Enoblituzumab Plus Retifanlimab or Tebotelimab in Head and Neck Cancer

Study Overview
=================
Brief Summary
-----------------
This is a Phase 2 study of enoblituzumab combined with either retifanlimab or tebotelimab administered as first-line treatment to patients with recurrent or metastatic squamous cell carcinoma of the head and neck.

Official Title
-----------------
A Phase 2 Open-Label Trial to Evaluate Enoblituzumab in Combination With Retifanlimab or Tebotelimab in the First-Line Treatment of Patients With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck

Conditions
-----------------
Head and Neck Cancer, Head and Neck Neoplasms, Head and Neck Squamous Cell Carcinoma

Intervention / Treatment
-----------------
* Biological: Enoblituzumab
* Biological: Retifanlimab
* Biological: Tebotelimab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically proven, recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) not curable by local therapy No prior systemic therapy for SCCHN in the recurrent or metastatic setting (with the exception of systemic therapy completed > 6 months prior if given as part of multimodal treatment for locally advanced disease) Primary tumor locations of oropharynx, oral cavity, hypopharynx, or larynx. Patients may not have a primary tumor site of upper esophagus, salivary gland, or nasopharynx (any histology) Availability of formalin-fixed, paraffin embedded tumor specimen or contemporary biopsy for immunohistochemical evaluation of pharmacodynamic markers of interest Willing to consent for baseline and on-treatment biopsy. Performance status 0 or 1 Life expectancy of 6 months or more Adequate end organ function At least one radiographically measurable lesion PD-L1 expression level that is either Positive (combined positive score [CPS] ≥ 1) for the retifanlimab cohort, or Negative (CPS < 1) for the tebotelimab cohort Results available from human papilloma virus p16 status for oropharyngeal cancer Acceptable laboratory results Exclusion Criteria: Disease suitable for local therapy administered with curative intent Progressive disease within 6 months of completion of curatively intended systemic treatment for locoregionally advanced SCCHN Radiation or other non-systemic therapy within 2 weeks prior to the first dose of study drug Prior therapy with an anti-B7-H3, anti-PD-1, anti-PD-L1, or anti-LAG-3 agent

