Clinical trial NCT02970318: A Study of Acalabrutinib vs Investigator's Choice of Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in R/R CLL
Official title: A Randomized, Multicenter, Open-Label, Phase 3 Study of Acalabrutinib (ACP-196) Versus Investigator's Choice of Either Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Subjects With R/R Chronic Lymphocytic Leukemia
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Chronic Lymphocytic Leukemia
Keywords: CLL
BTK
Bruton Tyrosine Kinase
acalabrutinib
ACP-196
Lead sponsor: Acerta Pharma BV
Sponsor class: INDUSTRY
First posted: 2016-11-22
Enrollment: 310
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study is designed to evaluate the efficacy of acalabrutinib compared with rituximab in combination with idelalisib or bendamustine in previously treated subjects with chronic lymphocytic leukemia (CLL).


Eligibility criteria: Inclusion Criteria:

1. Men and women ≥ 18 years of age.
2. ECOG performance status of 0 to 2.
3. Diagnosis of 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 10\^9 B lymphocytes/L (5000/μL) in the peripheral blood (at any point since initial diagnosis).
4. Must have documented CD20-positive CLL.
5. 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 10\^9/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 (ECOG performance score 2; inability to work or perform usual activities).

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

   iv. Night sweats for \> 1 month before screening without evidence of infection.
6. Meet the following laboratory parameters:

   1. ANC ≥ 750 cells/μL (0.75 x 10\^9/L), or ≥ 500 cells/μL (0.50 x 10\^9/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 10\^9/L), or ≥ 30,000 cells/μL (30 x 10\^9/L) in subjects with documented bone marrow involvement, and without transfusion support 7 days before assessment. Subjects with transfusion-dependent thrombocytopenia are excluded. If an Investigator has chosen bendamustine/rituximab as the Arm B treatment, platelets must be ≥ 75,000 cells/μL (75 x 10\^9/L).
   3. Serum AST and ALT ≤ 2.0 x ULN.
   4. Total bilirubin ≤ 1.5 x ULN.
   5. Estimated creatinine clearance of ≥ 30 mL/min, calculated using the formula of Cockcroft and Gault \[(140-Age) • Mass (kg)/(72 • creatinine mg/dL); multiply by 0.85 if female\].
7. Must have received ≥ 1 prior systemic therapies for CLL. Note: Single-agent steroids or localized radiation are not considered a prior line of therapy. If a single-agent anti-CD20 antibody was previously administered, subjects must have received ≥ 2 doses.
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, 90 days after the last dose of idelalisib, 6 months after the last dose of bendamustine, or 12 months after the last dose of rituximab, whichever is longer. Highly effective forms of contraception are defined in Section 9.2.5.
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 idelalisib, 6 months after the last dose of bendamustine, or 12 months after the last dose of rituximab, whichever is longer. Highly effective forms of contraception are defined in Section 9.2.5.
10. Men must agree to refrain from sperm donation during the study and for 90 days after the last dose of idelalisib, 6 months after the last dose of bendamustine, or 12 months after the last dose of rituximab, whichever is longer.
11. Willing and able to participate in all required evaluations and procedures in this study protocol, including swallowing capsules without difficulty.
12. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national and local patient privacy regulations).

Exclusion Criteria:

1. Known CNS lymphoma or leukemia.
2. Known prolymphocytic leukemia or history of, or currently suspected, Richter's syndrome.
3. 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 or equivalent).
4. Prior exposure to a BCL-2 inhibitor (e.g., venetoclax/ABT-199) or a BCR inhibitor (e.g., BTK inhibitors or PI3K inhibitors). Prior bendamustine is allowed if Investigator's choice for treatment in Arm B is idelalisib with rituximab. Bendamustine retreatment is allowed if the prior response to bendamustine lasted \> 24 months.
5. Received any chemotherapy, external beam radiation therapy, anticancer antibodies, or investigational drug within 30 days before first dose of study drug.
6. Corticosteroid use \> 20 mg daily prednisone equivalent 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 white blood cell count lowering are excluded.
7. Prior radio- or toxin-conjugated antibody therapy.
8. Prior allogeneic stem cell transplant or prior autologous transplant within 6 months of first dose of study drug(s) or presence of graft-vs-host disease or receiving treatment for graft-vs-host disease.
9. Major surgical procedure within 30 days of first dose of study drug. Note: If a subject had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug.
10. 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 2 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 nonmelanomatous skin cancer.
    3. Adequately treated carcinoma in situ without current evidence of disease.
11. Significant cardiovascular disease such as uncontrolled or untreated 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 (calculated using Fridericia's formula: QT/RR\^0.33) at screening. Exception: Subjects with controlled, asymptomatic atrial fibrillation during screening are allowed to enroll on study.
12. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach, or extensive small bowel resection that is likely to affect absorption, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass.
13. Received a live virus vaccination within 28 days of first dose of study drug.
14. Known history of infection with HIV or any uncontrolled active systemic infection (e.g., bacterial, viral, or fungal). For study sites in Germany: active infection with human immunodeficiency virus (seropositivity for HIV-1 or HIV-2 antibodies, and if positive, reactivity against the HIV-specific p24 antigen).
15. Active CMV infection (active viremia as evidenced by positive polymerase chain reaction \[PCR\] result for CMV DNA).
16. Serologic status reflecting active hepatitis B or C infection.

