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).
NCT05657639Phase 2Recruiting
The First Affiliated Hospital of Soochow University · The First Affliated Hospital of Soochow University, Suzhou, Jiangsu
This study aims to investigate the efficacy and safety of cladribine, combined with low-dose cytarabine and venetoclax (CAV regimen) for relapsed/refractory acute myeloid leukemia (R/R AML).
Eligibility: 16 Years to 70 Years · All · 1. Aged 16-70 years old.
2. Diagnosed with R/R AML.
3. Patients with AML must meet one of the following criteria, A or B: A: Refractory AML disease was defined as follows: (1) failure to attain CR following exposure to at least 2 courses of standard or intensive induction therapy; or (2) bone marrow leukemia cell decline index (BMCDI) \< 50% and \> 20% after 1 course of standard or intensive induction therapy. B: Relapsed AML disease was defined as follows:
(1) reappearance of leukemic blasts in the peripheral blood after CR; or (2) detection of ≥ 5% blasts in the BM not attributable to another cause (e.g., BM regeneration after consolidation therapy); or (3) extramedullary relapse.
4\. ECOG performance status score less than 2. 5. Expected survival time ≥12 weeks. 6. Without serious heart, lung, liver, or kidney dysfunction. 7. Able to understand and provide informed consent.
NCT03661307Phase 1, Phase 2Recruiting
M.D. Anderson Cancer Center · M D Anderson Cancer Center, Houston, Texas
This phase I/II trial studies how well quizartinib, decitabine, and venetoclax work in treating participants with acute myeloid leukemia or high risk myelodysplastic syndrome that is untreated or has come back (relapsed). Quizartinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as decitabine and venetoclax, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving quizartinib and decitabine may work better at treating acute myeloid leukemia and myelodysplastic syndrome.
Eligibility: 18 Years to · All · * Diagnosis of 1) AML (World Health Organization \[WHO\] classification definition of \>= 20% blasts) excluding acute promyelocytic leukemia (APL) or 2) MDS with \> 10% blasts (defined by the International Prognostic Scoring System \[IPSS\] classification).
* For frontline Cohort: Patients aged \>= 60 years old who are not candidates for intensive induction therapy and agree to receive the proposed combination therapy will be enrolled.
* Not considered candidates for intensive remission induction chemotherapy at time of enrollment based on EITHER:
* 75 years of age OR
* \< 75 years of age with at least 1 of the following:
* Poor performance status (Eastern Cooperative Oncology Group \[ECOG\]) score of 2-3.
* Clinically significant heart or lung comorbidities, as reflected by at least 1 of:
* Left ventricular ejection fraction (LVEF) =\< 50%.
* Lung diffusing capacity for carbon monoxide (DLCO) =\< 65% of expected.
* Forced expiratory volume in 1 second (FEV1) =\< 65% of expected.
* Chronic stable angina or congestive heart failure controlled with medication.
* Liver transaminases \> 3 x upper limit of normal (ULN).
* Other contraindication(s) to anthracycline therapy (must be documented).
* Other comorbidity the investigator judges incompatible with intensive remission induction chemotherapy, which must be documented and approved by the principal investigator (PI).
* Patients with newly diagnosed AML with poor risk complex karyotype and/or TP53 deletions/mutations equal or younger than 60 year old
* For relapsed cohort: Patients aged \>= 18 years old. (Patients who are candidates for relapse cohort will be enrolled into the study regardless of their fitness for intensive chemotherapy). (a) Patients with relapsed/refractory AML are eligible if they are not eligible for potentially curative therapy such as effective salvage therapy or hematopoietic stem cell transplantation or who refuse these options at the time of enrollment.
* Detection of FLT3-ITD mutation or FLT3-ITD/TKD co-mutations in bone marrow and/or peripheral blood samples within 30 days prior to study enrollment.
