Study to Determine the Safety, Tolerability, Pharmacokinetics and Recommended Phase 2 Dose (RP2D) of Livmoniplimab (ABBV-151) as a Single Agent and in Combination With Budigalimab (ABBV-181) in Participants With Locally Advanced or Metastatic Solid Tumors

Study Overview
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Brief Summary
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The study will determine the recommended Phase 2 dose (RP2D) of livmoniplimab (ABBV-151) administered as monotherapy and in combination with budigalimab (ABBV-181) as well as to assess the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of livmoniplimab alone and in combination with budigalimab. The study will consist of 2 parts: dose escalation and dose expansion.

Official Title
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A Phase 1 First-in Human, Multi-Center, Open Label Dose-Escalation Study to Determine the Safety, Tolerability, Pharmacokinetics and RP2D of Livmoniplimab (ABBV-151) as a Single Agent and in Combination With Budigalimab (ABBV-181) in Subjects With Locally Advanced or Metastatic Solid Tumors

Conditions
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Advanced Solid Tumors Cancer

Intervention / Treatment
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* Drug: Livmoniplimab
* Drug: Budigalimab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For Dose Escalation only: Participants with an advanced solid tumor who are considered refractory to or intolerant of all existing therapy(ies) known to provide a clinical benefit for their condition. Additionally, participants who have been offered standard therapies and refused, or who are considered ineligible for standard therapies, may be eligible for this study on a case-by-case basis, after discussion with and agreement from the sponsor. Participants with pancreatic adenocarcinoma, urothelial cancer, hepatocellular carcinoma (HCC), or head and neck squamous cell carcinoma (HNSCC) who are being considered for the dose escalation cohorts must also meet the histology specific eligibility criteria described below for dose expansion. For Dose Expansion only participants must meet criteria specific to the type of cancer: Pancreatic adenocarcinoma and have disease progression during or after 1 systemic therapy (gemcitabine monotherapy or in combination with other agents, FOLFIRINOX [or another regimen including both 5-fluorouracil and oxaliplatin], capecitabine monotherapy or in combination with other agents) administered in the adjuvant, locally advanced, or metastatic setting. If the therapy was used in an adjuvant setting, disease progression must have occurred within 6 months of completing adjuvant therapy. Urothelial cancer of the bladder and urinary tract and must have progressed following treatment with a platinum-based regimen (administered in any line of therapy) and a programmed death 1/programmed death ligand 1 (PD1/PDL1) antagonist administered in the recurrent or metastatic setting (progression following a PD1/PDL1 antagonist is defined as unequivocal progression on or within 3 months of the last dose of anti-PD1 or anti-PDL1 therapy). HCC and must have disease progression during or after 1 prior line of systemic therapy. HNSCC (arising from the oral cavity, oropharynx, hypopharynx, or larynx) and must have progressed following treatment with platinum-based regimen (administered in any line of therapy) and a PD1/PDL1 antagonist administered in the recurrent or metastatic setting (progression following a PD1/PDL1 antagonist is defined as unequivocal progression on or within 3 months of the last dose of anti-PD1 or anti-PDL1 therapy). Microsatellite stable colorectal cancer (MSS-CRC) [unselected] participants with microsatellite stable or mismatch repair proficient colorectal adenocarcinoma (as determined by polymerase chain reaction (PCR)/Next-Generation sequencing (NGS) or immunohistochemistry (IHC), respectively) who have received 1-2 prior chemotherapy regimens. Non-small cell lung cancer (NSCLC) relapsed/refractory (R/R): Participants with histologically or cytologically confirmed advanced or metastatic NSCLC who have received 1 prior line of chemotherapy and 1 prior anti-PD-(L)1 antibody, administered either concurrently or sequentially in the metastatic setting. NSCLC (1L PD-L1 high) with liver metastasis enrichment: Participants with histologically or cytologically confirmed advanced or metastatic