Beschreibung

Rekrutierung gestartet

A Randomized, Open-label, Phase 3 Study of Acalabrutinib in Combination with Rituximab and Reduced Dose CHOP (R-miniCHOP) in Older Adults with Untreated Diffuse Large B-Cell Lymphoma

Studientherapie

Pre-phase treatment (both arms, exceptions apply): prednisolone (or equivalent) 50-100 mg p.o. or i.v. for approx. 7 days.
Immunchemotherapy: six cycles R-miniCHOP [rituximab i.v.: 375 mg/m2 (D0), cyclophosphamide i.v.: 400 mg/m² (D1), doxorubicine i.v.: 25 mg/m² (D1), vincristine i.v.: 1 mg (D1) prednisolone p.o.: 40 mg/m² D1 to D5, repeated every 3 weeks]
Standard arm: six cycles of R-miniCHOP
Experimental arm: six cycles of R-miniCHOP together with acalabrutinib 100mg p.o. twice daily starting from D1 of first R-miniCHOP cycle continuously for a total treatment duration of 12 months.

Studienstatus

Rekrutierung gestartet/nimmt Patienten auf

Allgemeine Infos zum Antrag

Herr Dr. med. Konstantinos Christofyllakis
Konstantinos.Christofyllakis@uks.eu

Universität des Saarlandes - Homburg (Institution, 12033)
Klinik für Innere Medizin I
Geb. 41.1, Kirrberger Str. 100
66421 Homburg

Improvement of progression free survival (PFS) by adding acalabrutinib to R-miniCHOP followed by acalabrutinib maintenance compared with R-miniCHOP alone.

• To determine whether survival can be improved by adding acalabrutinib to standard R-miniCHOP.
• To determine whether event free survival can be improved by adding acalabrutinib to standard R-miniCHOP, according to investigator and blinded independent central review (BICR).
• To determine whether PFS can be improved by adding acalabrutinib to standard R-miniCHOP, according to BICR.
• To analyze outcomes according to cell of origin as per immunohistochemistry and gene expression analysis, as well as and molecularly defined DLBCL genotype.
• To compare complete (CR), partial (PR) and overall (ORR) remission rates as well as duration of response (DoR) between both treatment (acalabrutinib plus R-miniCHOP versus R-miniCHOP alone) and molecular groups (COO, molecular genotype).
• To compare progression rate, relapse rate as well as central nervous system (CNS) relapse rate between both treatment (acalabrutinib plus R-miniCHOP versus R-miniCHOP alone) and molecular groups (COO, molecular genotype).
• To determine toxicity and protocol adherence of R-miniCHOP with or without acalabrutinib.
• To evaluate quality of life with R-miniCHOP with or without acalabrutinib.

Patients with newly diagnosed, histologically proven, previously untreated CD20+ DLBCL (WHO classification 2017) who are above 80 years of age or above the age of 60 and ineligible for full dose R-CHOP according to investigator assessment, with Ann Arbor disease stage I with bulk e7.5cm, II, III or IV.

National, multicentre, randomised, open-label, phase 3 study
It is hypothesized that PFS at 1-year is 59% in treatment arm without acalabrutinib and 74% in treatment arm with acalabrutinib. A two-sided log rank test with an overall sample size of 314 patients (100 events) achieves 80% power at a 5% significance level (two-sided) to detect these 1-year PFS difference of 15%. This corresponds to a hazard ratio of 0.571. We anticipate that about 5% of patients will be lost of follow-up. Therefore, a total of 330 patients (165 in each arm) will be included.

Progression-free survival, investigator assessed

• Overall survival
• Event-free survival, investigator assessed and per blinded independent central review (BICR)
• Progression-free survival, per BICR
• Outcomes according COO and molecularly defined genotype
• Complete response rate
• Partial response rate
• Overall response rate
• Duration of response
• Progression rate
• Relapse rate and CNS relapse rate
• Toxicity
• Rate of treatment-related deaths
• Protocol adherence
• Quality of life as assessed by the EQ-5D-5L.

