A Clinical Study Using MEDI-551 in Adult Participants With Relapsed or Refractory Advanced B-Cell Malignancies

Optimal biologic dose (OBD) was defined as the dose lower than the maximum tolerated dose (MTD), used for dose expansion. The MTD is defined as the highest dose at which less than equal to (<=) 1 out of 6 participants experience a dose limiting toxicities (DLT) from the time of first administration of MEDI-551 through the first 28-day cycle.

Highest protocol-defined dose is dose of MEDI-551 in the absence of exceeding the MTD in participants with relapsed or rituximab-refractory chronic lymphocytic leukemia (defined as those with less than a partial response (PR) or progression within 6 months after completing therapy with rituximab). The MTD is defined as the highest dose at which <= 1 out of 6 participants experience a DLT from the time of first administration of MEDI-551 through the first 28-day cycle.

Highest protocol-defined dose is the dose of MEDI-551 in combination with rituximab at the MTD or the highest protocol-defined dose in the absence of exceeding the MTD in participants with aggressive lymphomas. The MTD is defined as the highest dose at which <= 1 out of 6 participants experience a DLT from the time of first administration of MEDI-551 through the first 28-day cycle.

An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. TEAEs are 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.

A dose limiting toxicities (DLT) for arm A, B, and C was defined as MEDI-551 (or rituximab for Arm C) treatment-related AE of any toxicity grade that led to an inability to receive a full cycle of MEDI-551 (or rituximab for Arm C) or any Grade 3 or higher toxicity (except Grade 3 fever, transient Grade 3 rigors or chills, Grade 3 tumor lysis syndrome, any Grade 3 or 4 electrolyte alteration, any Grade 3 liver function test elevation,>= Grade 3 or 4 lymphopenia or leukopenia, <= Grade 4 neutropenia, <= Grade 4 thrombocytopenia, <= Grade 4 anemia, and Grade 3 infusion-related reaction and infusion reaction), during DLT evaluable period.

Number of participants with clinical laboratory abnormalities reported as TEAEs are reported. Clinical laboratory abnormalities are defined as any abnormal findings in analysis of serum chemistry, hematology, and urine.

Number of participants with abnormal vital signs reported as TEAEs are reported. Abnormal vital signs are defined as any abnormal findings in the vital signs parameters (temperature, blood pressure, pulse rate, respiratory rate, and pulse oximetry).

Number of participants with abnormal electrocardiograms (ECGs) reported as TEAEs are reported. Abnormal ECGs are defined as any abnormal findings in heart rate, RR interval, PR interval, QRS, axis, and QT intervals from the primary lead of the digital 12-lead ECG.

Complete response (CR) is defined as disappearance of all evidence of disease according to International Working Group criteria (IWG). For nodal masses; fluorodeoxyglucose (FDG)-avid or polyethylene terephthalate (PET) positive prior to therapy; mass of any size permitted if PET negative .Variably FDG-avid or PET negative; regression to normal size on computed tomography (CT). For spleen; not palpable, nodules disappeared. For bone marrow; infiltrate cleared on repeat biopsy; if indeterminate by morphology, immunohistochemistry (IHC) was negative.

The PR is defined as regression of measurable disease and no new sites according to IWG criteria. Nodal masses: >= 50% decrease in sum of the product diameters (SPD) of up to 6 largest dominant masses; no increase in size of other nodes (a) FDG-avid or PET positive prior to therapy; one or more PET positive at previously involved site (b) FDG-avid or PET negative; regression on CT. Spleen and liver: >= 50% decrease in SPD of nodules (for single nodule in greatest transverse diameter); no increase in size of liver or spleen. Bone marrow: irrelevant if positive prior to therapy.

Duration of CR is from the first documentation of a CR to the time of progressive disease/relapse according to IWG criteria. The CR is disappearance of all evidence of disease according to IWG criteria. For nodal masses; FDG-avid or PET positive prior to therapy; mass of any size permitted if PET negative. Variably FDG-avid or PET negative; regression to normal size on CT. For spleen; not palpable, nodules disappeared. For bone marrow; infiltrate cleared on repeat biopsy; if indeterminate by morphology, IHC was negative. Kaplan-Meier method was used to evaluate duration of CR.

Objective response rate (ORR) is proportion of participants with CR or partial response (PR) as per IWG criteria. CR is disappearance of all evidence of disease. Nodal masses; FDG-avid/PET positive prior to therapy; mass of any size permitted if PET negative. FDG-avid or PET negative; regression to normal size on CT. Spleen; not palpable, nodules disappeared. Bone marrow; infiltrate cleared on repeat biopsy; if unknown by morphology, IHC was negative. PR is regression of measurable disease and no new sites. Nodal masses: >= 50% decrease in sum of the product diameters (SPD) of up to 6 largest dominant masses; no increase in size of other nodes (a) FDG-avid or PET positive prior to therapy; one or more PET positive at previously involved site (b) FDG-avid or PET negative; regression on CT. Spleen and liver: >= 50% decrease in SPD of nodules (for single nodule in greatest transverse diameter); no increase in size of liver or spleen. Bone marrow: irrelevant if positive prior to therapy.

