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Trial registered on ANZCTR


Registration number
ACTRN12609001077257
Ethics application status
Approved
Date submitted
5/12/2008
Date registered
16/12/2009
Date last updated
2/06/2017
Type of registration
Retrospectively registered

Titles & IDs
Public title
'A multi-centre phase II trial of early treatment intensification with R-ICE (rituximab – ifosfamide, carboplatin, etoposide) chemotherapy followed by BEAM ( BCNU(BCNU is Carmustine), etoposide, ara-C (ara-C is Cytarabine), melphalan) high dose chemotherapy and autologous stem cell transplantation for patients with poor prognosis diffuse large B-cell lymphoma
Scientific title
This is a multi-centre phase II trial of early treatment intensification with R-ICE (rituximab – ifosfamide, carboplatin, etoposide) chemotherapy followed by BEAM ( BCNU(BCNU is Carmustine), etoposide, ara-C (ara-C is Cytarabine), melphalan) high dose chemotherapy and autologous stem cell transplantation for patients with poor prognosis diffuse large B-cell lymphoma as identified by interim-treatment PET/CT (Positron emission tomography - computed tomography) performed after four cycles of R-CHOP-14 (rituximab and Cyclophosphamide, Doxorubicin, Vincristine, Prednisone - CHOP - every 14 days) chemotherapy.
Universal Trial Number (UTN)
Trial acronym
ALLG NHL21
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Patients with CD20+ diffuse large B cell lymphoma (DLBCL) with low intermediate, high intermediate, or high risk disease or low risk disease with bulky tumour (> 7.5 cm) who are considered fit and eligible for high dose chemotherapy (HDCT) with Z-BEAM ( Zevalin - BEAM ( BCNU(BCNU is Carmustine), etoposide, ara-C (ara-C is Cytarabine), melphalan) and autologous stem cell transplantation (ASCT). 4074 0
Condition category
Condition code
Cancer 4282 4282 0 0
Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients will receive 4 cycles of R-CHOP (rituximab Cyclophosphamide, Doxorubicin, Vincristine, Prednisone administered every 14 days (R-CHOP-14) and supported with Pegfilgrastim. Cycle 5 of R-CHOP-14 will be delayed one week, and an interim PET/CT scan will be performed as close as possible (ie, day 17 to day 20) to the planned 5th cycle of R CHOP-14. Patients who have metabolically inactive disease (PET/CT-negative) will proceed to complete a further two cycles of R-CHOP-14 (total of 6 cycles) plus two doses of rituximab. Patients who display metabolically active disease (PET/CT-positive) will then receive treatment intensification with rituximab, Ifosfamide, Carboplatin and Etoposide (R-ICE) supported by Pegfilgrastim or Filgrastim for 3 cycles at intervals of 21 days. Peripheral blood stem cells will be collected following one of the cycles (typically the second or third) of R ICE. Subsequently, responding patients will undergo High Dose Chemotherapy (HDCT) with Zevalin-BEAM ( Z-BEAM) and autologous stem cell transplantation (ASCT).Dose is based on the individual patient Body Surface Area (BSA) calculation.
Intervention code [1] 3796 0
Treatment: Drugs
Intervention code [2] 3797 0
Treatment: Other
Comparator / control treatment
Active - PET+ patients recieve R-ICE and Z-BEAM Transplant. whereas the PET- patients will recieve R-CHOP chemotherapy only.
Control group
Active

Outcomes
Primary outcome [1] 5169 0
Primary objective and endpoint:
The primary objective is to demonstrate an absolute improvement of 25% in two-year progression-free survival (PFS) from 20% to 45% in those patients with advanced stage DLBCL who have been identified with a positive interim-treatment PET/CT scan and switched to early treatment intensification using R-ICE chemotherapy followed by HDCT/ASCT in comparison with historical outcomes.

The primary endpoint for this trial is progression-free survival (PFS).
Timepoint [1] 5169 0
progression-free survival (PFS). PFS is defined as the time from the interim PET/CT scan (after the 4th cycle of R-CHOP-14) to the first observation of disease progression or death from any cause.
Secondary outcome [1] 8702 0
Secondary objectives and endpoints:
Event-free survival (EFS). measured for all patients who have a positive interim PET/CT scan after the 4th cycle of treatment. Also using complete metabolic response(CMR), or non-CMR or partial metabolic response, using qualative and semi-qualitative analysis
Timepoint [1] 8702 0
2 years post completion of treatment regimen
Secondary outcome [2] 244844 0
Complete remission rates. disappearance of all detectable clinical evidence of disease and disease-related symptoms if present prior to therapy by a PET scan
Timepoint [2] 244844 0
2 years post completion of treatment regimen
Secondary outcome [3] 244845 0
Relapse rates. by a PET scan
Timepoint [3] 244845 0
2 years post completion of treatment regimen
Secondary outcome [4] 244846 0
Overall survival rates.
Timepoint [4] 244846 0
2 years post completion of treatment regimen

