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Biomarker Driven Intensified ChemoImmunotherapy With Early CNS Prophylaxis (Bio-CHIC)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03293173
Recruitment Status : Recruiting
First Posted : September 26, 2017
Last Update Posted : March 4, 2020
Sponsor:
Collaborators:
Helsinki University Central Hospital
Aarhus University Hospital
Information provided by (Responsible Party):
Nordic Lymphoma Group

Study Description
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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).

Condition or disease Intervention/treatment Phase
Lymphoma, Large B-Cell, Diffuse Combination Product: R-CHOEP Combination Product: DA-EPOCH-R Phase 2

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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Stratification into group A (standard) or group B (experimental) based on biological risk factors
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : August 4, 2017
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : June 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma

Arms and Interventions
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Arm Intervention/treatment
Experimental: Group A
Biologically low risk group, R-CHOEP-14
 Combination Product: R-CHOEP
rituximab, cyclophosphamide, doxorubicin, etoposide, vincristine, prednisone
Experimental: Group B
Biologically high risk group, DA-EPOCH-R
 Combination Product: DA-EPOCH-R
dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab


Outcome Measures
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Primary Outcome Measures :
  1. Time to treatment failure (TTF) of the patients with biological risk factors [ Time Frame: At 3 years ]
    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.


Secondary Outcome Measures :
  1. Time to treatment failure (TTF) at 3 years from date of registration of all patients and the patients in the low risk group [ Time Frame: At 3 years ]
    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.

  2. Incidence of treatment-emergent adverse events (Safety and tolerability) [ Time Frame: 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. ]
    Number of patients with treatment-related adverse events graded according to the NCI CTCAE v 4.03

  3. Clinical response rate of all patients and the patients with biological risk factors [ Time Frame: At the end of treatment cycles 2 and 7. Each cycle is two (group A) or three weeks (group B) ]
    Number of patients with complete or partial response

  4. CNS relapse rate [ Time Frame: At 1,5 years ]
    Number of patients with CNS progression

  5. Progression free survival rate (PFS) of all patients and the patients with biological risk factors [ Time Frame: At 3 years ]
  6. Overall survival rate (OS) of all patients and the patients with biological risk factors [ Time Frame: At 3 years ]
  7. Molecular correlates for survival [ Time Frame: At 3 years ]
    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


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 64 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03293173


Contacts
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Contact: Laura K Hakala +358503729043 ext-laura.k.hakala@hus.fi

Locations
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Denmark
Aarhus University Hospital Recruiting
Aarhus, Denmark
Contact: Judit Joergensen, MD, PhD         
Principal Investigator: Judit Joergensen         
Dept of Haematology, Rigshospitalet Recruiting
Copenhagen, Denmark, 2100
Contact: Peter Brown, MD, PhD         
Principal Investigator: Peter Brown         
Dept of Haematology, Herlev Hospital, Copenhagen Recruiting
Herlev, Denmark
Contact: Danny Stoltenberg, MD, PhD         
Principal Investigator: Danny Stoltenberg         
Dept haematology, Odense University hospital Recruiting
Odense, Denmark, 5000
Contact: Thomas Stauffer Larsen, MD, PhD         
Principal Investigator: Thomas Stauffer Larsen         
Dept of Haematology, Sjaellands University hospital, Roskilde Recruiting
Roskilde, Denmark, 4000
Contact: Christian Bjorn Poulsen, MD, PhD         
Principal Investigator: Christian Bjorn Poulsen         
Finland
Helsinki University Hospital Cancer Centre Recruiting
Helsinki, Finland, 00029
Contact: Laura K Hakala    +358503729043    ext-laura.k.hakala@hus.fi   
Principal Investigator: Sirpa Leppä, prof         
Keski-Suomen keskussairaala Recruiting
Jyväskylä, Finland, 40620
Contact: Kaija Vasala, MD, PhD         
Principal Investigator: Kaija Vasala         
Kuopio University Hospital Recruiting
Kuopio, Finland, 70029
Contact: Annikki Aromaa-Häyhä, MD, PhD         
Principal Investigator: Annikki Aromaa-Häyhä         
TAYS Recruiting
Tampere, Finland, 33521
Contact: Kaisa Sunela, MD, PhD         
Principal Investigator: Kaisa Sunela         
Turku University Hospital, Syöpäklinikka Recruiting
Turku, Finland, 20520
Contact: Sirkku Jyrkkiö, MD, PhD         
Principal Investigator: Sirkku Jyrkkiö         
Norway
Dept. of Oncology, Helse Bergen HF Haukeland sykehus Recruiting
Bergen, Norway, 5021
Contact: Oystein Fluge, MD, PhD         
Principal Investigator: Oystein Fluge         
Oslo University Hospital Recruiting
Oslo, Norway
Contact: Harald Holte, MD, PhD         
Principal Investigator: Harald Holte         
Dept. of Haematology and Oncology, Helse Stavander HF sykehuset Recruiting
Stavanger, Norway, 4011
Contact: Peter Meyer, MD, PhD         
Principal Investigator: Peter Meyer         
Dept. of Oncology, Universitetssykehuset i Nord-Norge HF Recruiting
Tromsø, Norway, 9038
Contact: Martin Maisenhölder, Md, PhD         
Principal Investigator: Martin Maisenhölder         
Dept of Oncology, St. Olavs hospital HF Recruiting
Trondheim, Norway, 7006
Contact: Unn Merete Fagerli, MD, PhD         
Principal Investigator: Unn Merete Fagerli         
Sweden
Skåne University Hospital Recruiting
Lund, Sweden
Contact: Kristina Drott, MD, PhD         
Principal Investigator: Kristina Drott         
Sponsors and Collaborators
Nordic Lymphoma Group
Helsinki University Central Hospital
Aarhus University Hospital
Investigators
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Principal Investigator: Sirpa Leppa, prof Helsinki University Hospital Cancer Centre
More Information
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Publications:

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Responsible Party: Nordic Lymphoma Group
ClinicalTrials.gov Identifier: NCT03293173    
Other Study ID Numbers: NLG-LBC-06
First Posted: September 26, 2017    Key Record Dates
Last Update Posted: March 4, 2020
Last Verified: March 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: individual deidentified participant data (including data dictionaries) will be shared
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Time Frame: Beginning 3 months and ending 5 years following article publication
Access Criteria: Researchers who provide a methodologically sound proposal.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Nordic Lymphoma Group:
DLBCL
Chemoimmunotherapy
High risk
CNS prophylaxis
Biomarker-driven
Additional relevant MeSH terms:
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Lymphoma
Lymphoma, Large B-Cell, Diffuse
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
 Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, B-Cell
Lymphoma, Non-Hodgkin