Inclusion Criteria:

1. Men or women at least 18 years of age or older at time of study entry
2. Written informed consent and HIPAA authorization (applies to covered entities in the USA only) obtained from the subject/legal representative prior to performing any protocol-related procedures, including screening evaluations
3. Diagnosis Arm A: CLL (including SLL), DLBCL, or FL; SLL, DLBCL, and FL must be histologically confirmed Arm B: Histologically confirmed SLL or previous confirmation of B-cell CLL with a characteristic immunophenotype by flow cytometry Arm C: Histologically confirmed aggressive B-cell DLBCL, including FL transforming to DLBCL, transformed indolent lymphoma, MCL, or Grade 3b FL, according to the World Health Organization (WHO)/American Joint Committee on Cancer (AJCC) criteria Arm D: Histologically confirmed anti-CD20-refractory (defined as any subject with less than a PR to any prior anti-CD20-based therapy or progression within 6 months after completing therapy with any anti-CD20-based regimen, including maintenance rituximab) aggressive B-cell DLBCL, including FL transforming to DLBCL, transformed indolent lymphoma, MCL, or Grade 3b FL, according to the WHO/AJCC criteria
4. Optional: Willing to provide a fresh tumor sample if a sufficient quantity of archival tumor sample is not available (Arms B, C, and D). See Section 5.3.9 for tumor sample details.
5. Evaluable/measurable disease

    

   Non-CLL B-cell malignancies (Arms A, C, and D):
   • Histologically confirmed B-cell NHL (FL or DLBCL), transformed indolent lymphoma, and MCL: 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). For Arms C and D: disease evaluable by the International Working Group criteria (Cheson et al, 2007)
   • Baseline PET or PET/CT scans must show positive lesions compatible with CT-defined anatomical tumor sites (only applicable for FL, DLBCL, MCL, transformed indolent lymphoma, and FL transforming to DLBCL)
   CLL (Arms A and B):
   • Confirmed B-cell CLL/SLL with a characteristic immunophenotype by flow cytometry, and symptomatic disease requiring treatment
   • CT scans showing involvement of ≥ 1clearly demarcated lesions measuring ≥ 1.5 cm
6. Prior therapy
   • Arm A:
     • Histologically confirmed B-cell NHL (FL or DLBCL): Relapsed from or refractory to ≥ 1 prior regimen containing rituximab, either alone or in combination, and not be a candidate for hematopoietic SCT or BM transplant
     • B-cell CLL: Relapsed from or refractory to ≥ 2 prior lines of treatment, ≥ 1 of which must have contained rituximab
   • Arm B: Relapsed from or refractory to ≥ 2 prior chemotherapy regimens with ≥ 1 regimen containing rituximab
   • Arm C: 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
   • Arm D: Refractory to ≥ 1 regimen containing any anti-CD20-based therapy, including salvage regimens and maintenance rituximab. Refractory subjects are defined as any subject with less than a PR to any prior anti-CD20-based therapies or progressed within 6 months after completing therapy with any anti-CD20-based regimens, including maintenance rituximab. These subjects must not be eligible for hematopoietic SCT or BM transplant
7. Prior radiation therapy is allowed provided exposure does not exceed an area of 25% of marrow space and occurred ≥ 6 weeks prior to the first dose of MEDI-551 (Arm A only)
8. Karnofsky performance status ≥ 70
9. Life expectancy of ≥ 12 weeks
10. Adequate hematologic function Arm A (except for CLL subjects with significant BM involvement by biopsy) must meet the following criteria:
    • Hemoglobin ≥ 9 g/dL, (≥ 8 g/dL for subjects who are transfusion dependent)
    • Absolute neutrophil count ≥ 1500/mm3
    • Platelet count ≥ 75,000/mm3

    Arms B, C, and D must meet the following criteria:

