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Trial registered on ANZCTR


Registration number
ACTRN12615000551594
Ethics application status
Approved
Date submitted
16/02/2015
Date registered
29/05/2015
Date last updated
26/07/2019
Date data sharing statement initially provided
26/07/2019
Date results information initially provided
26/07/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase II Study of Ibrutinib, Rituximab and mini-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy in very elderly patients with newly diagnosed Diffuse Large B-Cell Lymphoma (DLBCL)
Scientific title
A Phase II Study of Ibrutinib, Rituximab and mini-CHOP therapy in very elderly patients with newly diagnosed DLBCL
Secondary ID [1] 286181 0
ALLG NHL29
Universal Trial Number (UTN)
Trial acronym
IRiC study: Ibrutinib R-mini-CHOP in elderly DLBCL
Linked study record

Health condition
Health condition(s) or problem(s) studied:
elderly DLBCL 294209 0
Condition category
Condition code
Cancer 294525 294525 0 0
Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Pre-phase prednisone at a dose of either 40mg/m2 IV or 100mg orally (depending on drug available IV or oral) daily for 5-7 days will be mandatory. All subjects will receive ibrutinib 560mg orally daily, rituximab 375mg/m2 IV (rounded up as per local investigator discretion to the nearest 100mg) on day 1, cyclophosphamide 400mg/m2 IV day 1, doxorubicin 25mg/m2 IV day 1, vincristine 1mg IV and prednisone 40mg/m2 IV or 100mg orally daily on a 21 day schedule aiming for a total of 6 cycles. This will be followed directly by 2 cycles of ibrutinib 560mg orally daily and rituximab 375mg/m2 IV on day 1 (rounded up as per local investigator discretion to the nearest 100mg) on a 21 day schedule.
Pegfilgrastim G-CSF 6mg subcutaneous injection on day 4-5 of each cycle as tolerated.
Intervention code [1] 291190 0
Treatment: Drugs
Comparator / control treatment
Single arm study
Control group
Uncontrolled

Outcomes
Primary outcome [1] 294304 0
The primary objective of this study is to assess the safety of ibrutinib-R-mini-CHOP in subjects with DLBCL as measured by deliverability.
Timepoint [1] 294304 0
Deliverability of Ibrutinib-R-mini-CHOP as measured by:
Average Relative Total Dose (ARTD), and
Average Relative Dose Intensity (ARDI) Hyrniuk’s model RDI = Total Dose Delivered/Total Time (DDI) / SDI for each cycle and for the total of 8 cycles.

Primary outcome [2] 294911 0
The primary objective of this study is to assess the efficacy of ibrutinib-R-mini-CHOP in subjects with DLBCL as measured by overall survival.
Timepoint [2] 294911 0
Overall survival (OS) at 2 years.
Secondary outcome [1] 312997 0
Secondary objectives include assessing the:
toxicity of ibrutinib-R-mini-CHOP

Treatment related toxicities that are Grade 3 or worse will be captured using NCI CTC V4.03.

Cardiac toxicity will be measured by left ventricular ejection fraction (LVEF).


The number (%) of patients with treatment related toxicities that are Grade 3 or worse will be calculated and summarised.

The number (%) of patients with cardiac toxicity as measured by left ventricular ejection fraction (LVEF) will be calculated and summarised. Cardiac toxicity is defined as >=10% absolute decline of LVEF to a LVEF <=50%.
Timepoint [1] 312997 0
Secondary safety analyses will be based upon the safety population. Assessed bi-annually for a minimum of 2 years post treatment (follow up period).
The number (%) of patients with treatment related toxicities that are Grade 3 or worse will be calculated and summarised.

