Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12617000087358
Ethics application status
Approved
Date submitted
6/12/2016
Date registered
16/01/2017
Date last updated
13/04/2024
Date data sharing statement initially provided
10/04/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Treatment optimisation trial in the first-line treatment of advanced stage Hodgkin lymphoma; comparison of 6 cycles of escalated BEACOPP with 6 cycles of BrECADD.
Scientific title
Treatment optimisation trial in the first-line treatment of advanced stage Hodgkin lymphoma; comparison of 6 cycles of escalated BEACOPP with 6 cycles of BrECADD.
Secondary ID [1] 290140 0
ClinicalTrials.gov ID: NCT02661503
Secondary ID [2] 290141 0
EudraCT No: 2014-005130-55
Secondary ID [3] 290142 0
Sponsor Code: Uni-Koeln-1762
Secondary ID [4] 290143 0
ALLG HD10
Universal Trial Number (UTN)
Trial acronym
GHSG HD21
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Advanced stage Hodgkin lymphoma 300257 0
Condition category
Condition code
Cancer 300122 300122 0 0
Hodgkin's

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is an international, prospective, randomised and open-label phase III trial. The aim of the main trial is to prove that the new chemotherapy regimen, BrECADD, is non-inferior to BEACOPP as first line treatment in advanced stage classical Hodgkin lymphoma.

Main trial: Patients in the main trial will be randomised in a 1:1 ratio to either arm1 or arm2.

Arm1 (standard group): Patients will either receive 4 cycles (if PET-negative) or 6 cycles (if PET-positive) of the escalated BEACOPP regimen as follows- Cyclophosphamide (1250 mg/m^2, IV over 60 minute infusion, day 1); Adriamycin (35 mg/m^2, IV over 30 minute infusion, day 1); Etoposide (200 mg/m^2 per day, IV over 60 minute infusion, day 1 to day 3); Procarbazine (100 mg/m^2 per day, oral capsule, day 1 to day 7); Prednisone (40 mg/m^2 per day, oral tablet, day 1 to day 14); Vincristine (1.4 mg/m^2, IV bolus, day 8); Bleomycin (10 mg/m^2, IV bolus, day 8); Pegylated G-CSF ( 6 mg, subcutaneous injection, day 4).
Each cycle is 21 days.

Arm2 (experimental group): Patients will either receive 4 cycles (if PET-negative) or 6 cycles (if PET-positive) of the BrECADD regimen as follows- Brentuximab vedotin (1.8 mg/kg, IV over 30 minute infusion, day 1); Cyclophosphamide (1250 mg/m^2, IV over 60 minute infusion, day 2); Adriamycin (40 mg/m^2, IV over 30 minute infusion, day 2); Etoposide (150 mg/m^2 per day, IV over 60 minute infusion, day 2 to day 4); Dacarbazine (250 mg/m^2 per day, IV over 120 minute infusion, day 3 to day 4); Dexamethasone (40 mg/m^2 per day, oral tablet, day 2 to day 5); Pegylated G-CSF (6 mg, subcutaneous injection, day 5).
Each cycle is 21 days.

Older cohort: Patients will not be randomised. Older patients will either receive 2 cycles (if PET-negative) or 4 cycles (if PET-positive) of the BrECADD regimen as follows- Brentuximab vedotin (1.8 mg/kg, IV over 30 minute infusion, day 1); Cyclophosphamide (1250 mg/m^2, IV over 60 minute infusion, day 2); Adriamycin (40 mg/m^2, IV over 30 minute infusion, day 2); Etoposide (150 mg/m^2 per day, IV over 60 minute infusion, day 2 to day 4); Dacarbazine (250 mg/m^2 per day, IV over 120 minute infusion, day 3 to day 4); Dexamethasone (40 mg/mm^2 per day, oral tablet, day 2 to day 5); Pegylated G-CSF (6 mg, subcutaneous injection, day 5).
Each cycle is 21 days.

In both the main study and in the older cohort, restaging will take place in the last week of the second treatment cycle (“PET-2”), at the end of chemotherapy (“PET-6”), and at the end of radiotherapy if given (restaging after radiotherapy). In both groups, PET-2 is to take place in the last week of the 2nd chemotherapy cycle (between day 17 and day 21) PET-6 is to take place within 3 weeks after day 21 of the 6th chemotherapy cycle.
Patients will undergo restaging by FDG-PET with low dose CT, of the whole trunk of the body; images of the lower extremities are only required if a primary tumour was located there. Each restaging will always include an examination of all initially involved lymph nodes or organs using adequate methods. The objective of the PET-2 interim restaging is to document the response to chemotherapy and whether 4 - 6 cycles are required based on the patient's response to treatment, and to reassess if the patient is still qualified for the trial.