    • Hemoglobin ≥ 8 g/dL
    • Absolute neutrophil count ≥ 1000/mm3
    • Platelet count ≥ 75,000/mm3
    • In the event of significant BM involvement, the above hematologic criteria will not be required for enrollment eligibility
11. Adequate organ function defined as follows:
    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2 × institutional upper limit of normal (ULN)
    • Bilirubin ≤ 1.5 × ULN except for subjects with documented Gilbert's disease, ≤ 2.5 × ULN;
    • Serum creatinine ≤ 1.5 mg/dL or a calculated creatinine clearance of ≥ 60 mL/min as determined by the Cockcroft-Gault equation
12. Female subjects of childbearing potential who are sexually active with a nonsterilized male partner must use highly effective contraception from screening and must agree to continue using such precautions for at least 180 days after the last dose of investigational product. Depending on the investigational product received, this period may be longer. Cessation of birth control after this point should be discussed with a responsible physician
    • Females of childbearing potential are defined as those who are not surgically sterile (ie, bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or those who are postmenopausal (defined as 12 months with no menses without an alternative medical cause or follicle-stimulating hormone/luteinizing hormone levels consistent with a menopausal state)
    • A highly effective method of contraception is defined as one that results in a low failure rate (ie, less than 1% per year) when used consistently and correctly. Acceptable methods of contraception are described in Table 4.2.1-1. Sustained abstinence is an acceptable practice; however, periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception
13. Non-sterilized males who are sexually active with a female partner of childbearing potential must use a highly effective method of contraception (Table 4.2.1-1) from at least Day 1 through 90 days after the last dose of investigational product
14. Negative serum beta human chorionic gonadotropin (βhCG) test (for women of childbearing potential only)
15. Females or female partners not of childbearing potential must have been surgically sterilized or postmenopausal (as defined above in inclusion criterion #12). Sterilized males must be at least 1 year post vasectomy

Exclusion Criteria:

1. Any available standard line of therapy known to be life-prolonging or life-saving
2. Any concurrent chemotherapy, radiotherapy, immunotherapy, biologic or hormonal therapy for treatment of cancer
3. History of allergy or reaction to any component of the MEDI-551 formulation
4. Receipt of any chemotherapy or small molecule targeted therapy (such as imatinib or other tyrosine kinase inhibitors, and including any experimental therapies) or radiation therapy within 28 days or 5 half-lives, whichever is shorter, prior to the first dose of MEDI-551
5. Receipt of any biological or immunological-based therapies (including experimental therapies) for leukemia, lymphoma, or myeloma (including, but not limited to, MAb therapy such as rituximab, or cancer vaccine therapies) within 28 days or 5 half-lives, whichever is shorter, prior to the first dose of MEDI-551
6. Previous therapy directed against CD19, such as MAbs or MAb conjugates
7. Live or attenuated vaccines (other than experimental cancer vaccine therapy) within 28 days prior to receiving the first dose of MEDI-551
8. Evidence of significant active infection requiring antimicrobial, antifungal, antiparasitic, or antiviral therapy or for which other supportive care is given
9. Autologous SCT within 12 weeks prior to study entry (Arms A and D only)
10. Prior allogeneic SCT or organ transplant (Arms A and D only)
11. Human immunodeficiency virus (HIV) positive serology or AIDS
12. Active hepatitis B as defined by seropositivity for hepatitis B surface antigen or positive hepatitis B core antibody. Subjects with hepatitis C antibody will be eligible provided that they do not have elevated liver transaminases
13. Ongoing ≥ Grade 2 toxicities from previous cancer therapies unless specifically allowed in the Inclusion/Exclusion criteria. Use of immunosuppressive medication other than steroids within 28 days before the first dose of MEDI-551
14. Use of systemic steroids within 7 days before the first dose of MEDI-551 (inhaled and topical corticosteroids are permitted). Subjects may take replacement doses of steroids (defined as ≤ 30 mg/day hydrocortisone or the equivalent) if on a stable dose for at least 2 weeks prior to the first dose of MEDI-551. This does not include required steroid prophylaxis prior to the first infusion of MEDI-551
15. Documented current central nervous system involvement by leukemia or lymphoma
16. Pregnancy or lactation
17. Previous medical history, or evidence, of an intercurrent illness that at the discretion of the principal investigator may compromise the safety of the subject in the study
18. Clinically significant abnormality on electrocardiogram (ECG). The corrected QT interval (QTc, Fridericia) must be < 470 milliseconds for men and < 490 milliseconds for women (Must be confirmed by at least 2 additional 12-lead ECGs at least 2 minutes apart such that average manually over-read QTcF based on 3 ECGs exceeds stated thresholds)
19. Any physical, social, or psychiatric condition that would prevent effective cooperation or participation in the study
20. Concurrent enrollment in another clinical study, unless in a follow-up period or it is an observational study
21. Employees of the clinical study site who are directly involved with the conduct of the study, or immediate family members of such individuals. These subjects may be treated at another site participating in the study