The number (%) of patients with cardiac toxicity as measured by left ventricular ejection fraction (LVEF) will be calculated and summarised. Cardiac toxicity is defined as >=10% absolute decline of LVEF to a LVEF <=50%.
Secondary outcome [2] 314324 0
Secondary objectives include assessing the:
efficacy of ibrutinib-R-mini-CHOP measured by response rate
Timepoint [2] 314324 0
Response rate (CR, PR, SD, PD, relapse after CR) after cycle 4 and end of treatment
Secondary outcome [3] 314325 0
Secondary objectives include assessing the:
progression free survival, and disease free survival (for subjects in CR) in subjects with DLBCL.
Composite outcome.
Timepoint [3] 314325 0
Secondary endpoints include:
Progression free survival. An event is defined as death from any cause, relapse for CR subjects, progression during or after treatment, and changes of therapy during treatment.

Disease free survival for patient in CR. An event is defined as relapse, progression during or after treatment, or death.

The number (%) of patients who are progression free and disease free at 2-years will be calculated.

Secondary outcome [4] 335612 0
Overall survival by IPI (International Prognostic Index) subgroup and ABC (Activated B-Cell) phenotype/genotype will be assessed.
Timepoint [4] 335612 0
Overall survival at 2 years.

Eligibility
Key inclusion criteria
1. Subject must be 75 years of age or older
2. No prior treatment for DLBCL excluding prednisone
3. Histologically confirmed de novo CD20+ DLBCL
4. Stage I bulky (largest dimension of lesion >/= 6cm), II, III or IV disease by the Ann Arbor Classification
5. At least 1 measurable site of disease according to the 2014 Recommendations for Initial Evaluation, Staging and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma – the Lugano Classification. The site of disease must be greater than 1.5 cm in the long axis regardless of short axis measurement. An extranodal lesion should have a longest diameter of > 1cm.
6. Eastern Cooperative Oncology Group performance status score of 0, 1, or 2 (this can be as measured after any pre-phase prednisone)
7. LVEF within institutional normal limits, as determined by Gated Heart Pool Scan, or if not available, echocardiogram
8. Minimum life expectancy of 3 months
9. Haematology values must be within the following limits:
a. Absolute neutrophil count (ANC) >=1.0 x10^9/Lindependent of growth factor support
b. Platelets >=100x10^9/L or >=50x10^9/L if bone marrow involvement independent of transfusion support in either situation
10. Biochemical values within the following limits:
a. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <= 3 x upper limit of normal (ULN)
b. Total bilirubin <= 1.5 x ULN unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin
c. Creatinine Clearance (as measured by Cockroft Gault) >/= 40 mL/min/1.73m2
11. Each subject (or their legally acceptable representative) must sign an informed consent form (ICF) indicating that he or she understands the purpose of and procedures required for the study and are willing to participate in the study.
12. Men who are sexually active must be practicing a highly effective method of birth control during and after the study consistent with local regulations regarding the use of birth control methods for subjects participating in clinical trials. Men must agree to not donate sperm during and after the study.
Minimum age
75 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. History of treated lymphoma of any subtype
2. CNS or meningeal involvement
3. Contraindication to any drug in the chemotherapy regimen
4. Serious active co-morbid disease according to the investigator’s decision
5. Poor renal function, defined as a Creatinine Clearance Rate (as measured by Cockcroft Gault) < 40 mL/min/1.73m2
6. Poor hepatic function, defined as Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) > 3 x upper limit of normal (ULN) and/or total bilirubin > 1.5 x ULN unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin
7. Poor bone-marrow reserve, defined as absolute neutrophil count (ANC) < 1.0x10^9/L independent of growth factor support and/or platelet count < 100x10^9/L or < 50x10^9/L if bone marrow involvement independent of transfusion support in either situation
8. History of malignancy during the past 3 years, with the exception of non-melanoma skin cancers or stage 0 (in situ) carcinoma.
9. Treatment with any investigational drug within 30 days before the planned first cycle of chemotherapy
10. Requires anticoagulation with warfarin or equivalent vitamin K antagonists
11. Requires dual antiplatelet therapy with aspirin and a P2Y12 antagonist
12. Requires treatment with strong CYP3A inhibitors
13. Requires treatment with fish oil
14. Prior anthracycline use >= 150 mg/m2
15. History of stroke or intracranial haemorrhage within 6 months of enrolment
16. Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction
17. Known bleeding disorders (e.g. von Willebrand’s disease)
18. Major surgery within 4 weeks of enrolment
19. Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator’s opinion, could compromise the subject’s safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk
20. Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification
21. Known history of human immunodeficiency virus (HIV) or active Hepatitis C Virus (HCV; RNA polymerase chain reaction [PCR]-positive) or active Hepatitis B Virus (HBV; DNA PCR-positive) infection. Only patients who are HBV surface antigen (HBVsAg) and/or HBV core antibody (HBVcAb) positive are required to undergo HBV DNA PCR testing. Subjects with PCR-negative HBV or who are HBV core antibody positive are permitted in the study but must be on HBV prophylaxis.
22. Any uncontrolled active systemic infection requiring intravenous (IV) antibiotics.
23. Vaccinated with live, attenuated vaccines within 4 weeks of enrolment.