Duration of objective response (DOR) is the first documentation of objective response to the first documented progressive disease (PD) or relapse according to IWG criteria. PD is defined as any new lesion or increase by >=50% of previously involved sites from nadir. For nodal masses: appearance of a new lesion(s) > 1.5 cm in any axis, >= 50% increase in SPD of more than one node, or >= 50% increase in longest diameter of a previously identified node > 1 cm in short axis lesions PET positive if FDG-avid lymphoma or PET positive prior to therapy. For spleen: > 50% increase from nadir in the SPD of any previous lesions. For bone marrow: New or recurrent involvement. Kaplan-Meier method was used to evaluate DOR.

Disease control includes CR, PR, or stable disease (SD) for at least 8 weeks according to IWG criteria. The CR is disappearance of all evidence of disease. Nodal masses; FDG-avid or PET positive prior to therapy; mass of any size permitted if PET negative. FDG-avid or PET negative; regression to normal size on CT. Spleen; not palpable, nodules disappeared. Bone marrow; infiltrate cleared on repeat biopsy; if indeterminate by morphology, IHC was negative. PR is regression of measurable disease and no new sites. Nodal masses: >= 50% decrease in SPD of up to 6 largest dominant masses; no increase in size of other nodes (a) FDG-avid or PET positive prior to therapy; one or more PET positive at previously involved site (b) Variably FDG-avid or PET negative; regression on CT. Spleen and liver: >= 50% decrease in SPD of nodules; no increase in size of liver or spleen. For bone marrow: irrelevant if positive prior to therapy. SD is failure to attain CR/PR or PD.

Duration of disease control is defined as the time period from start of MEDI-551 administration to the event of PD/relapse. PD is defined as any new lesion or increase by >=50% of previously involved sites from nadir. For nodal masses: appearance of a new lesion(s) > 1.5 cm in any axis, >= 50% increase in SPD of more than one node, or >= 50% increase in longest diameter of a previously identified node > 1 cm in short axis lesions PET positive if FDG-avid lymphoma or PET positive prior to therapy. For spleen: > 50% increase from nadir in the SPD of any previous lesions. For bone marrow: New or recurrent involvement. Kaplan-Meier method was used to evaluate duration of disease control.

Time to response (TTR) is measured from the start of MEDI-551 administration to the first documentation of response (CR or PR) and assessed in participants who have achieved objective response. Kaplan-Meier method was used to evaluate TTR.

Progression-free survival (PFS) is measured from the start of MEDI-551 treatment until the first documentation of disease progression, relapse or death, whichever occurs first. The PFS was censored on the date of last disease assessment for participants who have no documented PD/relapse or death prior to data cutoff, dropout, or the initiation of alternative anticancer therapy. Kaplan-Meier method was used to evaluate PFS.

Overall survival (OS) is measured from the start of MEDI-551 treatment until death. For participants who are alive at the end of study or lost to follow-up, OS will be censored on the last date when participants were known to be alive. Kaplan-Meier method was used to evaluate OS.

An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. TEAEs are 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.

Number of participants with clinical laboratory abnormalities reported as TEAEs are reported. Clinical laboratory abnormalities are defined as any abnormal findings in analysis of serum chemistry, hematology, and urine.

Number of participants with abnormal vital signs reported as TEAEs are reported. Abnormal vital signs are defined as any abnormal findings in the vital signs parameters (temperature, blood pressure, pulse rate, respiratory rate, and pulse oximetry).

Number of participants with abnormal ECGs reported as TEAEs are reported. Abnormal ECGs are defined as any abnormal findings in heart rate, RR interval, PR interval, QRS, axis, and QT intervals from the primary lead of the digital 12-lead ECG.

The CR is defined as disappearance of all evidence of disease according to IWG criteria. For nodal masses; FDG-avid or PET positive prior to therapy; mass of any size permitted if PET negative .Variably FDG-avid or PET negative; regression to normal size on CT. For spleen; not palpable, nodules disappeared. For bone marrow; infiltrate cleared on repeat biopsy; if indeterminate by morphology, IHC was negative.

The PR is defined as regression of measurable disease and no new sites according to IWG criteria. Nodal masses: >= 50% decrease in sum of the product diameters (SPD) of up to 6 largest dominant masses; no increase in size of other nodes (a) FDG-avid or PET positive prior to therapy; one or more PET positive at previously involved site (b) FDG-avid or PET negative; regression on CT. Spleen and liver: >= 50% decrease in SPD of nodules (for single nodule in greatest transverse diameter); no increase in size of liver or spleen. Bone marrow: irrelevant if positive prior to therapy.

Duration of CR is from the first documentation of a CR to the time of progressive disease/relapse according to IWG criteria. The CR is disappearance of all evidence of disease. For nodal masses; FDG-avid or PET positive prior to therapy; mass of any size permitted if PET negative. Variably FDG-avid or PET negative; regression to normal size on CT. For spleen; not palpable, nodules disappeared. For bone marrow; infiltrate cleared on repeat biopsy; if indeterminate by morphology, IHC was negative. Kaplan-Meier method was used to evaluate duration of CR.

