NCT04989491Phase 4Recruiting
University Hospital, Strasbourg, France · Les Hôpitaux Universitaires de Strasbourg, Strasbourg
Epstein Barr virus infects over 90% of human population and persists during lifetime. After infecting B lymphocytes, EBV remains latent in memory B cells. In immunocompromised patients, primary infection could lead to an uncontrolled EBV infected B cells proliferation because of impaired T cell specific cytotoxicity. The latent EBV infection is characterized by expression of restricted latent gene products, which drive cell proliferation and progression to PTLD. As a consequence, EBV seronegativity and EBV mismatch are major risk factors for developing PTLD. The investigators reported in a previous work from the French Registry that the incidence of PTLD was multiplied by ten in adult EBV negative kidney transplant recipients. Moreover, even if the event is relatively rare after transplantation, the prognosis is severe with high morbidity and an overall mortality rate around 50%.
Nowadays, few and inconsistent data exist regarding beneficial preventing strategies like antiviral therapy, reduction of immunosuppression or immunoglobulin infusion in this high-risk population of EBV negative recipients. Therefore, an efficient and safe preventive treatment is still lacking to decrease PTLD incidence.
Rituximab, has been already proposed in stem cell transplant recipients as a preemptive therapy in patients with a persistent EBV viremia independently of their EBV status. A pilot study was performed in EBV negative kidney transplant recipients but in a very small population. Schachtner60 reported the cases of 5 EBV negative recipients receiving kidney from EBV positive donors after a treatment with Rituximab. Only 2 patients showed a seroconversion and no patients developed neither a viremia nor a PTLD after 49 months of follow-up.
The main objective of the investigators study is to evaluate the efficacy of early infusion of Rituximab in the prevention of EBV primary infection and post-transplant lymphoproliferative disorder (PTLD) occurrence in adult EBV negative kidney transplant recipients transplanted with an EBV positive donor.
Eligibility: 18 Years to · All · * Adult patients (age ≥18 years at transplantation)
* Kidney and kidney pancreas simultaneous transplantation
* EBV seronegative patients (IgG anti EBNA, IgG anti VCA and IgM anti VCA negative) (from 6 months before transplantation to the day of transplantation, included)
* Patient who have given written informed consent
* Negative pregnancy test and use of contraception during all the study
* EBV positive donor
* Patient affiliated to a social security scheme
Exclusion criteria:
* Patient with known HBV active infection
* Allergy to Rituximab
* Severe Immune deficiency
* Severe cardiac insufficiency
* Pregnant or lactating women
* Women of child bearing potential unless they are using a birth control method
* Patient under judicial protection or under guardianship
* Patient currently participating in another clinical trial investigating drugs. Observational studies are not considered as an exclusion criterion
* Any form of substance abuse, psychiatric disorder or condition, which, in the opinion of the investigator, is incompatible with the participation in the study
* Unlikely to comply with the visits scheduled in the protocol.
NCT05099471Phase 2Recruiting
Christian Buske · Onkologische Schwerpunktpraxis Bielefeld, Bielefeld
In Waldenström's macroglobulinemia (WM) chemotherapy induces only low CR/VGPR rates and response duration is limited. In addition, WM patients are often elderly, partly not tolerating chemotherapy related toxicities. Thus, innovative approaches are needed which combine excellent activity and tolerability in WM. Chemotherapy-free approaches are highly attractive for this patient group. Based on its high activity and favorable toxicity profile in indolent B-NHL such as CLL, Venetoclax was approved for the treatment of this diseases by the FDA and the European Medicines Agency (EMA). First data in relapsed/refractory WM have documented high activity and low toxicity of Venetoclax also in WM, including patients with prior Ibrutinib treatment or patients carrying CXCR4 mutations. Ibrutinib itself has high activity and a relatively low toxicity profile in WM, but has also major disadvantages: the main disadvantage is the need to apply this drug continuously. Furthermore, Ibrutinib efficacy depends largely on the genotype with a substantial drop in major responses and PFS in the presence of CXCR4 mutations and non-mutated MYD88. In particular the need of continuous treatment for Ibrutinib has prevented that Ibrutinib has become the standard of care outcompeting conventional Rituximab/chemotherapy. This is reflected in current guidelines such as the NCCN and the ESMO guidelines, which still see immunochemotherapy as a backbone of treatment, largely because of the advantage of a timely fixed application. Data in CLL in the relapsed as well as in the first line setting have convincingly shown that in contrast to Ibrutinib Venetoclax is highly efficient also when used in a timely defined application scheme over 12 months in combination with the anti-CD20 antibody Rituximab. Data documented deep responses including molecular responses and a highly significant advantage over immunochemotherapy in large international Phase III trials, changing the standard of care in this disease.
