Assessing a ctDNA and PET-oriented Therapy in Patients With DLBCL A Multicenter, Open-label, Phase II Trial.
Assessing a ctDNA and PET-oriented Therapy in Patients With DLBCL A Multicenter, Open-label, Phase II Trial.
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) 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 R-CHOP, and further improve to
 Deauville score 1-2 and absence of ctDNA after two more R-CHOP courses.
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) 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 R-CHOP, and further improve to
 Deauville score 1-2 and absence of ctDNA after two more R-CHOP courses.

 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) 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, which further improve
 to Deauville score 1-2 and absence of ctDNA after two additional R-CHOP courses (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)
 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
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 10 days is allowed after PET/CT and baseline liquid biopsy
 have been collected)

 -  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)

 -  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 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 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 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 with strong or moderate CYP3A inducers or
 inhibitors (see http://medicine.iupui.edu/), co-administration 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.