TTX-080 HLA-G Antagonist in Subjects With Advanced Cancers

Study Overview
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Brief Summary
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TTX-080-001 is a Phase 1, open label, dose escalation and dose expansion clinical study to determine the safety, tolerability, and recommended Phase 2 dose of TTX-080 monotherapy (HLA-G inhibitor) and in combination with either pembrolizumab (PD-1 inhibitor) or cetuximab (EGFR inhibitor) in patients with advanced refractory / resistant solid malignancies. The study is enrolling in the dose expansion arms.

Detailed Description
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TTX-080 is a fully human mAb designed to block the interaction of HLA-G with its known ligands, ILT2 and ILT4 molecules. The Phase 1a was an open label, multicenter, dose escalation clinical trial to determine the safety, tolerability, MTD or OBD and the RP2D of TTX-080 when administered as a single agent. The Phase 1b is a dose expansion of TTX-080 monotherapy and in combination with either pembrolizumab or cetuximab in adult subjects with advanced refractory/resistant solid malignancies, including Head and Neck squamous cell carcinoma (HNSCC), Non-Small Cell Lung Cancer (NSCLC), Colorectal cancer (CRC), triple negative breast cancer (TNBC), renal cell carcinoma (RCC), and acral melanoma. Additionally, the study will seek to evaluate the pharmacokinetics and immunogenicity of TTX-080, and preliminary efficacy of TTX-080 as a monotherapy and in combination with pembrolizumab or cetuximab. The study is enrolling in the dose expansion cohorts.

Official Title
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A Phase 1a/1b Dose Escalation/Expansion Study of TTX-080, an HLA-G Antagonist, as Monotherapy and in Combination With Pembrolizumab or Cetuximab in Patients With Advanced Solid Refractory/Resistant Malignancies

Conditions
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Cancer

Intervention / Treatment
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* Drug: TTX-080
* Drug: TTX-080
* Drug: pembrolizumab
* Drug: cetuximab


Participation Criteria
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Eligibility Criteria
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Abbreviated Inclusion Criteria: Subject with histological diagnosis of advanced/metastatic cancer Age 18 years or older, is willing and able to provide informed consent Evidence of measurable disease Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 AND life expectancy of at least 12 weeks Abbreviated Exclusion Criteria: History of allergy or hypersensitivity to study treatment components. Subjects with a history of severe hypersensitivity reaction to any monoclonal antibody Use of an investigational agent within 28 days prior to the first dose of study treatment and throughout the study Receiving high-dose systemic steroid therapy or any other form of immunosuppressive therapy History of severe autoimmune disease Uncontrolled intercurrent illness or other active malignancy requiring ongoing treatment

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1a, Monotherapy Dose Escalation<br> | Drug: TTX-080<br>* Variable dose (Q3W)<br>|
| Experimental: Phase 1b, Dose Expansion: TTX-080 in combination with pembrolizumab (HNSCC)<br>Arm 1 will enroll subjects with advanced/metastatic, prior checkpoint inhibitor treated Head and Neck Squamous Cell Carcinoma (HNSCC) | Drug: TTX-080<br>* Specified dose (Q3W)<br>Drug: pembrolizumab<br>* Specified dose (Q3W)<br>|
| Experimental: Phase 1b, Dose Expansion: TTX-080 in combination with cetuximab (HNSCC)<br>Arm 2 will enroll subjects with advanced/metastatic Head and Neck Squamous Cell Carcinoma (HNSCC) | Drug: TTX-080<br>* Specified dose (Q3W)<br>Drug: cetuximab<br>* Specified dose on specified days<br>|
| Experimental: Phase 1b, Dose Expansion: TTX-080 monotherapy (CRC)<br>Arm 3 will enroll subjects with advanced/metastatic colorectal cancer (CRC) | Drug: TTX-080<br>* Specified dose (Q3W)<br>|
| Experimental: Phase 1b, Dose Expansion: TTX-080 in combination with cetuximab (CRC), prior anti-EGFR therapy<br>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 | Drug: TTX-080<br>* Specified dose (Q3W)<br>Drug: cetuximab<br>* Specified dose on specified days<br>|
| Experimental: Phase 1b, Dose Expansion: TTX-080 in combination with cetuximab (CRC), no prior anti-EGFR therapy<br>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 | Drug: TTX-080<br>* Specified dose (Q3W)<br>Drug: cetuximab<br>* Specified dose on specified days<br>|
| Experimental: Phase 1b, Dose Expansion: TTX-080 monotherapy (NSCLC)<br>Arm 6 will enroll subjects with advanced/metastatic non-small cell lung cancer (NSCLC) | Drug: TTX-080<br>* Specified dose (Q3W)<br>|
| Experimental: Phase 1b, Dose Expansion: TTX-080 in combination with pembrolizumab (NSCLC)<br>Arm 7 will enroll subjects with advanced/metastatic prior checkpoint inhibitor treated non-small cell lung cancer (NSCLC) | Drug: TTX-080<br>* Specified dose (Q3W)<br>Drug: pembrolizumab<br>* Specified dose (Q3W)<br>|
| Experimental: Phase 1b, Dose Expansion: TTX-080 as monotherapy OR in combination with pembrolizumab<br>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 | Drug: TTX-080<br>* Specified dose (Q3W)<br>Drug: pembrolizumab<br>* Specified dose (Q3W)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1. To determine the anti-tumor activity of TTX-080 by objective response rate [complete response + partial response) for each tumor arm per RECIST 1.1 |  | Up to 48 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response, Progression Free Survival per RECIST 1.1 |  | Up to 48 months | 
| Overall Survival |  | Up to 48 months | 
| Adverse events (AEs) as characterized by the incidence, type, frequency, severity (graded according to NCI-CTCAE v5.0), timing, seriousness, and relationship to investigational product, and/or combination therapy, and/or individual approved therapies |  | Up to 48 months | 
| Tolerability: The number of cycles of TTX-080 received by patients before discontinuing due to unmanageable drug reactions |  | Up to 48 months | 
| Serum levels of Anti Drug Antibody against TTX-080 |  | Up to 48 months | 
| Cmax: Maximum Observed Plasma Concentration for TTX-080 |  | Up to 48 months | 
| Tmax: Time to Reach the Cmax for TTX-080 |  | Up to 48 months | 
| AUC(0-t): Area Under the Plasma Concentration-time Curve From Zero Time to the Last Measurable Point for TTX-080 |  | Up to 48 months | 
| AUC(0-Inf): Area Under the Plasma Concentration-time Curve From Zero to Infinity for TTX-080 |  | Up to 48 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HLA-G, TTX-080, Advanced Solid Tumor, Cancer, Ovarian Cancer, Endometrial Cancer, Cervical Cancer, Kidney Cancer, Head and Neck Squamous Cell Carcinoma, Squamous Cell Lung Cancer, Prostate Cancer, Colorectal Cancer, Gastric Cancer, Breast Cancer, Bladder Cancer, Lung Adenocarcinoma, Melanoma, Metastatic Solid Tumor, Renal cell carcinoma, Acral melanoma, Triple Negative Breast Cancer, Pembrolizumab, Cetuximab, Antineoplastic Agents, Immunological, Antineoplastic Agents, Head and Neck Cancer, Lung Cancer