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

Study Overview
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Brief Summary
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This is a Phase 1b/2 open-label study to evaluate the safety/efficacy of MEDI-551 + MEDI0680 in participants with relapsed or refractory aggressive B-cell lymphomas who have failed 1-2 prior lines of therapy.

Detailed Description
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This is a Phase 1b/2, multicenter, open-label, study of MEDI-551 in combination with immunomodulating therapy evaluating the safety, tolerability, pharmacokinetics, immunogenicity and anti-tumor activity in subjects with relapsed or refractory aggressive B-cell lymphomas

Official Title
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A Phase 1b/2 Open-label Study to Evaluate the Safety/Efficacy of MEDI-551 in Combination With Immunomodulating Therapy in Subjects With Relapsed or Refractory Aggressive B-cell Lymphomas

Conditions
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Relapsed/Refractory Aggressive B-cell Lymphomas

Intervention / Treatment
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* Drug: MEDI-551 12 mg/kg
* Drug: MEDI0680 2.5 mg/kg
* Drug: MEDI0680 10 mg/kg


Participation Criteria
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Eligibility Criteria
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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 greater than or equal to (>= 1) lesion less than or equal to (<=) 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MEDI-551 12 mg/kg and MEDI0680 2.5 mg/kg<br>Participants will receive intravenous (IV) infusion of MEDI-551 12 mg/kg on Days 1 and 8 of Cycle 1 and Day 1 of Cycle 2 through Cycle 13 (each cycle of 28 days) and IV infusion of MEDI0680 2.5 mg/kg on Days 2 and 15 of Cycle 1 and Days 1 and 15 of Cycle 2 through Cycle 13. | Drug: MEDI-551 12 mg/kg<br>* Participants will receive intravenous (IV) infusion of MEDI-551 12 mg/kg on Days 1 and 8 of Cycle 1 and Day 1 of Cycle 2 through Cycle 13<br>Drug: MEDI0680 2.5 mg/kg<br>* Participants will receive IV infusion of MEDI0680 2.5 mg/kg on Days 2 and 15 of Cycle 1 and Days 1 and 15 of Cycle 2 through Cycle 13.<br>|
| Experimental: MEDI-551 12 mg/kg and MEDI0680 10 mg/kg<br>Participants will receive IV infusion of MEDI-551 12 mg/kg on Days 1 and 8 of Cycle 1 and Day 1 of Cycle 2 through Cycle 13 (each cycle of 28 days) and IV infusion of MEDI0680 10 mg/kg on Days 2 and 15 of Cycle 1 and Days 1 and 15 of Cycle 2 through Cycle 13. | Drug: MEDI-551 12 mg/kg<br>* Participants will receive intravenous (IV) infusion of MEDI-551 12 mg/kg on Days 1 and 8 of Cycle 1 and Day 1 of Cycle 2 through Cycle 13<br>Drug: MEDI0680 10 mg/kg<br>* Participants will receive IV infusion of MEDI0680 10 mg/kg on Days 2 and 15 of Cycle 1 and Days 1 and 15 of Cycle 2 through Cycle 13.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) of MEDI-551 | The Maximum Tolerated Dose, defined as the highest dose where less than or equal to (<= 1) out of 6 subjects experiences a dose limiting toxicity (DLT) during the DLT evaluation period (Day 1 to Day 28 of Cycle 1) or the highest protocol specified dose not exceeding MTD. | Day 1 to Day 28 of Cycle 1 (28-day cycle) | 
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) or Treatment-Emergent Serious Adverse Events (TESAEs) | An Adverse Event (AE) is any unfavourable and unintended signs, symptoms, or diseases temporally associated with use of study drug, whether or not considered related to study drug. SAE is any AE that resulted in death, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, life-threatening, a congenital anomaly/birth defect, or an important medical event. TEAEs are defined as AEs present at baseline that worsened in intensity after administration of study drug, or events absent at baseline that emerged after administration of study drug, up to 90 days after the end of treatment (EOT). | From treatment administration to 90-days after last dose of study drug (up to approximately 2 years) | 
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Related to Clinical Laboratory Abnormalities | An abnormal laboratory findings that was judged by the investigator to be medically significant was reported as an AE. TEAEs were defined as events present at baseline that worsened in intensity after administration of study drug, or events absent at baseline that emerged after administration of study drug, for the period extending to 90 days after the end of study drug. | From treatment administration to 90-days after last dose of study drug (up to approximately 2 years) | 