The objective of the PET-6 restaging is to document the response to chemotherapy, and to recommend patients for radiotherapy where tumour masses are greater than or equal to 2.5 cm after chemotherapy. If a patient is scheduled for radiotherapy following PET-6 restaging, an additional FDG-PET will take place within 6 weeks after completion of radiotherapy. The decision and organisation of the radiotherapy is up to the discretion of the treating physician on site.
Intervention code [1] 295894 0
Treatment: Drugs
Comparator / control treatment
Arm1 (standard group): Patients will receive 6 cycles of the escalated BEACOPP regimen as follows- Cyclophosphamide (1250 mg/m^2, IV over 60 minute infusion, day 1); Adriamycin (35 mg/m^2, IV over 30 minute infusion, day 1); Etoposide (200 mg/m^2 per day, IV over 60 minute infusion, day 1 to day 3); Procarbazine (100 mg/m^2 per day, oral capsule, day 1 to day 7); Prednisone (40 mg/m^2 per day, oral tablet, day 1 to day 14); Vincristine (1.4 mg/m^2, IV bolus, day 8); Bleomycin (10 mg/m^2, IV bolus, day 8); Pegylated G-CSF ( 6 mg, subcutaneous injection, day 4).
Each cycle is 21 days.
Control group
Active

Outcomes
Primary outcome [1] 299611 0
The primary outcome of the trial is the determine if non-inferior efficacy of 6 cycles of BrECADD compared to 6 cycles of escalated BEACOPP, each followed by radiotherapy to PET-positive residual lesions greater than or equal to 2.5cm, improves PFS rates.
Timepoint [1] 299611 0
Progression free survival is the time from the date of randomisation until the date of the first occurrence of:
- progression of disease;
- relapse; or
- death from any cause.
The PFS will be censored at the data of the last information on tumour status if none of these events have occurred.
The date of disease progression or relapse will always be the diagnosis date (date of biopsy taken, if available) even if it is not diagnosed at a scheduled visit.
Patients without a tumour assessment post-baseline will be censored at the date of randomisation. Patients will neither be censored nor deemed failures if more than one visit is missed, or if an additional anti-cancer treatment is initiated without evidence of objective progression. Each patient will be follow up for a period of at least 5 years.
Primary outcome [2] 299612 0
The co-primary endpoint for this trial is the rate of serious treatment-related morbidity- "TRMorbidity".
TRMorbidity is defined as any CTCAE organ toxicity of grade 3 or 4 or severe haematological toxicity of grade 4 during primary chemotherapy of the following SOC categories as documented on the CTCAE toxicities section of the eCRF:
- Cardiac disorders grade 3 or 4;
- Gastrointestinal disorder grade 3 or 4 (excluding vomiting, nausea and mucositis);
- Hepatobiliary disorders grade 3 or 4;
- Nervous system disorder grade 3 or 4;
- Renal and urinary disorders grade 3 or 4;
- Respiratory, thoracic, and mediastinal disorders grade 3 or 4;
- Anaemia grade 4;
- Thrombocytopenia grade 4, and
- Infections grade 4.