Eligibility
Key inclusion criteria
Inclusion criteria
1. Age 18 - 70 years
2. Male and female patients
3. Diagnosis of CD20-positive diffuse large B-cell lymphoma on biopsy
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-3
5. Low-intermediate, high-intermediate, high risk, or low risk disease with bulk (>7.5 cm)
6. Previously untreated (except for corticosteroids if required)
Patients considered suitable for dose-intense chemotherapy with R-CHOP-14 with Pegfilgrastim support
Eligible and fit for high dose chemotherapy with Z-BEAM and autologous stem-cell transplantation
Signed informed consent form
A positive baseline fluorodeoxyglucose(FDG) positron emission tomography(PET)
Minimum age
18 Years
Maximum age
70 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion criteria
1. Life-expectancy < 3 months
2. Transformed NonHodgkin lymphoma (NHL) or types of NHL other than DLBCL
3. Primary Central Nervous System (CNS) or gastrointestinal Mucosa-Associated Lymphoid Tissue (MALT)lymphoma
4. CD20-negative NHL
5. Documented Human Immunodeficiency Viris (HIV)
6. Seropositivity for Hepatitis B [Either 1. HbsAg (surface antigen) positive or 2. HbcAb (core antibody) positive and HbsAb (surface antibody) titre of < 100 iu/ml] unless clearly due to vaccination
7. Patients with good prognosis low risk disease (IPI = 0, 1) plus absence of bulk (= 7.5 cm).
8. Hypersensitivity to components of Zevalin including ibritumomab tiuxetan, Yttrium chloride, other murine proteins, or to any exipients
9. Pregnant woman
10. Previously treated lymphoma
11. Any serious active disease or co-morbid medical condition (according to investigator’s decision)
12. Non-compensated cardiac failure
13. Chronic lung disease with hypoxaemia
14. Severe psychiatric disease
15. Poor renal function (creatinine > 150 micromol/L), poor hepatic function (total bilirubin level > 30 mmol/L, transaminases > 2.5 maximum normal level) unless abnormalities are related to the lymphoma
16. Poor bone marrow reserve as defined by neutrophils < 1.5 x 109/L or platelets < 100 x 109/L, unless related to bone marrow infiltration
17. Any history of cancer during the last 5 years, with the exception of non-melanoma skin tumours or stage 0 (in situ) cervical carcinoma
18. Treatment with any investigational drug within 30 days before planned first cycle of chemotherapy and during the study

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC

Funding & Sponsors
Funding source category [1] 4252 0
Other Collaborative groups
Name [1] 4252 0
Australasian Leukaemia and Lymphoma Group (ALLG)
Address [1] 4252 0
Level 2, 10 St Andrews Place
East Melbourne
3002
Victoria
Country [1] 4252 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australasian Leukaemia and Lymphoma Group (ALLG)
Address
Level 2, 10 St Andrews Place
East Melbourne
3002
Victoria
Country
Australia
Secondary sponsor category [1] 3825 0
None
Name [1] 3825 0
Address [1] 3825 0
Country [1] 3825 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 6304 0
Ethics committee address [1] 6304 0
Ethics committee country [1] 6304 0
Date submitted for ethics approval [1] 6304 0
01/11/2008
Approval date [1] 6304 0
05/03/2009
Ethics approval number [1] 6304 0

Summary
Brief summary
This study looks at the effectiveness of early treatment intensification with R-ICE chemotherapy followed by high dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) if positive PET/CT, or a further 2 cycles of R-CHOP-14 if negative PET/CT in patients with lymphoma which is classified as CD20 positive diffuse large B cell type who have received an initial 4 cycles of R-CHOP-14 chemotherapy.

Who is it for?
You can join this study if you: have lymphoma which is CD20 positive diffuse large B cell type (DLBCL) have either low intermediate, high intermediate, or high risk disease, or low risk disease with bulky tumour (> 7.5 cm) are considered fit and eligible for high dose chemotherapy(HDCT) and autologous stem cell transplantation (ASCT) have not received previous treatment for lymphoma.

Trial details
All participants will receive treatment with R-CHOP-14 chemotherapy every fourteen days over four cycles. They will then undergo PET/CT scanning. Participants who have scans that show the disease remains active will have their treatment intensified with R-ICE chemotherapy followed by HDCT with Z-BEAM (a special chemotherapy regimen) and ASCT. If the scans show that the cancer is no longer active, they will receive a further two cycles of the R-CHOP-14 chemotherapy. The study aims to monitor participants to see the effectiveness of this new treatment, particularly in relation to an expected increase in the number of patients who remain disease free after two years.
Trial website
www.petermac.org/allg/
Trial related presentations / publications
1) Early treatment intensification with R-ICE and 90Y-ibritumomab tiuxetan (Zevalin)-BEAM stem cell transplantation in patients with high-risk diffuse large B-cell lymphoma patients and positive interim PET after 4 cycles of R-CHOP-14. M. Hertzberg et. al., (2017). Haematologica, 102: 356-363; doi:10.3324/haematol.2016.154039

2) Early Treatment Intensification with R-ICE Chemotherapy Followed By Autologous Stem Cell Transplantation (ASCT) Using Zevalin-BEAM for Patients with Poor Risk Diffuse Large B-Cell Lymphoma (DLBCL) As Identified By Interim PET/CT Scan Performed after Four Cycles of R-CHOP-14: A Multicenter Phase II Study of the Australasian Leukaemia Lymphoma Study Group (ALLG). M. Hertzberg et. al., (2015). Blood, 126: 815. American Society of Hematology, oral presentation.
Public notes

Contacts
Principal investigator
Name 29202 0
Address 29202 0
Country 29202 0
Phone 29202 0
Fax 29202 0
Email 29202 0
Contact person for public queries
Name 12359 0
Delaine Smith
Address 12359 0
Level 2, 10 St Andrews Place
East Melbourne
3002
Victoria
Country 12359 0
Australia
Phone 12359 0
+61 3 96563656
Fax 12359 0
+61 3 96561420
Email 12359 0
delaine.smith@petermac.org
Contact person for scientific queries
Name 3287 0
Associate Professor Mark Hertzberg
Address 3287 0
Department of Haematology
Westmead Hospital
Westmead
2145
New South Wales
Country 3287 0
Australia
Phone 3287 0
+610298456274
Fax 3287 0
Email 3287 0
mark_hertzberg@wmi.usyd.edu.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary