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
Brief SummaryThe primary goal of this Phase 1 study is to characterize the safety and tolerability of MGD013 and establish the maximum tolerated dose (MTD) of MGD013. Pharmacokinetics (PK), immunogenicity, pharmacodynamics (PD), and the anti-tumor activity of MGD013 will also be assessed.
Detailed DescriptionThis is a Phase 1, open-label, dose escalation and cohort expansion study designed to characterize the safety, tolerability, PK, PD, immunogenicity, and preliminary antitumor activity of MGD013 administered by IV infusion every 2 weeks. The study consists of a Dose Escalation Phase to determine the MTD or maximum administered dose (MAD) of MGD013 if no MTD is defined, followed by a Cohort Expansion Phase to further define the safety and initial antitumor activity of MGD013 with the dose established in the Dose Escalation Phase. In the Dose Escalation Phase, MGD013 will be evaluated in sequential escalating flat doses in successive cohorts of 1 to 6 patients each. Upon completion of the Dose Escalation Phase, a Cohort Expansion Phase will be initiated at the MTD/MAD. Patients with unresectable, locally advanced or metastatic solid tumors of any histology will be enrolled in the Dose Escalation Phase. The Cohort Expansion Phase will be limited to selected cohorts of patients with unresectable, locally advanced or metastatic solid tumors or hematologic malignancies for whom there is no available therapy likely to confer clinical benefit. Two additional cohorts will enroll patients with gastric/gastroesophageal cancer or epithelial ovarian cancer, with MGD013 given every 3 weeks. A separate cohort will evaluate the combination of MGD013 with margetuximab (anti-HER2 monoclonal antibody) in approximately 99 patients, in subgroups with HER2-positive gastric or gastroesophageal cancer, HER2-positive breast cancer, and any other HER2-positive cancer.
Inclusion and Exclusion 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 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
- 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.
- 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
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