TTX-080 +/− Cetuximab/Pembrolizumab for Cancer

Recruiting in Palo Alto (17 mi)

+19 other locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Tizona Therapeutics, Inc

Must not be taking: Immunosuppressants, Steroids

Disqualifiers: Severe autoimmune, Active malignancy, others

No Placebo Group

Breakthrough Therapy

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.

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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.

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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.

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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

Trial 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

Participant Groups

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.

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.

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Texas Oncology - Dallas Dallas, TX

Sarah Cannon Research Institute Nashville, TN

Yale Cancer Center New Haven, CT

Regions Hospital Cancer Care Center Saint Paul, MN

More Trial Locations

Who Is Running the Clinical Trial?

Tizona Therapeutics, Inc Lead Sponsor

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] Pembrolizumab and cetuximab are antibodies under investigation in head and neck squamous cell carcinoma (HNSCC) either as single agents or combined with cisplatin and other chemotherapeutic drugs, e.g., 5-fluorouracil and/or docetaxel. However, also the combination of both antibodies may have potential in recurrent/metastatic (R/M) HNSCC, in particular in cisplatin-resistant or -refractory cases or patients with comorbid disease, e.g. patients with impaired renal function.

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

Pembrolizumab: An Immunotherapeutic Agent Causing Endocrinopathies. [2020] Pembrolizumab is an immune checkpoint inhibitor (programmed cell death 1) approved for use in non-small cell lung carcinoma (NSCLC). Pembrolizumab has shown remarkable results in regression of the size of tumors in NSCLC and has shown survival advantage. However, immune-related adverse effects are a serious negative outcome of therapy. The number of immune-related adverse effects with pembrolizumab has increased significantly over the recent past. We present a case of type 1 diabetes mellitus and autoimmune thyroiditis with pembrolizumab treatment for NSCLC.

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

Immune-mediated necrotizing myopathy with pembrolizumab: a specific neuromuscular entity. [2022] Pembrolizumab is a humanized monoclonal antibody that binds to the programmed cell-death protein-1 (PD-1) on immune T-cells, thus blocking PD-1 activity. Pembrolizumab is indicated for the treatment of advanced melanoma, metastatic non-small-cell lung cancer, and head and neck squamous cell carcinoma. However, it is associated with immune-related adverse events.

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

Pembrolizumab for the treatment of PD-L1 positive advanced or metastatic non-small cell lung cancer. [2020] The emergence of immune checkpoint inhibitors marked an important advancement in the development of cancer therapeutics. Pembrolizumab is a selective humanized IgG4 kappa monoclonal antibody that inhibits the programmed death-1 (PD-1) receptor, an integral component of immune checkpoint regulation in the tumor microenvironment. The drug is currently approved by the Food and Drug Administration for the treatment of advanced melanoma and metastatic squamous and nonsquamous non-small cell lung cancer (NSCLC). Several published studies demonstrate that single-agent pembrolizumab is safe and has efficacy in patients with NSCLC. Many ongoing protocols are investigating the role of pembrolizumab in combination with other agents in lung cancer and various other cancer types. We review the available data on pembrolizumab in NSCLC and examine the role of potential predictive biomarkers of response to therapy.

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

PD-1 Blockers. [2022] Nivolumab and pembrolizumab are monoclonal antibodies that block the programmed death-1 receptor (PD-1, CD279), resulting in dis-inhibition of tumor-specific immune responses. Both are recently approved for use in the treatment of metastatic melanoma, and nivolumab as well for non-small cell lung cancer.

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

An unusual case of checkpoint-inhibitor-induced pleuropericarditis. [2023] Pembrolizumab is an immune checkpoint inhibitor that promotes effector T-cell functions on malignant cells by binding to programmed cell death protein 1 (PD-1). Pembrolizumab is well tolerated in most cases with an adverse event profile consisting mainly of pruritus, fatigue, and anorexia. Cardiotoxicity comprises 1% of the total adverse events.

