International Multicentric Phase II Trial to Evaluate the Efficacy and Safety of Pirtobrutinib in Combination With Rituximab in Patients With Indolent Clinical Forms of Mantle Cell Lymphoma
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 50
- 试验地点
- 15
- 主要终点
- Efficacy of Pirtobrutinib in combination with rituximab after 6 cycles
研究概览
简要总结
This is a multicenter, international, open-label, single-arm phase II clinical trial designed to evaluate the activity and safety of a combination therapy with pirtobrutinib and rituximab (P-R) in treatment-naïve adult patients diagnosed with indolent clinical forms of Mantle Cell Lymphoma (MCL). The study applies a Simon's two-stage design, with an interim analysis after the first 16 patients to determine continuation based on complete remission rate (CRR) after 6 cycles.
详细描述
The current evidence obtained from clinical trials exploring the incorporation of BTK inhibitors in first-line treatment of MCL points toward a clear significant improvement in both patient responses and progression-free survival. Until new data from randomized clinical trials become available, the inclusion of new combinations of BTK inhibitors with chemoimmunotherapy or with new targeted combinations alone, remains a matter of debate. In addition, there is some concern regarding the additional toxicity associated with some of these combinations, which could be ameliorated by a fixed duration of treatment or by the use of newer generation BTK inhibitors, associated with significantly better tolerability. The new non-covalent BTK inhibitor pirtobrutinib has recently shown more promising activity in MCL relapsed/refractory to prior covalent BTK inhibitors therapy, and also with very favourable safety profile (3% of discontinuations due to drug-induced adverse events). Pirtobrutinib could be a very interesting drug to be tested in the upfront setting to try to sort out the significant toxicity more frequently observed with covalent BTK inhibitors. Indeed, indolent clinical forms of MCL that represent around 20% of new MCL diagnosis could be particularly suitable to receive pirtobrutinib as a first-line treatment in combination with rituximab in order to maximize responses and the rate of undetectable molecular minimal residual disease while improving the treatment tolerance. This combination could also limit treatment duration, except for MRD detectable and TP53 mutated cases, according to the data shown in the IMCL-2015 trial. By testing pirtobrutinib in combination with rituximab in a population of indolent MCL patients, the investigators aim to improve and refine the potential new standard treatment for this particular subset of MCL patients. Moreover, the Sponsor plan to conduct a clinical study that will allow not only a deep molecular MRD analysis but also a thorough biological study with different bulk and single-cell level multi-omic platforms in order to gain insight into pirtobrutinib performance in indolent clinical forms of MCL. For this purpose, the Sponsor have designed a multicenter, international, open-label, phase II clinical to assess the efficacy of pirtobrutinib in combination with rituximab in patients with indolent MCL.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adult patients (≥18 years of age).
- •Written informed consent must be obtained before any study-specific assessment is performed.
- •Subjects with confirmed diagnosis of Mantle Cell Lymphoma according to the International Consensus Classification, (ICC) 2022] or World Health Organization (WHO) Classification
- •Classical, small-cell variants and marginal-zone variants can be included.
- •Naïve patients for MCL management (no prior therapies, excluding diagnostic splenectomy)
- •Asymptomatic patients
- •Eastern Cooperative Oncology Group (ECOG) performance status <2 (0-1)
- •Clinical stage I-IV according to the Ann Arbor classification with no symptoms attributable to MCL
- •Patients with a leukemic non-nodal presentation with mainly bone marrow or peripheral blood involvement are eligible. Other asymptomatic clinical presentations are acceptable in case of low tumour burden, including MCL with lymph node enlargement ≤ 3 cm in the largest diameter and with low proliferation index (Ki67 < 30%)
- •The following laboratory values at screening:
- •Neutrophil count ≥ 1×109/L, Haemoglobin level ≥ 100 g/L and platelet count ≥100×109/L
- •Transaminases (AST and ALT) ≤ 3 x ULN
- •Total bilirubin ≤1.5 x ULN unless bilirubin rise is due to Gilbert's disease
- •Calculated creatinine clearance ≥ 30 ml/min according to Cockcroft/Gault Formula (140 - age) × body weight (kg) × 0.85 (if female)/ serum creatinine (mg/dL) × 72
- •Adequate coagulation, defined as activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT) and prothrombin (PT) or (international normalized ratio (INR) not greater than 1.5 x ULN.
