A Study to Evaluate the Safety and Tolerability of AB680 in Participants With Gastrointestinal Malignancies

Study Overview
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Brief Summary
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This is a Phase 1, open-label, dose-escalation, and dose-expansion, with a gated randomization portion, study to evaluate the safety, tolerability, pharmacokinetic, pharmacodynamic and clinical activity of AB680 in combination with Zimberelimab (AB122), nab-paclitaxel and gemcitabine in participants with advanced pancreatic cancer.

Detailed Description
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Dose escalation of AB680 in combination with Zimberelimab (AB122), nab-paclitaxel and gemcitabine will be assessed in participants with advanced pancreatic cancer. In this dose escalation combination study, participants with advanced pancreatic cancer will receive escalating doses of AB680 in combination with Zimberelimab at the recommended phase 2 dose (RP2D), and nab-paclitaxel and gemcitabine at standard doses. AB680, Zimberelimab, nab-paclitaxel and gemcitabine are all administered via IV infusion. In the dose expansion portion of the study in front-line (1L) pancreatic patients, participants will receive AB680 at the RP2D determined from the dose escalation study in combination with Zimberelimab at the RP2D and nab-paclitaxel and gemcitabine at standard doses or AB680 at the RP2D in combination with nab-paclitaxel and gemcitabine at standard doses. In the dose-expansion portion of the study in second-line (2L) pancreatic patients, participants will receive AB680 at the RP2D determined from the dose-escalation study in combination with Zimberelimab at the RP2D and nab-paclitaxel and gemcitabine at standard doses.

Official Title
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A Phase 1 Study to Evaluate the Safety and Tolerability of AB680 Combination Therapy in Participants With Gastrointestinal Malignancies

Conditions
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Advanced Pancreatic Cancer

Intervention / Treatment
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* Drug: AB680
* Drug: Zimberelimab
* Drug: Nab-paclitaxel
* Drug: Gemcitabine


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 Histologically or cytologically confirmed metastatic pancreatic adenocarcinoma Naïve to any prior treatment, including chemotherapy, biological therapy, or targeted therapy for metastatic disease Prior adjuvant therapy (including chemotherapy and/or radiotherapy) for pancreatic adenocarcinoma is permitted if neoadjuvant or adjuvant therapy was completed at least 6 months prior to study enrollment. Prior adjuvant therapy may include Nab- paclitaxel or gemcitabine Participants initially diagnosed with locally advanced pancreatic cancer who have undergone chemotherapy then resection and had no evidence of disease are eligible if relapse of metastatic disease has occurred and if the last dose of chemotherapy was received more than 6 months before study entry 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 Confirmation that an archival tissue sample is available; if not, a new biopsy of a tumor must be obtained 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) or short pulses of corticosteroids (≤ 3 days) 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 attenuated 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 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