    1. Subjects who are anti-HBc positive and who are surface antigen negative will need to have a negative PCR result before randomization. Those who are HbsAg-positive or hepatitis B PCR positive will be excluded.
    2. Subjects who are hepatitis C antibody positive will need to have a negative PCR result before randomization. Those who are hepatitis C PCR positive will be excluded.
17. Ongoing, drug-induced liver injury, alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, ongoing extrahepatic obstruction caused by cholelithiasis, cirrhosis of the liver, or portal hypertension.
18. History of or ongoing drug-induced pneumonitis.
19. History of serious allergic reactions including anaphylaxis and toxic epidermal necrolysis.
20. History of stroke or intracranial hemorrhage within 6 months before first dose of study drug.
21. History of bleeding diathesis (e.g., hemophilia, von Willebrand disease).
22. Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) within 7 days of first dose of study drug.
23. Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening.
24. Requires treatment with a strong CYP3A inhibitor/inducer.
25. Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Subjects receiving proton-pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment to this study.
26. Breast feeding or pregnant.
27. Concurrent participation in another therapeutic clinical trial.
28. Prothrombin time/INR or aPTT (in the absence of a Lupus anticoagulant) \> 2.0 x ULN. Exception: Subjects receiving warfarin are excluded, however, those receiving other anticoagulant therapy who have a higher INR/aPTT may be permitted to enroll to this study after discussion with the medical monitor.
29. History of confirmed progressive multifocal leukoencephalopathy (PML)

