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Trial registered on ANZCTR


Registration number
ACTRN12614000376640
Ethics application status
Approved
Date submitted
14/02/2014
Date registered
8/04/2014
Date last updated
4/08/2023
Date data sharing statement initially provided
24/07/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
An Australasian, phase II, multicentre, randomised, study investigating efficacy and safety for dose reduced fludarabine, cyclophosphamide and intravenous obinutuzumab (G-FC3) versus oral chlorambucil and intravenous obinutuzumab (G-Clb) in previously untreated, comorbid, elderly patients with chronic lymphocytic leukaemia (CLL).
Scientific title
An Australasian, phase II, multicentre, randomised, study investigating efficacy and safety for dose reduced fludarabine, cyclophosphamide and intravenous obinutuzumab (G-FC3) versus oral chlorambucil and intravenous obinutuzumab (G-Clb) in previously untreated, comorbid, elderly patients with chronic lymphocytic leukaemia (CLL).
Secondary ID [1] 284014 0
Nil
Universal Trial Number (UTN)
Trial acronym
ALLG CLL07
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic Lymphoblastic Leukemia (CLL) 291051 0
Condition category
Condition code
Cancer 291392 291392 0 0
Leukaemia - Chronic leukaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention includes; ARM 1 obinutuzumab combined with fludarabine and cyclophosphamide (G-FC3). A treatment cycle is 28 days in length. A maximum of 6 cycles of therapy will be administered to each patient. GA101 (intravenous) 100 mg day 1 cycle 1, 900 mg day 2 cycle 1, 1000 mg day 8 and 15 cycle 1, 1000 mg day 1 cycles 2-6. Fludarabine (oral), 24mg/m2 day 1-3 cycles 1-6. Cyclophosphamide (oral) 150mg/m2 days 1-3 cycle 1-6.
Intervention code [1] 288698 0
Treatment: Drugs
Comparator / control treatment
ARM 2 obinutuzumab with chlorambucil (G-Clb) (Oral). GA101 (intravenous) 100 mg day 1 cycle 1, 900 mg day 2 cycle 1, 1000 mg day 8 and 15 cycle 1, 1000 mg day 1 cycles 2-6. Chlorambucil (Oral) day 1 and 15, at 0.5mg/kg cycles 1-6.
Control group
Active

Outcomes
Primary outcome [1] 291386 0
To evaluate the safety of G-FC3 and G-Clb as measured by the incidence of grade 3+ non-haematological and grade 4 haematological adverse events. All non-haematological and haematological AEs (e.g. grade 3-4 infection and grade 3; thrombocytopenia, neutropenia) in the grades mentioned will be evaluated. As there are 3 chemotherapeutic agents details are in the investigators brochure and patient information and consent form.
Timepoint [1] 291386 0
To assess the safety of protocol treatment, the primary endpoint will be defined as the incidence of any one of the following (according to NCI CTC version 4.0) from the commencement of the first cycle of therapy until 28 days following the last dose of GA101:
A grade 3+ non-haematological adverse event
A grade 4 haematological adverse event
Secondary outcome [1] 306644 0
To evaluate and compare the proportion of patients achieving minimal residual disease-negative complete remission (MRD negative) at final staging, two months after completion of protocol treatment in each treatment arm (G- FC3 versus G- Clb).
Timepoint [1] 306644 0
at final staging, two months after completion of protocol treatment
Secondary outcome [2] 306645 0
To evaluate and compare the two treatment arms in terms of the following additional measures of efficacy:
- Overall response rate (ORR), defined as the achievement of complete remission (CR) or partial remission (PR) at final staging, two months after completion of protocol treatment
- Best overall response rate defined as the achievement of CR or PR during treatment or within 6 months of completion of protocol treatment
- Event-free survival (EFS)
- Progression-free survival (PFS)
- Time to next therapy (TTNT)
- Overall survival (OS).
The Kaplan-Meier product-limit method will be used to estimate EFS, PFS, OS and TTNT curves for each treatment arm. Annual survival probabilities and associated 95% confidence intervals will be calculated for each treatment arm. For each endpoint, the difference between treatment arms will be estimated with a hazard ratio (HR) and associated 95% confidence interval, calculated using Cox proportional hazards regression.
Cox proportional hazards regression models will also be used to investigate associations between patient pre-treatment characteristics and time-to-event endpoints. Patient characteristics that will be considered include: gender, age at time of randomisation, pre-treatment comorbidity assessments (including CIRS score), pre-treatment Beta-2 microglobulin, LDH, white-cell and platelet counts and CD38 expression as well as 17p deletion, 13q deletion, trisomy 12 and 11q deletion cytogenetic abnormalities and molecular genetics variables including NOTCH-1, SF3B1 and BRIC-3.
Efficacy will be assessed by the investigator according to the National Cancer Institute/International Workshop on Chronic Lymphocytic Leukemia (NCI/IWCLL) guidelines (Hallek et al. 2008; see Table 6 page 48) at the time points shown in the Schedule of Assessments.