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: 3+3 Dose escalation design
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation<br>Dose escalation is a 3+3 design, including a Dose Limiting Toxicity (DLT) evaluation period. The dose expansion dose level will be determined in this part with escalating doses of AB680 in combination with Zimberelimab at the recommended phase 2 dose (RP2D) and the standard nab-paclitaxel and gemcitabine chemotherapy regimen in participants with advanced pancreatic cancer. | Drug: AB680<br>* AB680 is a Cluster of Differentiation (CD)73 Inhibitor.<br>Drug: Zimberelimab<br>* Zimberelimab is a fully human immunoglobulin G4 (IgG4) monoclonal antibody targeting human PD-1.<br>* Other names: AB122;Drug: Nab-paclitaxel<br>* Nab-paclitaxel is a chemotherapy agent. Chemotherapy agents are medicines that kill cancer cells.<br>* Other names: Abraxane;Drug: Gemcitabine<br>* Gemcitabine is a chemotherapy agent. Chemotherapy agents are medicines that kill cancer cells.<br>* Other names: Gemzar;|
| Experimental: Dose Expansion(AB680+Zimberelimab+nab-paclitaxel(NP) & gemcitabine (Gem):Cohort A1 (front-line/1L)<br>Participants with advance pancreatic cancer, naïve to any prior treatment will receive AB680 (at the RP2D identified during dose escalation) combined with Zimberelimab and the standard nab-paclitaxel (NP) and gemcitabine (Gem) (NP/Gem) chemotherapy regimen | Drug: AB680<br>* AB680 is a Cluster of Differentiation (CD)73 Inhibitor.<br>Drug: Zimberelimab<br>* Zimberelimab is a fully human immunoglobulin G4 (IgG4) monoclonal antibody targeting human PD-1.<br>* Other names: AB122;Drug: Nab-paclitaxel<br>* Nab-paclitaxel is a chemotherapy agent. Chemotherapy agents are medicines that kill cancer cells.<br>* Other names: Abraxane;Drug: Gemcitabine<br>* Gemcitabine is a chemotherapy agent. Chemotherapy agents are medicines that kill cancer cells.<br>* Other names: Gemzar;|
| Experimental: Dose Expansion (AB680 + NP/Gem): Cohort A2 (front-line/1L)<br>Participants with advance pancreatic cancer who are naïve to any prior treatment will receive AB680 (at the RP2D identified during dose escalation) and the standard NP/Gem chemotherapy regimen. | Drug: AB680<br>* AB680 is a Cluster of Differentiation (CD)73 Inhibitor.<br>Drug: Nab-paclitaxel<br>* Nab-paclitaxel is a chemotherapy agent. Chemotherapy agents are medicines that kill cancer cells.<br>* Other names: Abraxane;Drug: Gemcitabine<br>* Gemcitabine is a chemotherapy agent. Chemotherapy agents are medicines that kill cancer cells.<br>* Other names: Gemzar;|
| Experimental: Dose Expansion (AB680 + Zimberelimab + NP/Gem): Cohort B (second-line/2L)<br>Participants with advance pancreatic cancer who have received 1 prior line of treatment will receive AB680 (at the RP2D identified during dose escalation) combined with Zimberelimab and NP-Gem chemotherapy regimen. | Drug: AB680<br>* AB680 is a Cluster of Differentiation (CD)73 Inhibitor.<br>Drug: Zimberelimab<br>* Zimberelimab is a fully human immunoglobulin G4 (IgG4) monoclonal antibody targeting human PD-1.<br>* Other names: AB122;Drug: Nab-paclitaxel<br>* Nab-paclitaxel is a chemotherapy agent. Chemotherapy agents are medicines that kill cancer cells.<br>* Other names: Abraxane;Drug: Gemcitabine<br>* Gemcitabine is a chemotherapy agent. Chemotherapy agents are medicines that kill cancer cells.<br>* Other names: Gemzar;|
| Experimental: Dose Expansion (AB680 + Zimberelimab + NP/Gem): Cohort C (front-line/1L)<br>Participants with advance pancreatic cancer naïve to any prior treatment will receive AB680 combined with Zimberelimab and NP-Gem chemotherapy regimen. | Drug: AB680<br>* AB680 is a Cluster of Differentiation (CD)73 Inhibitor.<br>Drug: Zimberelimab<br>* Zimberelimab is a fully human immunoglobulin G4 (IgG4) monoclonal antibody targeting human PD-1.<br>* Other names: AB122;Drug: Nab-paclitaxel<br>* Nab-paclitaxel is a chemotherapy agent. Chemotherapy agents are medicines that kill cancer cells.<br>* Other names: Abraxane;Drug: Gemcitabine<br>* Gemcitabine is a chemotherapy agent. Chemotherapy agents are medicines that kill cancer cells.<br>* Other names: Gemzar;|

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) | Safety will be assessed by monitoring adverse events and clinically relevant changes in 12 lead Electrocardiogram (ECG) and Physical examination findings | From first dose date to 90 days after the last dose (approximately 1 year) | 
| Number of Participants With Dose Limiting Toxicities |  | From First dose to day 28 | 
| Number of participants with clinically significant changes in vital signs and clinical laboratory parameters |  | From first dose date to 90 days after the last dose (approximately 1 year) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| Progression free survival | Number of participants without disease progression per RECIST v1.1 | First dose date to first progression/death, up to 1 year | 
| AB680 peak plasma concentration (Cmax) | Peak plasma concentration (Cmax) of AB680 | Day 1 (sequential), day 2, day 3, day 8, day 15, day 29, day 36, day 43, day 57, day 85, day 197, day 309, day 421, 30 days after last dose, and 90 days after last dose | 
| Zimberelimab peak plasma concentration (Cmax) | Peak plasma concentration (Cmax) of Zimberelimab | Day 1 (sequential), day 2, day 3, day 8, day 15, day 29, day 43, day 57, day 85, day 197, day 309, day 421, 30 days after last dose, and 90 days after last dose | 
| AB680 time of peak concentration (Tmax) | Time of peak concentration (Tmax) of AB680 | Day 1 (sequential), day 2, day 3, day 8, day 15, day 29, day 36, day 43, day 57, day 85, day 197, day 309, day 421, 30 days after last dose, and 90 days after last dose | 
| Zimberelimab time of peak concentration (Tmax) | Time of peak concentration of Zimberelimab | Day 1 (sequential), day 2, day 3, day 8, day 15, day 29, day 43, day 57, day 85, day 197, day 309, day 421, 30 days after last dose, and 90 days after last dose | 
| AB680 area under the plasma concentration versus time curve (AUC) | Area under the plasma concentration versus time curve (AUC) of AB680 | Day 1 (sequential), day 2, day 3, day 8, day 15, day 29, day 36, day 43, day 57, day 85, day 197, day 309, day 421, 30 days after last dose, and 90 days after last dose | 
| 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 8, day 15, day 29, day 43, day 57, day 85, day 197, day 309, day 421, 30 days after last dose, and 90 days after last dose | 
| Immunogenicity indicators: anti-drug antibodies (ADA) | Number of participants who develop anti-drug antibodies to Zimberelimab | Day 1, day 15, day 29, day 57, day 85, day 197, day 309, and day 421 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AB680, Zimberelimab, Pancreatic cancer