L19TNF plus doxorubicin in patients with STS

Prior treatment

• Prior therapy (except surgery and radiation) for unresectable or metastatic malignant soft tissue sarcoma.
• Presence of active and uncontrolled infections or other severe concurrent disease, which, in the opinion of the investigator, would place the patient at undue risk or interfere with the study.
• Previous treatment with anthracycline-containing chemotherapy.
• Concurrent malignancies other than Soft Tissue Sarcoma, unless the patient has been disease-free for at least 2 years.
• Growth factors or immunomodulatory agents within 7 days prior to the administration of study treatment.
• Anticoagulation therapy with P2Y12 antagonists (e.g., clopidogrel, ticagrelor) and vitamin K antagonists (e.g., phenprocoumon, warfarin)
• Concurrent use of other anti-cancer treatments or agents other than study medication.
• Radiotherapy within 4 weeks prior to therapy
• Previous therapy with recombinant TNF.
• Any severe concomitant condition which makes it undesirable for the patient to participate in the study or which could jeopardize compliance with the protocol.

Other illness

• History within the last year of acute or subacute coronary syndromes including myocardial infarction, unstable or severe stable angina pectoris.
• Heart insufficiency (> Grade II, New York Heart Association (NYHA) criteria).
• Clinically significant cardiac arrhythmias or requiring permanent medication.
• Uncontrolled hypertension, despite optimal therapy.
• Ischemic peripheral vascular disease (Grade IIb-IV according to Leriche-Fontaine classification).
• Major trauma including major surgery (such as abdominal/cardiac/thoracic surgery) within 4 weeks of administration of study treatment.
• Requirement of chronic administration of corticosteroids or other immunosuppressant drugs. Limited use of corticosteroids to treat or prevent acute hypersensitivity reactions is not considered an exclusion criterion.
• Known active or latent tuberculosis (TB).
• Serious, non-healing wound, ulcer or bone fracture.
• Allergy to study medication or excipients in study medication.
• Deep vein thrombosis, pulmonary embolism or other acute vascular events within 6 months.
• Known history of allergy to TNFα, anthracyclines or other intravenously administered human proteins/peptides/antibodies.

Lab values

• Absolute neutrophil count (ANC) < 1.5 x 109/L, platelets < 100 x 109/L and haemoglobin (Hb) < 9.0 g/dl.
• Chronically impaired renal function as expressed by creatinine ≥ 2.0 x ULN.
• Inadequate liver function (ALT, AST, ALP or total bilirubin ≥ 2.5 x ULN).

Other

• Severe diabetic retinopathy such as severe non-proliferative retinopathy and proliferative retinopathy.
• Pregnancy or breast-feeding.

• Age 18 - 75 years.
• Patients must have histological evidence of advanced unresectable and/or metastatic high-grade soft tissue sarcoma (grade 2 – 3 according to the FNCLCC grading system) not amenable to curative treatment with surgery or radiotherapy and for which doxorubicin treatment is considered appropriate. Participants with Osteosarcoma, Chondrosarcoma, Ewing Sarcoma/ Primitive Neuroectodermal Tumor (PNET), Kaposi’s Sarcoma, Dermatofibrosarcoma protuberans, and Gastrointestinal Stromal Tumors (GIST) will be excluded
• Patients must have at least one unidimensionally measurable lesion by computed tomography as defined by RECIST criteria 1.1. This lesion should not have been irradiated during previous treatments.
• Life expectancy of at least 3 months.
• ECOG ≤ 2.
• Documented negative test for HIV-HBV-HCV. For HBV serology: the determination of HBsAg and anti-HBcAg-Ab is required. In patients with serology documenting previous exposure to HBV, negative serum HBV-DNA is required. For HCV: HCV-RNA or HCV antibody test. Subjects with a positive test for HCV antibody but no detection of HCV-RNA indicating no current infection are eligible.
• Female patients: negative serum pregnancy test at screening for women of childbearing potential (WOCBP)*. WOCBP must agree to use, from the screening to six months following the last administration of L19TNF and/or Doxorubicin, highly effective contraception methods, as defined by the "Recommendations for contraception and pregnancy testing in clinical trials" issued by the Head of Medicine Agencies' Clinical Trial Facilitation Group (www.hma.eu/ctfg.html) and which include, for instance, progesterone-only or combined (estrogen- and progesterone-containing) hormonal contraception associated with inhibition of ovulation, intrauterine devices, intrauterine hormone-releasing systems, bilateral tubal occlusion, vasectomized partner or sexual abstinence. Male patients: Male subjects able to father children must agree to use two acceptable methods of contraception from the screening to four months following the last administration of L19TNF and/or Doxorubicin (e.g. condom with spermicidal gel). Double-barrier contraception is required.
• Informed consent signed and dated to participate in the study
• Willingness and ability to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures. * Women of childbearing potential are defined as females who have experienced menarche, are not postmenopausal (12 months with no menses without an alternative medical cause) and are not permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral oophorectomy or bilateral salpingectomy)