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 (ARCHED/GLA 2022-1)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

University Of Saarland

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15], Diseases [C] - Neoplasms [C04]

Trial duration

24 Apr 2023 → ongoing

Decision date (initial)

2023-04-03

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

AstraZeneca

External identifiers

EU CT number

2022-501187-18-00

WHO UTN

U1111-1284-7084

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Therapy

To evaluate if the addition of acalabrutinib to R-miniCHOP prolongs progression-free survival (PFS), compared to R-miniCHOP alone in patients >80 years or >60 years and ineligible for full-dose R-CHOP with previously untreated DLBCL, based on investigator-assessed response.

Secondary objectives 10

1. To evaluate overall survival (OS) with acalabrutinib plus R-miniCHOP compared with R-miniCHOP alone in patients >80 years or >60 years and ineligible for full-dose R-CHOP with previously untreated DLBCL.
2. To evaluate PFS with acalabrutinib plus R-miniCHOP compared with R-miniCHOP alone in patients >80 years or >60 years and ineligible for full-dose R-CHOP with previously untreated DLBCL, based on blinded independent central review (BICR).
3. To evaluate event-free survival (EFS) with acalabruntib plus R-miniCHOP compared with R-miniCHOP alone in patients >80 years or >60 years and ineligible for full-dose R-CHOP with previously untreated DLBCL, based on investigator assessment and BICR.
4. To analyze outcomes according to cell of origin (COO) as per immunohistochemistry and gene expression analysis with acalabrutinib plus R-miniCHOP compared with R-miniCHOP alone in patients >80 years or >60 years and ineligible for full-dose R-CHOP with previously untreated DLBCL.
5. To analyze outcomes according to DLBCL molecular genotype with acalabrutinib plus R-miniCHOP compared to R-miniCHOP alone in patients >80 years or >60 years and ineligible for full-dose R-CHOP with previously untreated DLBCL.
6. To analyze outcomes with acalabrutinib plus R-miniCHOP versus R-miniCHOP alone between age groups (>60 - 80 years vs >80 years) and according to gender and serum albumin.
7. 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).
8. To compare progression rate, relapse rate and central nervous system (CNS) relapse rate between both treatment (acalabrutinib plus R-miniCHOP versus R-miniCHOP alone) and molecular groups (COO, molecular genotype).
9. To evaluate the safety and tolerability of acalabrutinib plus R-miniCHOP relative to R-miniCHOP alone in patients >80 years or >60 years and ineligible for full-dose R-CHOP.
10. To evaluate protocol adherence of acalabrutinib plus R-miniCHOP relative to R-miniCHOP alone in patients >80 years or >60 years and ineligible for full-dose R-CHOP.

Conditions and MedDRA coding

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. primary mediastinal (thymic) large B-cell lymphoma, g. B-cell lymphoma, with intermediate features between DLBCL and classical Hodgkin lymphoma, h. follicular lymphoma grade 3B, i. high-grade B-cell lymphoma NOS, j. high-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements, k. T-cell/histiocyte-rich large B-cell lymphoma, l. DLBCL associated with chronic inflammation, m. ALK+ large B-cell lymphoma, n. large B-cell lymphoma with IRF4 rearrangement

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

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). b. 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.
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 after standardized geriatric assessment
5. Male patients who are sexually active with women of childbearing potential (definitions see section 17.8 of the protocol) 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 of the protocol) as well as to the restrictions mentioned in section 9.13 of the protocol
6. Female patients of childbearing potential (definitions see 17.8 in the protocol) 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. of the protocol
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. primary mediastinal (thymic) large B-cell lymphoma g. B-cell lymphoma, with intermediate features between DLBCL and classical Hodgkin lymphoma h. follicular lymphoma grade 3B i. high-grade B-cell lymphoma, NOS j. high-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements k. T-cell/histiocyte-rich large B-cell lymphoma l. DLBCL associated with chronic inflammation m. ALK+ large B-cell lymphoma n. 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
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: a. Absolut neutrophil count (ANC) ≥ 1500 cells/µl or platelet count ≥ 100.000/µl unless directly attributable to lymphoma. b. Serum AST and ALT ≤3 x upper limit of normal (ULN) unless directly attributable to lymphoma. c. Total bilirubin ≤1.5 x ULN, unless directly attributable to Gilbert’s syndrome or lymphoma. d. Estimated creatinine clearance of ≥30 mL/min, calculated by Cockcroft-Gault (using actual body weight) (if male, [140-Age] x Mass [kg] / [72 x serum creatinine mg/dL]; multiply by 0.85 if female), or serum creatinine ≤2.5 x ULN.

