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

Diffuse Large B-cell Lymphoma Clinical 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.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04604067
• Other study ID #: SAKK 38/19
• Secondary ID: 2020-003876-42
• Status: Recruiting
• Phase: Phase 2
• Start date: June 25, 2021
• Est. completion date: December 2030

Study information

• Verified date: April 2024
• Source: Swiss Group for Clinical Cancer Research
• Contact: Jana Musilova, PhD
• Phone: +41 31 389 91 91
• Email: trials[@]sakk.ch
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 260
• Est. completion date: December 2030
• Est. primary completion date: October 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Diffuse Large B-cell Lymphoma
• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Large B-Cell, Diffuse

Intervention

Drug:
• Acalabrutinib
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

Locations

Country	Name	City	State
Italy	Ospedale Papa Giovanni XXIII	Bergamo
Italy	Azienda Ospedaliera Universitaria Maggiore della Carita di Novara	Novara
Italy	Policlinico Agostino Gemelli	Roma
Switzerland	Kantonsspital Aarau	Aarau
Switzerland	Kantonsspital Baden (Baden/Brugg)	Baden
Switzerland	St. Claraspital	Basel
Switzerland	Istituto Oncologico della Svizzera Italiana	Bellinzona
Switzerland	Inselspital, Bern	Bern
Switzerland	Kantonsspital Graubünden	Chur
Switzerland	Hopital Fribourgeois	Fribourg
Switzerland	Hopitaux Universitaire de Genève (HUG)	Geneva
Switzerland	Centre Hospitalier Universitaire Vaudois	Lausanne
Switzerland	Kantonsspital Luzern	Luzerne
Switzerland	Réseau Hospitalier Neuchâtelois (RHNe)	Neuchâtel
Switzerland	Kantonsspital Olten	Olten
Switzerland	Kantonsspital St. Gallen	St. Gallen
Switzerland	Kantonsspital Winterthur	Winterthur
Switzerland	City Hospital Triemli	Zurich
Switzerland	UniversitätsSpital Zürich	Zürich

Sponsors (1)

Lead Sponsor	Collaborator
Swiss Group for Clinical Cancer Research

Countries where clinical trial is conducted

Italy,  Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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	Adverse events (AEs)	All AEs will be assessed according to NCI CTCAE v5.0.	record throughout treatment phase (until 28 days after last dose of trial treatment)
Secondary	Overall survival (OS)	OS will be calculated from registration until death from any cause. Patients not experiencing an event will be censored at the last date they were known to be alive.	from registration to date of death from any cause (estimated 5 years)
Secondary	Progression free survival in cohort B	Analogous to the evaluation of the primary endpoint of cohorts A, C and D, but in cohort B.	from registration until the first event as defined in PFS (estimated 2 years)
Secondary	Complete remission rate in cohorts A, C and D	Analogous to the evaluation of the primary endpoint of cohort B, but in cohorts A, C and D.	estimated 9 months after registration
Secondary	Overall response rate (ORR)	ORR at the end of therapy is defined as either PR or CR (OR) according to the Lugano criteria. Patients with no tumor assessment at the end of therapy will be considered: non-OR, 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-OR at the following tumor assessment after the end of therapy.; OR, if they have OR at the following tumor assessment after end of therapy before starting a new treatment	estimated 9 months after registration
Secondary	Duration of response (DoR)	The DoR will be calculated from when the criteria for CR or PR are met, until documentation of progressive disease thereafter. Only patients with a CR or PR will be included in this analysis. Patients without any documentation of progressive disease thereafter will be censored at the last date of tumor assessment without progression and before the start of a new anti-lymphoma treatment, if any.	estimated 2 years