Assessing a ctDNA and PET-oriented Therapy in Patients With DLBCL A Multicenter, Open-label, Phase II Trial.

NCT04604067 | Active Not Recruiting Phase 2 DMC

• 2 other identifiers: SAKK 38/192020-003876-42
• Study Type: interventional
• Target: 260
• Locations: 2 countries
• Sites: 19

Brief Summary

Within this exploratory multicohort phase II trial, SAKK aims to evaluate a PET/CT and ctDNA oriented therapy in DLBCL in order to test the following working hypothesis.

• acalabrutinib-R-CHOP may improve the progression free survival in genetically defined DLBCL harboring the MYD88 L265P and/or CD79A/B mutations;
• treatment escalation to acalabrutinib-R-CHOP in DLBCL patients who have positive PET/CT (with residual disease scored as Deauville score 4 or 5 with centrally defined response) and no molecular response (\<2log10 reduction of ctDNA) after two courses of R-CHOP could improve the anti-tumour activity of R-CHOP;
• treatment de-escalation to 4 total R-CHOP courses plus 2 rituximab single agent infusions does not compromise the outcome in patients lacking both MYD88 L265P and CD79A/B mutations and quickly obtaining both negative PET/CT (Deauville score 1-3) and molecular response (\>2log10 reduction of ctDNA) after two cycles of R-CHOP.

Conditions

Diffuse Large B-cell Lymphoma

Keywords

Diffuse large B-cell lymphoma; Circulating tumor DNA (ctDNA); PET-oriented therapy; acalabrutinib-R-CHOP; acalabrutinib

Outcome Measures

Primary Outcomes (2)

• Cohorts A, C and D: Progression free survival (PFS) according to the Lugano criteria

  PFS is defined as the time from registration until the first event of interest: * Progressive disease according to the Lugano Classification * Death from any cause Patients not having an event at the time of analysis and patients starting a new anticancer therapy in the absence of an event will be censored at the date of their last tumor assessment showing non-progression before starting a new treatment.

  from registration until the first event as defined in PFS (estimated 2 years)

• Cohort B: Complete remission (CR) rate at the end of therapy according to the Lugano criteria

  Patients with CR at the end of therapy will be considered CR. Patients with no tumor assessment at the end of therapy will be considered: * non-CR, if they have no following tumor assessment within the trial (patient died, refused, started a new treatment or was lost to follow-up) or if they have non-CR at the following tumor assessment after the end of therapy. * CR, if they have CR at the following tumor assessment after end of therapy before starting a new treatment.

  estimated 9 months after registration

Secondary Outcomes (6)

• Adverse events (AEs)

  record throughout treatment phase (until 28 days after last dose of trial treatment)

• Overall survival (OS)

  from registration to date of death from any cause (estimated 5 years)

• Progression free survival in cohort B

  from registration until the first event as defined in PFS (estimated 2 years)

• Complete remission rate in cohorts A, C and D

  estimated 9 months after registration

• Overall response rate (ORR)

  estimated 9 months after registration

Study Arms (1)

Arm with 4 cohorts

EXPERIMENTAL

Cohort A: MYD88 L265P and/or CD79A/B mutations at baseline Treatment: Acalabrutinib-R-CHOP for a total number of 6 cycles. Cohort B, C D: Without MYD88 L265P and CD79A/B mutations at baseline: Assignment of cohort B, C and D after 2 cycles of R-CHOP according to PET (Deauville score (DS)) and molecular response (MR) (\>2log10 reduction of ctDNA) results: Cohort B: DS 4 and No MR Treatment: 2 cycles of acalabrutinib-R-CHOP. After PET3/ctDNA3: patients with DS 1-3 and no MR OR DS4 with MR will receive 2 additional cycles of acalabrutinb-R-CHOP and 2 cycles of acalabrutinib single agent. Cohort C: DS 1-3 and MR Treatment: 2 additional cycles of R-CHOP (4x RCHOP in total) followed by 2 cycles of rituximab single agent. Cohort D: DS 4 and no MR OR DS 1-3 and MR Treatment: 4 additional cycles of RCHOP (6 cycles in total). Follow up: Patients off treatment will be followed for 5 years.