NSCLC, with high expression PD-L1 as defined by Tumor Proportion Score (TPS) >=50%, no known (EGFR) mutations or ALK gene rearrangements, who have received no prior therapy in the advanced or metastatic setting. MSS-CRC (CMS4 enriched): Participants with microsatellite stable or mismatch repair proficient colorectal adenocarcinoma who have received prior fluorouracil-based combination chemotherapy regimens including oxaliplatin and irinotecan (with or without VEGF and/or EGFR targeted agents) and with a CMS4 subtype as determined by NGS of tumor biopsies. Archival tissue must be submitted for assessment of CMS4 subtype status during prescreening. Participant has an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1. Participant has adequate bone marrow, renal, hepatic, and coagulation function. Must have a viral status consistent with the requirements described in the protocol specific to type of cancer and stage of study (Dose Escalation or Dose Expansion). Exclusion Criteria: For Dose Expansion only: Participants with HCC, pancreatic adenocarcinoma, or MSS-CRC having prior exposure to a prior PD-1/PD-L1 antagonist in any line of therapy. Participants (except for participants with urothelial cancer or HNSCC) who have had prior exposure to immunotherapies as listed in the protocol. Has received anticancer therapy including chemotherapy, immunotherapy, radiation therapy, biologic, herbal therapy, or any investigational therapy within a period of 5 half-lives or 28 days (whichever is shorter), prior to the first dose of the study drug. Participant has unresolved AEs > Grade 1 from prior anticancer therapy except for alopecia. Has a history of primary immunodeficiency, bone marrow transplantation, solid organ transplantation, or previous clinical diagnosis of tuberculosis. Has a known uncontrolled metastases to the central nervous system (with certain exceptions). Current or prior use of immunosuppressive medication within 14 days prior to the first dose of the study drug. Has clinically significant uncontrolled condition(s). History of inflammatory bowel disease, interstitial lung disease or pneumonitis, myocarditis, Stevens-Johnson syndrome, toxic epidermal necrolysis or drug reaction with eosinophilia and systemic symptoms (DRESS). Live vaccine administration <= 28 days prior to the first dose of study drug.

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: Cohort 1 Livmoniplimab<br>Various doses of Livmoniplimab administered during dose escalation to determine the Recommended Phase 2 Dose (RP2D). | Drug: Livmoniplimab<br>* Liquid for intravenous infusion.<br>* Other names: ABBV-151;|
| Experimental: Dose Escalation: Cohort 2 Livmoniplimab + Budigalimab<br>Various doses of Livmoniplimab + Budigalimab administered during dose escalation to determine the Recommended Phase 2 Dose (RP2D). | Drug: Livmoniplimab<br>* Liquid for intravenous infusion.<br>* Other names: ABBV-151;Drug: Budigalimab<br>* Lyophilized powder for solution for intravenous infusion.<br>* Other names: ABBV-181;|
| Experimental: Dose Expansion: Cohort 3 Livmoniplimab + Budigalimab<br>Participants with programmed cell death protein 1 (PD-1)-naïve pancreatic adenocarcinoma will receive livmoniplimab at the RP2D Q2W plus budigalimab Dose A administered Q4W. | Drug: Livmoniplimab<br>* Liquid for intravenous infusion.<br>* Other names: ABBV-151;Drug: Budigalimab<br>* Lyophilized powder for solution for intravenous infusion.<br>* Other names: ABBV-181;|
| Experimental: Dose Expansion: Cohort 4 Livmoniplimab + Budigalimab<br>Participants with PD-1-ref urothelial cancer will receive livmoniplimab at the RP2D Q2W plus budigalimab Dose A administered Q4W. | Drug: Livmoniplimab<br>* Liquid for intravenous infusion.<br>* Other names: ABBV-151;Drug: Budigalimab<br>* Lyophilized powder for solution for intravenous infusion.<br>* Other names: ABBV-181;|
| Experimental: Dose Expansion: Cohort 5 Livmoniplimab + Budigalimab<br>Participants with PD-1-naïve hepatocellular carcinoma (HCC) will receive livmoniplimab at the RP2D Q2W plus budigalimab Dose A administered Q4W. | Drug: Livmoniplimab<br>* Liquid for intravenous infusion.<br>* Other names: ABBV-151;Drug: Budigalimab<br>* Lyophilized powder for solution for intravenous infusion.<br>* Other names: ABBV-181;|