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Related to Vital Signs, Physical Findings Abnormalities | Vital signs included parameters such as blood pressure, temperature, respiratory rate, and pulse oximetry. An abnormal vital signs and physical findings that was judged by the investigator to be medically significant was reported an AE. TEAEs were defined as events present at baseline that worsened in intensity after administration of study drug, or events absent at baseline that emerged after administration of study drug, for the period extending to 90 days after the end of study treatment. | From treatment administration to 90-days after last dose of study drug (up to approximately 2 years) | 
| Number of Participants With Best Overall Response | The best overall response was calculated, based upon the disease assessments recorded during the study visits, and summarized with the number of participants for the following categories: complete response (disappearance of all evidence of disease), partial response (regression of measurable disease and no new sites), stable disease (SD), progessive disease (PD), and non- evaluable (NE). | Day 1 to Day 28 of Cycle 13 (28-day cycle) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Peak and Trough Concentrations of MEDI551 | The mean peak and Trough concentration of MEDI551 were observed. Peak is the end of infusion measurement and the Trough is the pre-dose measurement. | End of Infusion (EOI) of Cycle 1 Day 1; Pre-dose and EOI of C1D8, C2D1, C3D1 and C4D1 | 
| Mean Peak and Trough Concentrations of MEDI0680 | The mean peak and Trough concentration of MEDI0680 were observed. Peak is the end of infusion measurement and the Trough is the pre-dose measurement. | EOI of Cycle 1 Day 2; Pre-dose and EOI of C1D15, C2D1, C3D1 and C4D1 | 
| Terminal Half-Life (t1/2) of MEDI551 | Terminal phase elimination half-life (t1/2) is the time required for half of the drug to be eliminated from the serum. | EOI of Cycle 1 Day 1; Pre-dose and EOI of C1D8, C2D1, C3D1 and C4D1 | 
| Terminal Half-Life (t1/2) of MEDI0680 | Terminal phase elimination half-life (t1/2) is the time required for half of the drug to be eliminated from the serum. | EOI of Cycle 1 Day 2; Pre-dose and EOI of C1D15, C2D1, C3D1 and C4D1 | 
| Number of Participants With Positive Anti-Drug Antibodies (ADA) for MEDI-551 and MEDI0680 | A participant was considered ADA-positive across the study if they had a positive reading (titer of 50 or higher) at any time point during the study. | 30 min prior to infusion of MEDI-551 on Day 1 of Cycles 1, 2, 6, 9, and 12 and up to 90-days after last dose of study drug (up to approximately 2 years) | 
| Duration of Complete Response | Duration of Complete Response defined as time from start of first documented Complete Response [CR] to the time of disease progression or death, whichever occurs first. Only participants who have achieved complete response assessed by investigator were evaluated. | From treatment administration to 90-days after last dose of study drug (up to approximately 2 years) | 
| Number of Participants With Disease Control | Disease control includes CR (disappearance of all evidence of disease), PR (regression of measurable disease and no new sites), or SD for at least 8 weeks. | From treatment administration to 90-days after last dose of study drug (up to approximately 2 years) | 
| Duration of Disease Control | Duration of disease control is defined as the time period from the start of disease control event to the event of disease progression. | From treatment administration to 90-days after last dose of study drug (up to approximately 2 years) | 
| Progression-free Survival (PFS) | Progression-free survival (PFS) is defined as the time from the start of study drug administration until the first documentation of disease progression or death due to any cause, whichever occurs first. | From treatment administration to 90-days after last dose of study drug (up to approximately 2 years) | 
| Overall Survival (OS) | Overall survival defined as the time from the start of study drug administration until death due to any cause. | From treatment administration to 90-days after last dose of study drug (up to approximately 2 years) | 
| Time to Response (TTR) | Time to response (TTR) defined as the time from the start of study drug administration until the first documentation of disease response. Only participants who have achieved objective response (confirmed CR or confirmed PR) assessed by investigator were evaluated for TTR. | From treatment administration to 90-days after last dose of study drug (up to approximately 2 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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aggressive lymphoma, DLBCL, NHL