A Phase I/II Study of the Tumor-targeting Human L19-IL2 Monoclonal Antibody-cytokine Fusion Protein in Combination With Rituximab in Relapsed or Refractory Diffuse Large B-cell Lymphoma (DLBCL)

Phase I/II, open-label, multicenter, prospective study.

Phase I - Dose definition: A prospective, open-label, multi-center Phase I dose escalation study in which cohorts of 3-6 patients will receive escalating doses of L19-IL2 in combination with a fixed dose of Rituximab (375 mg/m2).

Phase II - Activity Evaluation: Open-label, multi-center, prospective study during which 14 enrolled patients will receive a fixed dose of Rituximab (375 mg/m2) in combination with L19-IL2 at the RD defined during the Phase I part of the study.

The study is designed to establish whether L19-IL2, administered in combination with Rituximab is well tolerated and can achieve objective responses and clinical benefit to patients with relapsed or refractory DLBCL.

Eligibility Criteria:
Inclusion Criteria:

* Histologically confirmed CD 20-positive DLBCL
* Patients must have experienced relapse after or not have achieved CR with standard R-CHOP-like treatment and must be ineligible for autologous stem cell transplantation or must have relapsed/progressed after autologous or allogeneic stem cell transplantation. In this last case, time lapse between autologous stem cell transplantation and beginning of L19-IL2 treatment must not be less than 4 weeks; in case of allogeneic stem cell transplantation, L19-IL2 treatment can start 4 weeks after removal of immunosuppressive drug(s).
* Presence of measurable lesions according to Revised response criteria for malignant lymphoma
* Males or females, age ≥ 18 years
* ECOG performance status ≤ 2
* Life expectancy of at least 12 weeks
* Absolute neutrophil count \> 1.5 x 109/L
* Hemoglobin \> 8.0 g/dL
* Platelets \> 50 x 109/L
* Total bilirubin ≤ 30 µmol/L (or ≤ 2.0 mg/dl)
* No abnormal electrocardiogram findings requiring treatment
* ALT and AST ≤ 3.0 x the upper limit of normal range (ULN) (5.0 x ULN for patients with hepatic involvement with lymphoma)
* Serum creatinine \< 2 x ULN
* Negative tuberculosis test (e.g. Quantiferon-assay)
* All acute toxic effects (excluding alopecia) of any prior therapy must have resolved to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (v4.03) Grade ≤ 1 unless otherwise specified above
* Negative serum pregnancy test (for women of child-bearing potential only) at screening
* If of childbearing potential, agreement to use adequate contraceptive methods (e.g., oral contraceptives, condoms, or other adequate barrier controls, intrauterine contraceptive devices, or sterilization) beginning at the screening visit and continuing until 3 months following last treatment with study drug
* Able to provide written Informed Consent
* Willingness and ability to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures

Exclusion Criteria:

* Evidence of central nervous system lymphoma
* Previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study except cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (TA, Tis \& Ti) or any cancer curatively treated \< 5 years prior to study entry
* Hypersensitivity to Rituximab or to murine proteins, or to any of its excipients (Sodium citrate, Polysorbate 80, Sodium chloride, Sodium hydroxide, Hydrochloric acid)
* History of HIV infection or infectious hepatitis B or C
* Presence of active, severe infections (e.g., tuberculosis, sepsis and opportunistic infections or any infection requiring antimicrobial therapy) or other severe concurrent disease, which, in the opinion of the investigator, would place the patient at undue risk or interfere with the study. Patients with a history of recurring or chronic infections or with underlying conditions which may further predispose them to serious infections should be excluded from the study.
* Active graft-versus-host disease in patients with a history of allogeneic stem cell transplantation
* History within the last year of acute or subacute coronary syndromes including myocardial infarction, unstable or severe stable angina pectoris
* Inadequately controlled cardiac arrhythmias including atrial fibrillation
* Heart insufficiency (\> Grade II, New York Heart Association (NYHA) criteria)
* Uncontrolled hypertension
* Ischemic peripheral vascular disease (Grade IIb-IV)
* Severe diabetic retinopathy
* Active autoimmune disease
* History of solid organ allograft
* Recovery from major trauma including surgery within 4 weeks prior to administration of study treatment
* Known history of allergy to IL2 or other human proteins/peptides/antibodies
* Positive serum pregnancy test (for women of child-bearing potential only) at screening
* Breast feeding female
* Anti-tumor therapy within 4 weeks of the administration of study treatment (except small surgery)
* Patient requires or is taking corticosteroids or other immunosuppressant drugs on a long-term basis. Limited use of corticosteroids to treat or prevent acute hypersensitivity reactions is not considered an exclusion criterionAny conditions that in the opinion of the investigator could hamper compliance with the study protocol