Phase I/II Study of the Tumor-targeting Human L19TNFα Monoclonal Antibody-cytokine Fusion Protein in Patients With Advanced Solid Tumors
- Phase I: histologically or cytologically confirmed relapsed or refractory locally
advanced or metastatic solid tumor of any origin, not amenable to standard therapy.
- Phase II: histologically or cytologically confirmed relapsed or refractory locally
advanced or metastatic colorectal cancer not amenable to standard therapy.
- For both phase I and II:
- Subjects aged ≥ 18 years.
- ECOG performance status ≤ 2.
- Subjects must have at least one unidimensionally measurable lesion by computed
tomography as defined by RECIST criteria (see Section 8) or tumour markers
parameters of disease such as PSA and CA125 for Prostate cancer and Ovarian
cancer, respectively. This lesion must not have been irradiated during previous
- Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L, platelets ≥ 100 x 10^9/L, and
haemoglobin (Hb) ≥ 9.5 g/dl.
- All acute adverse effects (excluding alopecia) of any prior therapy (including
surgery, radiation therapy, chemotherapy) must have resolved to ≤ Grade 1,
except elevated liver transaminases judged to be associated with tumor
infiltration (see below) (graded according to National Cancer Institute [NCI]
Common Terminology Criteria for Adverse Events, version 3.0 [CTCAE, v.3.0]).
- Alkaline phosphatase (ALP), alanine aminotransferase (ALT) and/or aspartate
aminotransferase (AST) ≤ 2.5 x upper limit of normal (ULN), and total bilirubin
≤ 2.0 mg/gL unless liver involvement by the tumor, in which case the
transaminase levels up to 5 x ULN are allowed.
- Creatinine ≤ 1.5 ULN or 24 h creatinine clearance ≥ 60 mL/min.
- Testing negative for acute or chronic infection with hepatitis B or C virus, or
human immunodeficiency virus 1 or 2.
- Negative pregnancy test for females of childbearing potential at the screening
- Commitment from subject to practice medically appropriate/acceptable method of
birth control (e.g., hormonal, condoms or other adequate barrier controls,
intrauterine contraceptive device, or sterilization) beginning at the screening
visit and continuing until 3 months following the last treatment with study
- Able to provide written Informed Consent.
- Breastfeeding women.
- Presence of active infections (e.g. requiring antimicrobial therapy) or other severe
concurrent disease, which, in the opinion of the Investigator, would place the
subject at undue risk or interfere with the study.
- Known brain metastases or signs and/or symptoms suggestive of brain metastases.
- Known cancer of other primary origin (excluding Stage I non-melanoma skin cancer)
within the prior 5 years.
- Active autoimmune disease.
- Cardiac disease as manifested by any of the following:
- > Grade II heart failure, graded per New York Heart Association (NYHA) criteria.
- Unstable angina pectoris.
- Acute or subacute coronary syndromes, including myocardial infarction, occurring
with 1 year prior to study treatment.
- Arrhythmia needing continuous treatment.
- Ejection fraction less than the institutional lower limit of normal as assessed
by multigated radionuclide angiography (MUGA) scan or echocardiogram.
- Uncontrolled hypertension.
- Ischemic peripheral vascular disease (Grade IIb-IV).
- Severe diabetic retinopathy.
- Major surgery or trauma within 4 weeks prior to start of study treatment.
- Known history of allergy to TNFα or other intravenously administered human
- Chemotherapy, radiation therapy or therapy with an investigational agent within 4
weeks prior start of study treatment.
- Previous in vivo exposure to monoclonal antibodies for biological therapy in the 6
weeks before administration of study treatment.
- Growth factors or immunomodulatory agents within 7 days prior to the administration
of the study treatment.
- Subject 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 criterion.
- Concurrent therapy with warfarin at doses greater than 1 mg/day or equivalent doses
of other coumarin derivatives.
- Participation in another interventional clinical trial during participation in this
- Expectation that the subject will not be able to complete at least 6 weeks of
- Any conditions that in the opinion of the Investigator could hamper compliance with
the study protocol.