MGD019 DART® Protein in Unresectable/Metastatic Cancer

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the safety and tolerability, pharmacokinetics (PK) pharmacodynamics and preliminary antitumor activity of lorigerlimab. This Phase 1, open-label study will characterize safety, dose-limiting toxicities (DLTs), and maximum tolerated/administered dose (MTD/MAD) of MGD019. Dose escalation will occur in a 3+3+3 design in patients with advanced solid tumors of any histology. Once the MTD/MAD is determined, a Cohort Expansion Phase will be enrolled to further characterize safety and initial anti-tumor activity in patients with specific tumor types anticipated to be sensitive to dual checkpoint blockade.

Official Title
-----------------
A Phase 1, First-in-Human, Open-Label, Dose Escalation and Cohort Expansion Study of MGD019, a Bispecific DART® Protein Binding PD-1 and CTLA-4 in Patients With Unresectable or Metastatic Neoplasms

Conditions
-----------------
Squamous Cell Non Small Cell Lung Cancer, Prostate Cancer Metastatic, Cutaneous Melanoma, Colorectal Cancer, Advanced Cancer, Solid Tumor, Adult

Intervention / Treatment
-----------------
* Biological: Lorigerlimab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Dose escalation: Patients with histologically proven, unresectable, locally advanced or metastatic solid tumors for whom no approved therapy with demonstrated clinical benefit is available or patients who are intolerant to standard therapy. Cohort Expansion Phase: Checkpoint inhibitor-naïve squamous cell NSCLC, including: Patients that have progressed during or following treatment with platinum-based chemotherapy for advanced disease. Patients harboring an activating epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) rearrangement must have progressed following at least one available EGFR or ALK targeted therapy. ROS1 rearrangement or BRAF mutation must have progressed following at least 1 available EGFR (including osimertinib for EGFR T790M-mutated NSCLC), ALK, ROS1 or BRAF targeted therapy, respectively Patients that have progressed during or following treatment with platinum-based chemotherapy for advanced disease and patients with previously untreated squamous cell NSCLC without activating mutations for whom checkpoint inhibitor therapy is not approved or available. Advanced non-microsatellite instability-high colorectal cancer (CRC) with recurrence, progression, or intolerance to standard therapy consisting of at least 2 prior standard regimens. CRC harboring an activating EGFR mutation must have progressed during or following at least one available EGFR targeted therapy. Patients who are inappropriate candidates for or have refused treatment with these regimens are also eligible. Patients should have received no more than 4 prior lines of systemic therapy. Checkpoint inhibitor-naïve mCRPC that has progressed during or following no more than 2 prior lines of an androgen receptor antagonist or androgen synthesis inhibitor (e.g., enzalutamide or abiraterone, respectively), if approved and available, with a PSA value of at least 2 ng/mL and meeting at least one of the following: Progression in measurable disease (RECIST v1.1). Appearance of 2 or more new bone lesions according to Prostate Cancer Working Group 2 (PCWG-2). Rising PSA defined as at least two sequential rises in PSA. Eligible patients may have received prior chemotherapy (i.e. docetaxel), and patients with known homologous recombination (HRR) pathway gene alterations must have received the applicable approved therapy (e.g. olaparib). Cutaneous melanoma that has progressed during or following systemic treatment for unresectable, locally advanced, or metastatic disease. Patients will have received PD-(L)1 and/or CTLA-4 pathway inhibitors where available and indicated. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 Life expectancy ≥ 12 weeks. Measurable disease as per RECIST 1.1 for the purpose of response assessment must either (a) not reside in a field that has been subjected to prior radiotherapy or (b) have demonstrated clear evidence of radiographic progression since the completion of prior radiotherapy and prior to study enrollment. All patients must have an identified formalin-fixed, paraffin embedded (FFPE) tumor specimen (up to 20 slides or a block) for immunohistochemical evaluation of pharmacodynamic markers of interest. Patients may undergo a fresh tumor biopsy during the screening period if a tumor sample is not available. Patients in the mCRPC expansion cohort with bone only disease not amenable to fresh biopsy may be eligible in consultation with the Sponsor. Acceptable laboratory parameters and adequate organ reserve. Exclusion Criteria: In patients who have previously received an immune checkpoint inhibitor (e.g., anti-PD-L1, anti-PD-1, anti-CTLA-4), toxicities related to the checkpoint inhibitor must have resolved to ≤ Grade 1 or baseline. Patients with well controlled immune endocrinopathies secondary to prior checkpoint therapy are eligible. Patients with symptomatic CNS metastases. Patients with history of prior CNS metastasis must have been treated, must be asymptomatic, and must not have concurrent treatment for the CNS disease, progression of CNS metastases on magnetic resonance imaging (MRI) or computed tomography (CT) for at least 14 days after last day of prior therapy for the CNS metastases, or concurrent leptomeningeal disease or cord compression. Patients who sustained the following Grade 3 immune checkpoint inhibitor related AEs are ineligible: Ocular AE, changes in liver function tests that