The ORR is defined as proportion of participants with CR or PR according to IWG criteria. CR is disappearance of all evidence of disease. For nodal masses; FDG-avid or PET positive prior to therapy; mass of any size permitted if PET negative. FDG-avid or PET negative; regression to normal size on CT. For spleen; not palpable, nodules disappeared. For bone marrow; infiltrate cleared on repeat biopsy; if unknown by morphology, IHC was negative. PR is regression of measurable disease and no new sites. For nodal masses: >= 50% decrease in SPD of up to 6 largest dominant masses; no increase in size of other nodes (a) FDG-avid or PET positive prior to therapy; one or more PET positive at previously involved site (b) FDG-avid or PET negative; regression on CT. For spleen and liver: >= 50% decrease in SPD of nodules (for single nodule in greatest transverse diameter); no increase in size of liver or spleen. For bone marrow: irrelevant if positive prior to therapy.

The DOR is the first documentation of objective response to the first documented PD or relapse according to IWG criteria. PD is defined as any new lesion or increase by >=50% of previously involved sites from nadir. For nodal masses: appearance of a new lesion(s) > 1.5 cm in any axis, >= 50% increase in SPD of more than one node, or >= 50% increase in longest diameter of a previously identified node > 1 cm in short axis lesions PET positive if FDG-avid lymphoma or PET positive prior to therapy. For spleen: > 50% increase from nadir in the SPD of any previous lesions. For bone marrow: New or recurrent involvement. Kaplan-Meier method was used to evaluate DOR.

Disease control includes CR, PR, or SD for at least 8 weeks according to IWG criteria. The CR is disappearance of all evidence of disease. For nodal masses; FDG -avid or PET positive prior to therapy; mass of any size permitted if PET negative. FDG-avid or PET negative; regression to normal size on CT. For spleen; not palpable, nodules disappeared. For bone marrow; infiltrate cleared on repeat biopsy; if indeterminate by morphology, IHC was negative. PR is regression of measurable disease and no new sites. For nodal masses: >= 50% decrease in SPD of up to 6 largest dominant masses; no increase in size of other nodes (a) FDG-avid or PET positive prior to therapy; one or more PET positive at previously involved site (b) Variably FDG-avid or PET negative; regression on CT. For spleen and liver: >= 50% decrease in SPD of nodules; no increase in size of liver or spleen. For bone marrow: irrelevant if positive prior to therapy. SD is failure to attain CR/PR or PD.

Duration of disease control is defined as the time period from start of MEDI-551 administration to the event of PD/relapse according to IWG criteria. PD is defined as any new lesion or increase by >=50% of previously involved sites from nadir. For nodal masses: appearance of a new lesion(s) > 1.5 cm in any axis, >= 50% increase in SPD of more than one node, or >= 50% increase in longest diameter of a previously identified node > 1 cm in short axis lesions PET positive if FDG-avid lymphoma or PET positive prior to therapy. For spleen: > 50% increase from nadir in the SPD of any previous lesions. For bone marrow: New or recurrent involvement. Kaplan-Meier method was used to evaluate duration of disease control.

The TTR is measured from the start of MEDI-551 administration to the first documentation of response (CR or PR) and assessed in participants who have achieved objective response. Kaplan-Meier method was used to evaluate TTR.

The PFS is measured from the start of MEDI-551 treatment until the first documentation of disease progression, relapse or death, whichever occurs first. Kaplan-Meier method was used to evaluate PFS. The PFS was censored on the date of last disease assessment for participants who have no documented PD/relapse or death prior to data cutoff, dropout, or the initiation of alternative anticancer therapy.

The OS is measured from the start of MEDI-551 treatment until death. For participants who are alive at the end of study or lost to follow-up, OS will be censored on the last date when participants were known to be alive. Kaplan-Meier method was used to evaluate OS.

Trough serum concentration (Ctrough) is defined as lowest concentration reached by a drug before the next dose is administered. The Ctrough concentration of MEDI-551 by treatment cycle is reported.

Peak serum concentration is concentration that a drug achieves in a specified compartment or test area of the body after the drug has been administrated and before the administration of a second dose.

Area under the concentration-time curve at steady state (Css, AUC) of MEDI-551 is reported.

Apparent clearance of MEDI-551 is reported.

Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of a drug. Central volume of distribution (Vd1) is defined as hypothetical volume into which a drug initially distributes upon administration and peripheral volume of distribution (Vd2) is defined as the sum of all tissue spaces outside the central compartment.

Terminal half-life is the time required for the plasma concentration of MEDI-551 to fall by 50% during the terminal phase.

Number of participants with positive Anti-drug antibodies (ADA) titer to MEDI-551 is reported.

B-cell Concentration in serum is reported.

Immunoglobin (Ig) concentration in serum is reported.