A Study of MGD013 in Patients With Unresectable or Metastatic Neoplasms

Study Overview
=================
Brief Summary
-----------------
The primary goal of this Phase 1 study is to characterize the safety and tolerability of tebotelimab and establish the maximum tolerated dose (MTD) of tebotelimab in advanced solid tumors, and tebotelimab in combination with margetuximab in HER2+ advanced solid tumors. Pharmacokinetics (PK), immunogenicity, pharmacodynamics (PD), and the anti-tumor activity of tebotelimab will also be assessed.

Official Title
-----------------
A Phase 1, First-in-Human, Open-Label, Dose Escalation Study of MGD013, A Bispecific DART® Protein Binding PD-1 and LAG-3 in Patients With Unresectable or Metastatic Neoplasms

Conditions
-----------------
Advanced Solid Tumors, Hematologic Neoplasms, Ovarian Cancer, HER2-positive Advanced Solid Tumors, Non Small Cell Lung Cancer, Small-cell Lung Cancer, Squamous Cell Carcinoma of Head and Neck, Cholangiocarcinoma, Cervical Cancer, TNBC - Triple-Negative Breast Cancer

Intervention / Treatment
-----------------
* Biological: tebotelimab 1 mg
* Biological: tebotelimab 3 mg
* Biological: tebotelimab 10 mg
* Biological: tebotelimab 30 mg
* Biological: tebotelimab 120 mg
* Biological: tebotelimab 300 mg
* Biological: tebotelimab 400 mg
* Biological: tebotelimab 600 mg
* Biological: tebotelimab 800 mg
* Biological: tebotelimab 1200 mg
* Biological: margetuximab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically proven, locally advanced unresectable or metastatic solid tumors (or hematologic malignancies, Cohort Expansion only) for whom no approved therapy with demonstrated clinical benefit is available or standard treatment was declined. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Life expectancy ≥ 12 weeks Measurable disease Tissue specimen available for retrospective analysis of PD-1, PD-L1, LAG-3, and MHC-II expression Acceptable laboratory parameters HER2+ Cohort: - Locally advanced or metastatic HER2+ locally advanced or metastatic solid tumors, regardless of organ of origin. i. The cancer must have progressed following standard therapy, or has progressed during or after HER2-directed therapy if approved and available for patients with HER2+ breast, gastric, or gastroesophageal junction cancer. ii. History of HER2 positivity defined as 3+ by IHC or 2+ by Immunohistochemistry (IHC) in combination with in situ hybridization (ISH) positivity most recent tumor biopsy. All patients in the HER2+ cohort must be willing to provide consent for a baseline and on-treatment tumor biopsy during the screening period and within 14 days prior to Cycle 3 Day 1. Exceptions may be made based on a medical contraindication at the discretion of the Sponsor's Medical Monitor. This requirement will be discontinued after an adequate number of samples are collected, as determined by the Sponsor. Exclusion Criteria: Symptomatic central nervous system (CNS) metastases or primary CNS lymphoma History of allogeneic bone marrow, stem-cell, or solid organ transplant History of known or suspected autoimmune disease with the specific exceptions of vitiligo, resolved childhood atopic dermatitis, psoriasis not requiring systemic treatment (within the past 2 years), and patients with a history of Grave's disease that are now euthyroid clinically and by laboratory testing. Treatment with any systemic chemotherapy within 3 weeks prior to the initiation of study drug; treatment with biologics or investigational therapy within the 4 weeks prior to the initiation of study drug. Major surgery within 4 weeks prior to the initiation of study drug. Prior treatment with combination of monoclonal antibodies against PD-1 and LAG-3 (Cohort Expansion only). Treatment with radiation therapy within 2 weeks prior to the initiation of study drug. Clinically significant cardiovascular disease. QTcF prolongation > 480 milliseconds HER2+ cohort: left ventricular ejection fraction less than 50% Clinically significant pulmonary compromise, including a requirement for supplemental oxygen use to maintain adequate oxygenation. Active pneumonitis or history of non-infectious pneumonitis. Clinically significant gastrointestinal disorders. Evidence of active viral, bacterial, or systemic fungal infection requiring parenteral treatment within 7 days prior to the initiation of study drug. Known history of positive testing for human immunodeficiency virus or history of acquired immune deficiency syndrome. Known history of hepatitis B (except in hepatocellular carcinoma) or hepatitis C infection or known positive test for hepatitis B surface antigen, hepatitis B core antigen, or hepatitis C polymerase chain reaction (PCR) Vaccination with any live virus vaccine within 4 weeks prior to the initiation of study drug administration. Inactivated annual influenza vaccination is allowed Dementia or altered mental status that would preclude understanding and rendering of informed consent Confirmed or presumed COVID-19/SARS-CoV-2 infection. While SARS-CoV-2 testing is not mandatory for study entry, testing should follow local clinical practice guidelines/standards. Patients with a positive test result for SARS-CoV-2 infection, known asymptomatic infection, or presumed infection are excluded. Patients may be considered eligible after a resolved SARS-CoV-2 infection once he or she remains afebrile for at least 72 hours and after other SARS-CoV-2-related symptoms have fully recovered to baseline for a minimum of 72 hours.

