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

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.

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 chilhood 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.

This study is a Phase 1 open-label, dose escalation, cohort expansion, and efficacy follow-up study of enoblituzumab administered intravenously (IV) on a weekly schedule for up to 51 doses in combination with IV pembrolizumab administered on an every-3-week schedule for up to 17 doses. The dose escalation phase is designed to characterize the safety and tolerability of the combination of enoblituzumab and pembrolizumab and to define the maximum tolerated or maximum administered dose (MTD/MAD). Patients with methothelioma, urethelial cancer, NSCLC, SCCHN, clear cell renal cell carcinoma (ccRCC), ovarian cancer, melanoma, thyroid cancer, triple negative breast cancer (TBNC), pancreatic cancer, colon cancer, soft tissue sarcoma, or prostate cancer will be enrolled in this study phase. An additional dose escalation cohort of up to 15 patients is designed to characterize the safety and tolerability of the combination of enoblituzumab and MGA012 in patients with melanoma, SCCHN, NSCLC, urothelial cancer, and other cancers, and any dose level not exceeding the MTD may be expanded to further evaluate safety and efficacy of this combination. During the Cohort Expansion Phase, additional cohorts of patients with B7-H3 expressing unresectable, locally-advanced or metastatic melanoma (up to n=16), 2 cohorts of NSCLC (n= up to 20 in each cohort), 2 cohorts of SCCHN (up to n=20 in each cohort) or urothelial cancer (up to n=16) will be enrolled to receive MGA271 in combination with pembrolizumab at the MTD (or MAD) established from the Dose Escalation Phase of the study. The efficacy follow-up period consists of the 2-year period after the final dose of study drug. All tumor evaluations will be carried out by both Response Evaluation Criteria in Solid Tumors (RECIST) and immune-related response criteria (irRC).

Lead Organization
MacroGenics Inc