* For frontline cohort: Patients must be chemonaive, i.e. not have received any chemotherapy (except hydrea or 1-2 doses of ara-C for transient control of hyperleukocytosis) for AML or MDS. They may have received transfusions, hematopoietic growth factors or vitamins for an antecedent hematological disorder (AHD) or for AML. Temporary prior measures such as apheresis, all-trans-retinoic acid (ATRA), steroids or hydrea while diagnostic work-up is being performed are allowed and not counted as a prior salvage. Supportive care therapy for MDS (growth factors, transfusions) will not be considered as prior therapy for MDS/AML and these patients will be enrolled to the frontline cohort of the study if they are otherwise eligible.
* For relapsed cohort: Patients who have received at least one prior therapy for AML or for MDS with \> 10% blasts will be eligible. Patients may have received up to 4 prior salvages for AML and/or MDS (defined by the IPSS classification). Prior therapy for AML or MDS will be counted as a prior salvage. Patients who receive MDS directed therapies considered not purely supportive such as HMAs, lenalidomide, investigational therapies, will be enrolled to the salvage cohort if they are otherwise eligible.
* In the absence of rapidly progressing disease, the interval from prior treatment to time of initiation of protocol therapy will be at least 2 weeks for cytotoxic agents or at least 5 half-lives for cytotoxic/noncytotoxic agents. The half-life for the therapy in question will be based on published pharmacokinetic literature (abstracts, manuscripts, investigator brochure's, or drug-administration manuals) and will be documented in the protocol eligibility document
* The use of chemotherapeutic or anti-leukemic agents is not permitted during the study with the following exceptions: (1) intratheca
NCT07277231Phase 3Recruiting
BeOne Medicines · City of Hope National Medical Center, Duarte, California
The purpose of this study is to investigate the efficacy and safety of fixed-duration sonrotoclax (also known as BGB-11417) plus zanubrutinib (also known as BGB-3111) (SZ) compared with fixed-duration of venetoclax plus acalabrutinib (AV) in participants with previously untreated chronic lymphocytic leukemia (CLL).
Eligibility: 18 Years to · All · * Treatment-naïve (TN) adults with confirmed diagnosis of CLL which requires treatment
* Eastern Cooperative Oncology Group (ECOG) score 0, 1, or 2
* Measurable disease by Computer Tomography/Magnetic Resonance Imaging
* Adequate bone marrow and organ function
NCT05197192Phase 3Recruiting
German CLL Study Group · Helios Klinikum Bad Saarow, Bad Saarow
This multicenter, prospective, open-label, randomized, superiority phase 3 study is designed to demonstrate that treatment with a triple combination of acalabrutinib, obinutuzumab and venetoclax (GAVe) prolong the progression-free survival (PFS) as compared to treatment with the combination of obinutuzumab and venetoclax (GVe) in pa-tients with high risk CLL (defined as having at least one of the follow-ing risk factors: 17p-deletion, TP53-mutation, complex karyotype or an unmutated IGHV-gene status).
Eligibility: 18 Years to 120 Years · All · * Documented CLL/SLL requiring treatment according to iwCLL criteria
* Age at least 18 years
* At least one of the following risk factors: 17p-deletion, TP53-mutation, complex karyotype (defined as defined as the presence of 3 or more chromosomal aberrations in 2 or more metaphases) or an unmutated IGHV gene status.
* Life expectancy ≥ six months
* Adequate bone marrow function indicated by a platelet count \>30 x10\^9/l
* Creatinine clearance ≥ 30ml/min
* Adequate liver function as indicated by a total bilirubin ≤ 2 x, AST/ ALT ≤ 2.5 x the institutional ULN value, unless directly attributable to the patient's CLL or to Gilbert's Syndrome
* Negative testing for hepatitis B (HbsAg negative and anti-HBc negative; patients positive for anti-HBc may be included if PCR for HBV DNA is negative and HBV-DNA PCR is performed every month until 12 months after last treatment cycle),or hepatitis C (negative testing for hepatitis C RNA within 6 wee
* ks prior to registration for study screening (i.e. PCR only required when serology was positive))
* ECOG (Eastern Cooperative Oncology Group Performance Status) status 0-2
NCT06152809Phase 1Recruiting
Dana-Farber Cancer Institute · Brigham and Women's Hospital, Boston, Massachusetts
The purpose of this research study is to test the safety and to explore the effectiveness of infusing cytokine- induced memory-like (CIML) natural killer (NK) cells in combination with Interleukin-2 (IL-2) and standard-of-care venetoclax as a treatment for Acute Myeloid Leukemia (AML) with measurable residual disease or oligoblastic (\< 20% blasts in the bone marrow) disease.