Patients will be followed by clinical/laboratory signs and symptoms until progression is identified. A scan by computed tomography (CT) will be performed in patients who have achieved a complete or partial response two to three months after end of treatment. In those patients who have achieved a CR (or cytopenic CR), bone marrow aspirates for biopsy and flow cytometry will be obtained. If progressive disease is detected by physical examination in the absence of any objective haematological progression, a CT scan of the involved nodes will be performed.
Timepoint [2] 306645 0
End of study
Secondary outcome [3] 306646 0
To evaluate Patient Reported Outcomes (PROs) over the course of treatment and follow-up in patients in both treatment arms using overall health-related QOL scores obtained from the EuroQol EQ-5D and EORTC QLQ-C30 as well as the five individual EORTC QLQ-C30 subscales.
Timepoint [3] 306646 0
Patient reported outcomes will be assessed during Screening, interim staging (after 3 cycles before the beginning of cycle 4), initial response assessment (1 month (+/-7 days) after beginning of cycle 6), final staging (2 months (+28 days) after Initial Response Assessment), 3 monthly during the first year of follow up and annually thereafter.

Eligibility
Key inclusion criteria
Documented CD20+ B-cell CLL according to NCI/IWCLL criteria (Hallek et al. 2008)

Previously untreated CLL requiring treatment according to NCI/IWCLL criteria (Hallek et al. 2008).

CIRS score >= 6
Age >= 65 years old

An ECOG performance status score of 0-2 at Screening

Able to comply with study protocol procedures and a minimum of 14 months of follow-up

Has provided written informed consent

Life expectancy at least 6 months

Haematological parameters at Screening as defined by:
a. ANC (segs + bands) >1.5 x 10^9/L unless related to CLL
b. Platelet count >50 x 10^9/L

Calculated creatinine clearance >= 40ml/min at Screening (Cockcroft-Gault formula)

In men who are not surgically sterile, must agree to use a barrier method of contraception for >= 3 months after the last obinutuzumab dose. In addition, male participants must agree to request that their female partners of childbearing potential use an additional method of contraception.
Minimum age
65 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients who have received previous CLL treatment

Transformation of CLL to aggressive NHL (Richter’s transformation)

Prior treatment with corticosteroids during the 4 weeks prior to the start of Cycle 1, unless administered for indications other than CLL at a dose equivalent to less than or equal to 30 mg/day prednisolone

Any of the following abnormal laboratory values (unless any of these abnormalities are due to underlying leukemia):
a. AST or ALT > 2.5 × ULN
b. Total bilirubin greater than or equal to 3 × ULN

One or more individual organ / system impairment score(s) of 4 as assessed by the CIRS definition, excluding the Eyes, Ears, Nose, Throat and Larynx organ system

Prior diagnosis of malignancy, unless:
a. the malignancy has been treated with a curative intent and there is no evidence of recurrence or
b. in remission without treatment for greater than or equal to 2 years prior to study enrolment

Previous adverse reaction to any of the trial drug/s

Previous severe allergic or anaphylactic reaction to monoclonal antibody therapy

Vaccination with live vaccines within 28 days prior to start of treatment

Recent major surgery (within 4 weeks prior to the start of Cycle 1), other than for diagnosis

Participation in other therapeutic studies in the last 28 days except for studies with a non-medical intervention. Documented evidence of receiving placebo will be required.

Evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results, including significant cardiovascular disease (such as New York Heart Association Class III or IV cardiac disease, severe arrhythmia, myocardial infarction within the previous 6 months, unstable arrhythmias, or unstable angina) or pulmonary disease (including obstructive pulmonary disease and history of bronchospasm)

Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) or any major episode of infection requiring treatment with IV antibiotics or hospitalisation (relating to the completion of the course of antibiotics, except if for tumour fever) within 4 weeks prior to the start of Cycle 1

Positive test results for hepatitis C infection:
a. Positive Hepatitis C virus [HCV] antibody serology testing. Participants positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA

Hepatitis B infection defined as positive hepatitis B virus surface antigen (HBsAg) serology or hepatitis B core antibody (HBcAb). Known history of human immunodeficiency virus (HIV) seropositive status

Positive test results for human T-lymphotropic virus 1 (HTLV 1):
a. HTLV testing is required in participants from endemic countries (Japan, countries in the Caribbean basin, South America, Central America, sub Saharan Africa, and Melanesia)

Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule. This condition must be discussed with the patient prior to signing consent and registration in the trial.

