A Study to Determine the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of ABBV-368 Plus Tilsotolimod and Other Therapy Combinations in Participants With Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma

• ABBV-368 (Drug): Intravenous (IV) infusion
• Tilsotolimod (Drug): Intratumoral (IT) injection
• Nab-paclitaxel (Drug): Intravenous (IV) infusion
• ABBV-181 (Drug), also known as Budigalimab: Intravenous (IV) infusion

Primary outcomes

• Number of Participants with Adverse Events (AEs) [Up to approximately 2 years following the first dose]: 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.
• Change in Vital Signs [Up to approximately 2 years following the first dose]: Number of participants with clinically significant change from baseline in vital signs like systolic and diastolic blood pressure will be reported.
• Change in Clinical Laboratory Test Results [Up to approximately 2 years following the first dose]: Number of participants with clinically significant change from baseline in clinical laboratory test results like hematology will be reported.
• Maximum Observed Serum Concentration (Cmax) of ABBV-368 [Cycle 1 through Cycle 3 (each cycle is approximately 28 days)]: Maximum Serum Concentration (Cmax) of ABBV-368
• Time to Maximum Serum Concentration (Tmax) of ABBV-368 [Cycle 1 through Cycle 3 (each cycle is approximately 28 days)]: Time to Maximum Serum Concentration (Tmax) of ABBV-368
• Area Under Serum Concentration-Time Curve of ABBV-368 From Time 0 to the Time of Last Measurable Concentration (AUCt) [Cycle 1 through Cycle 3 (each cycle is approximately 28 days)]: Area Under Serum Concentration-Time Curve of ABBV-368 From Time 0 to the Time of Last Measurable Concentration (AUCt)
• Terminal-Phase Elimination Rate Constant (β) of ABBV-368 [Cycle 1 through Cycle 3 (each cycle is approximately 28 days)]: Terminal-Phase Elimination Rate Constant (β) of ABBV-368
• Terminal Half-Life (t1/2) of ABBV-368 [Cycle 1 through Cycle 3 (each cycle is approximately 28 days)]: Terminal Half-Life (t1/2) of ABBV-368
• Maximum Plasma Concentration (Cmax) of Tilsotolimod [Cycle 1 through Cycle 3 (each cycle is approximately 28 days)]: Maximum Observed Plasma Concentration (Cmax) of Tilsotolimod
• Time to Maximum Plasma Concentration (Tmax) of Tilsotolimod [Cycle 1 through Cycle 3 (each cycle is approximately 28 days)]: Time to Maximum Plasma Concentration (Tmax) of Tilsotolimod
• Area Under Plasma Concentration-Time Curve of Tilsotolimod From Time 0 to the Time of Last Measurable Concentration (AUCt) [Cycle 1 through Cycle 3 (each cycle is approximately 28 days)]: Area Under Plasma Concentration-Time Curve of Tilsotolimod From Time 0 to the Time of Last Measurable Concentration (AUCt)
• Terminal-Phase Elimination Rate Constant (β) of Tilsotolimod [Cycle 1 through Cycle 3 (each cycle is approximately 28 days)]: Terminal-Phase Elimination Rate Constant (β) of Tilsotolimod
• Terminal Half-Life (t1/2) of Tilsotolimod [Cycle 1 through Cycle 3 (each cycle is approximately 28 days)]: Terminal Half-Life (t1/2) of Tilsotolimod
• Maximum Observed Serum Concentration (Cmax) of ABBV-181 (Arm 3 Only) [Cycle 1 through Cycle 3 (each cycle is approximately 28 days)]: Maximum Observed Serum Concentration (Cmax) of ABBV-181
• Time to Maximum Serum Concentration (Tmax) of ABBV-181 (Arm 3 Only) [Cycle 1 through Cycle 3 (each cycle is approximately 28 days)]: Time to Maximum Serum Concentration (Tmax) of ABBV-181
• Area Under Serum Concentration-Time Curve of ABBV-181 From Time 0 to the Time of Last Measurable Concentration (AUCt) (Arm 3 Only) [Cycle 1 through Cycle 3 (each cycle is approximately 28 days)]: Area Under Serum Concentration-Time Curve of ABBV-181 From Time 0 to the Time of Last Measurable Concentration (AUCt)
• Terminal-Phase Elimination Rate Constant (β) of ABBV-181 (Arm 3 Only) [Cycle 1 through Cycle 3 (each cycle is approximately 28 days)]: Terminal-Phase Elimination Rate Constant (β) of ABBV-181
• Terminal Half-Life (t1/2) of ABBV-181 (Arm 3 Only) [Cycle 1 through Cycle 3 (each cycle is approximately 28 days)]: Terminal Half-Life (t1/2) of ABBV-181

Secondary outcomes

• Objective Response Rate (ORR) [Up to approximately 2 years following the first dose]: ORR is measured as the percentage of participants with a complete response (CR) or partial response (PR) as a confirmed response.
• Clinical Benefit Rate (CBR) [Up to approximately 2 years following the first dose]: CBR is measured as the percentage of participants with a confirmed complete response (CR), confirmed partial response (PR), or stable disease (SD)
• Time to Response (TTR) [Up to approximately 2 years following the first dose]: TTR is the time from date of first study drug exposure to the first instance of a complete response (CR) or partial response (PR) as a confirmed response, whichever occurs first.
• Progression Free Survival (PFS) [Up to approximately 2 years following the first dose]: PFS is the time from date of first study drug exposure to disease progression or death, whichever occurs first.
• Duration of Response (DOR) [Up to approximately 2 years following the first dose]: DOR is the time from the participant's initial response (CR or PR as a confirmed response) to disease progression or death, whichever occurs first.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Participants should weigh at least 35 kg.
* Eastern Cooperative Oncology Group performance status of 0 or 1 and a life expectancy of >= 3 months.
* Participant have >= 1 lesion accessible for intratumoral injection.
* Histologically or cytologically confirmed R/M HNSCC (of the following 4 subsites: oral cavity, oropharynx, larynx, and hypopharynx) who previously progressed either during or after <= 3 prior treatment regimens administered in the recurrent or metastatic setting.

  * Must have received 1 immunotherapy regimen which included a PD-(L)1 inhibitor.
  * Must have received platinum-based therapy, or be considered ineligible for platinum-based therapy by the investigator.

Exclusion Criteria:

* Uncontrolled metastases to the central nervous system (CNS).

  * Participants with brain metastases are eligible provided that evidence of clinical and radiographic stable disease for at least 4 weeks after definitive therapy is given and participants have not used prohibited levels of steroids for at least 4 weeks prior to first dose of the study.
* Received prior treatment with OX40 or toll-like receptor (TLR) agonists (excluding topical agents).

• Results publication: Daste A, Le X, Makkouk A, Patel M, Le Tourneau C, Perets R, Popovtzer A, Ochsenreither S, Haderlein M, Oliva M, Sukari A, Hong J, Blaney M, Ramathal C, McDevitt M, Rosenberg AJ. Phase 1b study of ABBV-368, tilsotolimod, budigalimab, and nab-paclitaxel in patients with recurrent/metastatic head and neck squamous cell carcinoma. J Immunother Cancer. 2026 Apr 9;14(4):e014086. doi: 10.1136/jitc-2025-014086. PMID 41956545

• ABBVIE INC., Study director, AbbVie

NIH grants: 2019