Biomarker Driven Intensified ChemoImmunotherapy With Early CNS Prophylaxis

Study Overview
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Brief Summary
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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
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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.

Official Title
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Biomarker Driven and Dose Intensified Chemoimmunotherapy With Early CNS Prophylaxis in Patients Less Than 65 Years With High Risk Diffuse Large B-Cell Lymphoma

Conditions
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Lymphoma, Large B-Cell, Diffuse

Intervention / Treatment
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* Combination Product: R-CHOEP
* Combination Product: DA-EPOCH-R


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Stratification into group A (standard) or group B (experimental) based on biological risk factors
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A<br>Biologically low risk group, R-CHOEP-14 | Combination Product: R-CHOEP<br>* rituximab, cyclophosphamide, doxorubicin, etoposide, vincristine, prednisone<br>|
| Experimental: Group B<br>Biologically high risk group, DA-EPOCH-R | Combination Product: DA-EPOCH-R<br>* dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to treatment failure (TTF) of the patients with biological risk factors | Interval between the registration date and the date of documented progression or lack of response, first relapse, death for any reason or discontinuation/change of therapy because of toxicity, whichever occurs first. Otherwise, patients will be censored at the last date they were known to be alive. For patients not responding at any time point on study treatment, TTF is defined as one day. | At 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to treatment failure (TTF) at 3 years from date of registration of all patients and the patients in the low risk group | Interval between the registration date and the date of documented progression or lack of response, first relapse, death for any reason or discontinuation/change of therapy because of toxicity, whichever occurs first. Otherwise, patients will be censored at the last date they were known to be alive. For patients not responding at any time point on study treatment, TTF is defined as one day. | At 3 years | 
| Incidence of treatment-emergent adverse events (Safety and tolerability) | Number of patients with treatment-related adverse events graded according to the NCI CTCAE v 4.03 | 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. | 
| Clinical response rate of all patients and the patients with biological risk factors | Number of patients with complete or partial response | At the end of treatment cycles 2 and 7. Each cycle is two (group A) or three weeks (group B) | 
| CNS relapse rate | Number of patients with CNS progression | At 1,5 years | 
| Progression free survival rate (PFS) of all patients and the patients with biological risk factors |  | At 3 years | 
| Overall survival rate (OS) of all patients and the patients with biological risk factors |  | At 3 years | 
| Molecular correlates for survival | Identification of genomic aberrations (for example mutations and translocations), gene expression profiles and protein expression from the tumor tissue and circulation that predict clinical course of the disease | At 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DLBCL, Chemoimmunotherapy, High risk, CNS prophylaxis, Biomarker-driven