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
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Stopped early
Data analysis
Data analysis is complete
Reason for early stopping/withdrawal
Safety concerns
Date of first participant enrolment
Anticipated
31/08/2015
Actual
11/12/2015
Date of last participant enrolment
Anticipated
Actual
15/11/2017
Date of last data collection
Anticipated
1/08/2019
Actual
30/01/2020
Sample size
Target
120
Accrual to date
Final
32
Recruitment in Australia
Recruitment state(s)
ACT,NSW,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 7054 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [2] 7055 0
Border Medical Oncology - Albury
Recruitment hospital [3] 7056 0
Nepean Hospital - Kingswood
Recruitment hospital [4] 7057 0
Royal Hobart Hospital - Hobart
Recruitment hospital [5] 7058 0
Sydney Adventist Hospital - Wahroonga
Recruitment hospital [6] 7059 0
Western Hospital - Footscray
Recruitment hospital [7] 7060 0
Westmead Hospital - Westmead
Recruitment hospital [8] 7061 0
St George Hospital - Kogarah
Recruitment hospital [9] 8050 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [10] 8051 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [11] 8052 0
Barwon Health - Geelong Hospital campus - Geelong
Recruitment hospital [12] 11590 0
Princess Alexandra Hospital - Woolloongabba
Recruitment postcode(s) [1] 14782 0
2065 - St Leonards
Recruitment postcode(s) [2] 14783 0
3690 - Wodonga
Recruitment postcode(s) [3] 14784 0
2747 - Kingswood
Recruitment postcode(s) [4] 14785 0
7000 - Hobart
Recruitment postcode(s) [5] 14786 0
2076 - Wahroonga
Recruitment postcode(s) [6] 14787 0
5022 - Henley Beach
Recruitment postcode(s) [7] 14788 0
2145 - Westmead
Recruitment postcode(s) [8] 14789 0
2217 - Kogarah
Recruitment postcode(s) [9] 16092 0
6009 - Nedlands
Recruitment postcode(s) [10] 16093 0
5042 - Bedford Park
Recruitment postcode(s) [11] 16094 0
3220 - Geelong
Recruitment postcode(s) [12] 23634 0
4102 - Woolloongabba

Funding & Sponsors
Funding source category [1] 288637 0
Commercial sector/Industry
Name [1] 288637 0
Roche Products Pty Limited
Country [1] 288637 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australasian leukemia and lymphoma group (ALLG)
Address
Ground Floor, 35 Elizabeth Street, Richmond, VIC 3121
Country
Australia
Secondary sponsor category [1] 287349 0
None
Name [1] 287349 0
Address [1] 287349 0
Country [1] 287349 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 290493 0
South Eastern Sydney Local Health District
Ethics committee address [1] 290493 0
Ethics committee country [1] 290493 0
Australia
Date submitted for ethics approval [1] 290493 0
28/01/2014
Approval date [1] 290493 0
18/06/2015
Ethics approval number [1] 290493 0

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

Contacts
Principal investigator
Name 45942 0
A/Prof Stephen Mulligan
Address 45942 0
Department of Haematology
Royal North Shore Hospital
St Leonards, Sydney 2065
NSW, Australia
Country 45942 0
Australia
Phone 45942 0
+61 2 9926 7601
Fax 45942 0
Email 45942 0
stephen.mulligan@sydney.edu.au
Contact person for public queries
Name 45943 0
Stephen Mulligan
Address 45943 0
Department of Haematology
Royal North Shore Hospital
St Leonards, Sydney 2065
NSW, Australia
Country 45943 0
Australia
Phone 45943 0
+61 2 9926 7601
Fax 45943 0
Email 45943 0
stephen.mulligan@sydney.edu.au
Contact person for scientific queries
Name 45944 0
Stephen Mulligan
Address 45944 0
Department of Haematology
Royal North Shore Hospital
St Leonards, Sydney 2065
NSW, Australia
Country 45944 0
Australia
Phone 45944 0
+61 2 9926 7601
Fax 45944 0
Email 45944 0
stephen.mulligan@sydney.edu.au

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.