A Study to Evaluate the Safety and Tolerability of AB154 in Participants With Advanced Malignancies

Study Overview
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Brief Summary
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This is a Phase 1, multicenter, open-label, dose-escalation study to evaluate the safety, tolerability, PK, PD, and clinical activity of domvanalimab (AB154) as monotherapy and in combination with zimberelimab (AB122) in participants with advanced solid malignancies.

Detailed Description
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This is a Phase 1, multicenter, open-label, dose-escalation study to evaluate the safety, tolerability, PK, PD, and clinical activity of domvanalimab as monotherapy and in combination with zimberelimab in participants with advanced solid malignancies. In this dose escalation study, participants will receive domvanalimab administered intravenously as monotherapy or in combination with zimberelimab. Treatment will continue until progressive disease, unacceptable toxicity, withdrawal of consent, or other reasons for study drug discontinuation occurs.

Official Title
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A Phase 1 Study to Evaluate the Safety and Tolerability of AB154 Monotherapy and Combination Therapy in Participants With Advanced Malignancies

Conditions
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Solid Tumor, Unspecified, Adult

Intervention / Treatment
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* Drug: Domvanalimab
* Drug: Zimberelimab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Capable of giving signed informed consent Male or female participants ≥ 18 years of age at the time of screening Negative serum pregnancy test at screening and prior to dosing on Cycle 1 Day 1; negative serum or urine pregnancy test on the first day of each subsequent treatment period Participants with any pathologically confirmed solid tumor type for which no standard of care therapy exists Must have at least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. The measurable lesion must be outside of a radiation field if the participant received prior radiation Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 7. Confirmation that an archival tissue sample is available and ≤ 6 months old; if not, a new biopsy of a tumor must be obtained 8. Immunosuppressive doses of systemic medications, such as corticosteroids or absorbed topical corticosteroids (doses > 10 mg/day prednisone or equivalent) must be discontinued at least 2 weeks (14 days) before investigational product administration. Physiologic doses of corticosteroids ≤ 10 mg/day of prednisone or its equivalent may be permitted Prior surgery that required general anesthesia or other major surgery as defined by the Investigator must be completed at least 4 weeks before investigational product administration Negative tests for hepatitis B surface antigen, hepatitis C virus antibody (or hepatitis C qualitative ribonucleic acid [RNA; qualitative]), and human immunodeficiency virus (HIV)-1 and HIV-2 antibody at screening Adequate organ and marrow function Exclusion Criteria: Use of any live vaccines against infectious diseases (eg, influenza, varicella) within 4 weeks (28 days) of initiation of investigational product Underlying medical conditions that, in the Investigator's or Sponsor's opinion, will make the administration of investigational product hazardous (eg, interstitial lung disease, active infections requiring antibiotics, recent hospitalization with unresolved symptoms) Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the pre-screening or screening visit through 100 days after the last dose of domvanalimab as monotherapy and in combination with zimberelimab. Participants who require a Legally Authorized Representative (LAR) to provide informed consent on their behalf. Any active autoimmune disease or a documented history of autoimmune disease or history of a syndrome that required systemic steroids or immunosuppressive medications, except for vitiligo or resolved childhood asthma/atopy. Participants with asthma who require intermittent use of bronchodilators (such as albuterol) will not be excluded from this study Prior malignancy active within the previous year except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix, breast, or prostate cancer Has had prior chemotherapy, targeted small-molecule therapy, immunotherapy (tumor vaccine, cytokine, or growth factor given to control the cancer), biologic agents or radiation therapy within 4 weeks (or 5 half-lives) prior to Day 1 or has not recovered from AEs due to a previously administered agent Use of other investigational drugs within 28 days or at least 5 half-lives before investigational product administration.