PFS and TRMorbidity are not considered composite endpoints for this study.
Timepoint [2] 299612 0
TRMorbidity will be assessed during protocol conform therapy in both arms, and until 30 days after the last dose of chemotherapy. Events occurring after this time-period have to be reported if they are rated to be at least possibly related to chemotherapy.
Primary outcome [3] 329974 0
Older patients: The primary objective is to estimate efficacy of the BrECADD treatment of older patients with advanced-stage classical HL. Efficacy will be determined using the rate of complete response after completion of chemotherapy. Interim staging after completion of 2nd cycle (CT-2/PET-2) and re-staging after completion of chemotherapy treatment (CT-4/PET-4 or CT-6/PET-6)) with CT / PET scans will be used to assess complete response.
Timepoint [3] 329974 0
Older patients: Complete remission (CR) rate at the end of chemotherapy (4 cycles if PET-negative, 6 cycles if PET-positive).
Secondary outcome [1] 328821 0
Overall Survival (OS)
Timepoint [1] 328821 0
Calculated from the date of the initial staging until the date of death. If the patient is alive, the OS is censored at the date of last information including follow up visits and quality of life questionnaires.. Each patient will be in follow up for a period of at least 5 years.
Secondary outcome [2] 328822 0
Tumour response (final treatment outcome)- the rate of complete remissions at the restaging after the primary study treatment including radiotherapy if applicable.
A complete remission has been attained if one of the following conditions is met:
- complete radiologic response with regress of all residual masses to less than or equal to 1.5 cm in the largest diameter in the absence of signs of active lymphoma
- Complete metabolic response (score 1-3) with or without residual masses in absence of clinical signs of active lymphoma.
Timepoint [2] 328822 0
Tumour response will be measured at CT-2/PET-2 (between days 17-21 of the 2nd chemotherapy cycle) and CT-6/PET-6 (following 6 cycles of chemotherapy, within 3 weeks after day 21 of the last cycle).
Secondary outcome [3] 328823 0
Infertility rate at 1 year will be measured using a questionnaire used previously in GHSG advanced Hodgkin Lymphoma trials- HD15 and HD18.
Timepoint [3] 328823 0
At screening (before treatment, at time of restaging after end of chemotherapy, and 12 months after the end of chemotherapy. It is to be decided at the discretion of the treating physician, in consultation with the patient, if and when further examinations should be performed.
Secondary outcome [4] 328824 0
Secondary Malignancies- including Acute Myeloid Leukaemia and Myelodysplastic Syndrome . The documentation in medical records and adverse event reports must include the date of diagnosis and the type of secondary malignancy (leukaemia/MDS, NHL, solid tumour).
Timepoint [4] 328824 0
From randomisation, during chemotherapy, and until end of follow up. Each patient will be in follow up for a period of at least 5 years.

Eligibility
Key inclusion criteria
- Histologically proven classical Hodgkin lymphoma;
- First diagnosis, no previous treatment
- Stage IIB with large mediastinal mass and/or extranodal lesions, stage III or IV.
- Main cohort: 18 to 60 years of age;
- Older cohort: 61 - 75 years of age.
Minimum age
18 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Composite lymphoma or nodular lymphocyte predominant Hodgkin lymphoma;
- Previous malignancy (exceptions: basalioma, carcinoma in situ of the cervic uteri, completely resected melanoma TNMpT1);
- Prior chemotherapy or radiotherapy;
- Concurrent disease which precludes protocol treatment;
- Pregnancy, lactation;
- Non-compliance.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled 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
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
30/04/2018
Actual
20/04/2018
Date of last participant enrolment
Anticipated
30/04/2022
Actual
8/03/2022
Date of last data collection
Anticipated
13/04/2028
Actual
Sample size
Target
1585
Accrual to date
Final
1585
Recruitment in Australia
Recruitment state(s)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 13585 0
Prince of Wales Private Hospital - Randwick
Recruitment hospital [2] 13586 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [3] 13587 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [4] 13588 0
Concord Repatriation Hospital - Concord
Recruitment hospital [5] 13589 0
Gosford Hospital - Gosford
Recruitment hospital [6] 13590 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [7] 13591 0
Barwon Health - Geelong Hospital campus - Geelong
Recruitment hospital [8] 13592 0
Royal Hobart Hospital - Hobart
Recruitment hospital [9] 13593 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [10] 13594 0
St George Hospital - Kogarah
Recruitment hospital [11] 13595 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment hospital [12] 13596 0
The Townsville Hospital - Douglas
Recruitment hospital [13] 13597 0
Westmead Hospital - Westmead
Recruitment hospital [14] 13598 0
Wollongong Hospital - Wollongong
Recruitment postcode(s) [1] 26246 0
2031 - Randwick
Recruitment postcode(s) [2] 26247 0
5000 - Adelaide
Recruitment postcode(s) [3] 26248 0
6009 - Nedlands
Recruitment postcode(s) [4] 26249 0
2139 - Concord
Recruitment postcode(s) [5] 26250 0
2250 - Gosford
Recruitment postcode(s) [6] 26251 0
4102 - Woolloongabba
Recruitment postcode(s) [7] 26252 0
3220 - Geelong
Recruitment postcode(s) [8] 26253 0
7000 - Hobart
Recruitment postcode(s) [9] 26254 0
2065 - St Leonards
Recruitment postcode(s) [10] 26255 0
2217 - Kogarah
Recruitment postcode(s) [11] 26256 0
3065 - Fitzroy
Recruitment postcode(s) [12] 26257 0
4814 - Douglas
Recruitment postcode(s) [13] 26258 0
2145 - Westmead
Recruitment postcode(s) [14] 26259 0
2500 - Wollongong
Recruitment outside Australia
Country [1] 8361 0
Germany
State/province [1] 8361 0
Country [2] 8463 0
New Zealand
State/province [2] 8463 0
Country [3] 10272 0
Austria
State/province [3] 10272 0
Country [4] 10273 0
Denmark
State/province [4] 10273 0
Country [5] 10274 0
Netherlands
State/province [5] 10274 0
Country [6] 10275 0
Poland
State/province [6] 10275 0
Country [7] 10276 0
Sweden
State/province [7] 10276 0
Country [8] 10277 0
Switzerland
State/province [8] 10277 0
Country [9] 10278 0
Norway
State/province [9] 10278 0

