Study to Investigate the Use of Acalabrutinib in the Treatment of Patients With Chronic Lymphocytic Leukemia

NCT04178798 | Completed Phase 3 DMC

• 1 other identifier: GLLC-EARLY
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 8

Brief Summary

Study Phase III Randomized Study to Investigate the Use of Acalabrutinib in the Treatment of Patients with Early Stage CLL With High Risk of Early Disease Progression. The study will consist of a screening phase, a treat¬ment/observation phase until progression, and a follow-up phase for progression in patients who discontinue treatment with Acalabrutinib without confirmed progression. Patients who progress will be followed for survival and initiation of subsequent antileukemic therapy. In the study, 130 patients from 20 centers in Spain with intermediate, high or very high risk will be randomized (1:1) to receive Acalabrutinib (n=65) or clinical observation (n=65). Acalabrutinib will be administered orally 100 mg twice daily on a continuous schedule. Even though the majority of patients with CLL are currently diagnosed at early stages of the disease, there is a consensus that the standard of care in these patients is clinical observation (watch \& wait) despite of the presence of risk factors for premature disease progression. Early treatment in patients with adverse prognostic parameters could prevent a disease evolving to a more advanced stage, and therefore more difficult to treat. So far, conventional chemotherapy did not show any benefit in terms of overall survival in patients with early stage CLL. (Dighiero 1998, Hoechstetter Leukemia 2017) Alongside this, treatment with chemotherapy may provoke two undesired effects: first, the occurrence of bone marrow toxicity that may hamper the subsequent administration of other treatments during the course of the disease; second, but not less relevant, genotoxic drug delivery may elicit a phenomenon of clonal selection leading to the appearance of CLL cells with genetic aberrations associated with refractoriness and aggressive outcome (i.e., TP53). Against this background, it is of interest to investigate the role of new non-genotoxic drugs in the treatment of patients with CLL in early stages. Among different scores for selecting cases that are likely to progress rapidly, the German CLL Study Group (GCLLSG) risk score that includes 8 independent predictors for OS and PFS, differentiates patients with low-risk PFS vs. those with risk of early disease progression (median PFS 87 months vs. less than 27 months), allowing for a risk-adapted treatment approach in early stage CLL. (Pflug 2014, Langerbeins 2015). Acalabrutinib, a second-generation, selective inhibitor of BTK, has shown substantial activity in patients with CLL. Acalabrutinib is a non-genotoxic drug active in cases with genetic lesions associated with chemorefratoriness and adverse outcome, including patients with alterations of TP53. Therefore, acalabrutinib represents a suitable compound for the treatment of patients with CLL in early stages with risk of early disease progression, including the high-risk CLL patient population with TP53 alterations.

Conditions

Chronic Lymphocytic Leukemia- Binet Staging System

Keywords

CLL

Outcome Measures

Primary Outcomes (1)

• Event-Free Survival (EFS)

  EFS is defined as the time between the date of randomization and time point of symptomatic disease progression with treatment indication according to the iwCLL-Guidelines, initiation of subsequent treatment for CLL or death by any cause, whichever occurs first.

  From randomization to 60 months

Secondary Outcomes (4)

• Progression-Free Survival (PFS)

  From randomization to 60 months

• Overall Survival (OS)

  From randomization to 60 months

• Time To Next Treatment (TTNT)

  From randomization to 60 months

• Objetive Response Rate (ORR)

  From randomization to 60 months

Study Arms (2)

Arm A_Acalabrutinib

EXPERIMENTAL

Patients assigned to arm A, will receive acalabrutinib as one capsule of 100 mg orally twice daily on a continuos schedule until disease progression, unacceptable toxicity or early withdrawal.

Drug: Acalabrutinib 100 MG Oral Capsule

Arm B_Standard of care

NO INTERVENTION

Patients assigned to arm B, will receive standard of care for the management of early Binet stage A patients "clinical observation (watch \& wait)" until disease progression or early withdrawal.

Interventions

Acalabrutinib 100 MG Oral Capsule DRUG

Patients in Arm A will receive acalabrutinib as one capsule of 100 mg orally twice daily on a continuos Schedule.

