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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT02475681




Registration number
NCT02475681
Ethics application status
Date submitted
12/06/2015
Date registered
19/06/2015
Date last updated
29/05/2024

Titles & IDs
Public title
Acalabrutinib, Obinutuzumab and Chlorambucil in Treatment naïve CLL
Scientific title
A Randomized, Multicenter, Open-Label, 3 Arm Phase 3 Study of Obinutuzumab in Combination With Chlorambucil, Acalabrutinib (ACP-196) in Combination With Obinutuzumab, and Acalabrutinib Monotherapy in Subjects With Previously Untreated CLL
Secondary ID [1] 0 0
2014-005582-73
Secondary ID [2] 0 0
ACE-CL-007
Universal Trial Number (UTN)
Trial acronym
ElevateTN
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic Lymphocytic Leukemia 0 0
Condition category
Condition code
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Acalabrutinib
Treatment: Drugs - Obinutuzumab
Treatment: Drugs - Chlorambucil

Active Comparator: Arm A - Obinutuzumab in Combination with Chlorambucil - Obinutuzumab IV infusions will be administered over a total of 6 treatment cycles starting at Cycle 1 Day 1. Chlorambucil will be orally administered on Days 1 and 15 of Cycles 1 through 6.

Experimental: Arm B - Acalabrutinib in Combination with Obinutuzumab - Obinutuzumab IV infusions will be administered over a total of 6 treatment cycles starting at Cycle 2 Day 1. Acalabrutinib (ACP-196) will be orally administered starting on Cycle 1 Day 1. Daily administration of Acalabrutinib (ACP-196) will continue until disease progression or unacceptable toxicity.

Experimental: Arm C - Acalabrutinib Monotherapy - Acalabrutinib (ACP-196) will be orally administered on Cycle 1 Day 1 until disease progression or unacceptable toxicity.


Treatment: Drugs: Acalabrutinib


Treatment: Drugs: Obinutuzumab


Treatment: Drugs: Chlorambucil
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Progression-free Survival by IRC (Independent Review Committee) Assessment in Arm A Compared to Arm B
Timepoint [1] 0 0
IRC assessments were done from randomization date until disease progression or death or IRC discontinuation date on 08Feb2019 (as the IA based on this data cutoff date showed the study crossing superiority boundary) whichever comes first up to 40 months.
Secondary outcome [1] 0 0
Progression-free Survival by IRC Assessment Arm A Versus Arm C
Timepoint [1] 0 0
IRC assessments were done from randomization date until disease progression or death or IRC discontinuation date on 08Feb2019 (as the IA based on this data cutoff date showed the study crossing superiority boundary) whichever comes first up to 40 months.
Secondary outcome [2] 0 0
IRC-assessed Objective Response Rate (ORR) in Arm A Versus Arm B and Arm A Versus Arm C
Timepoint [2] 0 0
IRC assessments were done from randomization date until disease progression or death or IRC discontinuation date on 08Feb2019 (as the IA based on this data cutoff date showed the study crossing superiority boundary) whichever comes first up to 40 months.
Secondary outcome [3] 0 0
Time to Next Treatment (TTNT) in Arm A Versus Arm B and Arm A Versus Arm C
Timepoint [3] 0 0
From randomization date to start of non-protocol specified subsequent anticancer therapy for CLL or death due to any cause, whichever came first assessed up to 40 months of follow-up.
Secondary outcome [4] 0 0
Overall Survival (OS) in Arm A Versus Arm B and Arm A Versus Arm C
Timepoint [4] 0 0
From randomization date until death, withdrawal by subject, lost to follow-up, or by analysis data cut off date on 08Feb2019 whichever comes first up to 40 months of follow-up.

Eligibility
Key inclusion criteria
Inclusion Criteria

1. Men and women:

a. = 65 years of age OR b. > 18 and < 65 years of age, provided that they meet at
least one of the following criteria: i. Creatinine clearance 30 to 69 mL/min using the
Cockcroft-Gault equation ii. A score higher than 6 on the CIRS-G (Appendix L).

2. ECOG performance status of 0, 1, or 2.

3. Diagnosis of CD20+ CLL that meets published diagnostic criteria (Hallek 2008):

1. Monoclonal B cells (either kappa or lambda light chain restricted) that are
clonally co-expressing = 1 B-cell marker (CD19, CD20, or CD23) and CD5.

