Bio-CHIC: Biomarker Driven Intensified ChemoImmunotherapy With Early CNS Prophylaxis

Sponsor

Nordic Lymphoma Group (Other)

Overall Status

Recruiting

CT.gov ID

NCT03293173

Collaborator

Helsinki University Central Hospital (Other), Aarhus University Hospital (Other)

120

Enrollment

Locations

Arms

81.9

Anticipated Duration (Months)

7.5

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

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).

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

Study Type:

Interventional

Anticipated 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 factorsStratification 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 :

Aug 4, 2017

Anticipated Primary Completion Date :

Dec 1, 2020

Anticipated Study Completion Date :

Jun 1, 2024

Arms and Interventions

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

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

Primary Outcome Measures

Time to treatment failure (TTF) of the patients with biological risk factors [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

Time to treatment failure (TTF) at 3 years from date of registration of all patients and the patients in the low risk group [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.
Incidence of treatment-emergent adverse events (Safety and tolerability) [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
Clinical response rate of all patients and the patients with biological risk factors [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
CNS relapse rate [At 1,5 years]
Number of patients with CNS progression
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 [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

Criteria

Ages Eligible for Study:

18 Years to 64 Years

Sexes Eligible for Study:

All

Accepts 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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Aarhus University Hospital	Aarhus	Denmark
2	Dept of Haematology, Rigshospitalet	Copenhagen	Denmark	2100
3	Dept of Haematology, Herlev Hospital, Copenhagen	Herlev	Denmark
4	Dept haematology, Odense University hospital	Odense	Denmark	5000
5	Dept of Haematology, Sjaellands University hospital, Roskilde	Roskilde	Denmark	4000
6	Helsinki University Hospital Cancer Centre	Helsinki	Finland	00029
7	Keski-Suomen keskussairaala	Jyväskylä	Finland	40620
8	Kuopio University Hospital	Kuopio	Finland	70029
9	TAYS	Tampere	Finland	33521
10	Turku University Hospital, Syöpäklinikka	Turku	Finland	20520
11	Dept. of Oncology, Helse Bergen HF Haukeland sykehus	Bergen	Norway	5021
12	Oslo University Hospital	Oslo	Norway
13	Dept. of Haematology and Oncology, Helse Stavander HF sykehuset	Stavanger	Norway	4011
14	Dept. of Oncology, Universitetssykehuset i Nord-Norge HF	Tromsø	Norway	9038
15	Dept of Oncology, St. Olavs hospital HF	Trondheim	Norway	7006
16	Skåne University Hospital	Lund	Sweden