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
Interventional Model Description: Dose Escalation Design
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Domvanalimab Monotherapy<br>Varying Doses of domvanalimab Monotherapy | Drug: Domvanalimab<br>* Domvanalimabis a fully human immunoglobulin G1 (IgG1) monoclonal antibody targeting human TIGIT<br>* Other names: AB154;|
| Experimental: Domvanalimab + zimberelimab Q2W Combination Therapy<br>Varying Doses of domvanalimab in Combination With Varying Doses of zimberelimab | Drug: Domvanalimab<br>* Domvanalimabis a fully human immunoglobulin G1 (IgG1) monoclonal antibody targeting human TIGIT<br>* Other names: AB154;Drug: Zimberelimab<br>* Zimbererlimab is a fully human immunoglobulin G4 (IgG4) monoclonal antibody targeting human PD-1<br>* Other names: AB122;|
| Experimental: Domvanalimab + zimberelimab Q3W Combination Therapy<br>Varying Doses of domvanalimab in Combination With Varying Doses of zimberelimab | Drug: Domvanalimab<br>* Domvanalimabis a fully human immunoglobulin G1 (IgG1) monoclonal antibody targeting human TIGIT<br>* Other names: AB154;Drug: Zimberelimab<br>* Zimbererlimab is a fully human immunoglobulin G4 (IgG4) monoclonal antibody targeting human PD-1<br>* Other names: AB122;|
| Experimental: Domvanalimab + zimberelimab Q4W Combination Therapy<br>Varying Doses of domvanalimab in Combination With Varying Doses of zimberelimab | Drug: Domvanalimab<br>* Domvanalimabis a fully human immunoglobulin G1 (IgG1) monoclonal antibody targeting human TIGIT<br>* Other names: AB154;Drug: Zimberelimab<br>* Zimbererlimab is a fully human immunoglobulin G4 (IgG4) monoclonal antibody targeting human PD-1<br>* Other names: AB122;|
| Experimental: Domvanalimab and Zimberelimab Q6W combination therapy<br>Varying Doses of domvanalimab in Combination With Varying Doses of zimberelimab | Drug: Domvanalimab<br>* Domvanalimabis a fully human immunoglobulin G1 (IgG1) monoclonal antibody targeting human TIGIT<br>* Other names: AB154;Drug: Zimberelimab<br>* Zimbererlimab is a fully human immunoglobulin G4 (IgG4) monoclonal antibody targeting human PD-1<br>* Other names: AB122;|
| Experimental: Fixed dose Domvanalimab Q3W or Q4W and Zimberelimab Q3W, Q4W<br>Varying Doses of domvanalimab in Combination With Varying Doses of zimberelimab | Drug: Domvanalimab<br>* Domvanalimabis a fully human immunoglobulin G1 (IgG1) monoclonal antibody targeting human TIGIT<br>* Other names: AB154;Drug: Zimberelimab<br>* Zimbererlimab is a fully human immunoglobulin G4 (IgG4) monoclonal antibody targeting human PD-1<br>* Other names: AB122;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Treatment Emergent Adverse Events (TEAEs) as Assessed by CTCAE v5.0 | Number of Participants Treated with domvanalimab or domvanalimab in Combination with zimberelimab with Treatment Emergent Adverse Events (TEAEs) as Assessed by CTCAE v5.0 | From First Dose Date to 100 Days After Last Dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AB154 Peak Plasma Concentration (Cmax) | Peak Plasma Concentration (Cmax) of domvanalimab | Day 1 (sequential), Day 2, Day 3, Day 4, Day 8, Day 15, Day 22, Day 29 (sequential), Day 30, Day 31, Day 36, Day 43, Day 57, Day 64, Day 85, Day 106, Day 113, Day 141 and 30 Days After Last Dose, up to 52 weeks | 
| Zimberelimab Peak Plasma Concentration (Cmax) | Peak Plasma Concentration (Cmax) of zimberelimab | Day 1 (sequential), Day 2, Day 3, Day 4, Day 8, Day 15, Day 22, Day 29 (sequential), Day 30, Day 31, Day 36, Day 43, Day 57, Day 64, Day 85, Day 106, Day 113, Day 141 and 30 Days After Last Dose, up to 52 weeks | 
| Domvanalimab Time of Peak Concentration (Tmax) | Time of Peak Concentration (Tmax) of domvanalimab | Day 1 (sequential), Day 2, Day 3, Day 4, Day 8, Day 15, Day 22, Day 29 (sequential), Day 30, Day 31, Day 36, Day 43, Day 57, Day 64, Day 85, Day 106, Day 113, Day 141 and 30 Days After Last Dose, up to 52 weeks | 
| Zimberelimab Time of Peak Concentration (Tmax) | Time of Peak Concentration (Tmax) of zimberelimab | Day 1 (sequential), Day 2, Day 3, Day 4, Day 8, Day 15, Day 22, Day 29 (sequential), Day 30, Day 31, Day 36, Day 43, Day 57, Day 64, Day 85, Day 106, Day 113, Day 141 and 30 Days After Last Dose, up to 52 weeks | 
| Domvanalimab Area Under the Plasma Concentration Versus Time Curve (AUC) | Area Under the Plasma Concentration Versus Time Curve (AUC) of domvanalimab | Day 1 (sequential), Day 2, Day 3, Day 4, Day 8, Day 15, Day 22, Day 29 (sequential), Day 30, Day 31, Day 36, Day 43, Day 57, Day 64, Day 85, Day 106, Day 113, Day 141 and 30 Days After Last Dose, up to 52 weeks | 
| Zimberelimab Area Under the Plasma Concentration Versus Time Curve (AUC) | Area Under the Plasma Concentration Versus Time Curve (AUC) of zimberelimab | Day 1 (sequential), Day 2, Day 3, Day 4, Day 8, Day 15, Day 22, Day 29 (sequential), Day 30, Day 31, Day 36, Day 43, Day 57, Day 64, Day 85, Day 106, Day 113, Day 141 and 30 Days After Last Dose, up to 52 weeks | 
| Immunogenicity Indicators: Anti-Drug Antibodies (ADA) | Number of Participants who Develop Antidrug Antibodies to AB154 and/or AB122 | Day 1, Day 15, Day 29, Day 43, Day 57, Day 85 and 30 Days After Last Dose, up to 52 weeks | 
| Overall Response Rate | Number of Participants with Complete or Partial Response per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v.1.1 | First Dose Date to Progression or Last Tumor Assessment, up to 1 year | 
| Duration of Response | Time at Which Response Criteria are Met for Complete Response or Partial Response (Whichever Occurs First) Until the First Date of Recurrence, Progression or Death per RECIST v1.1 | Start Date of Response to First Progression/Death, up to 1 year | 
| Disease Control Rate | Number of Participants with Complete Response, Partial Response, or Stable Disease for Greater Than 6 Months per RECIST v1.1 | First Dose Date to First Progression/Death, up to 1 year | 
| Progression Free Survival | Number of Participants Without Disease Progression per RECIST v1.1 | First Dose Date to First Progression/Death, up to 1 year | 
| Overall Survival | Overall Survival Rate, Defined as Time Between First Dose Date and Date of Death | First Dose Date to Date of Death, up to 1 year |