Exclusion criteria 25

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. Diagnosis of primary central nervous system lymphoma or secondary central nervous system or meningeal involvement by lymphoma
3. Diagnosis of Richter’s Transformation/transformed CLL
4. 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.
5. 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.
6. 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 of the protocol
7. Prior exposure to a BTK inhibitor.
8. Prior anthracycline use >300 mg/m2 of doxorubicin equivalent.
9. Already initiated lymphoma therapy except for steroid (max. total dose of 1500mg of prednisolone equivalent), vincristine (max. 1 mg once) and/or rituximab (max. total dose of 375mg/m2) prephase.
10. Concurrent participation in another therapeutic clinical trial.
11. Any active significant infection (e.g., bacterial, viral or fungal) as assessed by the investigator.
12. Severe pulmonary dysfunction (CTCAE grade 3 or 4) unless associated with lymphoma.
13. 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.
14. Persistent neuropathy CTCAE grade 3 or 4
15. 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.
16. History of prior malignancy that could affect compliance with the protocol or interpretation of results, except for the following: a. 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. b. 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.
17. Received a live virus vaccination within 28 days of randomization.
18. Known history of infection with HIV.
19. History of or ongoing confirmed progressive multifocal leukoencephalopathy (PML).
20. Serologic status reflecting active hepatitis B or C infection. a. 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. b. 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.
21. History of stroke or intracranial hemorrhage within 6 months before randomization
22. History of clinically relevant bleeding diathesis (e.g., hemophilia, von Willebrand disease).
23. 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.
24. Breastfeeding or pregnant women
25. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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 adequate disease assessment (for definition see 10.6.1)..

Secondary endpoints 16

1. 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.
2. PFS, as defined above, based on blinded independent central review (BICR).
3. 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. Patients who have not experienced an event at the time of analysis will be censored at the most recent date of adequate disease assessment.
4. PFS, OS and EFS, as defined above, according to cell of origin (COO) as per immunohistochemistry and gene expression analysis
5. PFS, OS and EFS, as defined above according to DLBCL molecular genotype.
6. PFS, OS and EFS, as defined above, according to age groups (>60 - 80 years vs >80 years) and according to gender and serum albumin.
7. Rate of (metabolic) CR, defined as the number of patients achieving CR as best overall response after end of study treatment divided by the number of randomized patients.
8. Rate of PR, defined as the number of partial remissions after end of study treatment divided by the number of randomized patients.
9. Overall response rate (ORR), defined as the number of complete and partial remissions after end of study treatment, divided by the number of randomized patients.
10. Duration of response (DoR), defined as the time from documentation of tumor response to disease progression or relapse, or death of any cause.
11. Progression rate, defined as the number of progressions after end of study treatment divided by the number of randomized patients.
12. Relapse rate, defined as the number of relapses divided by the number of patients with complete remission after end of study treatment.
13. CNS relapse rate, defined as the cumulative CNS incidence rate.
14. AEs, SAEs, adverse events of special interest (AESIs), events of clinical interest, AEs leading to study treatment discontinuation or dose modification. Rate of secondary malignancies, defined as the number of patients with secondary malignancies divided by the number of randomized patients.
15. Treatment-related death rate, defined as the number of treatment related deaths during therapy or up to 2 months after the end of study treatment, but before the start of further treatment, divided by the number of randomized patients.
16. Number and duration of therapy cycles, cumulative and relative doses of miniCHOP, rituximab and acalabrutinib.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Auxiliary 8

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

University Of Saarland

Sponsor organisation

University Of Saarland

Address

Kirrberger Strasse

City

Homburg

Postcode

66421

Country

Germany

Scientific contact point

Organisation

University Of Saarland

Contact name

Central Trial Office

Public contact point

Organisation

University Of Saarland

Contact name

Central Trial Office

Third parties 1

Locations

2 EU/EEA countries · 57 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 27 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

9 submissions — initial application plus substantial / non-substantial modifications