Male or Female aged 18 to 80 years at the time of consent
Patients must have a histological or cytological diagnosis of advanced/metastatic immunotherapy responsive solid carcinoma or lymphoma, that has progressed on immune checkpoint-blockade therapy
Patients must have received an immune checkpoint blockade therapy-based regimen as immediate prior treatment
Only patients without other therapeutic alternatives with curative or survival prolonging potential per investigator judgement are able to participate
Subjects with DLBCL must have received 2 prior systemic therapies
Subjects must have had clinical benefit (CR/PR/SD) while on checkpoint inhibitor treatment defined as 3 month free from progression from initial imaging documenting metastatic disease followed by radiographic disease progression after checkpoint inhibitor per investigator's opinion
Tumor types of primary interest, include malignant melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma, urothelial carcinoma, head and neck squamous cell carcinoma (HNSCC), microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer, hepatocellular cancer, gastric cancer, squamous cell carcinoma of the skin and cervical cancer. For the dose expansion phase II part, diffuse large B-cell lymphoma (DLBCL) can be considered in addition
Yes for Tumor types of primary interest, include malignant melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma, urothelial carcinoma, head and neck squamous cell carcinoma (HNSCC), microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer, hepatocellular cancer, gastric cancer, squamous cell carcinoma of the skin and cervical cancer. For the dose expansion phase II part, diffuse large B-cell lymphoma (DLBCL) can be considered in addition inclusion criteria 7
No for Tumor types of primary interest, include malignant melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma, urothelial carcinoma, head and neck squamous cell carcinoma (HNSCC), microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer, hepatocellular cancer, gastric cancer, squamous cell carcinoma of the skin and cervical cancer. For the dose expansion phase II part, diffuse large B-cell lymphoma (DLBCL) can be considered in addition inclusion criteria 7
Not sure for Tumor types of primary interest, include malignant melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma, urothelial carcinoma, head and neck squamous cell carcinoma (HNSCC), microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer, hepatocellular cancer, gastric cancer, squamous cell carcinoma of the skin and cervical cancer. For the dose expansion phase II part, diffuse large B-cell lymphoma (DLBCL) can be considered in addition inclusion criteria 7
Patients may have previously received chemotherapy, immunotherapy or radiation therapy. Such therapies must be completed at least 4 weeks prior to study drug administration. Radiotherapy within 4 weeks of the first dose of study drug, is allowed for palliative radiotherapy to a limited field, such as for the treatment of bone pain or a focally painful tumor mass. During the expansion part, to allow evaluation of response to treatment, patients must have remaining measurable disease that has not been irradiated
Eastern cooperative oncology group (ECOG) performance status 2
Patient has an estimated life expectancy of at least 12 weeks
At least one unidimensionally measurable lesion either by computed tomography (CT), MRI or PET/CT as defined by RECIST (v. 1.1) for solid tumors or by LUGANO criteria for malignant lymphoma
Documented negative test for HIV-HBV-HCV. For HBV serology: the determination of HBsAg, anti-HBsAg-Ab and anti-HBcAg-Ab is required. In patients with serology documenting previous exposure to HBV (i.e., anti-HBs Ab with no history of vaccination and/or anti-HBc Ab), 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
All acute toxic effects (excluding alopecia and fatigue) of any prior therapy (including surgery, radiation therapy, chemotherapy) must have resolved to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (v. 5.0) Grade 1
Full resolution of checkpoint blockade therapy-related adverse effects (including immune-related adverse effects) and no treatment for these AEs for at least 4 weeks prior to the time of enrollment. The only exception are patients with checkpoint blockade induced hypothyroidism and hypophysitis if these patients are on stable maintenance therapy with on levothyroxine or steroids ( 10 mg prednisone equivalent) for at least 2 months prior dosing
No history of severe immune related adverse effects from prior given immune checkpoint blockade therapy (CTCAE Grade 4; CTCAE Grade 3 requiring treatment >4 weeks)
Female patients: negative blood pregnancy test at Screening for women of childbearing potential (WOCBP). WOCBP must agree to use, from the screening to six months following the last study drug administration, 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)](http://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 or vasectomized partner
Male patients: Male subjects able to father children must agree to use two acceptable methods of contraception throughout the study (e.g. condom with spermicidal gel). Double-barrier contraception is required
Negative TB test (e.g. Mantoux or Quantiferon assay)
A personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study and has given consent 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)
Informed consent must be obtained for all the patients prior to any screening
procedure for the present study
Subjects who participated in an investigational drug or device study within 4 weeks prior to study treatment start
Radiotherapy within 4 weeks prior to study treatment start
Active or history of autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent
Patients with primary brain tumors or CNS disease will be excluded
Patient taking herbal medications within 7 days prior to first dose of the study drug
Known history of allergy to an excipient in study medication or any other intravenously administered human proteins/peptides/antibodies
Absolute neutrophil count (ANC) < 1.5 x 10^9/L, platelets < 100 x 10^9/L or haemoglobin (Hb) < 9.0 g/dl
Chronically impaired renal function as indicated by creatinine clearance < 60 mL/min
Inadequate liver function (ALT, AST, ALP 2.5 x ULN or total bilirubin 2.0 x ULN). At the discretion of the investigator, an increased exclusion threshold for patients with liver metastasis can be accepted as follows: ALT, AST and ALP 5 x ULN
Any severe concomitant condition which makes it undesirable for the patient to participate in the study or which could jeopardize compliance with the protocol, in the opinion of the investigator
History within the last year of cerebrovascular disease and/or 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
Abnormal LVEF or any other abnormalities observed during baseline ECG and echocardiogram investigations that are considered as clinically significant by the investigator. Subjects with current, or a history of QT/QTc prolongation would be excluded. In particular
patients with a marked prolongation of QT/QTc interval (e.g., repeated demonstration of QTc >480 milliseconds using Fredricia's QT correction formula) are excluded
patients with a history of risk factors for Torsades de Pointes (e.g., heart failure, hypokalemia, family history of prolonged QT syndrome) are excluded
patients who require the use of concomitant medications that prolong the QT/QTc interval are excluded
Uncontrolled hypertension as defined by systolic blood pressure 140 mmHg and diastolic blood pressure 90 mmHg
Ischemic peripheral vascular disease (Grade IIb-IV according to Leriche-Fontaine classification)
Severe diabetic retinopathy such as severe non-proliferative retinopathy and proliferative retinopathy
Major trauma including major surgery (such as abdominal/cardiac/thoracic surgery) within 4 weeks of administration of study treatment
Pregnancy or breast-feeding
Systemic chronic steroid therapy (>10 mg/day prednisone or equivalent) or any other immunosuppressive therapy within 14 days of the first dose of study treatment. Topical, inhaled, nasal and ophthalmic steroids are allowed
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
Concurrent or previous malignancies (other than the indication for this trial), unless a complete remission without further recurrence was achieved at least 2 years prior to trial entry
Growth factors or immunomodulatory agents within 7 days prior to the administration of study treatment
Serious, non-healing wound, ulcer or bone fracture
Requirement of concurrent therapy with anticoagulants at full therapeutic doses
Requirement of concurrent use of other anti-cancer treatments or agents other than study medication
Any recent live vaccination within 4 weeks prior to treatment or plan to receive vaccination during the study