Phase 1 Study of INBRX-109 in Subjects With Locally Advanced or Metastatic Solid Tumors Including Sarcomas

Study Overview
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Brief Summary
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This is a first-in-human, open-label, non-randomized, three-part phase 1 trial of INBRX-109, which is a recombinant humanized tetravalent antibody targeting the human death receptor 5 (DR5).

Official Title
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An Open-Label, Multicenter, First-in-Human, Phase 1 Dose-Escalation and Multicohort Expansion Study of INBRX-109 in Subjects With Locally Advanced or Metastatic Solid Tumors Including Sarcomas

Conditions
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Sarcoma, Solid Tumors, Malignant Pleural Mesothelioma, Gastric Adenocarcinoma, Colorectal Adenocarcinoma, Pancreatic Adenocarcinoma, Ewing Sarcoma, Chondrosarcoma

Intervention / Treatment
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* Drug: INBRX-109
* Drug: Carboplatin
* Drug: Cisplatin
* Drug: Pemetrexed
* Drug: 5-fluorouracil
* Drug: Irinotecan
* Drug: Temozolomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Escalation: Histologically or cytologically-confirmed advanced/metastatic or non-resectable solid tumors, including sarcoma, that are refractory or intolerant to standard therapy, or for which no standard therapy exists that is likely to confer any clinical benefit. Expansion Cohorts: Malignant pleural mesothelioma, gastric adenocarcinoma, colorectal adenocarcinoma, pancreatic adenocarcinoma and certain sarcoma subtypes (e.g., chondrosarcoma, Ewing sarcoma), GIST, and SDH-def solid tumors with locally advanced or metastatic, non-resectable disease, that are refractory or intolerant to standard therapy, or for which no standard therapy exists that is likely to confer any clinical benefit. Measurable disease as defined by RECISTv1.1 (or modified RECIST for mesothelioma) criteria. Adequate hematologic, coagulation, hepatic and renal function as defined per protocol. Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 for Part 1 and ECOG PS of 0, 1 or 2 for Parts 2 and 3. Exclusion Criteria: Prior treatment with or exposure to DR5 agonists. Receipt of investigational agents or devices, anticancer therapy and radiotherapy (with the exception of palliative localized radiation) within 4 weeks prior to the first dose of study drug, and liver-directed therapies (i.e., RFA, TACE/embolization, cryotherapy, SBRT) within 12 weeks prior to the first dose of study drug. Exceptions per protocol. Subject has undergone allogeneic hematopoietic stem cell or bone marrow transplantation within the last 5 years. Exception: Participants who have had a stem cell or bone marrow transplant > 5 years ago are eligible for enrollment, as long as there are no symptoms of graft-versus-host disease (GVHD). Prior or concurrent malignancies. Exception: Subjects with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessments of INBRX-109. Hematologic malignancies. Known or active primary central nervous system (CNS) tumors, leptomeningeal disease and CNS metastases. Exception: Subjects with previously treated, asymptomatic, and clinically stable CNS metastases may be allowed study entry if certain criteria apply. Subjects with chronic liver diseases including but not limited to cirrhosis, NASH, alcohol-related liver disease, hemochromatosis, Wilson's disease, alpha-1 antitrypsin deficiency, hepatic or biliary autoimmune disorders (i.e., primary biliary cholangitis, autoimmune hepatitis). Acute viral or toxic liver disease within 4 weeks prior to the first dose of study drug. Evidence or history of hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection. Clinically significant cardiac condition, including myocardial infarction, uncontrolled angina, cerebrovascular accident, or other acute uncontrolled heart disease < 3 months; left ventricular ejection fraction (LVEF) < 50%; New York Heart Association (NYHA) Class III or IV congestive heart failure; or uncontrolled hypertension. Active, hemodynamically significant pulmonary embolism within 3 months prior to enrollment on this trial. Major surgery within 4 weeks prior to enrollment on this trial. Systemic infection requiring antibiotics within 2 weeks prior to the first dose of study drug. Part 3: Sensitivity or contraindications to carboplatin, cisplatin, pemetrexed, fluorouracil, irinotecan, or temozolomide.