Spezifische Infos zum Antrag

Informed consent
1. Ability to understand the purpose and risks of the study and capable of giving signed informed consent which includes:
a. Compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol
b. Authorization to use protected health information/data (in accordance with the currently applicable/valid data protection regulation)
2. Provision of signed and dated, written ICF prior to any mandatory study specific procedures, sampling, and analyses
3. Willing and able to participate in all required evaluations and procedures in this study protocol, including swallowing capsules and tablets without difficulty.
Age/Sex
4. Men and women >80 years of age or >60 years of age and ineligible for full dose R-CHOP according to investigator assessment.
5. Male subjects who are sexually active must agree to use highly effective forms of contraception with the addition of a barrier method (condom) during the study. They furthermore must agree to refrain from sperm donation during the study and 12 months after the last dose of rituximab or cyclophosphamide, 6 months after the last dose of doxorubicin, 30 days after the last dose of vincristine, and 2 days after the last dose of acalabrutinib, whichever is the longer.
6. Female subjects of childbearing potential who are sexually active and must agree to use highly effective forms of contraception while on the study and 12 months after the last dose of rituximab or cyclophosphamide, 6 months after the last dose of doxorubicin, 30 days after the last dose of vincristine, and 2 days after the last dose of acalabrutinib, whichever is the longer.
Disease characteristics
7. Histologically proven, previously untreated CD20+ diffuse large B-cell lymphoma (DLBCL) according to the 2017 WHO classification including:
a. diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS)
b. primary cutaneous DLBCL leg type
c. Intravascular large B-cell lymphoma
d. EBV+ DLBCL, NOS
e. HHV8+DLBCL, NOS
f. mediastinal (thymic) large B-cell lymphoma
g. transformed DLBCL from low grade lymphoma
h. B-cell lymphoma with intermediate features between DLBCL and classical Hodgkin lymphoma
i. follicular lymphoma grade 3B
j. high-grade B-cell lymphoma, NOS
k. high-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements
l. T-cell/histiocyte-rich large B-cell lymphoma
m. DLBCL associated with chronic inflammation
n. ALK+ large B-cell lymphoma
o. large B-cell lymphoma with IRF4 rearrangement
8. Disease Stage I with bulk e7.5cm, II, III or IV according to Ann Arbor Classification

Type of patient and clinical characteristics
9. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. An ECOG Score of 3 is also acceptable only if this is directly attributable to lymphoma.
10. Meet the following laboratory parameters:
a. Absolut neutrophil count (ANC) e 1500 cells/µl or platelet count e 100.000/µl unless directly attributable to lymphoma.
b. Serum AST and ALT d3 x upper limit of normal (ULN) unless directly attributable to lymphoma.
c. Total bilirubin d1.5 x ULN, unless directly attributable to Gilbert’s syndrome or lymphoma.
d. Estimated creatinine clearance of e30 mL/min, calculated by Cockcroft-Gault (using actual body weight) (if male, [140-Age] x Mass [kg] / [72 x creatinine mg/dL]; multiply by 0.85 if female), or serum creatinine d2.5 x ULN.