Drug: Acalabrutinib

Interventions

Acalabrutinib DRUG

Cohort A: 6 cycles of acalabrutinib-R-CHOP Cohort B: 2 cycles of R-CHOP and 2 cycles of acalabrutinb-R-CHOP followed by 2 cycles of acalabrutinib single agent Cohort C: 4 cycles of R-CHOP followed by 2 cycles of rituximab single agent Cohort D: 6 cycles of R-CHOP Rituximab 375 mg/m2 IV Day 1, cyclophosphamide 750 mg/m2 IV Day 1, doxorubicin 50 mg/m2 IV Day 1, vincristine 1.4 mg/m2 (maximum 2 mg) IV Day 1; prednisone 100 mg PO d1-5; Acalabrutinib 100 mg BID Day 1-21, cycles repeated every 21 days

Arm with 4 cohorts

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent according to ICH GCP E6(R2) regulations before registration and prior to any trial specific procedures.
• Histologically confirmed, treatment-naïve DLBCL, NOS that fulfill all the following:
• Patient eligible for 6 cycles of R-CHOP
• Ann Arbor stage I-IV
• Metabolically active measurable disease by 18FDG PET-CT
• No previous treatment with systemic chemotherapy or radiotherapy (a pre-phase treatment with steroids for up to a total of 10 days is allowed; baseline PET/CT, liquid biopsy and bone marrow biopsy and aspirate must be collected either before or within a maximum of 5 days after steroid pre-phase treatment starts. If a patient receives steroids, glucose levels must be checked and be normal on the day of PET/CT before the exam.
• At least 1 measurable site of disease according to Revised Response Criteria for Malignant Lymphoma. The site of disease must be greater than 1.5 cm in the long axis regardless of short axis measurement or greater than 1.0 cm in the short axis regardless of long axis measurement, and clearly measurable in 2 perpendicular dimensions.
• Quantifiable and qualifiable circulating tumor DNA
• Patients with a prior malignancy and treated with curative intention are eligible if all treatment of that malignancy was completed at least 2 years before registration and the patient has no evidence of disease at registration. Less than 2 years is acceptable for malignancies with low risk of recurrence and/or no late recurrence.
• Age ≥ 18 years
• EGOG performance status 0-2 (or 3 if due to disease)
• Adequate bone marrow function: neutrophil count ≥ 1.0 x 109/L, platelet count ≥ 75 x 109/L (unless due to bone marrow involvement: in this case the permitted limit is ≥ 50 x 109/L) with allowed premedication or supportive medication.
• Adequate hepatic function: total bilirubin ≤ 1.5 x ULN (except for patients with Gilbert's disease ≤ 3.0 x ULN), AST, ALT ≤ 2.5 x ULN, or ≤ 5 x ULN under the assumption that abnormal values are a result of liver involvement by lymphoma
• Adequate renal function: estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2 (according to CKD-EPI formula)
• Adequate cardiac function: Left ventricular Ejection Fraction (LVEF) ≥ 50% as determined by echocardiography (ECHO)

You may not qualify if:

