cohort Study with competing risk analysis. Zhou, J., Lee, S., Lakhani, I., et al.[2022]

Pembrolizumab, an immune checkpoint inhibitor known for its antitumor effects, can cause multiple inflammatory adverse events, highlighting the need for awareness of its side effects.

This case emphasizes the importance of early identification of various cutaneous side effects associated with immunotherapy, which can affect patient management and treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab-induced sarcoid granulomatous panniculitis and bullous pemphigoid in a single patient. Honigman, AD., Lai, F., Elakis, J., et al.[2021]

Pembrolizumab is a monoclonal antibody that effectively blocks the PD-1 receptor on T cells, enhancing their ability to attack cancer cells, particularly in melanoma patients.

In a Phase I study involving 411 patients, pembrolizumab demonstrated high durable response rates with minimal toxicity, indicating its potential as a safe and effective treatment option for melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab joins the anti-PD-1 armamentarium in the treatment of melanoma. Hersey, P., Gowrishankar, K.[2017]

Pembrolizumab, a monoclonal antibody targeting PD-1, has shown significant efficacy in treating advanced non-small-cell lung cancer (NSCLC) across multiple clinical trials, particularly in patients with PD-L1 expression levels of 1% or higher.

The KEYNOTE studies identified specific patient populations that benefit most from pembrolizumab, highlighting the importance of PD-L1 as a companion diagnostic, while future research will explore its role in earlier stages of cancer treatment and in combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in lung cancer: current evidence and future perspectives. Palumbo, G., Carillio, G., Manzo, A., et al.[2020]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Cytokine Profiles of Head and Neck Squamous Cell Carcinoma Undergoing Dual Immunotherapy With Cetuximab and Pembrolizumab Identify Interferon Gamma-Induced Protein 10 as Novel Biomarker. [2022]

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

Pembrolizumab: An Immunotherapeutic Agent Causing Endocrinopathies. [2020]

3. Germany pubmed.ncbi.nlm.nih.gov

Immune-mediated necrotizing myopathy with pembrolizumab: a specific neuromuscular entity. [2022]

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

Pembrolizumab for the treatment of PD-L1 positive advanced or metastatic non-small cell lung cancer. [2020]

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

PD-1 Blockers. [2022]

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

An unusual case of checkpoint-inhibitor-induced pleuropericarditis. [2023]

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

Biophysical and Immunological Characterization and In Vivo Pharmacokinetics and Toxicology in Nonhuman Primates of the Anti-PD-1 Antibody Pembrolizumab. [2021]

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

Adverse Cardiovascular Complications following prescription of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors: a propensity-score matched Cohort Study with competing risk analysis. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab-induced sarcoid granulomatous panniculitis and bullous pemphigoid in a single patient. [2021]

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

Pembrolizumab joins the anti-PD-1 armamentarium in the treatment of melanoma. [2017]

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

Pembrolizumab in lung cancer: current evidence and future perspectives. [2020]