Medical conditions
1. Evidence of disease (such as severe or uncontrolled systemic diseases, including uncontrolled hypertension and renal transplant) that, in the investigator’s opinion, make it undesirable for the patient to participate in the study or that would jeopardize compliance with the protocol.
2. Significant cardiovascular disease such as symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of randomization , or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification at Screening, corrected QT interval (QTc) > 480 msec at randomization (patients with pacemaker or bundle branch blocks excluded), or LVEF < 45%. Subjects with controlled, asymptomatic atrial fibrillation are allowed to enroll on study.
3. Severe pulmonary dysfunction (CTCAE grade 3 or 4) unless associated with lymphoma.
4. Severe psychiatric or neurologic disease that, in the investigator’s opinion, make it undesirable for the patient to participate in the study or that would jeopardize compliance with the protocol.
5. Persistent neuropathy CTCAE grade 3 or 4.
6. Refractory nausea and vomiting, inability to swallow the formulated product, or malabsorption syndrome; chronic severe gastrointestinal disease, gastric restrictions, or bariatric surgery such as gastric bypass; partial or complete bowel obstruction, or previous significant bowel resection that would preclude adequate absorption, distribution, metabolism, or excretion of study treatment.
7. History of prior malignancy that could affect compliance with the protocol or interpretation of results, except for the following:
a. Curatively treated basal cell carcinoma or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or carcinoma in situ / low risk carcinoma of the prostate at any time prior to study.
b. Other cancers not specified above that have been curatively treated by surgery and/or radiation therapy from which subject is disease-free for e2 years (e5 years for those treated with chemotherapy) without further treatment or which are not expected to limit survival to < 2 years.
8. Received a live virus vaccination within 28 days of first dose of study drug (cycle 1 day 1).
9. Known history of infection with HIV.
10. Any active significant infection (e.g., bacterial, viral or fungal, including subjects with positive cytomegalovirus [CMV] DNA polymerase chain reaction [PCR]) as assessed by the investigator.
11. History of or ongoing confirmed progressive multifocal leukoencephalopathy (PML).
12. Serologic status reflecting active hepatitis B or C infection.
a. Subjects who are hepatitis B core antibody (anti-HBc) positive and who are hepatitis B surface antigen (HBsAg) negative will need to have a negative PCR result before randomization and must be willing to undergo DNA PCR testing during the study. Those who are HbsAg-positive or hepatitis B PCR positive will be excluded.
b. Subjects who are hepatitis C antibody positive will need to have a negative PCR result before randomization. Those who are hepatitis C PCR positive will be excluded.
13. History of stroke or intracranial hemorrhage within 6 months before first dose of study drug.
14. History of clinically relevant bleeding diathesis (e.g., hemophilia, von Willebrand disease).
15. Major surgical procedure within 30 days before the first dose of study drug. Note: If a subject had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug.
16. Breastfeeding or pregnant.
17. Current life-threatening illness, medical condition, organ system dysfunction, social, geographical or economic condition which, in the Investigator’s opinion, could compromise the subject’s safety or put the study at risk.
18. Diagnosis of primary central nervous system lymphoma or secondary central nervous system or meningeal involvement by lymphoma.
Prior/Concomitant therapy
19. Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists. Patients using therapeutic low molecule weight heparin, direct oral anticoagulants or low dose aspirin will be eligible. Switching from vitamin K antagonists to one of the allowed anticoagulants above prior to trial entry is permitted.
20. Requires treatment with a strong cytochrome P450 3A (CYP3A) inhibitor or inducer. The use of strong CYP3A inhibitors/inducers within 1 week of the first dose of study drug (cycle 1 day 1) is prohibited. See details in Section 5.12.1.
21. Prior exposure to a BTK inhibitor.
22. Prior anthracycline use e300 mg/m2.
23. Already initiated lymphoma therapy except for steroid (max. total dose of 1000mg), vincristine (max. 1 mg once) or rituximab (max. 375mg/m2) prephase.
24. Concurrent participation in another therapeutic clinical trial.
25. Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Patients receiving proton pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrolment into this study.

We expect 3 fully eligible patients per centre per year. With 40 centres, this results in approximately 120 patients per year. For recruitment of 330 patients, approximately 3 years are required. We expect a slower recruitment during the beginning of the study, approximately 60 patients in the first, 110 patients in the second, and 160 patients in the third year. The last patient will be followed-up for 2 years. With the expected start of recruitment in Q4/2022, the recruitment period will finish in Q4/2025 and the follow-up in Q4/2027.

In Deutschland: 40

Sponsor: Universität des Saarlandes
Finazierung: AstraZeneca

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ca. 6800€ / Patient einschl. translationales Programm, zusätzlich set up fee/close out fee/archiving Pauschale 1x /Zentrum

Ja

• ARCHED_Trial synopsis_regarding_protocol_version_V01.4-F_clean