Names of the study therapies involved in this study are:
* Lymphodepleting therapy with Fludarabine and Cyclophosphamide prior to CIML NK cell infusion
* CIML NK (a cellular therapy)
* IL-2 (a recombinant, human glycoprotein)
* Venetoclax (a selective inhibitor of BCL-2 protein)
Eligibility: 18 Years to · All · Inclusion Criteria for Trial Enrollment (Registration Visit):
* Diagnosis of AML or MDS/AML (10-19% blasts) by 2022 ELN criteria. Historical test results (either peripheral blood or bone marrow) can be used to establish this diagnosis.
* Age ≥ 18 years old
* At time of screening patient has received any prior lines of therapy including prior chemotherapy and any prior stem cell transplant, provided that the stem cell transplant is \> 6 months ago with no ongoing need for immunosuppressive therapy for active graft-versus-host disease.
* Presence of molecular risk factors for relapse as defined by any of the following present at any time during a participant's history of AML:
* 2022 ELN adverse risk karyotype: t(6;9)(p23.3;q34.1)/DEK::NUP214; t(v;11q23.3)/KMT2A-rearranged; t(9;22)(q34.1;q11.2)/BCR::ABL1; t(8;16)(p11.2;p13.3)/KAT6A::CREBBP; inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2)/ GATA2, MECOM(EVI1), t(3q26.2;v)/MECOM(EVI1)-rearranged; -5 or del(5q); -7; Complex karyotype, monosomal karyotype
* 2022 ELN adverse risk mutations: Any one of the following mutations: Mutated TP53, ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, and/or ZRSR2
* Additional mutations associated with acquired resistance to venetoclax: Mutated NRAS, KRAS, FLT3 ITD/TKD
* ECOG performance status ≤2 (see Appendix A)
* Participants must meet the following organ function as defined below:
* Direct bilirubin: ≤1.5 x institutional upper limit of normal (ULN) (except Gilbert's or disease-related hemolysis, then \< 3 x ULN)
* AST(SGOT)/ALT(SGPT): ≤3 x institutional ULN
* creatinine clearance ≥ 45 mL/min; calculated by the Cockcroft Gault formula
* oxygen saturation ≥ 90% on room air
* left ventricular ejection fraction ≥ 40%
* Negative pregnancy test for women of childbearing potential only.
* The effects of CIML NK cells and IL-2 on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study and until 4 months after the last IL-2 dose administration.
* Participants with current symptoms of cardiac disease should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, participants should be class 2B or better.
* Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
* Ability to understand and the willingness to sign a written informed consent document. (Providing consents in as many languages as possible is encouraged)
* Subjects must be able to swallow pills.
* No laboratory evidence of ongoing hemolysis in the opinion of investigator (demonstration of hemolysis should include a haptoglobin level that is below assay).
Exclusion Criteria for Trial Enrollment (Registration visit)
* Participants are excluded if they received prior allogeneic stem cell transplant ≤ 6 months ago or require immunosuppressive therapy for active GVHD, received prior donor lymphocyte infusion (DLI) ≤ 2 months ago, or received prior organ transplant or donor lymphocyte infusion (DLI), CAR-T cell or NK cell therapy at any time.
* Persisting Grade \> 2 non hematologic toxicity related to prior therapy is excluded; however, alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting a safety risk based on investigator's judgment are acceptable.
* Autoimmune disease: Patients with a history of inflammatory bowel disease, inc