Arm A_Acalabrutinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adult patients with previously untreated CLL according to IWCLL criteria (Hallek, 2018).
• Must understand and voluntarily sign an informed consent form.
• Age ≥ 18 years at the time of signing the informed consent form and must be able to adhere to the study visit schedule and other Protocol requirements.
• Binet clinical stage A and Rai 0 or 1.
• Absence of criteria for the initiation of chemotherapy, defined by the IWCLL guidelines for diagnosis and treatment of CLL (Hallek, 2018):
• Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia.
• Massive (i.e. ≥6 cm below the left costal margin) or progressive or symptomatic splenomegaly.
• Massive nodes (i.e. ≥10 cm in longest diameter) or progressive or symptomatic lymphadenopathy.
• Progressive lymphocytosis with an increase of ≥50% over a 2-month period, or lymphocyte doubling time (LDT) of less than 6 months.
• A minimum of any one of the following disease-related symptoms: unintentional weight loss ≥10% within the previous 6 months, significant fatigue (i.e., ECOG PS 2 or worse; cannot work or unable to perform usual activities), fevers of ≥38.0°C for 2 or more weeks without other evidence of infection, or night sweats for more than 1 month without evidence of infection.
• Autoimmune complications including anemia or thrombocytopenia poorly responsive to corticosteroids.
• Symptomatic or functional extranodal involvement (e.g., skin, kidney, lung, spine).
• GCLLSG prognostic index with intermediate (3-5), high (6-10) or very high (11-14) risk scores.
• Must have an Eastern Cooperative Oncology Group (ECOG) performance status score of ≤1.
• All sexually active subjects with the capacity to reproduce (male and female) must use high-efficacy contraceptive methods during the course of the study. These restrictions apply for 3 months after the last dose of acalabrutinib. High-efficacy contraceptive methods include:

You may not qualify if:

• Prior treatment for CLL.
• Meets any criteria for the initiation of treatment defined by the IWCLL guidelines for diagnosis and treatment of CLL (Hallek, 2018).
• Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) and/or Hepatitis C Virus (HCV) infection and/or known history of progressive multifocal leukoencephalopathy (PML). Subjects who are hepatitis B core antibody (anti-HBc) positive and who are surface antigen negative will need to have a negative polymerase chain reaction (PCR). Those who are hepatitis B surface antigen (HbsAg) positive or hepatitis B PCR positive will be excluded. Subjects who are hepatitis C antibody positive will need to have a negative PCR result. Those who are hepatitis C PCR positive will be excluded.
• Estimated Glomerular Filtration Rate (Cockcroft-Gault Appendix C) ≤ 40 mL/min/1.73m2.
• Absolute neutrophil count (ANC) \< 1.0 X 109/L.
• Platelet count \< 100 X 109/L.
• Serum aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) or alanine transaminase (ALT)/serum glutamate pyruvate transaminase (SGPT) \>2.5 x upper limit of normal (ULN).
• Serum total bilirubin \>1.5 x ULN, except in cases of Gilbert's syndrome.
• Prothrombin time/INR or aPTT (in the absence of Lupus anticoagulant) \>2 x ULN.
• Active bleeding, history of bleeding diathesis (e.g., hemophilia or von Willebrand disease).
• 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 enrolment to this study.
• Unable to swallow capsules, or has disease significantly affecting gastrointestinal function that would limit absorption of oral medication.
• Currently active, clinically significant cardiovascular disease or a history of myocardial infarction within 3 months prior to enrolment. Exception: Subjects with controlled, asymptomatic atrial fibrillation during screening can enrol on study.
• Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) within 7 days of first dose of study drug.
• Systemic infection that has not resolved prior to initiating study treatment in spite of adequate anti-infective therapy.

Sponsors & Collaborators

• PETHEMA Foundation: lead

Study Sites (8)

Hospital de la Santa Creu i Sant Pau

Barcelona, 08025, Spain

Location

Hospital Universitari Vall d'Hebron

Barcelona, 08035, Spain

Location

ICO L´Hospitalet - Hospital Duran i Reynals

Barcelona, 08908, Spain

Location

Hospital Costa del Sol

Marbella, 29603, Spain

Location

Hospital Universitario Salamanca

Salamanca, 37007, Spain

Location

Hospital Universitario Marqués de Valdecilla

Santander, 39009, Spain

Location

Hospital Universitario Virgen de Valme

Seville, 41014, Spain

Location

Hospital Virgen de la Salud (Complejo Hospitalario de Toledo)

Toledo, 45004, Spain

Location

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MeSH Terms

Interventions

acalabrutinib

Study Officials

• Pau Abrisqueta Costa, MD

  University Hospital of Vall d'Hebron

  PRINCIPAL INVESTIGATOR

• Francesc Bosch Albareda, MD

  University Hospital of Vall d'Hebron

  PRINCIPAL INVESTIGATOR

• Carmen López Carrero

  Fundación Pethema

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: * Arm A (65 patients): Patients assigned to arm A, will receive acalabrutinib as one capsule of 100 mg orally twice daily on a continuos schedule until disease progression, unacceptable toxicity or early withdrawal. * Arm B (65 patients): Patients assigned to arm B, will remain on the w\&w approach until disease progression or early withdrawal.

Study Record Dates

• First Submitted: November 8, 2019
• First Posted: November 26, 2019
• Study Start: December 9, 2019
• Primary Completion: December 3, 2024
• Study Completion: December 3, 2024
• Last Updated: March 17, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will not share

Locations

ES (8)