SAKK 38/19 Therapy adjustment based on PET/CT and circulating tumor DNA in patients with diffuse large B-cell lymphoma
Descrizione riassuntiva dello studio
The study investigates the treatment of DLBCL: Group A: Evaluation of the efficacy and safety of a substance targeting a specific genetic alteration of a DLBCL in combination with the standard therapy R-CHOP. We want to investigate in this study whether the addition of the drug Acalabrutinib to the R-CHOP treatment (A-R-CHOP) can improve efficacy. Additionally, we examine the safety and tolerability of treatment with A-R-CHOP. Group C: Evaluation of a reduction in treatment cycles with R-CHOP in study participants without the specific genetic alteration with optimal imaging and molecular response. Using a positron emission tomography combined with computed tomography (PET-CT), the response to R-CHOP therapy can be investigated. Simultaneously with the PET/CT scan, samples of circulating tumor cells are measured. If the tumor responds well to the 2 cycles of R-CHOP, this is associated with a reduction in tumor mass. We assume that under these conditions, the standard treatment of 6 can be reduced to 4 cycles of R-CHOP, followed by 2 cycles of Rituximab. Group D: Evaluation of the clinical course of DLBCL with optimal imaging response but insufficient molecular response or vice versa, insufficient imaging response but optimal molecular response. If the tumor does not respond or responds insufficiently to the 2 cycles of R-CHOP, this is associated with little or no reduction in tumor mass. Under these conditions, the standard number of cycles should not be reduced. Group B: Evaluation of the efficacy of this substance in combination with the standard therapy in DLBCL that do not respond adequately to R-CHOP. If there is no reduction in signals in the PET/CT examination and no reduction in the circulating number of tumor cells, the further R-CHOP cycles will be supplemented with Acalabrutinib.
(BASEC)
Intervento studiato
• Treatment begins within the first seven days after enrollment in the study.
• During the study, medications are administered in cycles; one cycle lasts 21 days.
• Before enrollment in the study, a PET-CT is performed on all participants to determine the size and extent of the tumor.
• Before enrollment in the study, all participants are examined for how much genetic information of the cancer cells is present in the blood (circulating tumor DNA, ctDNA).
• The blood of all study participants is examined to see if either of the two genetic mutations MYD88 L265P and/or CD79A/B is present in the tumor cells.
• Study participants with one or both mutations are assigned to study group A.
• Study participants without these mutations first receive 2 cycles of R-CHOP. After that, another PET-CT is performed and the blood is re-examined for ctDNA. Based on these examination results, study participants are assigned to study group B, study group C, and study group D.
• For ctDNA examinations, no additional puncture is needed. About 20 ml of blood is taken for these examinations.
Treatment in study groups A, B, C, and D
• Study group A: These study participants receive 2 cycles of A-R-CHOP. After that, another PET-CT is performed and the blood is re-examined for ctDNA.
- If PET2 shows that the disease is progressing, participation in the study is terminated. These study participants will receive another treatment outside the study. The treating physician will inform these study participants about treatment options.
- All other study participants in study group A will receive 4 additional cycles of A-R-CHOP. After completing the total of 6 cycles of A-R-CHOP, another PET-CT and blood examination will take place. If these examinations show that the disease is progressing, these study participants will continue to be treated with another therapy outside the study.
• Study group B includes study participants in whom residual tumor disease has been shown in PET2 and in whom there is still relatively high ctDNA in the blood. This means that the tumor did not respond well to the first 2 cycles of R-CHOP. These study participants now receive 2 cycles of A-R-CHOP. After that, another PET-CT and a blood examination (ctDNA3) are performed.
- If the lymphoma has responded well to A-R-CHOP according to PET3 or ctDNA3, the study participants will receive 2 additional cycles of A-R-CHOP and then 2 cycles with Acalabrutinib. After that, another PET-CT and blood examination will follow.
- If the lymphoma has not responded well to treatment according to PET3 or ctDNA3, the study therapy will be terminated and the study participants will receive another treatment. The treating physician will inform these study participants about treatment options.
• Study group C includes study participants in whom it has been shown in PET2 and ctDNA2 examination that the lymphoma has responded well to the first two cycles of R-CHOP. These study participants receive 2 additional cycles of R-CHOP and then 2 cycles with Rituximab alone. After that, another PET-CT and blood examination will be performed.
• Study group D includes study participants in whom it has been shown in one of the two examination methods (PET2 or ctDNA2) that the tumor responds well to the treatment. These study participants receive 4 additional cycles of R-CHOP. After that, another PET-CT (PET3) and blood examination will be performed.