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] The programmed cell death 1 (PD-1) pathway represents a major immune checkpoint, which may be engaged by cells in the tumor microenvironment to overcome active T-cell immune surveillance. Pembrolizumab (Keytruda®, MK-3475) is a potent and highly selective humanized mAb of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. This blockade enhances the functional activity of T cells to facilitate tumor regression and ultimately immune rejection. Pembrolizumab binds to human and cynomolgus monkey PD-1 with picomolar affinity and blocks the binding of human and cynomolgus monkey PD-1 to PD-L1 and PD-L2 with comparable potency. Pembrolizumab binds both the C'D and FG loops of PD-1. Pembrolizumab overcomes human and cynomolgus monkey PD-L1-mediated immune suppression in T-cell cultures by enhancing IL2 production following staphylococcal enterotoxin B stimulation of healthy donor and cancer patient cells, and IFNγ production in human primary tumor histoculture. Ex vivo and in vitro studies with human and primate T cells show that pembrolizumab enhances antigen-specific T-cell IFNγ and IL2 production. Pembrolizumab does not mediate FcR or complement-driven effector function against PD-1-expressing cells. Pembrolizumab displays dose-dependent clearance and half-life in cynomolgus monkey pharmacokinetic and toxicokinetic studies typical for human IgG4 antibodies. In nonhuman primate toxicology studies, no findings of toxicologic significance were observed. The preclinical data for pembrolizumab are consistent with the clinical anticancer activity and safety that has been demonstrated in human clinical trials.

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] Programmed death-1 (PD-1) and programmed death- ligand 1 (PD-L1) inhibitors, such as pembrolizumab, nivolumab and atezolizumab, are major classes of immune checkpoint inhibitors that are increasingly used for cancer treatment. However, their use is associated with adverse cardiovascular events. We examined the incidence of new-onset cardiac complications in patients receiving PD-1 or PD-L1 inhibitors.

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

Pembrolizumab-induced sarcoid granulomatous panniculitis and bullous pemphigoid in a single patient. [2021] Pembrolizumab is an immune checkpoint inhibitor with antitumor activity in other organ malignancies. We present this case -demonstrating multiple inflammatory adverse events associated with Pembrolizumab (in a single patient), in order to increase awareness and facilitate earlier identification of the wide-ranging cutaneous side effects associated with immunotherapy.

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

Pembrolizumab joins the anti-PD-1 armamentarium in the treatment of melanoma. [2017] Pembrolizumab (MK-3475) is a monoclonal antibody that binds to the PD-1 receptor on T cells and prevents binding to its ligands PD-L1 and PD-L2. Blocking this receptor frees T cells from the inhibitory effects of PD-L1 and allows them to mediate antitumor effects against cancer cells. In a large Phase I study of 411 patients with melanoma, high durable response rates over a range of doses and schedules have been shown with very little toxicity. A Phase III study of pembrolizumab comparing two schedules of administration with the current standard treatment with the anti-CTLA-4 monoclonal antibody is in progress. Combinations with other checkpoint inhibitors as well as other anticancer agents are also being evaluated. Approval of pembrolizumab for the treatment of melanoma is expected.

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

Pembrolizumab in lung cancer: current evidence and future perspectives. [2020] Pembrolizumab is a humanized monoclonal antibody against PD-1 capable of enhancing antitumor immune activity. The KEYNOTE-001 study showed that pembrolizumab has activity in advanced non-small-cell lung cancer patients and identified programmed death ligand 1 (PD-L1) as a companion test to select patients most likely to benefit from pembrolizumab. Five randomized clinical trials showed the efficacy of pembrolizumab in non-small-cell lung cancer: in second-line setting PD-L1 ≥1% (KEYNOTE-010), in first-line setting PD-L1 ≥50% (KEYNOTE-024 and KEYNOTE-042) and in first-line setting in combination with platinum doublets, any expression of PD-L1 (KEYNOTE-189 and KEYNOTE-407). Future challenges are the identification of the role of pembrolizumab in adjuvant, neoadjuvant, locally advanced disease or oncogene-addicted patients, in combination with radiotherapy or other biological agents.