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tebotelimab: 1 mg<br> | Biological: tebotelimab 1 mg<br>* 1 mg IV every other week<br>* Other names: MGD013;|
| Experimental: Tebotelimab 3 mg<br> | Biological: tebotelimab 3 mg<br>* 3 mg IV every other week<br>* Other names: MGD013;|
| Experimental: Tebotelimab: 10 mg<br> | Biological: tebotelimab 10 mg<br>* 10 mg IV every other week<br>* Other names: MGD013;|
| Experimental: Tebotelimab: 30 mg<br> | Biological: tebotelimab 30 mg<br>* 30 mg IV every other week<br>* Other names: MGD013;|
| Experimental: Tebotelimab: 120 mg<br> | Biological: tebotelimab 120 mg<br>* 120 mg IV every other week<br>* Other names: MGD013;|
| Experimental: Tebotelimab: 400 mg<br> | Biological: tebotelimab 400 mg<br>* 400 mg IV every other wee<br>* Other names: MGD013;|
| Experimental: Tebotelimab: 600 mg<br> | Biological: tebotelimab 600 mg<br>* 600 mg IV every other week<br>* Other names: MGD013;|
| Experimental: Tebotelimab: 800 mg<br> | Biological: tebotelimab 800 mg<br>* 800 mg IV every other week<br>* Other names: MGD013;|
| Experimental: Tebotelimab: 1200 mg<br> | Biological: tebotelimab 1200 mg<br>* 1200 mg IV every other week<br>* Other names: MGD013;|
| Experimental: Combination cohort 1<br>Tebotelimab and margetuximab | Biological: tebotelimab 300 mg<br>* 300 mg IV every other wee<br>* Other names: MGD013;Biological: margetuximab<br>* 15 mg/kg IV every 3 weeks<br>* Other names: Margenza;|
| Experimental: Combination Cohort 2<br>Tebotelimab and margetuximab | Biological: tebotelimab 600 mg<br>* 600 mg IV every other week<br>* Other names: MGD013;Biological: margetuximab<br>* 15 mg/kg IV every 3 weeks<br>* Other names: Margenza;|
| Experimental: Monotherapy Cohort Expansion<br>Monotherapy expansion at 600 mg | Biological: tebotelimab 600 mg<br>* 600 mg IV every other week<br>* Other names: MGD013;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with Treatment-Emergent Adverse Events (TEAE) as assessed by CTCAE v4.03 (tebotelimab monotherapy) | Safety Safety is based on evaluation of adverse events (AEs) and serious adverse events (SAEs) from the time of study drug administration through the End of Study visit. | up to 24 months | 
| Number of participants with Treatment-Emergent Adverse Events as assessed by CTCAE v4.03 (tebotelimab plus margetuximab) | Safety | up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Plasma Concentration versus Time Curve (AUC) of tebotelimab | AUC | From Day 1 to Day 15 after the first and second doses | 
| Maximum Plasma Concentration (Cmax) of tebotelimab and tebotelimab plus margetuximab | Cmax | At the end of infusion on Study Days 1, 15, 29 and 43 in Cycles 1 and 2 and on Study Day 1 for all subsequent cycles until treatment discontinuation, up to 2 years | 
| Time to reach maximum (peak) plasma concentration (Tmax) of tebotelimab and tebotelimab plus margetuximab | Tmax | At the end of infusion on Study Days 1, 15, 29 and 43 in Cycles 1 and 2 and on Study Day 1 for all subsequent cycles until treatment discontinuation, up to 2 years | 
| Trough plasma concentration (Ctrough) of tebotelimab | Ctrough | Study Days 1, 15, 29, 43 in Cycles 1 and 2 and Day 1 of each subsequent cycle s until treatment discontinuation, up to 2 years | 
| Total body clearance of the drug from plasma (CL) of tebotelimab | CL | Cycle 1 Day 1 out to Cycle 1 Day 15 | 
| Apparent volume of distribution at steady state (Vss) of tebotelimab | Vss | Cycle 1 Day 1 out to Cycle 1 Day 15 | 
| Terminal half-life (t1/2) of tebotelimab | t1/2 | Cycle 1 Day 1 out to Cycle 1 Day 15 | 
| Number of patients with anti-drug antibody | immunogenicity | Study Day 1, 15, 29, 57, 85, 113, then every 56 days up to 2 years Tebotelimab plus margetuximab: Day 1, 22, 43, and then every 6 weeks until treatment discontinuation | 
| Objective response rate (ORR) | ORR is the percentage of participants who have a complete response or a partial response to treatment. | Throughout the study, up to 4 years. | 
| Median Duration of response (DoR) | DoR is defined as the time from the date of initial response (CR or PR) to the date of first documented PD or death from any cause, whichever occurs first. Median DoR is the time when 50% of responders are still in response. | Throughout the study, up to 4 years. | 
| Progression-free survival (PFS) | PFS is defined as the time from the first dose date to the date of first documented PD or death from any cause, whichever occurs first. Median PFS is the time when 50% of participants remain free of PD or death. | Throughout the study, up to 4 years. | 
| Median Overall survival (OS) | OS is defined as the time from the first dose date to the date of death from any cause. Median OS is the time when 50% of participants are still alive. | Throughout the study, up to 4 years. |