A Study of the Safety, Tolerability and Pharmacokinetics of ABBV-368 as a Single Agent and Combination in Subjects With Locally Advanced or Metastatic Solid Tumors

Study Overview
=================
Brief Summary
-----------------
The primary purpose of this Phase 1, open-label study is to evaluate the safety, pharmacokinetics, and preliminary efficacy of ABBV-368 as a monotherapy and in combination with ABBV-181 in participants with locally advanced or metastatic solid tumors. The study will consist of 3 parts: ABBV-368 dose escalation, ABBV-368 tumor-specific dose expansion (triple negative breast cancer [TNBC] cohort and head and neck cancer cohort) and 18F-AraG Imaging Substudy.

Detailed Description
-----------------
Recruitment is closed in Part 1A; subjects are in maintenance

Official Title
-----------------
A Multicenter, Phase 1, Open-Label, Dose-Escalation Study of the Safety, Tolerability and Pharmacokinetics of ABBV-368 as a Single Agent and Combination in Subjects With Locally Advanced or Metastatic Solid Tumors

Conditions
-----------------
Advanced Solid Tumors Cancer

Intervention / Treatment
-----------------
* Drug: ABBV-368
* Drug: ABBV-181


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Participants must have histologic or cytology diagnosis of a known immunogenic solid tumor, as described for Part 1 Dose Escalation and Part 2 Cohort Expansion: Part 1 Dose Escalation: Participants with advanced or metastatic solid tumors that have exhausted standard treatment for their incurable disease and for whom there is currently no programmed cell death 1 (PD-1)/ programmed cell death-ligand 1 (PD-L1) approved therapy, with immunogenic type tumors such as, but not limited to triple negative breast cancer (TNBC), ovarian cancer, small cell lung cancer, mesothelioma, and cholangiocarcinoma. Participants who are refractory to a PD-1/PD-L1 agent, with tumor types such as melanoma, NSCLC, platinum-pretreated head and neck cancer, second line bladder and RCC. Part 2A and 2B Cohort Expansion: 2A : TNBC ABBV-368 monotherapy cohorts: Subjects with locally advanced or metastatic TNBC that have exhausted standard treatment for their incurable disease. 2B : Head and Neck cohort: Participants with recurrent squamous cell head and neck carcinoma that are not candidates for curative treatment with local or systemic therapy, or metastatic (disseminated) head and neck squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, and larynx that is considered incurable by local therapies. Part 3A and 3B Imaging Substudy: 3A: Participants with locally advanced or metastatic TNBC that have exhausted standard treatment for their incurable disease and are treatment naïve to a PD-1/PD-L1 targeting agent. 3B: Participants with recurrent HNSCC that are not candidates for curative treatment with local or systemic therapy, or metastatic HNSCC of the oral cavity, oropharynx, hypopharynx, and larynx that is considered incurable by local therapies. Participants must be treatment naïve to a PD-1/PD-L1 targeting agent. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 to 2. Participants must have immune-related Response Evaluation Criteria for Solid Tumors (iRECIST) evaluable or measurable disease in the PART 1 and measurable disease per iRECIST in PART 2 Adequate bone marrow, kidney and liver function. Exclusion Criteria: Received anticancer therapy including chemotherapy, immunotherapy, radiation therapy, biologic, herbal therapy, or any investigational therapy within a period of 21 days prior to the first dose of ABBV-368. Prior treatment with an OX40 targeting agent. has known uncontrolled metastases to the central nervous system (CNS). History of active autoimmune disorders and other conditions that compromise or impair the immune system. Confirmed positive test results for human immunodeficiency virus (HIV), or subjects with chronic or active hepatitis A, B or C. Subjects who have a history of hepatitis B or C who have documented cures after anti-viral therapy may be enrolled. Has received live vaccine within 28 days prior to the first dose of study drug.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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: Part 1A: Monotherapy Dose Escalation<br>Part 1A: ABBV-368 (various dose levels) intravenous administration every 2 weeks (Q2W). One cycle of treatment is 28 days, thus there will be 2 doses with ABBV-368 per cycle. | Drug: ABBV-368<br>* Intravenous infusion<br>|
| Experimental: Part 2A: Monotherapy Cohort Expansion<br>Part 2A: Additional participants (triple negative breast cancer [TNBC]) will be enrolled in a dose expansion cohort that will further evaluate ABBV-368 (various dose levels) intravenous administration Q4W. | Drug: ABBV-368<br>* Intravenous infusion<br>|
| Experimental: Part 2B: Combination Therapy Cohort Expansion<br>Part 2B: Additional participants (with Head and Neck carcinoma) will be enrolled in a dose expansion cohort that will further evaluate ABBV-368 (various dose levels) intravenous administration Q4W plus ABBV-181. | Drug: ABBV-368<br>* Intravenous infusion<br>Drug: ABBV-181<br>* Intravenous infusion<br>|
