Clinical trial NCT04604067: Assessing a ctDNA and PET-oriented Therapy in Patients With DLBCL A Multicenter, Open-label, Phase II Trial.
Official title: Assessing a Circulating Tumor (ctDNA) and Positron Emission Tomography (PET)-Oriented Therapy in Patients With Diffuse Large B-cell Lymphoma (DLBCL). A Multicenter, Open-label, Phase II Trial.
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Diffuse Large B-cell Lymphoma
Keywords: Diffuse large B-cell lymphoma
Circulating tumor DNA (ctDNA)
PET-oriented therapy
acalabrutinib-R-CHOP
acalabrutinib
Lead sponsor: Swiss Group for Clinical Cancer Research
Sponsor class: OTHER
First posted: 2020-10-27
Enrollment: 260
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: 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.
Primary purpose: TREATMENT

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.

Detailed description: Despite advances in the clinical care of patients with DLBCL and in understanding the biology of this disease, cure rates have remained the same since the introduction of rituximab to CHOP chemotherapy, and R-CHOP chemoimmunotherapy remains the standard of care. Over the last years many phase III trials investigating new agents added to R-CHOP have been performed but they have all invariably failed to improve treatment outcomes. Importantly, three of the most recently completed phase III trials that were developed based on the cell of origin distinction of DLBCL and aimed to improve treatment outcome in the ABC (or non- Germinal center B-Cell (GCB)) subtype by adding a targeted agent to R-CHOP have also failed. This provides clinical evidence that cell of origin may not be an accurate biomarker for treatment decisions. The R - CHOP + investigational drug approach has thus failed either when broadly applied to unselected DLBCL patients or when applied to DLBCL patients selected according to inaccurate biomarkers such as COO.

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 courses R-CHOP.

Primary objectives:

* Assessing the efficacy of acalabrutinib-R-CHOP in DLBCL harboring MYD88 L265P and/or CD79A/B mutations (cohort A)
* Assessing the activity of treatment escalation to acalabrutinib-R-CHOP followed by acalabrutinib monotherapy in DLBCL patients who are double positive: PET/CT positive (Deauville score 4 or 5 with centrally defined response) and no molecular response (\<2log10 fold reduction) after two courses of R-CHOP (cohort B)
* Exploring the feasibility of treatment de-escalation to 4 total R-CHOP courses plus two infusions of single agent rituximab 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 (cohort C).
* Exploring clinical implications of having a negative PET/CT (Deauville score 1-3) but no molecular response (\<2log10 reduction of ctDNA) vs a positive PET/CT (Deauville score 4 or 5 with centrally defined response) but molecular response (\>2log10 reduction of ctDNA) after two R-CHOP courses (cohort D)

Secondary objectives:

* Safety and tolerability of acalabrutinib-R-CHOP
* Assessment of prognostic value of baseline PET radiomics indexes, alone or in association with other parameters

Eligibility criteria: Inclusion Criteria:

* 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)
* Adequate coagulation function: INR ≤ 1.5 x ULN (the ULN for INR is defined with the value 1.2 for all sites, in case no ULN is documented in the lab certificates/sheets), aPTT ≤ 1.5 x ULN.
* Women of childbearing potential must use highly effective contraception, are not pregnant or lactating and agree not to become pregnant during trial treatment and until 12 months after the last dose of investigational drug. A negative pregnancy test before inclusion into the trial is required for all women of childbearing potential. (www.swissmedicinfo.ch).
* Men agree not to donate sperm or to father a child during trial treatment and until 12 months after the last dose of investigational drug
* Patient is able and willing to swallow trial drug as whole capsule or tablet.
* Patient is willing to participate in translational research projects

Exclusion criteria:

* 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.
* Concomitant treatment to acalabrutinib capsules or tablets with strong CYP3A inducers or strong CYP3A inhibitors. The use of strong CYP3A inhibitors within 1 week or strong CYP3A inducers within 3 weeks of the first dose of acalabrutinib is prohibited.
* Co-administration of acalabrutinib capsules with proton pump inhibitors (PPIs).
* Any concomitant drugs contraindicated for use with the trial drugs according to the approved product information
* Known hypersensitivity to trial drug(s) or to any component of the trial drug(s)
* Any other serious underlying medical, psychiatric, psychological, familial or geographical condition, which in the judgment of the investigator may interfere with the planned staging, treatment and follow-up, affect patient compliance or place the patient at high risk from treatment-related complications.

Primary outcomes:
measure: Cohorts A, C and D: Progression free survival (PFS) according to the Lugano criteria
timeFrame: from registration until the first event as defined in PFS (estimated 2 years)
measure: Cohort B: Complete remission (CR) rate at the end of therapy according to the Lugano criteria
timeFrame: estimated 9 months after registration
Secondary outcomes:
measure: Adverse events (AEs)
timeFrame: record throughout treatment phase (until 28 days after last dose of trial treatment)
measure: Overall survival (OS)
timeFrame: from registration to date of death from any cause (estimated 5 years)
measure: Progression free survival in cohort B
timeFrame: from registration until the first event as defined in PFS (estimated 2 years)
measure: Complete remission rate in cohorts A, C and D
timeFrame: estimated 9 months after registration
measure: Overall response rate (ORR)
timeFrame: estimated 9 months after registration
measure: Duration of response (DoR)
timeFrame: estimated 2 years
Other outcomes:
Locations:
city: Bergamo
country: Italy
facility: Ospedale Papa Giovanni XXIII
city: Novara
country: Italy
facility: Azienda Ospedaliera Universitaria Maggiore della Carita di Novara
city: Roma
country: Italy
facility: Policlinico Agostino Gemelli
city: Aarau
country: Switzerland
facility: Kantonsspital Aarau
city: Baden
country: Switzerland
facility: Kantonsspital Baden (Baden/Brugg)
city: Basel
country: Switzerland
facility: St. Claraspital
city: Bellinzona
country: Switzerland
facility: Istituto Oncologico della Svizzera Italiana
city: Bern
country: Switzerland
facility: Inselspital, Bern
city: Chur
country: Switzerland
facility: Kantonsspital Graubünden
city: Fribourg
country: Switzerland
facility: Hopital Fribourgeois
city: Geneva
country: Switzerland
facility: Hopitaux Universitaire de Genève (HUG)
city: Lausanne
country: Switzerland
facility: Centre Hospitalier Universitaire Vaudois
city: Luzerne
country: Switzerland
facility: Kantonsspital Luzern
city: Neuchâtel
country: Switzerland
facility: Réseau Hospitalier Neuchâtelois (RHNe)
city: Olten
country: Switzerland
facility: Kantonsspital Olten
city: St. Gallen
country: Switzerland
facility: Kantonsspital St. Gallen
city: Winterthur
country: Switzerland
facility: Kantonsspital Winterthur
city: Zurich
country: Switzerland
facility: City Hospital Triemli
city: Zürich
country: Switzerland
facility: UniversitätsSpital Zürich
Study officials:
affiliation: IOSI, Ospedale San Giovanni Bellinzona
name: Anastasios Stathis, Prof
role: STUDY_CHAIR
References: