2024-513445-37-00招募中3 期
A prospective, open-label, randomized, multicenter phase-III trial to evaluate the efficacy of pirtobrutinib and epcoritamab compared with R-(mini)-CHOP for treatment of patients with Richter Transformation - CLLRT2
干预措施
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 71
- 试验地点
- 12
- 主要终点
- Investigator-assessed progression-free survival (PFS) according to Lugano criteria
研究概览
简要总结
The primary objective of the study is to evaluate the efficacy of a combinational therapy with pirtobrutinib and epcoritamab compared with standard R-(mini-)CHOP in patients with CLL and DLBCL-Richter transformation using formal hypothesis testing.
入排标准
- 年龄范围
- 18 years 至 65+ years（65+ Years, 18-64 Years）
- 接受健康志愿者
- 否
入选标准
- •Confirmed diagnosis of CLL or SLL according to iwCLL criteria (Hallek et al, 2018)
- •Age at least 18 years
- •ECOG performance status 0-
- •Life expectancy ≥ 3 months
- •Willingness of women of reproductive potential and their partners to observe highly effective birth control methods for the duration of treatment and for 1 month following the last dose of study treatment
- •Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements
- •Confirmed histopathological diagnosis of DLBCL-type RT
- •Previously untreated RT (prior CLL treatment or prephase treatement of RT with cortico-steroids is allowed)
- •Patients are required to have the below mentioned washout periods prior to planned Cycle 1 Day 1 (C1D1). In addition, prior treatment-related AEs must have recovered to Grade ≤ 1 with the exception of alopecia. • Targeted agents, investigational agents, therapeutic monoclonal antibodies or cytotoxic chemotherapy: 5 half-lives or 2 weeks, whichever is shorter • broad field radiation (≥ 30% of the bone marrow or whole brain radiotherapy) must be completed 14 days prior to study enrollment • palliative limited field radiation must be completed 7 days prior to study enrollment.
- •Creatinine clearance ≥40ml/min calculated according to the modified formula of Cockcroft and Gault or directly measured with 24hr urine collection or an equivalent method.
- •Adequate liver function as indicated by a total bilirubin ≤ 1.5 x, AST/ALT ≤ 3.0 x the institu-tional ULN value, unless directly attributable to the patient’s CLL/RT or to Gilbert’s Syn-drome, in which case a max. total bilirubin ≤ 3 x and AST/ALT ≤ 5 x the institutional ULN value are required.
- •Neutrophil count ≥ 1.0 G/l (G-CSF administration allowed), Hb ≥ 8 g/dl/ 4.96mmol/L (except for patients with bone marrow involvement due to CLL or RT in which the Hb must be ≥ 6.0G/dl/ 3.72 mmol/L), platelet count ≥ 50 G/l (except for patients with bone marrow involve-ment in which the platelet count must be ≥ 30,000).
- •Adequate coagulation, defined as activated partial thromboplastin time (aPTT) or partial thromboplastintime (PTT) and prothrombin (PT) or (international normalized ratio (INR) not greater than 1.5 x ULN.
- •Negative serological 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, treated with appro-priate antiviral therapy and HBV-DNA PCR is performed every month/every three months if persistently negative until 12 months after last study treatment), negative testing for hepa-titis-C RNA and negative HIV test within 6 weeks prior to registration.
排除标准
- •Patients with prior RT-directed therapy, including corticosteroids given for > 10 days with a daily dose above 50mg prednisolone or equivalent for more than 10 days.
- •Significant cardiovascular disease defined as: • unstable angina or acute coronary syndrome within the past 2 months prior to randomization • history of myocardial infarction within 3 months prior to randomization or • documented LVEF by any method of ≤ 40% in the 12 months prior to randomization • ≥ Grade 3 NYHA functional classification system of heart failure • Uncontrolled or symptomatic arrhythmias • Prolongation of the QT interval corrected for heart rate (QTcF) > 470 msec. QTcF is calcu-lated using Fridericia’s Formula (QTcF): QTcF = QT/(RR0.33). • Correction of suspected drug-induced QTcF prolongation can be attempted at the investi-gator’s discretion and only if clinically safe to do so with either discontinuation of the offend-ing drug or switch to another drug not known to be associated with QTcF prolongation. • Correction for underlying bundle branch block (BBB) allowed.
- •Unable to swallow capsules or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, bariatric surgery procedures, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction
- •Non-curatively treated malignancies other than the disease under the study (unless the malig-nant disease is in a stable remission [e.g. prostate cancer with SD under antihormonal therapy] and life expectancy > 2 years)
- •Active infection (e.g. persiting fever related to infection and not RT or persisting positive blood cultures) currently requiring systemic treatment
- •In case of suspicion for CMV infection, CMV testing (CMV PCR in Serum) should be done. Patients with unknown or negative status are eligible.
- •Any comorbidity or organ system impairment rated with a CIRS (cumulative illness rating scale) score of 4, excluding the eyes/ears/nose/throat/larynx organ system1, or any other life-threaten-ing illness, medical condition or organ system dysfunction that – in the investigator´s opinion could comprise the patients` safety or interfere with the absorption or metabolism of the study drugs (i.e. swallow study drug). This includes also patients with autoimmune condition other than autoimmune cytopenias requiring immunosuppressive therapy.