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation<br>INBRX-109 will be escalated (3+3 design) in subjects with locally advanced or metastatic solid tumors including sarcomas. | Drug: INBRX-109<br>* Tetravalent DR5 Agonist Antibody<br>|
| Experimental: Expansion Malignant Pleural Mesothelioma<br>Subjects with malignant pleural mesothelioma will be treated with single-agent INBRX-109 at either the MTD or RP2D. | Drug: INBRX-109<br>* Tetravalent DR5 Agonist Antibody<br>|
| Experimental: Expansion Gastric Adenocarcinoma<br>Subjects with gastric adenocarcinoma will be treated with single-agent INBRX-109 at either the MTD or RP2D. | Drug: INBRX-109<br>* Tetravalent DR5 Agonist Antibody<br>|
| Experimental: Expansion Colorectal Adenocarcinoma<br>Subjects with colorectal (CRC) adenocarcinoma will be treated with single-agent INBRX-109 at either the MTD or RP2D. | Drug: INBRX-109<br>* Tetravalent DR5 Agonist Antibody<br>|
| Experimental: Expansion Sarcomas<br>Subjects with certain sarcoma subtypes will be treated with single-agent INBRX-109 at either the MTD or RP2D. | Drug: INBRX-109<br>* Tetravalent DR5 Agonist Antibody<br>|
| Experimental: Combination Expansion Malignant Pleural Mesothelioma<br>Subjects with malignant pleural mesothelioma will be treated with INBRX-109 in combination with chemotherapies (carboplatin, cisplatin, carboplatin and pemetrexed, or cisplatin and pemetrexed) | Drug: INBRX-109<br>* Tetravalent DR5 Agonist Antibody<br>Drug: Carboplatin<br>* Chemotherapy<br>Drug: Cisplatin<br>* Chemotherapy<br>Drug: Pemetrexed<br>* Chemotherapy<br>|
| Experimental: Combination Expansion Pancreatic Adenocarcinoma<br>Subjects with pancreatic adenocarcinoma will be treated with INBRX-109 in combination with 5FU/irinotecan based chemotherapy | Drug: INBRX-109<br>* Tetravalent DR5 Agonist Antibody<br>Drug: 5-fluorouracil<br>* Chemotherapy<br>Drug: Irinotecan<br>* Chemotherapy<br>|
| Experimental: Combination Expansion Ewing Sarcoma<br>Subjects with Ewing Sarcoma will be treated with INBRX-109 in combination with irinotecan and temozolomide | Drug: INBRX-109<br>* Tetravalent DR5 Agonist Antibody<br>Drug: Irinotecan<br>* Chemotherapy<br>Drug: Temozolomide<br>* Chemotherapy<br>|
| Experimental: Combination Expansion Colorectal Adenocarcinoma<br>Subjects with colorectal adenocarcinoma will be treated with INBRX-109 in combination with FOLFIRI based chemotherapy | Drug: INBRX-109<br>* Tetravalent DR5 Agonist Antibody<br>Drug: 5-fluorouracil<br>* Chemotherapy<br>Drug: Irinotecan<br>* Chemotherapy<br>|
| Experimental: Expansion Solid Tumors<br>Subjects with Solid tumors and high BMI will be treated with single-agent INBRX-109 at either the MTD or RP2D. | Drug: INBRX-109<br>* Tetravalent DR5 Agonist Antibody<br>|
| Experimental: Combination Expansion SDH-deficient solid tumors or GIST<br>Subjects with SDH-deficient solid tumors or GIST will be treated with INBRX-109 in combination with temozolomide | Drug: INBRX-109<br>* Tetravalent DR5 Agonist Antibody<br>Drug: Temozolomide<br>* Chemotherapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency and severity of adverse events of INBRX-109 | Adverse events will be assessed and severity assigned by using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0. | Up to 2 years | 
| Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose (RP2D) of INBRX-109 | The MTD and/or RP2D of INBRX-109 will be determined. | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the serum concentration time curve (AUC) of INBRX-109 | Area under the serum concentration time curve (AUC) of INBRX-109 will be determined. | Up to 2 years | 
| Immunogenicity of INBRX-109 | Frequency of ant-drug antibodies (ADA) against INBRX-109 will be determined. | Up to 2 years | 
| Maximum observed serum concentration (Cmax) of INBRX-109 | Maximum observed serum concentration (Cmax) of INBRX-109 will be determined. | Up to 2 years | 
| Trough observed serum concentration (Ctrough) of INBRX-109 | Trough observed serum concentration (Cmax) of INBRX-109 will be determined. | Up to 2 years | 
| Time to Cmax (Tmax) of INBRX-109 | Time to Cmax (Tmax) of INBRX-109 will be determined. | Up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DR5, Phase 1, Phase 1 Clinical Trial, Solid Tumors, Sarcoma, Pleural Mesothelioma, Stomach Cancer, Colorectal Cancer, Colon Cancer, Rectal Cancer, Gastric Adenocarcinoma, Colorectal Adenocarcinoma, Pancreatic Adenocarcinoma, Ewing Sarcoma, Chondrosarcoma