Acalabrutinib, Obinutuzumab and Chlorambucil in Treatment naïve CLL

Chronic Lymphocytic Leukemia Clinical Trial

— ElevateTN  

Official 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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02475681
• Other study ID #: ACE-CL-007
• Secondary ID: 2014-005582-73
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: June 26, 2015
• Est. completion date: September 30, 2025

Study information

• Verified date: May 2024
• Source: Acerta Pharma BV
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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)

Description:

ELEVATE-TN is a global, phase 3, multicenter, open-label study in patients with treatment-naive chronic lymphocytic leukemia (CLL). Study enrollment is completed. The study randomized a total of 535 subjects in 142 study sites in 18 countries between 14 September 2015 through 08 February 2017. Patients were randomly assigned to receive Acalabrutinib and Obinutuzumab, Acalabrutinib monotherapy, or Obinutuzumab and oral Chlorambucil. The primary endpoint was progression-free survival between the two combination-therapy groups, defined as the time from randomization until disease progression by use of iwCLL 2008 criteria, or death, assessed by independent review committee (IRC). Crossover to Acalabrutinib was allowed in patients who progressed on Obinutuzumab-Chlorambucil.

The results of this study provide new evidence for therapy in patients with treatment-naive chronic lymphocytic leukemia by showing the efficacy of Acalabrutinib used with or without Obinutuzumab compared with chemoimmunotherapy.

Currently the study is in maintenance phase, with more than 430 subjects on study, to generate more evidence. We are not expecting any significant change in the near future.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 535
• Est. completion date: September 30, 2025
• Est. primary completion date: February 8, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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).

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.

Related Conditions & MeSH terms

• Chronic Lymphocytic Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell

Intervention

Drug:
• Acalabrutinib

• Obinutuzumab

• Chlorambucil

Locations

Country	Name	City	State
Australia	Research Site	Darlinghurst
Australia	Research Site	Frankston
Australia	Research Site	Geelong
Australia	Research Site	South Brisbane
Australia	Research Site	Waratah NSW
Australia	Research Site	Wollongong
Australia	Research Site	Woodville
Belgium	Research Site	Brugge
Belgium	Research Site	Brussels
Belgium	Research Site	Bruxelles
Belgium	Research Site	Ghent
Belgium	Research Site	Kortrijk
Belgium	Research Site	Leuven
Belgium	Research Site	Roeselare
Belgium	Research Site	Wilrijk
Belgium	Research Site	Yvoir
Brazil	Research Site	Barretos
Brazil	Research Site	Florianopolis
Brazil	Research Site	Passo Fundo
Brazil	Research Site	Porto Alegre
Brazil	Research Site	Porto Alegre
Brazil	Research Site	Sao Paulo
Canada	Research Site	Halifax	Nova Scotia
Canada	Research Site	Quebec City
Canada	Research Site	Saint John
Canada	Research Site	Vancouver	British Columbia
Canada	Research Site	Winnipeg
Chile	Research Site	Santiago
Chile	Research Site	Temuco
Colombia	Research Site	Medellin
Colombia	Research Site	Monteria
France	Research Site	Bobigny
France	Research Site	Dijon
France	Research Site	Pierre-Benite
France	Research Site	Strasbourg Cedex
France	Research Site	Villejuif
Germany	Research Site	Aschaffenburg
Germany	Research Site	Bielefeld
Germany	Research Site	Erlangen
Germany	Research Site	Heilbronn
Germany	Research Site	Warzburg
Hungary	Research Site	Budapest
Hungary	Research Site	Budapest
Hungary	Research Site	Debrecen
Hungary	Research Site	Kaposvár
Hungary	Research Site	Szolnok
Israel	Research Site	Ashkelon
Israel	Research Site	Beer Sheva
Israel	Research Site	Haifa
Israel	Research Site	Haifa
Israel	Research Site	Haifa
Israel	Research Site	Jerusalem
Israel	Research Site	Nahariya
Israel	Research Site	Petah Tikvah
Israel	Research Site	Petah Tikvah
Israel	Research Site	Rehovot
Israel	Research Site	Tel Aviv
Israel	Research Site	Tel Hashomer
Israel	Research Site	Tiberias
Italy	Research Site	Alessandria
Italy	Research Site	Aviano
Italy	Research Site	Brescia
Italy	Research Site	Firenze
Italy	Research Site	Meldola
Italy	Research Site	Milano
Italy	Research Site	Parma
Italy	Research Site	Ravenna
Italy	Research Site	Rimini
Italy	Research Site	Rome
Italy	Research Site	Rozzano
Lithuania	Research Site	Kaunas
Lithuania	Research Site	Klaipeda
Lithuania	Research Site	Vilnius
New Zealand	Research Site	Auckland
New Zealand	Research Site	Otahuhu
New Zealand	Research Site	Tauranga
Poland	Research Site	Bydgoszcz
Poland	Research Site	Gdansk
Poland	Research Site	Gdynia
Poland	Research Site	Kraków
Poland	Research Site	Lodz
Poland	Research Site	Lublin
Poland	Research Site	Olsztyn
Poland	Research Site	Opole
Poland	Research Site	Slupsk
Spain	Research Site	Barcelona
Spain	Research Site	Madrid
Spain	Research Site	Madrid
Spain	Research Site	Madrid
Spain	Research Site	Majadahonda
Spain	Research Site	Santander
Sweden	Research Site	Gothenburg
Sweden	Research Site	Linkoping
Sweden	Research Site	Lund
Sweden	Research Site	Orebro
United Kingdom	Research Site	Bournemouth
United Kingdom	Research Site	Cambridge
United Kingdom	Research Site	Leeds
United Kingdom	Research Site	Leicester
United Kingdom	Research Site	London
United Kingdom	Research Site	Plymouth
United Kingdom	Research Site	Southampton
United Kingdom	Research Site	Truro
United Kingdom	Research Site	Wolverhampton
United States	Research Site	Anaheim	California
United States	Research Site	Aurora	Colorado
United States	Research Site	Austin	Texas
United States	Research Site	Bedford	Texas
United States	Research Site	Billings	Montana
United States	Research Site	Blue Ash	Ohio
United States	Research Site	Brick	New Jersey
United States	Research Site	Canton	Ohio
United States	Research Site	COL	Maryland
United States	Research Site	Columbus	Ohio
United States	Research Site	Dallas	Texas
United States	Research Site	Fort Myers	Florida
United States	Research Site	Fort Sam Houston	Texas
United States	Research Site	Goodyear	Arizona
United States	Research Site	Hackensack	New Jersey
United States	Research Site	Houston	Texas
United States	Research Site	Jacksonville	Florida
United States	Research Site	Lafayette	Indiana
United States	Research Site	Lake Success	New York
United States	Research Site	Lone Tree	Colorado
United States	Research Site	Los Angeles	California
United States	Research Site	Los Angeles	California
United States	Research Site	Los Angeles	California
United States	Research Site	Louisville	Kentucky
United States	Research Site	Nashville	Tennessee
United States	Research Site	New Braunfels	Texas
United States	Research Site	New Orleans	Louisiana
United States	Research Site	New York	New York
United States	Research Site	Niles	Illinois
United States	Research Site	Northwest WA	Wisconsin
United States	Research Site	Oxnard	California
United States	Research Site	Palo Alto	California
United States	Research Site	Phoenix	Arizona
United States	Research Site	Roanoke	Virginia
United States	Research Site	Rochester	Minnesota
United States	Research Site	Round Rock	Texas
United States	Research Site	Saint Cloud	Minnesota
United States	Research Site	Salt Lake City	Utah
United States	Research Site	San Antonio	Texas
United States	Research Site	Seattle	Washington
United States	Research Site	Seattle	Washington
United States	Research Site	Spokane	Washington
United States	Research Site	Tacoma	Washington
United States	Research Site	Tallahassee	Florida
United States	Research Site	Tallahassee	Florida
United States	Research Site	Tampa	Florida
United States	Research Site	Texas City	Texas
United States	Research Site	Tyler	Texas
United States	Research Site	Washington	District of Columbia
United States	Research Site	Wichita	Kansas
United States	Research Site	Yakima	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Acerta Pharma BV