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)
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
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)
ACT,NSW,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 8263 0
Concord Repatriation Hospital - Concord
Recruitment hospital [2] 8264 0
Calvary Mater Newcastle - Waratah
Recruitment hospital [3] 8265 0
Orange Health Service - Orange
Recruitment hospital [4] 8266 0
Westmead Hospital - Westmead
Recruitment hospital [5] 8267 0
Nepean Hospital - Kingswood
Recruitment hospital [6] 8268 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [7] 8269 0
Wollongong Hospital - Wollongong
Recruitment hospital [8] 8270 0
The Tweed Hospital - Tweed Heads
Recruitment hospital [9] 8271 0
Gold Coast University Hospital - Southport
Recruitment hospital [10] 8272 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [11] 8273 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [12] 8274 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment hospital [13] 8275 0
Box Hill Hospital - Box Hill
Recruitment hospital [14] 8276 0
Border Medical Oncology - Albury
Recruitment hospital [15] 8277 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [16] 8278 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [17] 8279 0
The Canberra Hospital - Garran
Recruitment hospital [18] 8280 0
Royal Hobart Hospital - Hobart
Recruitment hospital [19] 8281 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [20] 8282 0
Fiona Stanley Hospital - Murdoch
Recruitment postcode(s) [1] 16323 0
2139 - Concord
Recruitment postcode(s) [2] 16324 0
2298 - Waratah
Recruitment postcode(s) [3] 16325 0
2800 - Orange
Recruitment postcode(s) [4] 16326 0
2145 - Westmead
Recruitment postcode(s) [5] 16327 0
2747 - Kingswood
Recruitment postcode(s) [6] 16328 0
2050 - Camperdown
Recruitment postcode(s) [7] 16329 0
2500 - Wollongong
Recruitment postcode(s) [8] 16330 0
2485 - Tweed Heads
Recruitment postcode(s) [9] 16331 0
4215 - Southport
Recruitment postcode(s) [10] 16332 0
4029 - Herston
Recruitment postcode(s) [11] 16333 0
4102 - Woolloongabba
Recruitment postcode(s) [12] 16334 0
3065 - Fitzroy
Recruitment postcode(s) [13] 16335 0
3128 - Box Hill
Recruitment postcode(s) [14] 16336 0
3690 - Wodonga
Recruitment postcode(s) [15] 16337 0
3084 - Heidelberg
Recruitment postcode(s) [16] 16338 0
5042 - Bedford Park
Recruitment postcode(s) [17] 16339 0
2605 - Garran
Recruitment postcode(s) [18] 16340 0
7000 - Hobart
Recruitment postcode(s) [19] 16341 0
6009 - Nedlands
Recruitment postcode(s) [20] 16342 0
6150 - Murdoch