Primary outcomes:
measure: Progression-free Survival (PFS) Per Independent Review Committee (IRC) Assessment
timeFrame: IRC assessments from randomization date until disease progression or death or IRC discontinuation on 15Jan2019 (as IA per this data cutoff showed crossing superiority boundary) whichever came first, up to 22 months of follow-up
Secondary outcomes:
measure: Progression-free Survival (PFS) Per Investigator Assessment
timeFrame: From randomization date to date of disease progression or death due to any cause or data cutoff date on 03Sep2021, whichever came first, regardless of use of subsequent anticancer therapy, until 53 months of follow-up.
measure: IRC-assessed Overall Response Rate (ORR) Per IWCLL 2008 Criteria Based on Data Cutoff 15 January 2019 From Interim Analysis
timeFrame: IRC assessments from randomization date until disease progression or death or IRC discontinuation on 15Jan2019 (as IA per this data cutoff showed crossing superiority boundary) whichever came first, up to 22 months of follow-up
measure: Investigator Assessed Overall Response Rate (ORR) Per IWCLL 2008 Criteria Based on Data Cutoff 03 September 2021
timeFrame: Investigator assessments were done from randomization date until date of death or date of exit from study or data cut off date on 03Sep2021, whichever came first, up to 53 months of follow-up.
measure: Overall Survival (OS)
timeFrame: From randomization date to date of death due to any cause, or date of study discontinuation, or date of data cutoff on 03Sep2021, whichever came first until 54 months of follow-up.
measure: Duration of Response (DOR) Per Independent Review Committee (IRC) Assessment Based on 15 January 2019 Data Cutoff From Interim Analysis.
timeFrame: IRC assessments from randomization date until disease progression or death or IRC discontinuation on 15Jan2019 (as IA per this data cutoff showed crossing superiority boundary) whichever came first, up to 22 months of follow-up
measure: Duration of Response (DOR) Per Investigator Assessment Based on 03 September 2021 Data Cutoff
timeFrame: Investigator assessments were done from randomization date until date of death or study discontinuation or data cutoff date on 03Sep2021, whichever came first up to 53 months of follow-up.
measure: Time to Next Treatment (TTNT) Based on 03 September 2021 Data Cutoff
timeFrame: From randomization date to start of non-protocol specified subsequent anticancer therapy for CLL or death due to any cause or study discontinuation or data cutoff date on 03Sep2021,, whichever came first up to 53 months of follow-up.
Other outcomes:
Locations:
city: Chandler
country: United States
facility: Research Site
state: Arizona
city: Oxnard
country: United States
facility: Research Site
state: California
city: Athens
country: United States
facility: Research Site
state: Georgia
city: Joliet
country: United States
facility: Research Site
state: Illinois
city: Cedar Rapids
country: United States
facility: Research Site
state: Iowa
city: Mount Sterling
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facility: Research Site
state: Kentucky
city: Saint Cloud
country: United States
facility: Research Site
state: Minnesota
city: Lincoln
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facility: Research Site
state: Nebraska
city: Brick
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facility: Research Site
state: New Jersey
city: Nyack
country: United States
facility: Research Site
state: New York
city: Canton
country: United States
facility: Research Site
state: Ohio
city: Fort Sam Houston
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state: Texas
city: Round Rock
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facility: Research Site
state: Texas
city: Adelaide
country: Australia
facility: Research Site
city: Box Hill
country: Australia
facility: Research Site
city: Frankston
country: Australia
facility: Research Site
city: Geelong
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facility: Research Site
city: Gosford
country: Australia
facility: Research Site
city: Hobart
country: Australia
facility: Research Site
city: Kogarah
country: Australia
facility: Research Site
city: Murdoch
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facility: Research Site
city: Nedlands
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facility: Research Site
city: South Brisbane
country: Australia
facility: Research Site
city: Woodville
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facility: Research Site
city: Linz
country: Austria
facility: Research Site
city: Salzburg
country: Austria
facility: Research Site
city: Wels
country: Austria
facility: Research Site
city: Wien
country: Austria
facility: Research Site
city: Wien
country: Austria
facility: Research Site
city: Antwerpen
country: Belgium
facility: Research Site
city: Ghent
country: Belgium
facility: Research Site
city: Roeselare
country: Belgium
facility: Research Site
city: Yvoir
country: Belgium
facility: Research Site
city: Pleven
country: Bulgaria
facility: Research Site
city: Plovdiv
country: Bulgaria
facility: Research Site
city: Stara Zagora
country: Bulgaria
facility: Research Site
city: Vratsa
country: Bulgaria
facility: Research Site
city: Barrie
country: Canada
facility: Research Site
state: Ontario
city: Calgary
country: Canada
facility: Research Site
city: Montreal
country: Canada
facility: Research Site
city: Ottawa
country: Canada
facility: Research Site
city: Regina
country: Canada
facility: Research Site
city: Saint John
country: Canada
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city: Toronto
country: Canada
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city: Toronto
country: Canada
facility: Research Site
city: Zadar
country: Croatia
facility: Research Site
city: Zagreb
country: Croatia
facility: Research Site
city: Brno
country: Czechia
facility: Research Site
city: Novy Hradec Kralove
country: Czechia
facility: Research Site
city: Olomouc
country: Czechia
facility: Research Site
city: Ostrava Poruba
country: Czechia
facility: Research Site
city: Plzen - Lochotin
country: Czechia
facility: Research Site
city: Praha 10
country: Czechia
facility: Research Site
city: Bordeaux
country: France
facility: Research Site
city: Brest
country: France
facility: Research Site
city: Montpellier
country: France
facility: Research Site
city: Nantes cedex 1
country: France
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city: Paris cedex 13