• CNS lymphoma involvement
• Stage I disease that has been completely surgically excised (not measurable)
• Specific diagnostic categories of large B-cell lymphoma such as high grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, primary central nervous system lymphoma, T-cell/histiocyte-rich large B-cell lymphoma, intravascular large B-cell lymphoma, plasmablastic lymphoma, lymphomatoid granulomatosis, primary effusion lymphoma or transformed lymphoma etc.
• Concomitant treatment with any other experimental drug
• Severe or uncontrolled cardiovascular disease (congestive heart failure NYHA III or IV; unstable angina pectoris, history of myocardial infarction within the last six months, serious arrhythmias requiring medication (with exception of asymptomatic or rate controlled atrial fibrillation or paroxysmal supraventricular tachycardia), significant QT-prolongation, uncontrolled hypertension.
• Uncontrolled systemic infection.
• History of or ongoing confirmed progressive multifocal leukoencephalopathy (PML).
• History of cerebrovascular accident or intracranial hemorrhage within 6 months prior to registration
• History of bleeding diathesis (eg, haemophilia, von Willebrand disease).
• Major surgery in the preceding 4 weeks of first dose of study drug. 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.
• Malabsorption syndrome, disease significantly affecting gastrointestinal function, resection of the stomach or small bowel, gastric bypass, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction or gastric restrictions and bariatric surgery, such as gastric bypass.
• History or presence of clinically relevant central nervous system (CNS) pathology as epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, psychosis.
• Known history of human immunodeficiency virus (HIV) or active chronic hepatitis C or hepatitis B virus infection or any uncontrolled active systemic infection requiring intravenous (iv) antimicrobial treatment. All patients must be screened for HIV up to 28 days prior to study drug start using a blood test for HIV according to local regulations. All patients must be screened for hepatitis up to 28 days prior to study drug start using the routine hepatitis virus laboratory panel. Patients positive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) will be eligible if they are negative for HBV-DNA, these patients should receive prophylactic antiviral therapy and have HBV-DNA testing every 4 months. Patients positive for anti-HCV antibody will be eligible if they are negative for HCV-RNA.
• Active, uncontrolled autoimmune phenomenon (autoimmune hemolytic anemia or immune thrombocytopenia) requiring steroid therapy with \> 20 mg daily of prednisone dose or equivalent.
• Requires or receiving anticoagulation with warfarin or equivalent antagonists (eg, phenprocoumon), 'dual' antiplatelet therapy (DAPT), such as aspirin and clopidogrel. However, use of therapeutic low molecule weight heparin, direct oral anticoagulants, or low dose anti-platelet agents is allowed.

Sponsors & Collaborators

• Swiss Cancer Institute: lead

Study Sites (19)

Ospedale Papa Giovanni XXIII

Bergamo, 24127, Italy

Location

Azienda Ospedaliera Universitaria Maggiore della Carita di Novara

Novara, 20503, Italy

Location

Policlinico Agostino Gemelli

Roma, 00168, Italy

Location

Kantonsspital Aarau

Aarau, CH-5001, Switzerland

Location

Kantonsspital Baden (Baden/Brugg)

Baden, 5404, Switzerland

Location

St. Claraspital

Basel, 4058, Switzerland

Location

Istituto Oncologico della Svizzera Italiana

Bellinzona, 6500, Switzerland

Location

Inselspital, Bern

Bern, CH-3010, Switzerland

Location

Kantonsspital Graubünden

Chur, 7000, Switzerland

Location

Hopital Fribourgeois

Fribourg, 1708, Switzerland

Location

Hopitaux Universitaire de Genève (HUG)

Geneva, 1211, Switzerland

Location

Centre Hospitalier Universitaire Vaudois

Lausanne, CH-1011, Switzerland

Location

Kantonsspital Luzern

Luzerne, CH-6000, Switzerland

Location

Réseau Hospitalier Neuchâtelois (RHNe)

Neuchâtel, 2000, Switzerland

Location

Kantonsspital Olten

Olten, CH-4600, Switzerland

Location

Kantonsspital St. Gallen

Sankt Gallen, 9007, Switzerland

Location

Kantonsspital Winterthur

Winterthur, 8401, Switzerland

Location

UniversitätsSpital Zürich

Zurich, 8091, Switzerland

Location

City Hospital Triemli

Zurich, CH-8063, Switzerland

Location

MeSH Terms

Conditions

Lymphoma, Large B-Cell, Diffuse

Interventions

acalabrutinib

Condition Hierarchy (Ancestors)

Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Study Officials

• Anastasios Stathis, Prof

  IOSI, Ospedale San Giovanni Bellinzona

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: All patients will have a PET/CT (PET1) and evaluation of circulating tumor DNA (ctDNA1) at baseline. The trial consists of four treatment cohorts (cohorts A, B, C and D) and a first assignment to treatment will be done at baseline based on the presence or absence of MYD88 L265P and/or CD79A/B mutations.

Study Record Dates

• First Submitted: October 22, 2020
• First Posted: October 27, 2020
• Study Start: June 25, 2021
• Primary Completion (Estimated): July 30, 2026
• Study Completion (Estimated): December 1, 2030
• Last Updated: December 30, 2025

Record last verified: 2025-12

Locations

IT (3); CH (16)