2. Prolymphocytes may comprise = 55% of blood lymphocytes.

3. Presence of = 5 x 109 B lymphocytes/L (5000 µL) in the peripheral blood (at any
point since diagnosis)

4. Active disease meeting = 1 of the following IWCLL 2008 criteria for requiring
treatment:

1. Evidence of progressive marrow failure as manifested by the development of, or
worsening of, anemia (hemoglobin < 10 g/dL) and/or thrombocytopenia (platelets <
100,000/µL).

2. Massive (i.e., = 6 cm below the left costal margin), progressive, or symptomatic
splenomegaly.

3. Massive nodes (i.e., = 10 cm in the longest diameter), progressive, or
symptomatic lymphadenopathy.

4. Progressive lymphocytosis with an increase of > 50% over a 2-month period or a
LDT of < 6 months. LDT may be obtained by linear regression extrapolation of ALC
obtained at intervals of 2 weeks over an observation period of 2 to 3 months. In
subjects with initial blood lymphocyte counts of < 30 x 109/L (30,000/µL), LDT
should not be used as a single parameter to define indication for treatment. In
addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL
(e.g., infections) should be excluded.

5. Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard
therapy.

6. Constitutional symptoms documented in the subject's chart with supportive
objective measures, as appropriate, defined as = 1 of the following
disease-related symptoms or signs:

i. Unintentional weight loss = 10% within the previous 6 months before Screening.

ii. Significant fatigue (i.e., ECOG performance status 2; inability to work or perform
usual activities).

iii. Fevers higher than 100.5°F or 38.0°C for 2 or more weeks before Screening without
evidence of infection.

iv. Night sweats for > 1 month before Screening without evidence of infection.

5. This criterion was deleted as of Protocol Amendment 3.

6. Meet the following laboratory parameters:

1. ANC = 750 cells/µL (0.75 x 109/L), or = 500 cells/µL (0.50 x 109/L) in subjects
with documented bone marrow involvement, and independent of growth factor support
7 days before assessment.

2. Platelet count = 50,000 cells/µL (50 x 109/L), or = 30,000 cells/µL (30 x 109/L)
in subjects with documented bone marrow involvement, and without transfusion
support 7 days before assessment. Subjects with transfusion-dependent
thrombocytopenia are excluded.

3. Serum AST and ALT/SGPT = 3.0 x ULN.

4. Total bilirubin = 1.5 x ULN.

5. Estimated creatinine clearance (i.e., eGFR using Cockcroft-Gault) = 30 mL/min

7. Able to receive all outpatient treatment, all laboratory monitoring, and all
radiologic evaluations.

8. Women who are sexually active and can bear children must agree to use highly effective
forms of contraception while on the study and for 2 days after the last dose of
acalabrutinib or 18 months after the last dose of obinutuzumab in combination with
chlorambucil, whichever is longer. Highly effective forms of contraception are defined
in Section 6.4.4.

9. Men who are sexually active and can beget children must agree to use highly effective
forms of contraception during the study and for 90 days after the last dose of
obinutuzumab or chlorambucil, whichever is later. Highly effective forms of
contraception are defined in Section 6.4.4.

10. Men must agree to refrain from sperm donation during the study and for 90 days after
the last dose of obinutuzumab or chlorambucil, whichever is later.

11. Must be willing and able to adhere to the study visit schedule, understand and comply
with other protocol requirements, and provide written informed consent and
authorization to use protected health information (in accordance with national and
local subject privacy regulations). Note vulnerable subjects, as defined in
International Conference on Harmonisation (ICH) GCP, are not allowed on this protocol
(e.g., prisoners or institutionalized subjects).
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Any prior systemic treatment for CLL (note: Prior localized radiotherapy is allowed).

2. Known CNS lymphoma or leukemia.

3. Known prolymphocytic leukemia or history of, or currently suspected, Richter's
syndrome.

4. Missing or incomplete documentation of FISH results reflecting the presence or absence
of 17p del and the percentage of cells with the deletion in subject records before
randomization.

5. Uncontrolled AIHA or ITP defined as declining hemoglobin or platelet count secondary
to autoimmune destruction within the screening period or requirement for high doses of
steroids (> 20 mg daily of prednisone daily or equivalent).

