Clinical trial NCT03293173: Biomarker Driven Intensified ChemoImmunotherapy With Early CNS Prophylaxis
Official title: Biomarker Driven and Dose Intensified Chemoimmunotherapy With Early CNS Prophylaxis in Patients Less Than 65 Years With High Risk Diffuse Large B-Cell Lymphoma
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Lymphoma, Large B-Cell, Diffuse
Keywords: DLBCL
Chemoimmunotherapy
High risk
CNS prophylaxis
Biomarker-driven
Lead sponsor: Nordic Lymphoma Group
Sponsor class: NETWORK
Collaborators: name: Helsinki University Central Hospital
name: Aarhus University Hospital
First posted: 2017-09-26
Enrollment: 120
Sex: ALL
Minimum age (years): 18
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Stratification into group A (standard) or group B (experimental) based on biological risk factors
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Time to treatment failure (TTF) of the patients with biological risk factors
timeFrame: At 3 years
Secondary outcomes:
measure: Time to treatment failure (TTF) at 3 years from date of registration of all patients and the patients in the low risk group
timeFrame: At 3 years
measure: Incidence of treatment-emergent adverse events (Safety and tolerability)
timeFrame: During the treatment period at the end of each cycle (14 or 21 days) up to 6 months. In addition, severe late toxicities during follow-up at 6 months intervals through study completion, an average of 5.5 years.
measure: Clinical response rate of all patients and the patients with biological risk factors
timeFrame: At the end of treatment cycles 2 and 7. Each cycle is two (group A) or three weeks (group B)
measure: CNS relapse rate
timeFrame: At 1,5 years
measure: Progression free survival rate (PFS) of all patients and the patients with biological risk factors
timeFrame: At 3 years
measure: Overall survival rate (OS) of all patients and the patients with biological risk factors
timeFrame: At 3 years
measure: Molecular correlates for survival
timeFrame: At 3 years
Other outcomes:
Locations:
city: Aarhus
country: Denmark
facility: Aarhus University Hospital
city: Copenhagen
country: Denmark
facility: Dept of Haematology, Rigshospitalet
city: Herlev
country: Denmark
facility: Dept of Haematology, Herlev Hospital, Copenhagen
city: Odense
country: Denmark
facility: Dept haematology, Odense University hospital
city: Roskilde
country: Denmark
facility: Dept of Haematology, Sjaellands University hospital, Roskilde
city: Helsinki
country: Finland
facility: Helsinki University Hospital Cancer Centre
city: Jyväskylä
country: Finland
facility: Keski-Suomen keskussairaala
city: Kuopio
country: Finland
facility: Kuopio University Hospital
city: Tampere
country: Finland
facility: TAYS
city: Turku
country: Finland
facility: Turku University Hospital, Syöpäklinikka
city: Bergen
country: Norway
facility: Dept. of Oncology, Helse Bergen HF Haukeland sykehus
city: Oslo
country: Norway
facility: Oslo University Hospital
city: Stavanger
country: Norway
facility: Dept. of Haematology and Oncology, Helse Stavander HF sykehuset
city: Tromsø
country: Norway
facility: Dept. of Oncology, Universitetssykehuset i Nord-Norge HF
city: Trondheim
country: Norway
facility: Dept of Oncology, St. Olavs hospital HF
city: Lund
country: Sweden
facility: Skåne University Hospital
Study officials:
affiliation: Helsinki University Hospital Cancer Centre
name: Sirpa Leppa, prof
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.