Acalabrutinib in Combination With R-miniCHOP in Older Adults With Untreated Diffuse Large B-Cell Lymphoma

Phase 3

Recruiting

• Conditions: Large B-cell Lymphoma; Diffuse Large B Cell Lymphoma
• Interventions: Drug: R-miniCHOP; Drug: R-miniCHOP + Acalabrutinib

• Registration Number: NCT05820841
• Lead Sponsor: Universität des Saarlandes

Brief Summary

The goal of this clinical trial is to study the addition of Acalabrutinib to standard R-miniCHOP in older adults with DLBCL. The main question it aims to answer is whether progression free survival kann be prolonged with the addition of Acalabrutinib.

Participants will be randomised to receive either R-miniCHOP alone or R-miniCHOP with Acalabrutinib.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2023-03-08
• Study First Submitted QC: 2023-04-19
• Study First Posted: 2023-04-20
• Study Start: 2023-06-07
• Status Verified: 2023-08
• Last Update Submitted: 2023-08-30
• Last Update Posted: 2023-08-31
• Primary Completion: 2028-04
• Study Completion: 2028-12

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 330

Inclusion Criteria

Informed consent

1. Ability to understand the purpose and risks of the study and capable of giving signed informed consent which includes:

   1. Compliance with the requirements and restrictions listed in the informed consent form (ICF).
   2. Authorization to use protected health information/data [in accordance with the General Data Protection Regulation (GDPR)].

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 up to 80 years of age and ineligible for full dose R-CHOP according to investigator assessment*.

   We recommend classifying patients aged 61-80 as full-dose R-CHOP ineligible if they fulfill one of the following criteria: ADL <5, IADL <6, CIRS-G ≥1 score = 3, or > 8 score = 2.

5. Male patients who are sexually active with women of childbearing potential (definitions see section 17.8) must agree to use highly effective forms of contraception with the addition of a barrier method (condom) during the study (see section 17.8.1) as well as to the restrictions mentioned in section 9.13.

6. Female patients of childbearing potential (definitions see 17.8) who are sexually active must agree to use highly effective forms of contraception while on the study as well as to the restrictions mentioned in section 9.13.

   Disease characteristics

7. Histologically proven, previously untreated CD20+ diffuse large B-cell lymphoma (DLBCL) according to the 2017 WHO classification including:

   1. diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS)
   2. primary cutaneous DLBCL leg type
   3. intravascular large B-cell lymphoma
   4. EBV+ DLBCL, NOS
   5. HHV8+DLBCL, NOS
   6. primary mediastinal (thymic) large B-cell lymphoma
   7. B-cell lymphoma, with intermediate features between DLBCL and classical Hodgkin lymphoma
   8. follicular lymphoma grade 3B
   9. high-grade B-cell lymphoma, NOS
   10. high-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements
   11. T-cell/histiocyte-rich large B-cell lymphoma
   12. DLBCL associated with chronic inflammation
   13. ALK+ large B-cell lymphoma
   14. large B-cell lymphoma with IRF4 rearrangement Please note: patients in whom indolent lymphoma is diagnosed concurrently with the one of the above listed diagnoses can also be included.

8. Disease Stage I with bulk ≥7.5cm, 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 acceptable only if this is directly attributable to lymphoma.

10. Meet the following laboratory parameters:

    1. Absolute neutrophil count (ANC) ≥ 1500 cells/µl or platelet count ≥ 100.000/µl unless directly attributable to lymphoma.
    2. Serum AST and ALT ≤3 x upper limit of normal (ULN) unless directly attributable to lymphoma.
    3. Total bilirubin ≤1.5 x ULN, unless directly attributable to Gilbert's syndrome or lymphoma.
    4. Estimated creatinine clearance of ≥30 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 ≤2.5 x ULN.

Exclusion Criteria

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 [e.g. a single score of 4 on one single category on the CIRS-G-Score (but not a cumulative score of 4)].

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, or LVEF < 40%. Patients 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 acalabrutinib, 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:

   1. Curatively treated localised basal cell carcinoma or localised squamous cell carcinoma of the skin or carcinoma in situ of the cervix or carcinoma in situ / low risk carcinoma of the prostate requiring only observation, as well as untreated low grade lymphoma except chronic lymphocytic leukemia.
   2. Other cancers not specified above that have been curatively treated by surgery and/or radiation therapy from which patient is disease-free for ≥2 years (≥5 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 randomization.

9. Known history of infection with HIV.

10. Any active significant infection (e.g., bacterial, viral or fungal) 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.

    1. Patients 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.
    2. Patients 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 randomization.

14. History of clinically relevant bleeding diathesis (e.g., hemophilia, von Willebrand disease).

15. Major surgical procedure within 30 days before randomization. Note: If a patient 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 women.

