Patient case: 48-year-old female with melanoma; genetic feature: tumor cells with >50% membranous PD-L1 expression

Clinical trial: Safety/Efficacy of MEDI-551 in Combination With Immunomodulating Therapies in Subjects With Aggressive B-cell Lymphomas

Summary: This is a Phase 1b/2 open-label study to evaluate the safety/efficacy of MEDI-551 + MEDI0680 (AMP-514) in participants with relapsed or refractory aggressive B-cell lymphomas who have failed 1-2 prior lines of therapy.
  The primary objectives are to determine the maximum tolerated dose (MTD) or highest protocol-defined dose (HPDD); in the absence of exceeding the MTD of MEDI-551 in combination with MEDI0680 (AMP-514); and to evaluate the safety, tolerability, and clinical activity of MEDI-551 in combination with MEDI0680 (AMP-514).

Detailed description: MEDI-551 is an IgG1k antibody-dependent cellular cytotoxicity (ADCC) enhanced anti-CD19 monoclonal antibody (mAb). MEDI0680 (AMP-514) a humanized IgG4κ mAb against programmed death-1 (PD-1) , blocks inhibitory PD-1 receptors (PD-L1) on T cells to augment immune responses. This study explores this novel combination regimen in patients with multiply relapsed or refractory aggressive B-cell lymphomas who have limited opportunities for cure, and may offer a regimen with less toxicity but equal or better efficacy versus traditional chemotherapy.
  The primary objectives are to determine the maximum tolerated dose (MTD) or highest protocol-defined dose (HPDD; in the absence of exceeding the MTD) of MEDI-551 in combination with MEDI0680 (AMP-514); and to evaluate the safety, tolerability, and clinical activity of MEDI-551 in combination with MEDI0680 (AMP-514). Secondary objective: to evaluate the pharmacokinetics and antidrug antibodies of MEDI-551 in combination with MEDI0680 (AMP-514) in patients with multiply relapsed or refractory aggressive B-cell lymphomas. Exploratory objectives will determine the impact of tumor programmed death-1 ligand (PD-L1) expression on clinical activity of the combination treatment and will follow soluble PD-1 and PD-L1 expression as biomarkers of activity.
  This study will determine the MTD or HPDD, safety, and activity of MEDI-551 in combination with MEDI0680 (AMP-514) in patients with multiply relapsed or refractory aggressive B-cell lymphomas who have failed 1-2 prior lines of therapy. Using a standard 3+3 design, 3 to 6 participants with relapsed or refractory aggressive B-cell lymphomas will be enrolled per cohort in the dose-escalation portion to determine the MTD of the combination of MEDI-551 with MEDI0680 (AMP-514). A maximum of 18 participants will be enrolled in the escalation portion of the study. Patients will receive MEDI-551 12 mg/kg once monthly with 1 of 3 possible doses of MEDI0680 (AMP-514) administered bimonthly for 1 year. If a patient experiences progressive disease after completing first year therapy, combination treatment may be resumed for up to 12 additional months. After MTD identification, additional patients will be enrolled in the dose expansion portion to ensure a total sample size of 26 efficacy-evaluable patients. Participants in the dose expansion portion will be adults with confirmed aggressive B-cell DLBCL only. Thirteen of 26 efficacy-evaluable patients receiving the MTD will be required to have PD-L1 expression. Patients will be stratified by refractoriness to chemotherapy, and CD20 therapy and PD-L1 status. Results will inform additional studies to find a chemotherapy-free regimen for frail participants with multiply relapsed or refractory Aggressive B-cell Lymphomas.

