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JOURNAL ONKOLOGIE – STUDIE

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

Rekrutierend

NCT-Nummer:
NCT04604067

Studienbeginn:
Juni 2021

Letztes Update:
15.04.2024

Wirkstoff:
Acalabrutinib

Indikation (Clinical Trials):
Lymphoma, Lymphoma, B-Cell, Lymphoma, Large B-Cell, Diffuse

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 2

Sponsor:
Swiss Group for Clinical Cancer Research

Collaborator:
-

Studienleiter

Anastasios Stathis, Prof
Study Chair
IOSI, Ospedale San Giovanni Bellinzona

Kontakt

Studienlocations
(3 von 19)

Azienda Ospedaliera Universitaria Maggiore della Carita di Novara
20503 Novara
ItalyRekrutierend» Google-Maps
Ansprechpartner:
Gianluca Gaidano, MD
Phone: +39 0321 660655
E-Mail: gianluca.gaidano@med.uniupo.it» Ansprechpartner anzeigen
Istituto Oncologico della Svizzera Italiana
6500 Bellinzona
SwitzerlandRekrutierend» Google-Maps
Ansprechpartner:
Anastasios Stathis, MD
Phone: +41 91 811 89 31
E-Mail: anastasios.stathis@eoc.ch» Ansprechpartner anzeigen
Alle anzeigen

Studien-Informationen

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

Ein-/Ausschlusskriterien

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.

Studien-Rationale

Primary outcome:

1. Cohorts A, C and D: Progression free survival (PFS) according to the Lugano criteria (Time Frame - from registration until the first event as defined in PFS (estimated 2 years)):
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.

2. Cohort B: Complete remission (CR) rate at the end of therapy according to the Lugano criteria (Time Frame - estimated 9 months after registration):
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.

Secondary outcome:

1. Adverse events (AEs) (Time Frame - record throughout treatment phase (until 28 days after last dose of trial treatment)):
All AEs will be assessed according to NCI CTCAE v5.0.

2. Overall survival (OS) (Time Frame - from registration to date of death from any cause (estimated 5 years)):
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.

3. Progression free survival in cohort B (Time Frame - from registration until the first event as defined in PFS (estimated 2 years)):
Analogous to the evaluation of the primary endpoint of cohorts A, C and D, but in cohort B.

4. Complete remission rate in cohorts A, C and D (Time Frame - estimated 9 months after registration):
Analogous to the evaluation of the primary endpoint of cohort B, but in cohorts A, C and D.

5. Overall response rate (ORR) (Time Frame - estimated 9 months after registration):
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

6. Duration of response (DoR) (Time Frame - estimated 2 years):
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.

Geprüfte Regime

  • 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

Quelle: ClinicalTrials.gov


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