search
Back to results

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

Primary Purpose

Lymphoma, Large B-Cell, Diffuse

Status
Recruiting
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
R-CHOEP
DA-EPOCH-R
Sponsored by
Nordic Lymphoma Group
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Lymphoma, Large B-Cell, Diffuse focused on measuring DLBCL, Chemoimmunotherapy, High risk, CNS prophylaxis, Biomarker-driven

Eligibility Criteria

18 Years - 64 Years (Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Aarhus University HospitalRecruiting
  • Dept of Haematology, RigshospitaletRecruiting
  • Dept of Haematology, Herlev Hospital, CopenhagenRecruiting
  • Dept haematology, Odense University hospitalRecruiting
  • Dept of Haematology, Sjaellands University hospital, RoskildeRecruiting
  • Helsinki University Hospital Cancer CentreRecruiting
  • Keski-Suomen keskussairaalaRecruiting
  • Kuopio University HospitalRecruiting
  • TAYSRecruiting
  • Turku University Hospital, SyöpäklinikkaRecruiting
  • Dept. of Oncology, Helse Bergen HF Haukeland sykehusRecruiting
  • Oslo University HospitalRecruiting
  • Dept. of Haematology and Oncology, Helse Stavander HF sykehusetRecruiting
  • Dept. of Oncology, Universitetssykehuset i Nord-Norge HFRecruiting
  • Dept of Oncology, St. Olavs hospital HFRecruiting
  • Skåne University HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Group A

Group B

Arm Description

Biologically low risk group, R-CHOEP-14

Biologically high risk group, DA-EPOCH-R

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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
Clinical response rate of all patients and the patients with biological risk factors
Number of patients with complete or partial response
CNS relapse rate
Number of patients with CNS progression
Progression free survival rate (PFS) of all patients and the patients with biological risk factors
Overall survival rate (OS) of all patients and the patients with biological risk factors
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

Full Information

First Posted
September 5, 2017
Last Updated
March 3, 2020
Sponsor
Nordic Lymphoma Group
Collaborators
Helsinki University Central Hospital, Aarhus University Hospital
search

1. Study Identification

Unique Protocol Identification Number
NCT03293173
Brief Title
Biomarker Driven Intensified ChemoImmunotherapy With Early CNS Prophylaxis
Acronym
Bio-CHIC
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

2. Study Status

Record Verification Date
March 2020
Overall Recruitment Status
Recruiting
Study Start Date
August 4, 2017 (Actual)
Primary Completion Date
December 2020 (Anticipated)
Study Completion Date
June 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Nordic Lymphoma Group
Collaborators
Helsinki University Central Hospital, Aarhus University Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Lymphoma, Large B-Cell, Diffuse
Keywords
DLBCL, Chemoimmunotherapy, High risk, CNS prophylaxis, Biomarker-driven