Eligibility: Key inclusion criteria:
  -  Histologically confirmed aggressive diffuse large B-cell lymphoma (DLBCL), including follicular lymphoma (FL) transforming to DLBCL, transformed indolent lymphoma, mantle cell lymphoma (MCL), or Grade 3B FL for dose-escalation cohorts. Only participants with DLBCL will be enrolled in the dose-expansion cohort.
  -  Willing to provide a fresh tumor sample
  -  Evaluable/measurable disease with measurable disease defined as ≥ 1 lesion ≥ 20 mm in one dimension or ≥ 15 mm in 2 dimensions as measured by conventional or high-resolution (spiral) computed tomography (CT). Disease evaluable by the International Working Group criteria (Cheson et al, 2007). (NOTE: Irradiated lesions will not be evaluable.)
  -  Baseline fludeoxyglucose positron emission tomography (FDG-PET) or FDG-PET/CT scans must show positive lesions compatible with CT-defined anatomical tumor sites.
  -  Relapsed from or refractory to ≥ 2 prior chemotherapy regimens with ≥ 1 regimen containing rituximab or failed 1 prior rituximab-containing regimen and unable to tolerate additional multiagent chemotherapy. NOTE: Subjects enrolled in the dose-escalation portion of the study must have exhausted all available standard therapy.
  -  At least 100 days past autologous stem cell transplant (ASCT).
  -  At least 1 year past allogeneic stem-cell transplant (SCT) and off immunosuppression therapy, with no evidence of graft-versus-host disease.
  -  Eastern Cooperative Oncology Group performance status 0-2.
  -  Adequate hematological function
  -  Adequate organ function
  -  Females of childbearing potential who are sexually active with a nonsterilized male partner must use a highly effective method of contraception for 30 days prior to the first dose of investigational product, and must agree to continue using such precautions for 180 days after the final dose of investigational product.
  -  Nonsterilized males who are sexually active with a female partner of childbearing potential must use a highly effective method of contraception from Day 1through 90 days after receipt of the final dose of investigational product.
  Key exclusion criteria:
  -  Any concurrent chemotherapy, radiotherapy, immunotherapy, biologic or hormonal therapy for treatment of cancer.
  -  Receipt of any experimental therapy, mAb, cancer vaccine, chemotherapy or small molecule within 28 days prior to Cycle 1 Day 1 or 5 half-lives of that therapy, whichever is shorter.
  -  Previous therapy directed against cluster of differentiation 19 (CD19)
  -  Prior exposure to immunotherapy such as but not limited to other anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), anti-PD 1, or anti-PD-L1 antibodies excluding cancer vaccines.
  -  Vaccination with a live virus within 28 days prior to receiving the first dose of study drug
  -  History of other invasive malignancy within 2 years except for cervical carcinoma in situ, non-melanomatous carcinoma of the skin or ductal carcinoma in situ of the breast that has been surgically cured.
  -  Evidence of significant active infection requiring antimicrobial, antifungal, antiparasitic, or antiviral therapy or for which other supportive care is given unless the subject is clinically stable.
  -  Human immunodeficiency virus (HIV) positive serology or acquired immunodeficiency syndrome (AIDS).
  -  Active hepatitis B
  -  Ongoing ≥ Grade 2 toxicities from previous cancer therapies or any unresolved > Grade 1 immune-related adverse event (irAE) event unless specifically allowed in the inclusion/exclusion criteria.
  -  No immunosuppressive therapy within 14 days of Cycle 1 Day 1 of MEDI0680 (AMP-514) dosing.
  -  Active or prior documented autoimmune or inflammatory disease except vitiligo.
  -  History of primary immunodeficiency.
  -  Major surgical procedures (as defined by the principal investigator) within 28 days of Cycle 1 Day 1 or still recovering from prior surgery.
  -  History of tuberculosis, including those who may have completed prophylactic isoniazid (INH) therapy.
  -  Documented current central nervous system (CNS) involvement, leptomeningeal disease, or spinal cord compression.
  -  Pregnancy or lactation.
  -  Clinically significant abnormality on electrocardiogram (ECG).
  -  Uncontrolled inter-current illness including, but not limited to, ongoing or active infection, current pneumonitis, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs from MEDI-551 or MEDI0680 (AMP-514), or compromise the ability of the subject to give written informed consent.

Relevance to patient case: not relevant