| Experimental: Part 3A: 18F-AraG Imaging Substudy in TNBC Participants<br>Part 3A: Additional participants (with TNBC) will be enrolled in 18F-AraG Imaging Substudy that will further evaluate ABBV-368 intravenous administration Q4W plus ABBV-181. | Drug: ABBV-368<br>* Intravenous infusion<br>Drug: ABBV-181<br>* Intravenous infusion<br>|
| Experimental: Part 3B: 18F-AraG Imaging Substudy in HNSCC Participants<br>Part 3B: Additional participants (with HNSCC) will be enrolled in 18F-AraG Imaging Substudy that will further evaluate ABBV-368 intravenous administration Q4W plus ABBV-181. | Drug: ABBV-368<br>* Intravenous infusion<br>Drug: ABBV-181<br>* Intravenous infusion<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Terminal half-life (t1/2) of ABBV-368 | Terminal half-life of ABBV-368 | Multiple time points in each cycle (each cycle is 28 days), throughout study completion, an average of 2 years, or participant becomes lost to follow up, or study termination | 
| Area under the serum concentration-time curve (AUC) of ABBV-368 | Area under the serum concentration-time curve of ABBV-368 | Multiple time points in each cycle (each cycle is 28 days), throughout study completion, an average of 2 years, or participant becomes lost to follow up, or study termination | 
| Maximum tolerated dose (MTD) of ABBV-368 when administered as monotherapy or in combination with ABBV-181 | The MTD of ABBV-368 when administered as monotherapy or as combination therapy with ABBV-181 will be determined during the dose escalation phase of the study. | Up to 1 year | 
| Recommended Phase 2 dose (RPTD) for ABBV-368 when administered as monotherapy or as combination therapy with ABBV-181 | Recommended Phase 2 dose (RPTD) for ABBV-368 when administered as monotherapy or as combination therapy with ABBV-181 will be established during the Dose expansion of the study | Up to 18 months | 
| Time to Cmax (Tmax) of ABBV-368 | Time to Cmax of ABBV-368 | Multiple time points in each cycle (each cycle is 28 days), throughout study completion, an average of 2 years, or participant becomes lost to follow up, or study termination | 
| Terminal phase elimination rate constant (β) of ABBV-368 | Terminal phase elimination rate constant of ABBV-368 | Multiple time points in each cycle (each cycle is 28 days), throughout study completion, an average of 2 years, or participant becomes lost to follow up, or study termination | 
| Number of Participants With Adverse Events | An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. The investigator assessed the relationship of each event to the use of study drug as either reasonable possibility or no reasonable possibility. 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 subject and may require medical or surgical intervention to prevent any of the outcomes listed above. Treatment-emergent events (TEAEs/TESAEs) are defined as any event that began or worsened in severity after the first dose of study drug. For more details on adverse events please see the Adverse Event section. | Multiple time points in each cycle (each cycle is 28 days), throughout study completion, an average of 2 years, or participant becomes lost to follow up, or study termination | 
| Maximum observed serum concentration (Cmax) of ABBV-368 | Maximum observed serum concentration of ABBV-368 | Multiple time points in each cycle (each cycle is 28 days), throughout study completion, an average of 2 years, or participant becomes lost to follow up, or study termination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | ORR is defined as the proportion of subjects with a confirmed partial or complete response to the treatment. | Multiple time points in each cycle (each cycle is 28 days), throughout study completion, an average of 2 years, or participant becomes lost to follow up, or study termination | 
| Clinical benefit rate (CBR) | CBR defined as the proportion of subjects with a confirmed partial response (PR), complete response (CR), or stable disease. | Multiple time points in each cycle (each cycle is 28 days), throughout study completion, an average of 2 years, or participant becomes lost to follow up, or study termination | 
| Duration of Objective Response (DOR) | DOR defined as the time from the initial objective response to disease progression or death, whichever occurs first. | Multiple time points in each cycle (each cycle is 28 days), throughout study completion, an average of 2 years, or participant becomes lost to follow up, or study termination | 
| Progression-Free Survival (PFS) | PFS time is defined as the time from the first dose of study drug (Day 1) to disease progression or death, whichever occurs first. | Multiple time points in each cycle (each cycle is 28 days), throughout study completion, an average of 2 years, or participant becomes lost to follow up, or study termination | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Solid Tumors, Cancer, Metastatic Solid Tumors, Advanced Solid Tumors, Triple negative breast cancer (TNBC), Ovarian cancer, Hepatocellular carcinoma (HCC), Gastric cancer, Mesothelioma, Small cell lung cancer (SCLC), Cholangiocarcinoma, Merkel cell carcinoma, Melanoma, Non-small cell lung cancer (NSCLC), 2'-Deoxy-2'-[18F]Fluoro-9-β-DArabinofuranosylguanine (18F-AraG)