| Experimental: Dose Expansion: Cohort 6 Livmoniplimab + Budigalimab<br>Participants with PD-1-ref head and neck squamous cell carcinoma (HNSCC) will receive livmoniplimab at the RP2D Q2W plus budigalimab Dose A administered Q4W. | Drug: Livmoniplimab<br>* Liquid for intravenous infusion.<br>* Other names: ABBV-151;Drug: Budigalimab<br>* Lyophilized powder for solution for intravenous infusion.<br>* Other names: ABBV-181;|
| Experimental: Dose Expansion: Cohort 7 Livmoniplimab + Budigalimab<br>Participants with PD-1-naïve microsatellite stable colorectal cancer (MSS-CRC) [unselected] will receive livmoniplimab at the RP2D Q2W plus budigalimab Dose A administered Q4W. | Drug: Livmoniplimab<br>* Liquid for intravenous infusion.<br>* Other names: ABBV-151;Drug: Budigalimab<br>* Lyophilized powder for solution for intravenous infusion.<br>* Other names: ABBV-181;|
| Experimental: Dose Expansion: Cohort 8 Livmoniplimab + Budigalimab<br>Participants with non-small cell lung cancer (NSCLC) [programmed death ligand 1 (PDL1) relapsed/refractory (R/R)] will receive livmoniplimab at the RP2D Q2W plus budigalimab Dose A administered Q4W. | Drug: Livmoniplimab<br>* Liquid for intravenous infusion.<br>* Other names: ABBV-151;Drug: Budigalimab<br>* Lyophilized powder for solution for intravenous infusion.<br>* Other names: ABBV-181;|
| Experimental: Dose Expansion: Cohort 9A Livmoniplimab + Budigalimab<br>Participants with NSCLC (1L PD-L1 high) Tumor Proportion Score (TPS) >= 50% will receive livmoniplimab at the dose B Q3W plus budigalimab Dose B administered Q3W. | Drug: Livmoniplimab<br>* Liquid for intravenous infusion.<br>* Other names: ABBV-151;Drug: Budigalimab<br>* Lyophilized powder for solution for intravenous infusion.<br>* Other names: ABBV-181;|
| Experimental: Dose Expansion: Cohort 9B Livmoniplimab + Budigalimab<br>Participants with NSCLC (1L PD-L1 high) TPS >= 50%; will receive livmoniplimab at the dose C Q3W plus budigalimab Dose B administered Q3W. | Drug: Livmoniplimab<br>* Liquid for intravenous infusion.<br>* Other names: ABBV-151;Drug: Budigalimab<br>* Lyophilized powder for solution for intravenous infusion.<br>* Other names: ABBV-181;|
| Experimental: Dose Expansion: Cohort 10A Livmoniplimab + Budigalimab<br>Participants with microsatellite stable colorectal cancer (MSS-CRC) [consensus molecular subtype 4 (CMS4) enriched] will receive livmoniplimab at the dose B Q3W plus budigalimab Dose B administered Q3W. | Drug: Livmoniplimab<br>* Liquid for intravenous infusion.<br>* Other names: ABBV-151;Drug: Budigalimab<br>* Lyophilized powder for solution for intravenous infusion.<br>* Other names: ABBV-181;|
| Experimental: Dose Expansion: Cohort 10B Livmoniplimab + Budigalimab<br>Participants with MSS-CRC (CMS4 enriched) will receive livmoniplimab at the dose C Q3W plus budigalimab Dose B administered Q3W. | Drug: Livmoniplimab<br>* Liquid for intravenous infusion.<br>* Other names: ABBV-151;Drug: Budigalimab<br>* Lyophilized powder for solution for intravenous infusion.<br>* Other names: ABBV-181;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Escalation: Recommended Phase 2 Dose (RP2D) Livmoniplimab Monotherapy | The RP2D is defined as the dose level chosen by the sponsor (in consultation with the investigators) for the dose expansion arms, based on safety, tolerability, efficacy, PK, and PD data collected during the dose escalation portion of the study. | Up to 28 days after the first dose of Livmoniplimab monotherapy | 
| Dose Escalation: RP2D Livmoniplimab + Budigalimab Combination Therapy | The RP2D is defined as the dose level chosen by the sponsor (in consultation with the investigators) for the dose expansion arms, based on safety, tolerability, efficacy, pharmacokinetics (PK), and pharmacodynamic (PD) data collected during the dose escalation portion of the study. | Up to 28 days after the first dose of Livmoniplimab and Budigalimab combination therapy | 
| Dose Expansion: Objective Response Rate (ORR) | ORR defined as the percentage of participants with a confirmed complete response (CR) or partial response (PR) based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. | Up to approximately 6 months after the first dose date of last participant in Dose Expansion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Expansion: Duration of Response (DOR) | The DOR for a responder is defined as the time from the participant's initial objective response to the first date of either disease progression or death, whichever occurs first. | Up to approximately 6 months after the first dose date of last participant in Dose Expansion | 