- •Stable disease without evidence of clinical progression for at least 3 months. Patients in prolonged observation may be included (over 3 months).
- •Female patients of child-bearing potential must have a negative serum pregnancy test at screening and agree to use highly effective contraception from the start of study treatment (See Appendix 4), during the treatment period and for at least 1 month following the last dose of pirtobrutinib and for 12 months following treatment with Rituximab.
- •Male patients must use highly effective contraception (if sexually active with a female of child-bearing potential) according to the recommendations provided by the Clinical Trial Facilitation and Coordination Group (CTFG), from start of study treatment, during the treatment period, and for at least 1 month following the last dose of pirtobrutinib and for 12 months following treatment with rituximab.
- •Willing and capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol.
- •Not included in other clinical trial or treated with an experimental drug unrelated to MCL within the past 2 years
排除标准
- •Subjects with aggressive histological variants: blastoid and pleomorphic variants of MCL
- •B-cell monoclonal lymphocytosis with MCL phenotype
- •Presence of B symptoms or any relevant symptoms related to the MCL.
- •Nodal clinical forms with lymph node enlargement > 3 cm (largest diameter).
- •Organ dysfunction related to MCL including creatinine level > 2 mg/dl or altered liver biochemistry (> 3x ULN).
- •Serum LDH over ULN
- •Known central nervous system (CNS) infiltration.
- •Expected MCL therapy requirement in a short time (< 3 months)
- •Anticoagulation requirement with vitamin K antagonists
- •History of bleeding diathesis
- •Past medical history of stroke or intracranial haemorrhage within 6 months prior to inclusion.
- •Significant cardiovascular disease defined as: i) unstable angina or acute coronary syndrome within the past 2 months prior to randomization; ii) history of myocardial infarction within 3 months prior to randomization or documented LVEF by any method of ≤ 40% in the 12 months prior to inclusion; iii) ≥ Grade 3 NYHA functional classification system of heart failure; iv) Uncontrolled or symptomatic arrhythmias.
- •Prolongation of the QT interval corrected for heart rate (QTcF) > 470 msec. QTcF is calculated using Fridericia's Formula (QTcF): QTcF = QT/(RR0.33). Correction of suspected drug-induced QTcF prolongation can be attempted at the investigator's discretion and only if clinically safe to do so with either discontinuation of the offending drug or switch to another drug not known to be associated with QTcF prolongation. Correction for underlying bundle branch block (BBB) allowed.
- •NOTE: Patients with pacemakers are eligible if they have no history of fainting or clinically relevant arrhythmias while using the pacemaker
- •Patients who have tested positive for Human Immunodeficiency Virus (HIV) are excluded due to risk of opportunistic infections with both HIV and BTK inhibitors. For patients with unknown HIV status, HIV testing will be performed at Screening and result must be negative for enrolment.
- •Known active hepatitis B virus (HBV) infection based on criteria below: Patients with positive hepatitis B surface antigen (HBsAg) are excluded. Patients with positive hepatitis B core antibody (anti-HBc) and negative HBsAg require a negative hepatitis B polymerase chain reaction (PCR) evaluation before inclusion. Patients who are HBV DNA PCR positive will be excluded. Prophylactic antiviral treatment will be required in the patients with positive anti-HBc finally eligible.
- •Hepatitis C virus (HCV): positive hepatitis C antibody. If positive hepatitis C antibody result, patient will need to have a negative result for hepatitis C ribonucleic acid (RNA) before inclusion. Patients who are hepatitis C RNA positive will be excluded.