- •Requirement for therapy with strong CYP3A4 inhibitors/inducers
- •Known active infection with HIV, or serologic status reflecting active hepatitis B or C infection and not meeting the inclusion criterion 9, which says: Negative serological 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, treated with appropriate antiviral therapy and HBV-DNA PCR is per-formed every two months until 12 months after last dose of study treatment), and for hepatitis C (anti-HCV-ab negative; in case of positive HCV anti-body test, negative HCV-PCR is re-quired).
- •Major surgery within 4 weeks of the first dose of study drug.
- •Use of investigational agents, e.g. monoclonal antibodies or other experimental drugs within clinical trials, which might interfere with the study drug within 28 days (or 5 times half-life [t1/2] of the compound, whichever is shorter) prior to registration bridging for CLL, e.g. with covalent BTK inhibitors or Bcl2 inhibitors may be used, if the abovementioned criteria for a time interval of 5 times half-life before day 1 cycle1 within the study protocol is maintained; bridging for RT is recommended with steroids.
- •Patients with previous progression on non-covalent BTK inhibitors or CD20 targeting T-cell en-gaging antibodies
- •Known hypersensitivity to epcoritamab, pirtobrutinib or any of the ingredients
- •Pregnant women and nursing mothers or planning to become pregnant during the study or within 1 months of the last dose of study treatment.
- •Fertile men or women of childbearing potential unless: a. surgically sterile or ≥ 2 years after the onset of menopause, or b. willing to use two methods of reliable contraception including one highly effective con-traceptive method (Pearl Index <1) and one additional effective (barrier) method during study treatment and for 12 months after the end of study treatment.
- •Vaccination with a live vaccine <28 days prior to registration for study screening
- •Legal incapacity
- •Prisoners or subjects who are institutionalized by regulatory or court order
- •Persons who are in dependence to the sponsor or an investigator
- •Patients with Richter transformation to Hodgkin’s lymphoma or patients with other types of lmpyhoma.
- •Allogenic stem cell transplantation or CAR T-cell therapy within the last 100 days as well as o active graft versus host disease (GVHD); o cytopenia from incomplete blood cell count recovery post-transplant not matching inclusion criterion 7; 1 For patients who start study treatment with elevated liver enzymes due to CLL/RT or Gilbert’s syndrome, toxicity and AE reporting will follow CTCAE grading once these values further increase. E.g. if a patient starts with a bilirubin value of 2.0 m/dl, which rises to 3.0 mg/dl after one cycle, this should be reported as grade 2 bilirubinemia (see CTCAE v5) or need for anti-cytokine therapy for toxicity from CAR-T therapy; residual symptoms of neurotoxicity > Grade 1 from CAR-T therapy; o ongoing systemic immunosuppressive therapy or > 20 mg prednisone or equivalent daily.
- •Patients with known CNS involvement of RT
- •Patients with confirmed PML
- •Decompensated auto-immune cytopenia (defined as ongoing drop in haemoglobin [AIHA] or in platelets [ITP] in spite of prednisolone and/or intravenous immunoglobulins treatment)
- •Increased risk of bleeding, e.g. due to: o History of severe bleeding disorder such as hemophilia A, hemophilia B, von Willebrand disease, or history of spontaneous bleeding requiring blood transfusion or other medical intervention o Anticoagulant therapy with warfarin or other vitamin K antagonists (anticoagulation with a direct oral Xa or thrombin inhibitor (DOAC) or heparin is permitted) o History of major stroke or intracranial hemorrhage within 6 months before first dose of study drug
- •Requiring supplemental oxygen.
研究组 & 干预措施
CYCLOPHOSPHAMIDE
Comparator
干预措施: CYCLOPHOSPHAMIDE (Drug)
PREDNISOLONE
Comparator
干预措施: PREDNISOLONE (Drug)
EPCORITAMAB, EPCORITAMAB
Test
干预措施: EPCORITAMAB (Drug)
VINCRISTINE
Comparator
干预措施: VINCRISTINE (Drug)
MabThera 100 mg concentrate for solution for infusion
Comparator
干预措施: MabThera 100 mg concentrate for solution for infusion (Drug)
Jaypirca 100 mg film-coated tablets
Test
干预措施: Jaypirca 100 mg film-coated tablets (Drug)
Caelyx pegylated liposomal 2 mg/ml concentrate for solution for infusion
Comparator
干预措施: Caelyx pegylated liposomal 2 mg/ml concentrate for solution for infusion (Drug)
结局指标
主要结局
Investigator-assessed progression-free survival (PFS) according to Lugano criteria
Investigator-assessed progression-free survival (PFS) according to Lugano criteria
次要结局
- Overall response rate (ORR; assessed by Lugano)
- Complete response rate (CRR; assessed by Lugano guidelines) at the end of (combination) treatment [EO(C)T]
- Best response (assessed by Lugano)
- Undetectable minimal residual disease (uMRD) rate in peripheral blood at EO(C)T
- Duration of response (DOR) according to Lugano criteria
- Overall survival (OS)
- Time-to-next treatment (TTNT)
- Treatment-free survival (TFS)
- Proportion of patients receiving allogeneic stem cell transplantation (SCT) for consolidation
研究者
Barbara Eichhorst
Scientific
University Of Cologne
研究点 (12)
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