met the criteria for Hy's law (> 3 × ULN of either ALT or AST with concurrent > 2 × ULN of total bilirubin and without alternate etiology), neurologic toxicity, colitis, renal toxicity, pneumonitis. Patients who have received prior therapy with a combination of monoclonal antibodies against PD-1/PD-L1 and CTLA-4 will be excluded in the Cohort Expansion (this does not apply to the melanoma expansion cohort). Patients with any history of known or suspected autoimmune disease with certain exceptions History of prior allogeneic bone marrow, stem-cell, or solid organ transplantation. History of trauma or major surgical procedure within 4 weeks prior to initiation of study drug administration. Systemic antineoplastic therapy, or investigational therapy (for all tumor types) or androgen receptor antagonist/androgen synthesis inhibitor for mCRPC (e.g., enzalutamide or abiraterone, respectively) within the 4 weeks prior to initiation of study drug administration. Treatment with radiation therapy within 2 weeks prior to initiation of study drug administration. Radioligand (e.g., radium-223) within 6 months prior to initiation of study drug administration for mCRPC in the Cohort Expansion Phase. Serum testosterone > 50 ng/dl or > 1.7 nmol/L for mCRPC in the Cohort Expansion Phase. 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: Cohort 1<br>0.03 mg/kg administered IV every 3 weeks. | Biological: Lorigerlimab<br>* Bispecific DART protein binding PD-1 and CTLA-4<br>* Other names: MGD019;|
| Experimental: Cohort 2<br>0.1 mg/kg administered IV every 3 weeks. | Biological: Lorigerlimab<br>* Bispecific DART protein binding PD-1 and CTLA-4<br>* Other names: MGD019;|
| Experimental: Cohort 3<br>0.3 mg/kg administered IV every 3 weeks. | Biological: Lorigerlimab<br>* Bispecific DART protein binding PD-1 and CTLA-4<br>* Other names: MGD019;|
| Experimental: Cohort 4<br>1.0 mg/kg administered IV every 3 weeks. | Biological: Lorigerlimab<br>* Bispecific DART protein binding PD-1 and CTLA-4<br>* Other names: MGD019;|
| Experimental: Cohort 5<br>30. mg/kg administered IV every 3 weeks. | Biological: Lorigerlimab<br>* Bispecific DART protein binding PD-1 and CTLA-4<br>* Other names: MGD019;|
| Experimental: Cohort 6<br>6.0 mg/kg administered IV every 3 weeks. | Biological: Lorigerlimab<br>* Bispecific DART protein binding PD-1 and CTLA-4<br>* Other names: MGD019;|
| Experimental: Cohort 7<br>10.0 mg/kg administered IV every 3 weeks. | Biological: Lorigerlimab<br>* Bispecific DART protein binding PD-1 and CTLA-4<br>* Other names: MGD019;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-emergent adverse events | 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. | 30 days after last dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax | Maximum Plasma Concentration of lorigerlimab | up to 108 weeks | 
| Tmax | Time to reach maximum (peak) plasma concentration of lorigerlimab | up to 108 weeks | 
| AUC | Area Under the Plasma Concentration versus Time Curve of lorigerlimab | up to 108 weeks | 
| Ctrough | Trough plasma concentration of lorigerlimab | up to 108 weeks | 
| CL | Total body clearance of the drug from plasma of lorigerlimab | up to 108 weeks | 
| Vss | Apparent volume of distribution at steady state of lorigerlimab | up to 108 weeks | 
| t1/2 | Terminal half life of lorigerlimab | up to 108 weeks | 
| Percent of patients with anti-drug antibodies against lorigerlimab | Immunogenicity | up to 108 weeks | 
| Objective response rate (ORR) | The number of participants who have a complete response (CR) or partial response (PR) to treatment. Efficacy assessed using conventional Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) | Every 12 weeks, up to 4 years | 
| 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 | Every 12 weeks until withdrawal of consent, lost to follow up, death, or end of 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. | Tumor status assessed every 12 weeks. Survival status is assessed approximately every 12 weeks after the last dose of study treatment until withdrawal of consent, lost to follow up, death, or end of the study, up to 4 years | 
| Overall survival (OS) | OS is defined as the time from the first dose date to the date of death from any cause. | OS status is assessed approximately every 12 weeks after the last dose of study treatment until withdrawal of consent, lost to follow up, death, or end of the study, up to 4 years | 
| Prostate specific antigen (PSA) response rate in mCRPC | Percent of patients with 50% or more decline in PSA and confirmed 3 weeks later | Every 3 weeks on treatment, then every 3 months up to 2 years post last treatment | 
| Best PSA percent change in mCRPC | Best percent change in PSA from baseline | Every 3 weeks on treatment, then every 3 months up to 2 years post last treatment | 
| Duration of PSA response | Time from PSA response to time of PSA progression | Every 3 weeks on treatment, then every 3 months up to 2 years post last treatment | 
| Radiographic progression-free survival (PFS) in metastatic castration-resistant prostate cancer (mCRPC) | Time from first dose to first occurrence of radiographic progression, or death | up to 2 years post last treatment | 
| Time to PSA progression in mCRPC | The time from the first dose of MGD019 to the first documented PSA progression. PSA progression is defined as an increase that is ≥ 25% and ≥ 2 ng/mL the baseline or lowest value observed, and which confirmed by a second value at least 3 weeks later | PSA is assessed every 3 weeks while on treatment, every 3 months for up to 2 years post-treatment |