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Stratification into group A (standard) or group B (experimental) based on biological risk factors
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
120 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Group A
Arm Type
Experimental
Arm Description
Biologically low risk group, R-CHOEP-14
Arm Title
Group B
Arm Type
Experimental
Arm Description
Biologically high risk group, DA-EPOCH-R
Intervention Type
Combination Product
Intervention Name(s)
R-CHOEP
Intervention Description
rituximab, cyclophosphamide, doxorubicin, etoposide, vincristine, prednisone
Intervention Type
Combination Product
Intervention Name(s)
DA-EPOCH-R
Intervention Description
dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab
Primary Outcome Measure Information:
Title
Time to treatment failure (TTF) of the patients with biological risk factors
Description
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.
Time Frame
At 3 years
Secondary Outcome Measure Information:
Title
Time to treatment failure (TTF) at 3 years from date of registration of all patients and the patients in the low risk group
Description
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.
Time Frame
At 3 years
Title
Incidence of treatment-emergent adverse events (Safety and tolerability)
Description
Number of patients with treatment-related adverse events graded according to the NCI CTCAE v 4.03
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.
Title
Clinical response rate of all patients and the patients with biological risk factors
Description
Number of patients with complete or partial response
Time Frame
At the end of treatment cycles 2 and 7. Each cycle is two (group A) or three weeks (group B)
Title
CNS relapse rate
Description
Number of patients with CNS progression
Time Frame
At 1,5 years
Title
Progression free survival rate (PFS) of all patients and the patients with biological risk factors
Time Frame
At 3 years
Title
Overall survival rate (OS) of all patients and the patients with biological risk factors
Time Frame
At 3 years
Title
Molecular correlates for survival
Description
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
Time Frame
At 3 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
64 Years
Accepts Healthy Volunteers
No
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Laura K Hakala
Phone
+358503729043
Email
ext-laura.k.hakala@hus.fi
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Sirpa Leppa, prof
Organizational Affiliation
Helsinki University Hospital Cancer Centre
Official's Role
Principal Investigator
Facility Information:
Facility Name
Aarhus University Hospital
City
Aarhus
Country
Denmark
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Judit Joergensen, MD, PhD
First Name & Middle Initial & Last Name & Degree
Judit Joergensen
Facility Name
Dept of Haematology, Rigshospitalet
City
Copenhagen
ZIP/Postal Code
2100
Country
Denmark
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Peter Brown, MD, PhD
First Name & Middle Initial & Last Name & Degree
Peter Brown
Facility Name
Dept of Haematology, Herlev Hospital, Copenhagen
City
Herlev
Country
Denmark
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Danny Stoltenberg, MD, PhD
First Name & Middle Initial & Last Name & Degree
Danny Stoltenberg
Facility Name
Dept haematology, Odense University hospital
City
Odense
ZIP/Postal Code
5000
Country
Denmark
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Thomas Stauffer Larsen, MD, PhD
First Name & Middle Initial & Last Name & Degree
Thomas Stauffer Larsen
Facility Name
Dept of Haematology, Sjaellands University hospital, Roskilde
City
Roskilde
ZIP/Postal Code
4000
Country
Denmark
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Christian Bjorn Poulsen, MD, PhD
First Name & Middle Initial & Last Name & Degree
Christian Bjorn Poulsen
Facility Name
Helsinki University Hospital Cancer Centre
City
Helsinki
ZIP/Postal Code
00029
Country
Finland
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Laura K Hakala
Phone
+358503729043
Email
ext-laura.k.hakala@hus.fi
First Name & Middle Initial & Last Name & Degree
Sirpa Leppä, prof
Facility Name
Keski-Suomen keskussairaala
City
Jyväskylä
ZIP/Postal Code
40620
Country
Finland
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kaija Vasala, MD, PhD
First Name & Middle Initial & Last Name & Degree
Kaija Vasala
Facility Name
Kuopio University Hospital
City
Kuopio
ZIP/Postal Code
70029
Country
Finland
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Annikki Aromaa-Häyhä, MD, PhD
First Name & Middle Initial & Last Name & Degree
Annikki Aromaa-Häyhä
Facility Name
TAYS
City
Tampere
ZIP/Postal Code
33521
Country
Finland
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kaisa Sunela, MD, PhD
First Name & Middle Initial & Last Name & Degree
Kaisa Sunela
Facility Name
Turku University Hospital, Syöpäklinikka
City
Turku
ZIP/Postal Code
20520
Country
Finland
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Sirkku Jyrkkiö, MD, PhD
First Name & Middle Initial & Last Name & Degree
Sirkku Jyrkkiö
Facility Name
Dept. of Oncology, Helse Bergen HF Haukeland sykehus
City
Bergen
ZIP/Postal Code
5021
Country
Norway
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Oystein Fluge, MD, PhD
First Name & Middle Initial & Last Name & Degree
Oystein Fluge
Facility Name
Oslo University Hospital
City
Oslo
Country
Norway
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Harald Holte, MD, PhD
First Name & Middle Initial & Last Name & Degree
Harald Holte
Facility Name
Dept. of Haematology and Oncology, Helse Stavander HF sykehuset
City
Stavanger
ZIP/Postal Code
4011
Country
Norway
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Peter Meyer, MD, PhD
First Name & Middle Initial & Last Name & Degree
Peter Meyer
Facility Name
Dept. of Oncology, Universitetssykehuset i Nord-Norge HF
City
Tromsø
ZIP/Postal Code
9038
Country
Norway
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Martin Maisenhölder, Md, PhD
First Name & Middle Initial & Last Name & Degree
Martin Maisenhölder
Facility Name
Dept of Oncology, St. Olavs hospital HF
City
Trondheim
ZIP/Postal Code
7006
Country
Norway
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Unn Merete Fagerli, MD, PhD
First Name & Middle Initial & Last Name & Degree
Unn Merete Fagerli
Facility Name
Skåne University Hospital
City
Lund
Country
Sweden
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kristina Drott, MD, PhD
First Name & Middle Initial & Last Name & Degree
Kristina Drott

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
individual deidentified participant data (including data dictionaries) will be shared
IPD Sharing Time Frame
Beginning 3 months and ending 5 years following article publication
IPD Sharing Access Criteria
Researchers who provide a methodologically sound proposal.
Citations:
PubMed Identifier
25284491
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.
Results Reference
background
PubMed Identifier
23247661
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.
Results Reference
background

Learn more about this trial

Biomarker Driven Intensified ChemoImmunotherapy With Early CNS Prophylaxis

We'll reach out to this number within 24 hrs