Patient case: 86-year-old female with melanoma; genetic feature: high tumor mutational burden

Clinical trial: Safety Study of Enoblituzumab (MGA271) in Combination With Pembrolizumab in Refractory Cancer

Summary: 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), 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.

Detailed description: 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.
  In the cohort expansion phase, 3 cohorts of 16 patients each will be enrolled to further evaluate the safety and potential efficacy of the combination administered at the MTD/MAD dose in patients with melanoma, NSCLC, and SCCHN. Pre- and on-study biopsies are required for melanoma patients in the cohort expansion phase.
  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).

Eligibility: 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
  -  Mesothelioma that has progressed during or following at least 1 and up to 3 prior systemic treatments for unresectable locally advanced or metastatic disease. The prior systemic chemotherapy must have included a pemetrexed (anti-folate)-based regimen in combination with platinum agent. For patients in whom pemetrexed was contraindicated or not tolerated or not an approved therapy (e.g., peritoneal mesothelioma), prior therapy with a first-line platinum-based regimen is required.
  -  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.
  -  Thyroid cancer that has progressed during or following at least 1 and up to 5 prior chemotherapy regimen(s). Prior therapy excludes experimental therapies given in Phase 1 trials.
  -  Pancreatic cancer that has progressed during or following at least 1 and up to 3 prior chemotherapy regimens. Prior therapy excludes experimental therapies given in Phase 1 trials.
  -  Ovarian cancer that has progressed during or following at least 2 and up to 4 prior therapeutic regimens (e.g., 2 prior platinum containing regimens or if platinum resistant, a liposomal doxorubicin or topotecan containing regimen). Prior therapy excludes experimental therapies given in Phase 1 trials
  -  Colon cancer that has progressed during or following at least 2 and up to 4 prior therapeutic regimens (e.g., fluoropyrimidine and/or irinotecan and/or oxaliplatin and/or anti-EGFR antibody containing regimens). Prior therapy excludes experimental therapies given in Phase 1 trials.
  -  Prostate cancer that has progressed during or following at least 1 and up to 5 prior therapeutic regimens (e.g., abiraterone, enzalutamide, docetaxel). Prior therapy excludes experimental therapies given in Phase 1 trials.
  -  Soft tissue sarcoma that has progressed during or following at least 1 and up to 5 prior therapeutic regimens. Prior therapy excludes experimental therapies given in Phase 1 trials.
  -  TNBC that has progressed during or following at least 1 and up to 5 prior therapeutic regimens. Prior therapy excludes experimental therapies given in Phase 1 trials.
  -  ccRCC that has progressed during or following at least 1 and up to 5 prior therapeutic regimens. Prior therapy excludes experimental therapies given in Phase 1 trials.
  -  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.

Relevance to patient case: not relevant