17. Current life-threatening illness, medical condition, organ system dysfunction, social, geographical or economic condition which, in the Investigator's opinion, could compromise the patient'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

19. Diagnosis of Richter's Transformation/transformed CLL Prior/Concomitant therapy

20. 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.

21. Requires treatment with a strong cytochrome P450 3A (CYP3A) inhibitor or inducer. The use of strong CYP3A inhibitors within 1 week or strong CYP3A inducers within 3 weeks of the first dose of study drug is prohibited. See details in section 9.12.1.

22. Prior exposure to a BTK inhibitor.

23. Prior anthracycline use ≥300 mg/m2.

24. Already initiated lymphoma therapy except for steroid (max. total dose of 1000mg), vincristine (max. 1 mg once) or rituximab (max. 375mg/m2) prephase.

25. Concurrent participation in another therapeutic clinical trial.

26. 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.

27. Received any investigational drug within 30 days or 5 half-lives (whichever is shorter) before first dose of study drug.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Standard arm	R-miniCHOP	6x R-miniCHOP + 2x Rituximab.
Experimental arm	R-miniCHOP + Acalabrutinib	6x R-miniCHOP + 2x Rituximab + Acalabrutinib.

Primary Outcome Measures

Name	Time	Method
Progression-free survival (PFS) investigator assessed	Up to 5 years	PFS, defined by the time between the day of randomization until one of the following events occurs, whichever comes first: Disease progression (PD), relapse after complete remission (CR) or death due to any cause, as per Lugano Classification of 2014. Patients who have not experienced an event at the time of analysis will be censored at the most recent date of disease assessment.

Secondary Outcome Measures

Name	Time	Method
PFS according to Cell of Origin as per immunohistochemistry	Up to 5 years
EFS according to Cell of Origin as per immunohistochemistry	Up to 5 years
PFS according to molecular genotype	Up to 5 years
EFS according to molecular genotype	Up to 5 years
Duration of Response (DoR)	Up to 5 years
Progression rate, relapse rate and central nervous system (CNS) relapse rate	Up to 5 years
Adverse events (AEs), Serious AEs, AEs of special interest, events of clinical interest, AEs leading to study treatment discontinuation or dose modification.	Up to 5 years
Treatment-related death rate	Up to 5 years
Dose intensity of miniCHOP, rituximab and acalabrutinib.	Up to 5 years
Overall survival (OS)	Up to 5 years	OS, defined by the time between the day of randomization until death due to any cause. Patients who have not experienced an event at the time of analysis will be censored at the date when the patient was last known to be alive.
PFS based on blinded independent central review (BICR)	Up to 5 years
Event-free survival (EFS)	Up to 5 years	EFS, defined by the time between the day of randomization until one of the following events occurs, whichever comes first: Progressive disease (PD), relapse after complete remission (CR), initiation of subsequent systemic anti-lymphoma treatment and/or irradiation or death due to any cause, as per Lugano Classification of 2014.
Complete (CR) partial (PR) and overall (ORR) remission rates	Up to 5 years
OS according to Cell of Origin as per immunohistochemistry	Up to 5 years
OS according to molecular genotype	Up to 5 years
Rate of secondary malignancies	Up to 5 years

Trial Locations

Locations (17)

Städtisches Klinikum Karlsruhe; 🇩🇪 Karlsruhe, Germany

Rheinland Klinikum-Lukaskrankenhaus Neuss; 🇩🇪 Neuss, Germany

MVZ am Klinikum Aschaffenburg; 🇩🇪 Aschaffenburg, Germany

Onkologische Schwerpunktpraxis Kurfürstendamm; 🇩🇪 Berlin, Germany

Helios Klinikum Emil von Behring; 🇩🇪 Berlin, Germany

Gemeinschaftspraxis Mohm/Prange-Krex; 🇩🇪 Dresden, Germany

Universitätsklinikum Gießen und Marburg, Standort Gießen; 🇩🇪 Gießen, Germany

Universitätsmedizin Halle (Saale); 🇩🇪 Halle, Germany

Johannes Wesling Klinikum; 🇩🇪 Minden, Germany

Universitätsmedizin Greifswald; 🇩🇪 Greifswald, Germany

Krankenhaus der Barmherzigen Brüder Trier; 🇩🇪 Trier, Germany

Universitätsklinikum Ulm; 🇩🇪 Ulm, Germany

Saarland University Medical Center; 🇩🇪 Homburg, Saarland, Germany

Brüderkrankenhaus St. Josef; 🇩🇪 Paderborn, Germany

CaritasKlinikum Saarbrücken St. Theresia; 🇩🇪 Saarbrücken, Germany

Klinikum Mutterhaus der Borromäerinnen; 🇩🇪 Trier, Germany

Bundeswehrkrankenhaus Ulm; 🇩🇪 Ulm, Germany