Funding & Sponsors
Funding source category [1] 294833 0
Commercial sector/Industry
Name [1] 294833 0
Millennium Pharmaceuticals
Country [1] 294833 0
United States of America
Primary sponsor type
University
Name
University of Cologne
Address
Cologne University Hospital
50935 Koln
Country
Germany
Secondary sponsor category [1] 293675 0
None
Name [1] 293675 0
Address [1] 293675 0
Country [1] 293675 0
Other collaborator category [1] 279291 0
Other Collaborative groups
Name [1] 279291 0
Australasian Leukaemia and Lymphoma Group
Address [1] 279291 0
Ground Floor, 35 Elizabeth Street
North Richmond, VIC, 3121
Country [1] 279291 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296417 0
South East Sydney Local Health District
Ethics committee address [1] 296417 0
Ethics committee country [1] 296417 0
Australia
Date submitted for ethics approval [1] 296417 0
10/02/2017
Approval date [1] 296417 0
06/11/2017
Ethics approval number [1] 296417 0
Ethics committee name [2] 303118 0
Sir Charles Gairdner Group Human Research Ethics
Ethics committee address [2] 303118 0
Ethics committee country [2] 303118 0
Australia
Date submitted for ethics approval [2] 303118 0
Approval date [2] 303118 0
06/07/2018
Ethics approval number [2] 303118 0
RGS0000000841
Ethics committee name [3] 303119 0
Tasmanian Health and Medical Human Research Ethics Committee
Ethics committee address [3] 303119 0
Ethics committee country [3] 303119 0
Australia
Date submitted for ethics approval [3] 303119 0
Approval date [3] 303119 0
25/09/2018
Ethics approval number [3] 303119 0
H001
Ethics committee name [4] 303120 0
Auckland Regional Cancer and Blood Services
Ethics committee address [4] 303120 0
Ethics committee country [4] 303120 0
New Zealand
Date submitted for ethics approval [4] 303120 0
25/06/2018
Approval date [4] 303120 0
26/08/2018
Ethics approval number [4] 303120 0
18/STH/138

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 68994 0
Prof Mark Hertzberg
Address 68994 0
Department of Haematology
Prince of Wales Hospital
Barker St .
Randwick, NSW, 2031
AUSTRALIA
Country 68994 0
Australia
Phone 68994 0
+61 2 9382 9036
Fax 68994 0
Email 68994 0
[email protected]
Contact person for public queries
Name 68995 0
Delaine Smith
Address 68995 0
Australasian Leukaemia and Lymphoma Group
Ground Floor
35 Elizabeth St
Richmond 3121
Country 68995 0
Australia
Phone 68995 0
+61 3 8373 9701
Fax 68995 0
+61 3 9429 8277
Email 68995 0
[email protected]
Contact person for scientific queries
Name 68996 0
Mark Hertzberg
Address 68996 0
Department of Haematology
Prince of Wales Hospital
Barker St
Randwick, NSW, 2031
AUSTRALIA
Country 68996 0
Australia
Phone 68996 0
+61 2 9382 9036
Fax 68996 0
Email 68996 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
No individual participant data will be publicly available as it is the aggregate data that is under investigation.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.