R-CHOP therapy
The R-CHOP therapy is administered in cycles, with one cycle lasting three weeks (21 days). The medications Rituximab, Cyclophosphamide, Doxorubicin, and Vincristine are given on day 1 of a cycle as an intravenous infusion (administration with a needle into a vein or into an implanted catheter system). Before the infusion, study participants receive a pre-treatment that alleviates the side effects of R-CHOP therapy, such as medications for nausea and vomiting as well as for allergic reactions. The medication Prednisone is taken as a tablet for the first five days of a cycle.
A-R-CHOP therapy
In addition to R-CHOP therapy, you will receive the medication Acalabrutinib. This is taken as a capsule every day, twice daily with water.
Therapy with Acalabrutinib alone
Study participants in group B receive Acalabrutinib alone for 2 therapy cycles (totaling 42 days). The medication is taken on all these days twice daily with water.
Therapy with Rituximab alone
Study participants in group C receive Rituximab alone for 2 therapy cycles. The medication is administered intravenously on the first day of a cycle.
(BASEC)
Malattie studiate
Diffuse large B-cell lymphoma (DLBCL)
(BASEC)
Individuals with a confirmed diagnosis of DLBCL who have not yet received treatment for this diagnosis may participate in the study. The disease must be detectable in the blood and by imaging methods. Participants must be over 18 years old and in relatively good general health. (BASEC)
Criteri di esclusione
- Study participants with a DLBCL where the disease has affected the brain or spinal cord. - A special form of DLBCL is present (for example, primary mediastinal or intravascular DLBCL). - Participation is also not possible for individuals with severe, uncontrolled heart disease, uncontrolled systemic infectious disease. (BASEC)
Luogo dello studio
Aarau, Bellinzona, Berna, Chur, Friburgo, Ginevra, Losanna, Lugano, Luzern, Neuchâtel, San Gallo, Winterthur, Zurigo, Altro
(BASEC)
Olten, Wil, Uznach, Grabs, La Chaux-de-Fonds, Baden, Brugg
(BASEC)
Sponsor
Swiss Group for Clinical Cancer Research (SAKK)
(BASEC)
Contatto per ulteriori informazioni sullo studio
Persona di contatto in Svizzera
SAKK, Dr. Jana Musilova
+41 31 389 91 91
trials@cluttersakk.chSwiss Group for Clinical Cancer Research (SAKK)
(BASEC)
Informazioni generali
IOSI, Ospedale San Giovanni Bellinzona
(ICTRP)
Informazioni scientifiche
IOSI, Ospedale San Giovanni Bellinzona
(ICTRP)
Nome del comitato etico approvante (per studi multicentrici solo il comitato principale)
Commissione d'etica Ticino
(BASEC)
Data di approvazione del comitato etico
11.05.2021
(BASEC)
ID di studio ICTRP
NCT04604067 (ICTRP)
Titolo ufficiale (approvato dal comitato etico)
Assessing a ctDNA and PET-oriented therapy in patients with DLBCL. A multicenter, open-label, phase II trial (BASEC)
Titolo accademico
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. (ICTRP)
Titolo pubblico
Assessing a ctDNA and PET-oriented Therapy in Patients With DLBCL A Multicenter, Open-label, Phase II Trial. (ICTRP)
Malattie studiate
Diffuse Large B-cell Lymphoma (ICTRP)
Intervento studiato
Drug: Acalabrutinib (ICTRP)
Tipo di studio
Interventional (ICTRP)
Disegno dello studio
Allocation: N/A. Intervention model: Single Group Assignment. Primary purpose: Treatment. Masking: None (Open Label). (ICTRP)
Criteri di inclusione/esclusione
Inclusion Criteria:
- Written informed consent according to ICH GCP E6(R2) regulations before registration
and prior to any trial specific procedures.
- Histologically confirmed, treatment-nave 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 compone (ICTRP)
non disponibile
Endpoint primari e secondari
Cohorts A, C and D: Progression free survival (PFS) according to the Lugano criteria;Cohort B: Complete remission (CR) rate at the end of therapy according to the Lugano criteria (ICTRP)
Adverse events (AEs);Overall survival (OS);Progression free survival in cohort B;Complete remission rate in cohorts A, C and D;Overall response rate (ORR);Duration of response (DoR) (ICTRP)
Data di registrazione
22.10.2020 (ICTRP)
Inclusione del primo partecipante
non disponibile
Sponsor secondari
non disponibile
Contatti aggiuntivi
Anastasios Stathis, Prof, IOSI, Ospedale San Giovanni Bellinzona (ICTRP)
ID secondari
2020-003876-42, SAKK 38/19 (ICTRP)
Risultati-Dati individuali dei partecipanti
non disponibile
Ulteriori informazioni sullo studio
https://clinicaltrials.gov/ct2/show/NCT04604067 (ICTRP)
Risultati dello studio
Riepilogo dei risultati
non disponibile
Link ai risultati nel registro primario
non disponibile