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Brazil,  Canada,  Chile,  Colombia,  France,  Germany,  Hungary,  Israel,  Italy,  Lithuania,  New Zealand,  Poland,  Spain,  Sweden,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free Survival by IRC (Independent Review Committee) Assessment in Arm A Compared to Arm B	To evaluate the efficacy of obinutuzumab in combination with chlorambucil (Arm A) compared with acalabrutinib in combination with obinutuzumab (Arm B) based on IRC assessment of progression-free survival (PFS) per International Workshop on Chronic Lymphocytic Leukemia criteria (IWCLL; Hallek et al. 2008) with incorporation of the clarification for treatment-related lymphocytosis (Cheson et al. 2012), hereafter referred to as IWCLL 2008 criteria, in subjects with previously untreated CLL. PFS, defined as the time from date of randomization to the date of first IRC-assessed disease progression or death due to any cause, whichever comes first.	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	Progression-free Survival by IRC Assessment Arm A Versus Arm C	To evaluate the efficacy of obinutuzumab in combination with chlorambucil (Arm A) compared with acalabrutinib monotherapy (Arm C) based on IRC assessment of progression-free survival (PFS) per International Workshop on Chronic Lymphocytic Leukemia criteria (IWCLL; Hallek et al. 2008) with incorporation of the clarification for treatment-related lymphocytosis (Cheson et al. 2012), hereafter referred to as IWCLL 2008 criteria, in subjects with previously untreated CLL. PFS, defined as the time from date of randomization to the date of first IRC-assessed disease progression or death due to any cause, whichever comes first.	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	IRC-assessed Objective Response Rate (ORR) in Arm A Versus Arm B and Arm A Versus Arm C	ORR was defined as the proportion of subjects who achieved a best response of CR, CRi, nPR, or PR at or before initiation of subsequent anticancer therapy. ORR including PRL was defined as the proportion of subjects who achieved a best response of CR, CRi, nPR, PR or PRL at or before initiation of subsequent anticancer therapy	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	Time to Next Treatment (TTNT) in Arm A Versus Arm B and Arm A Versus Arm C	TTNT was defined as the time from randomization to start date of non-protocol specified subsequent anticancer therapy for CLL or death due to any cause, whichever came first. TTNT was analyzed in the same fashion as that for the primary efficacy analysis	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	Overall Survival (OS) in Arm A Versus Arm B and Arm A Versus Arm C	OS was defined as the time from the date of randomization to death due to any cause.	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.

External Links

•   Protocol
•   Redacted Clinical Study Report synopsis
•   Statistical Analysis Plan Redacted