Based on this the hypothesis is that timely fixed application of the combination of Venetoclax and Rituximab induces significantly superior treatment outcomes compared to chemotherapy and Rituximab (DRC) in patients with treatment naïve WM, regardless of the genotype. A first indication for this assumption in the proposed trial will allow the performance of confirmatory phase 3 trials that might change the standard of care in WM.
Eligibility: 18 Years to · All · * Proven clinicopathological diagnosis of WM as defined by consensus panel one of the Second International Workshop on WM (IWWM). Histopathology has to be perfomed before randomization but within the last 4 months before start of treatment. In addition, pathological specimens have to be sent to the national pathological reference center prior to randomization for the determination of the mutational status of MYD88 and CXCR4 prior to randomization if the mutational status hasn't been determined before. Pathological reference center must confirm the diagnosis of WM.
* De novo WM independent of the genotype.
* Patients must have at least one of the following criteria to start study treatment as partly defined by consensus panel criteria from the Seventh IWWM and ESMO Guideline:
* Recurrent fever, night sweats, weight loss, fatigue (at least one of them).
* Hyperviscosity.
* Lymphadenopathy which is either symptomatic or bulky (≥ 5 cm in maximum diameter).
* Symptomatic hepatomegaly and / or splenomegaly.
* Symptomatic organomegaly and / or organ or tissue infiltration.
* Peripheral neuropathy due to WM.
* Symptomatic cryoglobulinemia.
* Symptomatic Cold agglutinin anemia.
* Autoimmune hemolytic anemia and/or thrombocytopenia.
* Nephropathy related to WM.
* Amyloidosis related to WM.
* Hemoglobin ≤ 10 g/dL (patients should not have received red blood cells transfusions for at least 7 days prior to obtaining the screening hemoglobin).
* Platelet count \< 100 x 109/L (caused by bone marrow \[BM\] infiltration of the lymphoma).
* Serum monoclonal protein \> 5 g/dL, even with no overt clinical symptoms.
* IgM serum concentration ≥ 6 g/dL.
* and other WM associated relevant symptoms
* Subject must be ≥ 18 years of age.
* Life expectancy \> 3 months.
* World Health Organization (WHO) / ECOG performance status ≤ 2.
* Left ventricular ejection fraction ≥ 40% as assessed by transthoracic echocardiogram (TTE).
* Baseline platelet count ≥ 50x109/L, absolute neutrophil count ≥ 0.75x109/L (if not due to BM infiltration by the lymphoma).
. Adequate hepatic function per local laboratory reference range as follows:
* Aspartate transaminase (AST) and alanine transaminase (ALT) \< 3.0 x ULN.
* Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin).
* Subject must have adequate renal function as demonstrated by a creatinine clearance ≥ 30 mL/min; calculated by the Cockcroft Gault formula or measured by 24 hours urine collection.
* Women of childbearing potential (WCBP), i.e. fertile, following menarche and until becoming postmenopausal must have negative results for pregnancy test and must agree to use a highly effective method of birth control for the duration of the therapy up to 12 months after end of therapy
* Men must agree not to father a child for the duration of therapy and 12 months after and must agree to advice their female partner to use a highly effective method of birth control. Males must refrain from sperm donation for the duration of treatment and at least 12 months after the last dose of study medication.
* Each patient must voluntarily date and sign an informed consent form in the native language of the patient indicating that he or she understands the purpose of and procedures required for the study and are willing to participate in the study. Patients must be willing and able to adhere to the prohibitions and restrictions specified in this protocol.
* Affiliation to a social security scheme (relevant for France only).