Funding & Sponsors
Funding source category [1] 290750 0
Commercial sector/Industry
Name [1] 290750 0
Janssen-Cilag Pty Ltd
Address [1] 290750 0
1-5 Khartoum Road
Macquarie Park, NSW, 2113
AUSTRALIA
Country [1] 290750 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australasian Leukaemia and Lymphoma Group
Address
Ground floor, 35 Elizabeth Street, Richmond, VIC 3121
Country
Australia
Secondary sponsor category [1] 289435 0
None
Name [1] 289435 0
Address [1] 289435 0
Country [1] 289435 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292380 0
Sydney Local Health District
Ethics committee address [1] 292380 0
Concord Hospital
Hospital Rd, Concord, NSW 2139, Australia
Ethics committee country [1] 292380 0
Australia
Date submitted for ethics approval [1] 292380 0
24/02/2015
Approval date [1] 292380 0
15/04/2015
Ethics approval number [1] 292380 0
Ethics committee name [2] 297878 0
Royal Perth Hospital Human Research Ethics Committee
Ethics committee address [2] 297878 0
Ethics committee country [2] 297878 0
Australia
Date submitted for ethics approval [2] 297878 0
Approval date [2] 297878 0
01/10/2015
Ethics approval number [2] 297878 0
Ethics committee name [3] 297879 0
Sir Charles Gairdner Group (SCGG) Human Research Ethics Committee (HREC)
Ethics committee address [3] 297879 0
Ethics committee country [3] 297879 0
Australia
Date submitted for ethics approval [3] 297879 0
Approval date [3] 297879 0
24/02/2016
Ethics approval number [3] 297879 0
Ethics committee name [4] 301251 0
Human Research Ethics Committee (Tasmania) Network
Ethics committee address [4] 301251 0
Office of Research Services
University of Tasmania
Private Bag 1
Hobart, Tasmania 7001
Ethics committee country [4] 301251 0
Australia
Date submitted for ethics approval [4] 301251 0
Approval date [4] 301251 0
17/08/2015
Ethics approval number [4] 301251 0
Ethics committee name [5] 301252 0
ACT Health Human Research Ethics Committee
Ethics committee address [5] 301252 0
PO Box 11
Woden ACT 2606
Ethics committee country [5] 301252 0
Australia
Date submitted for ethics approval [5] 301252 0
Approval date [5] 301252 0
09/11/2016
Ethics approval number [5] 301252 0

Summary
Brief summary
The study will evaluate the deliverability and efficacy of Ibrutinib-R-mini-CHOP chemotherapy in elderly patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). Who is it for? You may be eligible to join this study if you are aged 75 years or above and have been newly diagnosed with DLBCL for which you have received no prior treatment (excluding prednisone). Study details All participants in this study will be treated with a chemotherapy regime known as Ibrutinib-R-mini-CHOP. This will include treatment with the drugs prednisone (orally), ibrutinib (orally), rituximab intravenously ((IV) - i.e. administered directly into the vein), cyclophosphamide IV, doxorubicin IV, vincristine IV and Pegfilgrastim G-CSF (subcutaneous injection). Treatment duration will be for up to 8 x 28 day cycles as tolerated. All participants will be regularly assessed for a minimum of 2 years in order to evaluate the safety, toxicity and effectiveness of treatment.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 54942 0
Prof Judith Trotman
Address 54942 0
Concord Hospital
Hospital Rd, Concord, NSW 2139, Australia
Country 54942 0
Australia
Phone 54942 0
+612 9767 7243
Fax 54942 0
Email 54942 0
Judith.Trotman@health.nsw.gov.au
Contact person for public queries
Name 54943 0
Prof Judith Trotman
Address 54943 0
Concord Hospital
Hospital Rd, Concord, NSW 2139, Australia
Country 54943 0
Australia
Phone 54943 0
+612 9767 7243
Fax 54943 0
Email 54943 0
Judith.Trotman@health.nsw.gov.au
Contact person for scientific queries
Name 54944 0
Prof Judith Trotman
Address 54944 0
Concord Hospital
Hospital Rd, Concord, NSW 2139, Australia
Country 54944 0
Australia
Phone 54944 0
+612 9767 7243
Fax 54944 0
Email 54944 0
Judith.Trotman@health.nsw.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
No
Results – basic reporting
Results – plain English summary