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
Interventional Model Description: Enrollment into each cohort will occur independently in a non-randomized fashion, based on PD-L1 expression results. Patients may not crossover between cohorts.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Retifanlimab Cohort<br>Enoblituzumab 15 mg/kg every 3 weeks plus retifanlimab 375 mg every 3 weeks for up to 35 cycles | Biological: Enoblituzumab<br>* Anti-B7-H3 antibody<br>* Other names: MGA271;Biological: Retifanlimab<br>* Anti-PD-1 antibody<br>* Other names: Zynyz;|
| Experimental: Tebotelimab Cohort<br>Enoblituzumab 15 mg/kg every 3 weeks plus tebotelimab 600 mg every 3 weeks for up to 35 cycles | Biological: Enoblituzumab<br>* Anti-B7-H3 antibody<br>* Other names: MGA271;Biological: Tebotelimab<br>* PD-1 X LAG-3 bispecific DART molecule<br>* Other names: MGD013;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) of Enoblituzumab Plus Retifanlimab | Investigator-assessed ORR. defined as the percentage of patients in the response evaluable population who achieve the best overall response of complete response (CR) or partial response (PR),per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 criteria.. CR is defined as disappearance of all target and non-target lesions. PR is defined as at least a 30% decrease from baseline in the sum of diameters of target lesions | Tumor assessment is conducted 6 weeks after the first dose, then every 9 weeks until disease progression, up to 16.5 months. | 
| Number of Patients With Adverse Events (AEs) Receiving Enoblituzumab Plus Tebotelimab |  | Throughout the study, up to 16.5 months. | 
| ORR of Enoblituzumab Plus Tebotelimab | Investigator-assessed ORR. ORR, defined as the percentage of patients in the response evaluable population who achieve the a best overall response of complete response (CR) or partial response (PR), per RECIST, version 1.1 criteria. CR is defined as disappearance of all target and non-target lesions. PR is defined as at least a 30% decrease from baseline in the sum of diameters of target lesions | Tumor assessment is conducted 6 weeks after the first dose, then every 9 weeks until disease progression, up to 16.5 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | Time from the first dose date to the date of first documented progression or death from any cause, whichever occurs first, evaluated by cohort | Tumor assessment is conducted 6 weeks after the first dose, then every 9 weeks until disease progression, up to 16.5 months | 
| Disease-control Rate (DCR) | Percentage of response-evaluable patients with CR, PR, or stable disease (SD) for at least 3 months, evaluated by cohort | Tumor assessment is conducted 6 weeks after the first dose, then every 9 weeks until disease progression, up to 16.5 months | 
| Duration of Response | Time from the date of initial response (CR or PR) to the date of first documented progression or death from any cause, whichever occurs first, evaluated by cohort | Tumor assessment is conducted 6 weeks after the first dose, then every 9 weeks until disease progression, up to 16.5 months | 
| Overall Survival | Time from the first dose date to the date of death from any cause, evaluated by cohort | up to 16.5 months | 
| Best Overall Response (BOR) | The participants best response to treatment during their study participation. Responses are categorized as CR, PR, stable disease (SD), progressive disease (PD), or not evaluated (NE), per RECIST 1.1 criteria CR is defined as disappearance of all target and non-target lesions. PR is defined as at least a 30% decrease from baseline in the sum of diameters of target lesions, and non-PD in non-target lesions PD is defined as at least a 20% increase from nadir in the sum of diameters of target lesions or unequivocal progression in non-target lesions SD is defined as non-PD in target and non-target lesions | Tumor assessment is conducted 6 weeks after first dose, then every 9 weeks until disease progression, up to 16.5 months | 
| Number of Patients With AEs Receiving Enoblituzumab Plus Retifanlimab |  | Throughout the study, up to 16.5 months. | 
| Maximum Drug Concentration or Drug Concentration of Enoblituzumab at the End of Infusion of Enoblituzumab (Cmax) | The highest measured concentration of enoblituzumab in the bloodstream. | Cycle 1 Day 1: Pre-infusion, end of infusion (EOI [2 hours]), 4 hours after EOI; Cycle 1 Days 2, 3, 8 and 15 at any time; On Day 1 of Cycles 2, 3, 4, 5 and 6: Pre-infusion and EOI (each cycle is 21 days) | 
| Maximum Drug Concentration or Drug Concentration of Tebotelimab at the End of Infusion of Tebotelimab (Cmax) | The highest measured concentration of tebotelimab in the bloodstream. | Cycle 1 Day 1: Pre-infusion, end of infusion (EOI [1 hour]), 4 hours after EOI; Cycle 1 Days 2, 3, 8 and 15 at any time; On Day 1 of Cycles 2, 3, 4, 5 and 6: Pre-infusion and EOI (each cycle is 21 days) | 
| Maximum Drug Concentration or Drug Concentration of Retifanlimab at the End of Infusion of Enoblituzumab (Cmax) | The highest measured concentration of retifanlimab in the bloodstream. | Cycle 1 Day 1: Pre-infusion, end of infusion (EOI [1 hour]), 4 hours after EOI; Cycle 1 Days 2, 3, 8 and 15 at any time; On Day 1 of Cycles 2, 3, 4, 5 and 6: Pre-infusion and EOI (each cycle is 21 days) | 
| Trough Concentration of Enoblituzumab (Ctrough or Cmin) | The amount of enoblituzumab left in the bloodstream before the next dose is given. | Cycle 1 Day 1: Pre-infusion, end of infusion (EOI [2 hours]), 4 hours after EOI; Cycle 1 Days 2, 3, 8 and 15 at any time; On Day 1 of Cycles 2, 3, 4, 5 and 6: Pre-infusion and EOI (each cycle is 21 days | 
| Trough Concentration of Tebotelimab (Ctrough or Cmin) | The amount of tebotelimab left in the bloodstream before the next dose is given. | Cycle 1 Day 1: Pre-infusion, end of infusion (EOI [1 hour]), 4 hours after EOI; Cycle 1 Days 2, 3, 8 and 15 at any time; On Day 1 of Cycles 2, 3, 4, 5 and 6: Pre-infusion and EOI (each cycle is 21 days) | 
| Trough Concentration of Retifanlimab (Ctrough or Cmin) | The amount of retifanlimab left in the bloodstream before the next dose is given. | Cycle 1 Day 1: Pre-infusion, end of infusion (EOI [1 hour]), 4 hours after EOI; Cycle 1 Days 2, 3, 8 and 15 at any time; On Day 1 of Cycles 2, 3, 4, 5 and 6: Pre-infusion and EOI (each cycle is 21 days) | 
| Number of Patients Who Develop Antidrug Antibodies (ADA) to Enoblituzumab. |  | Prior to treatment (baseline) and at the beginning of every 3-week cycle of treatment (post baseline) up to 16.5 months | 
| Number of Patients Who Develop ADA to Tebotelimab |  | Prior to treatment (baseline) and at the beginning of every 3-week cycle of treatment (post baseline) up to 16.5 months | 
| Number of Patients Who ADA to Retifanlimab |  | Prior to treatment (baseline) and at the beginning of every 3-week cycle of treatment (post baseline) up to 16.5 months |