Biomarker Driven Intensified ChemoImmunotherapy With Early CNS Prophylaxis

NCT ID: NCT03293173

Last Updated: 2024-06-21

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 120 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-08-04
• Study Completion Date: 2024-12-31

Brief Summary

This study is testing whether stratification of the patients according to biological risk factors for different treatment groups will improve the outcome of patients with clinically high diffuse large B-cell lymphoma (DLBCL).

Detailed Description

For young clinically high-risk diffuse large B-cell lymphoma (DLBCL) patients the optimal therapy has not been established. Previous Nordic phase II studies, where dose-dense chemoimmunotherapy (R-CHOEP-14) with systemic CNS prophylaxis (HD-Mtx and HD-AraC) was given, demonstrated favorable outcome in comparison to historical controls. However, the patients with biological risk factors, such as translocation of bcl2 and myc oncogenes or and/or high BCL2 and MYC expression or deletion 17p and/or high P53 expression had significantly higher risk of death, as compared to patients without aberrations. The figures provide evidence for an unmet clinical need for the patients with biological risk factors, and underscore the importance of a clinical trial, where both biological and clinical risk factors play a role in the treatment planning.

In this trial treatment intensity varies according to presence or absence of biological risk factors. All patients receive a prephase medication consisting of prednisone and vincristine and two cycles of R-CHOP and high dose (HD) methotrexate. Subsequently, depending on the biological risk factors either four additional cycles of R-CHOEP (standard arm with no risk factors) or four dose adjusted R-EPOCH courses (experimental arm with risk factors) are given, followed by one course of high dose cytarabine (Ara-C) and R. R-CHOEP courses should be given with a two-week and R-EPOCH with a three-week interval.

Conditions

Lymphoma, Large B-Cell, Diffuse

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Group A

Biologically low risk group, R-CHOEP-14

Group Type: EXPERIMENTAL

R-CHOEP

Intervention Type: COMBINATION_PRODUCT

rituximab, cyclophosphamide, doxorubicin, etoposide, vincristine, prednisone

Group B

Biologically high risk group, DA-EPOCH-R

Group Type: EXPERIMENTAL

DA-EPOCH-R

Intervention Type: COMBINATION_PRODUCT

dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab

Interventions

R-CHOEP

rituximab, cyclophosphamide, doxorubicin, etoposide, vincristine, prednisone

Intervention Type: COMBINATION_PRODUCT

DA-EPOCH-R

dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab

Intervention Type: COMBINATION_PRODUCT

Eligibility Criteria

Inclusion Criteria

• Age 18 - 64 years
• Histologically confirmed CD20+ DLBCL based on revised WHO 2008 Lymphoma Classification. The following subgroups and variants can be included:

• ALK-positive large B-cell lymphoma
• Intravascular large B-cell lymphoma
• T-cell rich B-cell lymphoma
• Myc/BCL-2 double hit lymphoma
• Follicular lymphomas grade 3b
• DLBCL with previously undiagnosed concurrent small cell infiltration in bone marrow, lymph node, or extranodal site and lymphomas intermediate between DLBCL and Burkitt's lymphoma are allowed
• Posttransplantation lymphoma (PTLD), discordant or transformed lymphoma are NOT allowed
• Patients in at least stage II with age adjusted IPI score of 2 or 3:

• Stage III /IV and elevated LDH
• Stage III/IV and WHO performance status 2 - 3
• Stage II and elevated LDH and WHO performance status 2 - 3
• And/or patients with site specific risk factors for CNS recurrence defined as follows

• More than one extranodal site
• Testicular lymphoma, stage IIE and higher
• Paranasal sinus and orbital lymphoma with destruction of bone
• Large cell lymphoma infiltration of the bone marrow
• Previously untreated, except steroids allowed
• WHO performance status 0-3
• Written informed consent