| Dose Expansion: Progression-free Survival (PFS) | Progression-free survival is defined as the time from the participant's first dose of study treatment (livmoniplimab or budigalimab) to the first date of either disease progression or death, whichever occurs first. | Up to approximately 6 months after the first dose date of last participant in Dose Expansion | 
| Maximum Observed Serum Concentration (Cmax) of Livmoniplimab | Maximum Serum Concentration (Cmax) of livmoniplimab. | Up to approximately 70 days after initial dose of study drug | 
| Time to Maximum Observed Serum Concentration (Tmax) of Livmoniplimab | Time to maximum serum concentration (Tmax) of livmoniplimab. | Up to approximately 70 days after initial dose of study drug | 
| Area Under the Plasma Concentration-time Curve over time from 0 to last measurable concentration (AUCτ) of Livmoniplimab | Area under the serum concentration-time curve from time 0 to the time of the last measurable concentration (AUCτ) of livmoniplimab. | Up to approximately 70 days after initial dose of study drug | 
| Terminal-phase Elimination Rate Constant (β) of Livmoniplimab | Apparent terminal phase elimination rate constant (β or Beta) of livmoniplimab. | Up to approximately 70 days after initial dose of study drug | 
| Terminal Phase Elimination Half-life (t1/2) of Livmoniplimab | Terminal phase elimination half-life (t1/2) of livmoniplimab. | Up to approximately 70 days after initial dose of study drug | 
| Maximum Observed Serum Concentration (Cmax) of Budigalimab | Maximum Serum Concentration (Cmax) of budigalimab. | Up to approximately 70 days after initial dose of study drug | 
| Time to Maximum Observed Serum Concentration (Tmax) of Budigalimab | Time to maximum serum concentration (Tmax) of budigalimab. | Up to approximately 70 days after initial dose of study drug | 
| Area Under the Plasma Concentration-time Curve over time from 0 to last measurable concentration (AUCτ) of Budigalimab | Area under the serum concentration-time curve from time 0 to the time of the last measurable concentration (AUCτ) of budigalimab. | Up to approximately 70 days after initial dose of study drug | 
| Terminal-phase Elimination Rate Constant (β) of Budigalimab | Apparent terminal phase elimination rate constant (β or Beta) of budigalimab. | Up to approximately 70 days after initial dose of study drug | 
| Terminal Phase Elimination Half-life (t1/2) of Budigalimab | Terminal phase elimination half-life (t1/2) of budigalimab. | Up to approximately 70 days after initial dose of study drug | 
| Number of Participants With Adverse Events (AEs) | An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. The investigator assesses the relationship of each event to the use of study. A serious adverse event (SAE) is an event that results in death, is life-threatening, requires or prolongs hospitalization, results in a congenital anomaly, persistent or significant disability/incapacity or is an important medical event that, based on medical judgment, may jeopardize the participant and may require medical or surgical intervention to prevent any of the outcomes listed above. | Up to approximately 9 months after the first dose date of last participant | 
| Change in Vital Signs | Number of participants with clinically significant change from baseline in vital signs like systolic and diastolic blood pressure will be reported. | Up to approximately 6 months after the first dose date of last participant | 
| Change in Laboratory Parameters | Number of participants with clinically significant change from baseline in clinical laboratory test results like hematology will be reported. | Up to approximately 6 months after the first dose date of last participant | 
| Change in Electrocardiogram (ECG) | 12-lead resting ECGs will be recorded. Parameters include RR interval, PR interval, QT interval, and QRS duration. | Up to approximately 6 months after the first dose date of last participant | 
| Incidence of Anti-drug Antibody (ADA) | The number of participants with anti-drug antibodies. | Up to approximately 6 months after the first dose date of last participant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Solid Tumors, metastatic, monotherapy, combination therapy, triple negative breast cancer (TNBC), pancreatic adenocarcinoma, urothelial cancer, hepatocellular carcinoma (HCC), head and neck squamous cell carcinoma (HNSCC), Colorectal cancer, Advanced Solid Tumors Cancer, cancer