- •Known active cytomegalovirus (CMV) infection. Unknown or negative status are eligible.
- •Concomitant or previous malignancies the last 2 years other than basal skin cancer or in situ uterine cervix cancer.
- •Major surgery within 4 weeks of inclusion.
- •Vaccinated with live, attenuated vaccines within 4 weeks of inclusion.
- •Active uncontrolled auto-immune cytopenia (e.g., autoimmune haemolytic anaemia [AIHA], idiopathic thrombocytopenic purpura [ITP]) for which new therapy was introduced or existing therapy was escalated within the 4 weeks prior to study enrolment to maintain adequate blood counts.
- •Evidence of other clinically significant uncontrolled condition(s) including but not limited to, uncontrolled systemic bacterial, viral, fungal or parasitic infection (except for fungal nail infection), or any other clinically significant active disease process which in the opinion of the investigator may pose a risk for patient participation (screening for chronic conditions is not required).
- •Known hypersensitivity to any of the excipients of Pirtobrutinib or Rituximab or any intended study medications.
- •Females who are pregnant or breastfeeding or plan to become pregnant or initiate breastfeeding during the study or within 1 month of the last dose of pirtobrutinib or 12 months of the last dose of rituximab.
- •Patients unable to take oral medication or with clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal absorption of the study drug.
研究组 & 干预措施
Pirtobrutinib with rituximab
Patients will receive a P-R combination for at least 24 cycles (C24). The first cycle of P-R will be administered at day 1 (baseline) . Pirtobrutinib discontinuation will be decided after C24, according to the MRD response and the TP53 mutational status. Rituximab treatment will end up at C23.
干预措施: Pirtobrutinib and rituximab (Drug)
结局指标
主要结局
Efficacy of Pirtobrutinib in combination with rituximab after 6 cycles
时间窗: At the end of Cycle 6 (each cycle is 28 days)
To assess the activity of Pirtobrutinib in combination with rituximab (P-R) as a therapeutic alternative to immunochemotherapy (R-Bendamustine or R-CHOP regimen) in patients with an indolent clinical presentation of MCL. The primary objective will be assessed by the complete remission rate (CRR), defined as the percentage of patients who achieve a complete response (CR) at the end of Cycle 6 of the P-R combination according to the Lugano Classification.
次要结局
- To evaluate the activity of Pirtobrutinib-Rituximab combination along time in terms of ORR(At month 6, month 12 and month 24.)
- Evaluation of MRD(After cycle 6, cycle 12, cycle 30, cycle 36, cycle 42, cycle 48 (each cycle is 28 days), and End of treatment (28 days after las administration of Study drug).)
- To determine the safety and tolerability of P-R combination(Baseline, during all the cycles day 1 visit (each cycle is 28 days) and at EoT (28 days afert las administration of Study drug).)
- To assess the patient Health-related Quality of Life (HRQoL)(Between baseline and month 6, month 12, and month 24 and End of Study (month 48))
- To assess the patient Health-related Quality of Life (HRQoL).(Between baseline and month 6, month 12, and month 24 and End of Study (month 48))
- To perform a comprehensive biological characterization of cases with an indolent clinical presentation of MCL(After cycle 6, cycle 12, cycle 18, cycle 24, cycle 30, cycle 36, cycle 42 and cycle 48 (Each cycle is 28 days))
- To evaluate the activity of Pirtobrutinib-Rituximab combination along time in terms of CRR(At months 12 and 24)
- To evaluate the activity of Pirtobrutinib-Rituximab combination along time in terms of MRD response(At the end of Cycle 6, Cycle 12 and Cycle 24 (each cycle is 28 days))
- To evaluate the activity of Pirtobrutinib-Rituximab combination along time in terms of MRD response:(At the end of Cycle 6, Cycle 12 and Cycle 24 (each cycle is 28 days))
- To evaluate the activity of Pirtobrutinib-Rituximab combination along time in terms of clinical and molecular response duration and survival.(From the start of the study treatment with P-R until the date of death)