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

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

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).

Study Overview

• Status: Recruiting
• Conditions: Lymphoma, Large B-Cell, Diffuse
• Intervention / Treatment: Combination product: R-CHOEP; Combination product: DA-EPOCH-R

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 Type: Interventional
• Enrollment (Anticipated): 120
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Laura K Hakala; Phone Number: +358503729043; Email: ext-laura.k.hakala@hus.fi

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 62 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Nordic Lymphoma Group
• Collaborators: Helsinki University Central Hospital; Aarhus University Hospital
• Investigators: Principal Investigator: Sirpa Leppa, prof, Helsinki University Hospital Cancer Centre

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): August 4, 2017
• Primary Completion (Anticipated): December 1, 2020
• Study Completion (Anticipated): June 1, 2024

Study Registration Dates

• First Submitted: September 5, 2017
• First Submitted That Met QC Criteria: September 21, 2017
• First Posted (Actual): September 26, 2017

Study Record Updates

• Last Update Posted (Actual): March 4, 2020
• Last Update Submitted That Met QC Criteria: March 3, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Keywords: DLBCL; Biomarker-driven; Chemoimmunotherapy; High risk; CNS prophylaxis
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma, B-Cell; Lymphoma; Lymphoma, Large B-Cell, Diffuse
• Other Study ID Numbers: NLG-LBC-06

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD 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.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No