country: France
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city: Paris
country: France
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city: Perpignan
country: France
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city: Provence Alpes Cote D'Azur
country: France
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city: Rennes Cedex
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city: Rouen
country: France
facility: Research Site
city: Aschaffenburg
country: Germany
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city: Dresden
country: Germany
facility: Research Site
city: Munchen
country: Germany
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city: Mutlangen
country: Germany
facility: Research Site
city: Ulm
country: Germany
facility: Research Site
city: HongKong
country: Hong Kong
facility: Research Site
city: Pok Fu Lam
country: Hong Kong
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city: Budapest
country: Hungary
facility: Research Site
city: Debrecen
country: Hungary
facility: Research Site
city: Gyula
country: Hungary
facility: Research Site
city: Kaposvár
country: Hungary
facility: Research Site
city: Ashkelon
country: Israel
facility: Research Site
city: Haifa
country: Israel
facility: Research Site
city: Jerusalem
country: Israel
facility: Research Site
city: Kfar Saba
country: Israel
facility: Research Site
city: Nahariya
country: Israel
facility: Research Site
city: Petah Tikvah
country: Israel
facility: Research Site
city: Aviano
country: Italy
facility: Research Site
city: Bergamo
country: Italy
facility: Research Site
city: Brescia
country: Italy
facility: Research Site
city: Firenze
country: Italy
facility: Research Site
city: Genova
country: Italy
facility: Research Site
city: Genova
country: Italy
facility: Research Site
city: Meldola
country: Italy
facility: Research Site
city: Milano
country: Italy
facility: Research Site
city: Milan
country: Italy
facility: Research Site
city: Modena
country: Italy
facility: Research Site
city: Busan
country: Korea, Republic of
facility: Research Site
city: Daegu
country: Korea, Republic of
facility: Research Site
city: Dong-gu
country: Korea, Republic of
facility: Research Site
city: Gyeonggi-do
country: Korea, Republic of
facility: Research Site
city: Incheon
country: Korea, Republic of
facility: Research Site
city: Jeonju-si
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Addington
country: New Zealand
facility: Research Site
city: Dunedin
country: New Zealand
facility: Research Site
city: Palmerston North
country: New Zealand
facility: Research Site
city: Tauranga
country: New Zealand
facility: Research Site
city: Bialystok
country: Poland
facility: Research Site
city: Bydgoszcz
country: Poland
facility: Research Site
city: Gdansk
country: Poland
facility: Research Site
city: Kraków
country: Poland
facility: Research Site
city: Lodz
country: Poland
facility: Research Site
city: Lublin
country: Poland
facility: Research Site
city: Woj. Podkarpackie
country: Poland
facility: Research Site
city: Novosibirsk
country: Russian Federation
facility: Research Site
city: Obninsk
country: Russian Federation
facility: Research Site
city: Penza
country: Russian Federation
facility: Research Site
city: Ryazan
country: Russian Federation
facility: Research Site
city: Sochi
country: Russian Federation
facility: Research Site
city: St. Petersburg
country: Russian Federation
facility: Research Site
city: St. Petersburg
country: Russian Federation
facility: Research Site
city: Tula
country: Russian Federation
facility: Research Site
city: Volgograd
country: Russian Federation
facility: Research Site
city: Yaroslavl
country: Russian Federation
facility: Research Site
city: Yekaterinburg
country: Russian Federation
facility: Research Site
city: SGP
country: Singapore
facility: Research Site
city: SGP
country: Singapore
facility: Research Site
city: SGP
country: Singapore
facility: Research Site
city: Bratislava
country: Slovakia
facility: Research Site
city: Kosice
country: Slovakia
facility: Research Site
city: Badalona
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Majadahonda
country: Spain
facility: Research Site
city: Salamanca
country: Spain
facility: Research Site
city: Santander
country: Spain
facility: Research Site
city: Valencia
country: Spain
facility: Research Site
city: Goeteborg
country: Sweden
facility: Research Site
city: Lulea
country: Sweden
facility: Research Site
city: Stockholm
country: Sweden
facility: Research Site
city: Hualien
country: Taiwan
facility: Research Site
city: Tainan
country: Taiwan
facility: Research Site
city: Taipei
country: Taiwan
facility: Research Site
city: Cherkasy
country: Ukraine
facility: Research Site
city: Dnipropetrovsk
country: Ukraine
facility: Research Site
city: Ivano-Frankivsk
country: Ukraine
facility: Research Site
city: Khmelnytsky
country: Ukraine
facility: Research Site
city: Kyiv
country: Ukraine
facility: Research Site
city: Kyiv
country: Ukraine
facility: Research Site
city: Zhytomir
country: Ukraine
facility: Research Site
city: Birmingham
country: United Kingdom
facility: Research Site
city: Cambridge
country: United Kingdom
facility: Research Site
city: Canterbury
country: United Kingdom
facility: Research Site
city: Leicester
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: Maidstone
country: United Kingdom
facility: Research Site
city: Manchester
country: United Kingdom
facility: Research Site
city: Southampton
country: United Kingdom
facility: Research Site
city: Wolverhampton
country: United Kingdom
facility: Research Site
Study officials:
affiliation: 1-888-292-9613; acertamc@dlss.com
name: Acerta Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Eek D, Ivanescu C, Corredoira L, Meyers O, Cella D. Content validity and psychometric evaluation of the Functional Assessment of Chronic Illness Therapy-Fatigue scale in patients with chronic lymphocytic leukemia. J Patient Rep Outcomes. 2021 Mar 11;5(1):27. doi: 10.1186/s41687-021-00294-1.
citation: Ghia P, Pluta A, Wach M, Lysak D, Kozak T, Simkovic M, Kaplan P, Kraychok I, Illes A, de la Serna J, Dolan S, Campbell P, Musuraca G, Jacob A, Avery E, Lee JH, Liang W, Patel P, Quah C, Jurczak W. ASCEND: Phase III, Randomized Trial of Acalabrutinib Versus Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia. J Clin Oncol. 2020 Sep 1;38(25):2849-2861. doi: 10.1200/JCO.19.03355. Epub 2020 May 27.