Details
Title A Phase 1 Study to Assess Safety and Tolerability of REGN1979, an Anti-CD20 x Anti-CD3 Bispecific Monoclonal Antibody, and REGN2810, an Anti-Programmed Death-1 Monoclonal Antibody, in Patients with B-Cell Malignancies
IRB REGE1416
CC 16-833
Hospital Main Campus
Phase Phase 1
Disease Lymphoma - Diffuse Large B Cell, Lymphoma - Non - Hodgkin
Drug REGN1979 , REGN2810
Description
Primary Objective- To assess safety, tolerability and dose-limiting toxicity (DLT) of single-agent REGN2810 in patients with lymphoma.
- To determine a recommended dose for:
- REGN2810 as a single-agent in patients with lymphoma
- To characterize the pharmacokinetic (PK) profile of REGN2810 when administered to patients with lymphoma
- To assess the immunogenicity of REGN2810
- To study the preliminary antitumor activity of REGN2810 when administered to patients with lymphoma, as measured by overall response rate, duration of response, progression-free survival, median, and rate at 6 and 12 months; MRD for patients with bone marrow involvement at baseline.
- Observed toxicity, and potential antitumor activity including, but not limited to:
- Cytokine profiling
- Peripheral blood B- and T-cell subsets and immune phenotyping
- Changes in gene expression in peripheral blood
- Serum immunoglobulin
- Analysis of PD-1 occupancy on circulating T-cells
Inclusion Criteria
- Hematologic malignancy defined by either:
- B-NHL per WHO 2008 criteria (Campo 2011) (Appendix 5)
- Documented HL, per WHO 2008 criteria (Campo 2011), with active disease not responsive to prior therapy or relapsed after prior therapy for whom no standard of care options exist (Appendix 5)
- All patients must have at least 1 bi-dimensionally measurable lesion (≥1.5 cm) documented by diagnostic imaging (CT or MRI).
- Age ≥18 years
- Eastern Cooperative Oncology Group (ECOG) performance status ≤1
- Life expectancy of at least 6 months
- Adequate bone marrow function documented by:
- Platelet counts ≥75 x 109/L
- Hemoglobin level ≥9 g/dL
- ANC ≥1 x 109/L
NOTE: Patients with cell counts below thresholds listed above may be considered for enrollment if, in the opinion of the investigator, the reason is believed to be due to current bone marrow infiltration by underlying malignancy. In such cases, the investigator must discuss the eligibility with the sponsor and receive approval for enrollment in writing.
- Adequate hepatic function:
- Total bilirubin ≤1.5 x upper limit of normal (ULN) (≤3 x ULN if liver involvement)
- Transaminases ≤2.5 x ULN (≤5 x ULN if liver involvement)
- Alkaline phosphatase ≤2.5 x ULN (≤5 x ULN if liver involvement)
NOTE: Patients with liver involvement of their malignancy with concomitant 3 x ULN ≤ aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤5 x ULN AND 1.5 x ULN ≤ total bilirubin ≤3 x ULN will be excluded.
NOTE: Patients with Gilbert's syndrome do not need to meet this requirement provided their total bilirubin is unchanged from their baseline.
NOTE: Patients may be considered for enrollment if, in the opinion of the investigator, the abnormal laboratory results are due to current underlying malignancy. In such cases, the investigator must discuss the eligibility with the sponsor and receive approval for enrollment in writing.
- Serum creatinine ≤1.5 x ULN or calculated creatinine clearance by Cockcroft-Gault ≥50 mL/min
NOTE: Patients with creatinine clearance by Cockcroft-Gault that does not meet criteria may be considered for enrollment if a measured creatinine clearance (based on 24-hour urine or other reliable method) is ≥50 mL/min.
NOTE: Patients may be considered for enrollment if, in the opinion of the investigator, the abnormal laboratory results are due to current underlying malignancy. In such cases, the investigator must discuss the eligibility with the sponsor and receive approval for enrollment in writing.
- Normal cardiac ejection fraction by pretreatment MUGA or echocardiogram within 4 weeks prior to enrollment within the normal range of values for the institution
- Willingness to undergo mandatory tumor biopsy pretreatment, if in the opinion of the investigator, the patient has an accessible lesion that can be biopsied without significant risk to the patient
- Willing and able to comply with clinic visits and study-related procedures
- Provide signed informed consent
Exclusion Criteria
- Primary central nervous system (CNS) lymphoma, or known or suspected CNS involvement by nonprimary CNS NHL
- History of or current relevant CNS pathology such as:
- Epilepsy, seizure, paresis, aphasia, apoplexia, severe brain injuries, cerebellar disease, organic brain syndrome, psychosis, or
- Evidence for presence of inflammatory lesions and/or vasculitis on cerebral MRI during screening
- Ongoing or recent (within 2 years) evidence of significant autoimmune disease that required treatment with systemic immunosuppressive treatments, which may suggest risk for iAEs
- Standard anti-lymphoma chemotherapy (nonbiologic) or radiotherapy within 28 days prior to first administration of study drug(s)
- Treatment with an investigational nonbiologic agent within 28 days prior to first administration of study drug(s)
- Treatment with alemtuzumab within 12 weeks prior to first administration of study drug
- Treatment with rituximab, immune-modulating agents or other investigational or commercial biologic agent within 28 days prior to first administration of study drug(s). Examples of immune-modulating agents include blockers of CTLA-4, 4-1BB (CD137), LAG3, OX-40, therapeutic vaccines, or cytokine treatments.
- Prior allogeneic stem cell transplantation
- Prior treatment with an agent that blocks the PD-1/PD-L1 pathway, unless the patient demonstrated benefit
NOTE: Patients previously treated with an agent that blocks the PD-1/PD-L1 pathway may be eligible if the patient has demonstrated clinical benefit with previous treatment. Such patients should be discussed with the sponsor's medical monitor before enrollment.
- Concurrent active malignancy for which the patient is receiving treatment.
- Evidence of significant concurrent disease or medical condition that could interfere with the conduct of the study, or put the patient at significant risk including, but not limited to, significant cardiovascular disease (eg, New York Heart Association Class III or IV cardiac disease, myocardial infarction within 6 months prior to screening, unstable arrhythmias or unstable angina) and/or significant pulmonary disease (eg, obstructive pulmonary disease and history of symptomatic bronchospasm)
- Known active bacterial, viral, fungal, mycobacterial or other infection or any major episode of infection requiring hospitalization or treatment with IV anti-infectives within 14 days prior to first administration of study drug
- Infection with human immunodeficiency virus (HIV) and/or chronic/active infection with hepatitis B virus or hepatitis C virus.
- History of pneumonitis within the last 5 years.
- History of allergic reactions attributed to compounds of similar chemical or biologic composition of study drug(s)
- History of hypersensitivity to any compound in the tetracycline antibiotics group (precaution due to potential presence of trace components in study drug material)
- Known hypersensitivity to both allopurinol and rasburicase
- Pregnant or breastfeeding women
- Sexually active men or women of childbearing potential who are unwilling to practice adequate contraception during the study and up to 6 months after discontinuation of study medication (adequate contraceptive measures include stable use of oral contraceptives such as combined estrogen and progestogen, progestogen only hormonal contraception or other prescription pharmaceutical contraceptives for 2 or more menstrual cycles prior to screening; intrauterine device; intrauterine hormone-releasing system; bilateral tubal ligation; vasectomy; and sexual abstinence)