6. Corticosteroid use > 20 mg within 1 week before first dose of study drug, except as
indicated for other medical conditions such as inhaled steroid for asthma, topical
steroid use, or as premedication for administration of study drug or contrast. For
example, subjects requiring steroids at daily doses > 20 mg prednisone equivalent
systemic exposure daily, or those who are administered steroids for leukemia control
or WBC count lowering are excluded.

7. Major surgery within 4 weeks before first dose of study drug.

8. History of prior malignancy except for the following:

1. Malignancy treated with curative intent and with no evidence of active disease
present for more than 3 years before Screening and felt to be at low risk for
recurrence by treating physician.

2. Adequately treated lentigo maligna melanoma without current evidence of disease
or adequately controlled non-melanomatous skin cancer.

3. Adequately treated cervical carcinoma in situ without current evidence of
disease.

9. Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias,
congestive heart failure, or myocardial infarction within 6 months of screening, or
any Class 3 or 4 cardiac disease as defined by the New York Heart Association
Functional Classification, or QTc > 480 msec at screening.

10. Unable to swallow capsules or malabsorption syndrome, disease significantly affecting
gastrointestinal function, or resection of the stomach or small bowel or gastric
bypass, symptomatic inflammatory bowel disease, or partial or complete bowel
obstruction.

11. Uncontrolled active systemic fungal, bacterial, viral, or other infection (defined as
exhibiting ongoing signs/symptoms related to the infection and without improvement,
despite appropriate antibiotics or other treatment) or ongoing intravenous
anti-infective treatment.

12. Known history of infection with HIV. 13. Vaccinated with live, attenuated vaccines
within 4 weeks of first dose of study drug.

14. Serologic status reflecting active hepatitis B or C infection. Subjects with hepatitis
B core antibody positive who are surface antigen negative or who are hepatitis C antibody
positive will need to have a negative PCR result before randomization. Those who are
hepatitis B surface antigen positive or hepatitis B PCR positive and those who are
hepatitis C PCR positive will be excluded.

15. History of stroke or intracranial hemorrhage within 6 months before randomization.

16. Known history of a bleeding diathesis (e.g., hemophilia, von Willebrand disease).

17. Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists
(e.g., phenprocoumon) within 7 days of first dose of study drug.

18. Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole,
lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole).

19. Breast feeding or pregnant. 20. Current life-threatening illness, medical condition, or
organ system dysfunction which, in the Investigator's opinion, could compromise the
subject's safety or put the study at risk.

21. Concurrent participation in another therapeutic clinical trial. 22. Requires treatment
with a strong CYP3A inhibitor/inducer. 23. Presence of a gastrointestinal ulcer diagnosed
by endoscopy within 3 months before screening.

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
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
26/06/2015
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
30/09/2025
Actual
Sample size
Target
Accrual to date
Final
535
Recruitment in Australia
Recruitment state(s)
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Research Site - Darlinghurst
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Research Site - Frankston
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Research Site - Geelong
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Research Site - South Brisbane
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Research Site - Waratah NSW
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Research Site - Wollongong
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Research Site - Woodville
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2010 - Darlinghurst
Recruitment postcode(s) [2] 0 0
3199 - Frankston
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3220 - Geelong
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QLD 4101 - South Brisbane
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2298 - Waratah NSW
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2500 - Wollongong
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5011 - Woodville
Recruitment outside Australia
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Wolverhampton

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Acerta Pharma BV
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
This Primary objective is evaluating the efficacy of obinutuzumab in combination with
chlorambucil (Arm A) compared with acalabrutinib in combination with obinutuzumab (Arm B) for
the treatment of previously untreated chronic lymphocytic leukemia (CLL). Secondary
objectives: 1) To evaluate the efficacy of obinutuzumab in combination with chlorambucil (Arm
A) versus acalabrutinib monotherapy (Arm C) based on IRC assessment of PFS per IWCLL 2008
criteria.

2)To compare obinutuzumab plus chlorambucil (Arm A) versus acalabrutinib plus obinutuzumab
(Arm B) and obinutuzumab plus chlorambucil (Arm A) versus acalabrutinib monotherapy (Arm C)
in terms of: IRC-assessed objective response rate (ORR); Tine to next treatment (TTNT);
Overall Survival (OS)
Trial website
https://clinicaltrials.gov/ct2/show/NCT02475681
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
AstraZeneca Clinical Study Information Center
Address 0 0
1-877-240-9479 [email protected]
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT02475681