Exclusion Criteria

• Severe cardiac disease: cardiac function grade 3-4, left ventricular ejection fraction <45%
• Impaired bone marrow liver, renal or other organ function not caused by lymphoma, which will interfere with the treatment schedule (Hemoglobin < 9 g/dL, ANC < 1.5 × 109/L, Platelet count < 75 × 109/L, creatinine clearance < 40 mL/min, ALT/AST > 2.5 x ULN, bilirubin 1.5 x ULN, INR > 1.5)
• Pregnancy/lactation
• Men and women of reproductive potential not agreeing to use effective contraception during treatment and for 18 months after completion of treatment (Effective contraception is combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal or transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable or implantable), intrauterine device (IUD), hormone-releasing IUD, bilateral tubal occlusion, vasectomised partner, or sexual abstinence
• Patients with other severe medical problems, including active infections, cardiac or pulmonary disease, history of PML and with an expected short survival for non-lymphoma reasons
• Known HIV positivity
• Active or chronic hepatitis B virus (HBV) infection (defined as positive HBsAg serology), or active hepatitis C virus (HCV) infection (defined by antibody serology testing). HBsAg, HBcAb, and HCVAb must be tested during screening. Patients who have protective titers of HBsAb along negative HBsAg after vaccination or prior but cured hepatitis B are eligible.
• Vaccination with a live vaccine within one month prior to randomization
• Patients with a malignancy that has been treated but not with curative intent, unless the malignancy has been in remission without treatment for ≥ 5 years prior to enrollment
• Earlier treatment containing anthracyclines
• Psychiatric or mental disorder which make the patient unable to give an informed consent and/or adhere to the protocol
• CNS disease as diagnosed by MRI or CSF cytology. Positive CSF flow cytometry below diagnostic threshold level by cytology is allowed
• Transformed lymphoma
• Primary mediastinal B-cell lymphoma
• Pleural or peritoneal fluid that cannot be drained safely
• Hypersensitivity to the active substance or any of the other ingredients
• History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or known sensitivity or allergy to murine products
• Patients participating in other clinical studies, unless followed for survival
• Lower urinary tract constriction, which cannot be treated adequately
• Degenerative and toxic encephalopathy
• Neuromuscular disease

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 64 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Helsinki University Central Hospital

OTHER

Sponsor Role: collaborator

Aarhus University Hospital

OTHER

Sponsor Role: collaborator

Nordic Lymphoma Group

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Sirpa Leppa, prof

Role: PRINCIPAL_INVESTIGATOR

Helsinki University Hospital Cancer Centre

Locations

Aarhus University Hospital

Aarhus, , Denmark

Dept of Haematology, Rigshospitalet

Copenhagen, , Denmark

Dept of Haematology, Herlev Hospital, Copenhagen

Herlev, , Denmark

Dept haematology, Odense University hospital

Odense, , Denmark

Dept of Haematology, Sjaellands University hospital, Roskilde

Roskilde, , Denmark

Helsinki University Hospital Cancer Centre

Helsinki, , Finland

Keski-Suomen keskussairaala

Jyväskylä, , Finland

Kuopio University Hospital

Kuopio, , Finland

TAYS

Tampere, , Finland

Turku University Hospital, Syöpäklinikka

Turku, , Finland

Dept. of Oncology, Helse Bergen HF Haukeland sykehus

Bergen, , Norway

Oslo University Hospital

Oslo, , Norway

Dept. of Haematology and Oncology, Helse Stavander HF sykehuset

Stavanger, , Norway

Dept. of Oncology, Universitetssykehuset i Nord-Norge HF

Tromsø, , Norway

Dept of Oncology, St. Olavs hospital HF

Trondheim, , Norway

Skåne University Hospital

Lund, , Sweden

Countries

Denmark; Finland; Norway; Sweden

References

Fiskvik I, Beiske K, Delabie J, Yri O, Spetalen S, Karjalainen-Lindsberg ML, Leppa S, Liestol K, Smeland EB, Holte H. Combining MYC, BCL2 and TP53 gene and protein expression alterations improves risk stratification in diffuse large B-cell lymphoma. Leuk Lymphoma. 2015 Jun;56(6):1742-9. doi: 10.3109/10428194.2014.970550. Epub 2014 Nov 19.

Reference Type: BACKGROUND

PMID: 25284491 (View on PubMed)

Holte H, Leppa S, Bjorkholm M, Fluge O, Jyrkkio S, Delabie J, Sundstrom C, Karjalainen-Lindsberg ML, Erlanson M, Kolstad A, Fossa A, Ostenstad B, Lofvenberg E, Nordstrom M, Janes R, Pedersen LM, Anderson H, Jerkeman M, Eriksson M. Dose-densified chemoimmunotherapy followed by systemic central nervous system prophylaxis for younger high-risk diffuse large B-cell/follicular grade 3 lymphoma patients: results of a phase II Nordic Lymphoma Group study. Ann Oncol. 2013 May;24(5):1385-92. doi: 10.1093/annonc/mds621. Epub 2012 Dec 17.

Reference Type: BACKGROUND

PMID: 23247661 (View on PubMed)

Arffman M, Meriranta L, Autio M, Holte H, Jorgensen J, Brown P, Jyrkkio S, Jerkeman M, Drott K, Fluge O, Bjorkholm M, Karjalainen-Lindsberg ML, Beiske K, Pedersen MO, Leivonen SK, Leppa S. Inflammatory and subtype-dependent serum protein signatures predict survival beyond the ctDNA in aggressive B cell lymphomas. Med. 2024 Jun 14;5(6):583-602.e5. doi: 10.1016/j.medj.2024.03.007. Epub 2024 Apr 4.

Reference Type: DERIVED

PMID: 38579729 (View on PubMed)

Other Identifiers

NLG-LBC-06

Identifier Type: -

Identifier Source: org_study_id