Safety Study of Enoblituzumab (MGA271) in Combination With Pembrolizumab or MGA012 in Refractory Cancer

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety of enoblituzumab (MGA271) in combination with Keytruda (pembrolizumab) when given to patients with B7-H3-expressing melanoma, squamous cell carcinoma of the head and neck (SCCHN), non small cell lung cancer (NSCLC), Urothelial Cancer and other B7-H3 expressing cancers. The study will also evaluate what is the highest dose of enoblituzumab that can be given safely when given with pembrolizumab. Assessments will also be done to see how the drug acts in the body (pharmacokinetics (PK), pharmacodynamics) and to evaluate potential anti-tumor activity of MGA271 in combination with pembrolizumab. Safety and efficacy of enoblituzumab in combination with MGA012 (anti-PD-1 monoclonal antibody; also known as INCMGA00012) will also be evaluated.

Official Title
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A Phase 1, Open-Label, Dose Escalation Study of MGA271 in Combination With Pembrolizumab and in Combination With MGA012 in Patients With Melanoma, Squamous Cell Cancer of the Head and Neck, Non-Small Cell Lung Cancer, Urothelial Cancer, and Other Cancers

Conditions
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Urethelial Carcinoma, Melanoma, Head and Neck Cancer, Non Small Cell Lung Cancer

Intervention / Treatment
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* Biological: Enoblituzumab
* Biological: Pembrolizumab
* Biological: MGA012


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically-proven, unresectable, locally advanced or metastatic melanoma, SCCHN, NSCLC, and other cancers that express B7-H3. Melanoma that has progressed during or following at least 1 and up to 5 prior systemic treatments for unresectable locally advanced or metastatic disease, or melanoma patients who are intolerable of or have refused standard cancer therapy. Pre- and on-study biopsy required. SCCHN that has progressed during or following at least 1 and up to 5 prior systemic treatments for metastatic or recurrent disease deemed to be incurable. Patient who refuse radical resection for recurrent disease or are intolerant of or refused standard first line therapy are eligible to enroll NSCLC that has progressed during or following 1 - 5 prior systemic therapies for unresectable locally advanced or metastatic disease (at least one docetaxel, gemcitabine, or platinum analogue based therapy), or are intolerant of or refused standard cancer therapy. For squamous cell carcinoma, or adenocarcinoma without known activating mutation: the prior systemic therapy is at least one platinum analogue. For adenocarcinoma with known activating driver mutation: the prior systemic therapy is at least TKI directed Urothelial cancer arising in the bladder, renal pelvis, ureter or urethra that has progressed during or following at least 1 and up to 5 prior systemic treatments for unresectable locally advanced or metastatic disease (includes anti-PD-L1,anti-PD-1, but excludes other experimental therapies). Patients must have received at least one platinum-containing regimen (e.g., gemcitabine/cisplatin [GC], dose-dense methotrexate/vinblastine/doxorubicin/cisplatin [DDMVAC], or carboplatinum/gemcitabine). No more than 5 prior systemic regimens allowed. Measurable disease per RECIST 1.1 criteria Easter Cooperative Oncology Group (ECOG) performance status 0 or 1 Acceptable laboratory parameters and adequate organ reserve. Exclusion Criteria: Patients with a history of symptomatic central nervous system metastases, unless treated and asymptomatic Patients with history of autoimmune disease with certain exceptions such as vitiligo, resolved childhood atopic dermatitis, psoriasis not requiring systemic therapy within the past 2 years, patients with history of Grave's disease that are now euthyroid clinically and by lab testing History of allogeneic bone marrow, stem cell, or solid organ transplant Treatment with systemic cancer therapy or investigational therapy within 4 weeks of first study drug administration; radiation within 2 weeks; corticosteroids (greater than or equal to 10 mg prednisone or equivalent per day) or other immune suppressive drugs within 2 weeks of first study drug administration Trauma or major surgery within 4 weeks of first study drug administration History of clinically-significant cardiovascular disease; gastrointestinal perforation; gastrointestinal bleeding, acute pancreatitis or diverticulitis within 4 weeks of first study drug administration Active viral, bacterial, or systemic fungal infection requiring parenteral treatment within 7 days of first study drug administration Known history of hepatitis B or C infection or known positive test for hepatitis B surface antigen or core antigen, or hepatitis C polymerase chain reaction (PCR) Known positive testing for human immunodeficiency virus or history of acquired immune deficiency syndrome Known hypersensitivity to recombinant proteins, polysorbate 80, or any excipient contained in the drug or vehicle formulation for MGA271 or pembrolizumab.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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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: enoblituzumab 3 mg/kg plus pembrolizumab 2 mg/kg<br>enoblituzumab 3 mg/kg IV weekly plus pembrolizumab 2 mg/kg IV every 3 weeks | Biological: Enoblituzumab<br>* enoblituzumab is administered by IV infusion once per week for up to 51 doses.<br>* Other names: MGA271;Biological: Pembrolizumab<br>* Pembrolizumab is administered by IV infusion every 3 weeks for up to 17 doses.<br>* Other names: Keytruda;|
| Experimental: Cohort 2: enoblituzumab 10 mg/kg plus pembrolizumab 2 mg/kg<br>enoblituzumab 10 mg/kg IV weekly plus pembrolizumab 2 mg/kg IV every 3 weeks | Biological: Enoblituzumab<br>* enoblituzumab is administered by IV infusion once per week for up to 51 doses.<br>* Other names: MGA271;Biological: Pembrolizumab<br>* Pembrolizumab is administered by IV infusion every 3 weeks for up to 17 doses.<br>* Other names: Keytruda;|
| Experimental: Cohort 3: enoblituzumab 15 mg/kg plus pembrolizumab 2 mg/kg<br>enoblituzumab 15 mg/kg IV weekly plus pembrolizumab 2 mg/kg IV every 3 weeks | Biological: Enoblituzumab<br>* enoblituzumab is administered by IV infusion once per week for up to 51 doses.<br>* Other names: MGA271;Biological: Pembrolizumab<br>* Pembrolizumab is administered by IV infusion every 3 weeks for up to 17 doses.<br>* Other names: Keytruda;|
| Experimental: Cohort 4: enoblituzumab 15 mg/kg plus MGA012 375 mg<br>enoblituzumab 15 mg/kg IV weekly plus MGA012 375 mg | Biological: Enoblituzumab<br>* enoblituzumab is administered by IV infusion once per week for up to 51 doses.<br>* Other names: MGA271;Biological: MGA012<br>* anti-PD-1 monoclonal antibody<br>* Other names: INCMGA00012;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events | Adverse Events, Serious Adverse Events | one year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak plasma concentration | PK of MGA271 in combination with pembrolizumab | 7 weeks | 
| Number of participants that develop anti-drug antibodies | Proportion of patients who develop anti-MGA271 antibodies, immunogenicity | One year | 
| Change in tumor volume RECIST 1.1 criteria | Anti-tumor activity of MGA271 in combination with pembrolizumab and in combination with MGA012 using both conventional RECIST 1.1. | Weeks 6, 15, 24, 33, 42, 51 | 
| Change in tumor volume using immune-related RECIST criteria | Anti-tumor activity of MGA271 in combination with pembrolizumab and in combination with MGA012 using immune-related RECIST criteria. | Weeks 6, 15, 24, 33, 42, 51 |