ACALABRUTINIB for Chronic lymphocytic leukemia (CLL) | Small lymphocytic lymphoma (SLL) | Relapsed chronic lymphocytic leukemia

Inclusion criteria

• {"criterion_text":"-Documented CLL or SLL requiring treatment according to IWCLL criteria (appendix A) after at least (clinical) partial response as best response after the following initial study treatment: venetoclax-rituximab in HOVON 140/GAIA or venetoclax-obinutuzumab in HOVON 139/GIVE or HOVON 140/GAIA\n-Patient is capable of giving informed consent\n-Written informed consent\n-WHO/ECOG performance status 0-3), stage 3 only if attributable to CLL\n-Age at least 18 years\n-Adequate BM function defined as: Hemoglobin >5 mmol/l or Hb > 8 g/dL, Absolute neutrophil count (ANC) >0.75 x 109/L (750/μL), unless directly attributable to CLL infiltration of the BM, proven by BM biopsy, Platelet count >30 x 109/L (30,000/μL) without transfusion and irrespective whether it is attributable to CLL infiltration in the BM\n-Estimated Glomerular Filtration Rate (eGFR) (MDRD) or estimated creatinine clearance (CrCl) ≥ 30ml/min (Cockcroft-Gault)\n-Adequate liver function as indicated: Serum aspartate transaminase (ASAT) and alanine transaminase (ALAT) ≤ 3.0 x upper limit of normal (ULN), Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of nonhepatic origin)\n-Prothrombin time (PT)/International normal ratio (INR) <1.5 x ULN and activated partial thromboplastin time (aPTT) <1.5 x ULN\n-Negative serological testing for hepatitis B virus (HBV) (Hepatitis B surface antigen (HBsAg) negative and hepatitis B core antibody (anti-HBc) negative) and hepatitis C virus (hepatitis C antibody). Subjects who are positive for anti-HBc or hepatitis C antibody may be included if they have a negative PCR within 6 weeks before enrollment. Those who are PCR positive will be excluded\n-Patient is able and willing to adhere to the study visit schedule and other protocol requirements"}

Exclusion criteria

• {"criterion_text":"-Any prior therapy with BTK inhibitor\n-Active fungal, bacterial, and/or viral infection that requires systemic therapy\n-Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled: infection, auto-immune hemolysis, immune thrombocytopenia, diabetes, hypertension, hyperthyroidism or hypothyroidism etc.)\n-Patient known to be HIV-positive\n-Patient requiring treatment with a strong cytochrome P450 (CYP) 3A inhibitor/inducer (see appendix J) or anticoagulant therapy with warfarin or phenoprocoumon or other vitamin K antagonists\n-History of stroke or intracranial hemorrhage within 6 months prior to registration\n-Severe cardiovascular disease (arrhythmias requiring chronic treatment, congestive heart failure or symptomatic ischemic heart disease, myocardial infarction within 6 months) (CTCAE grade III-IV)\n-Severe pulmonary dysfunction (CTCAE grade III-IV)\n-Severe neurological or psychiatric disease (CTCAE grade III-IV)\n-Patient who has difficulty with or are unable to swallow oral medication, or have significant gastrointestinal disease that would limit absorption of oral medication\n-Vaccination with live vaccines within 28 days prior to registration\n-Prior treatment with venetoclax other than first line\n-Use of any other experimental drug or therapy within 28 days of registration\n-Major surgery within 28 days prior to registration\n-Steroid therapy within 10 days prior to registration, with the exception of inhaled steroids for asthma, topical steroids, steroids up to 20 mg or dose equivalents of prednisolone daily to control autoimmune phenomenon’s, or replacement/stress corticosteroids\n-Pregnant women and nursing mothers\n-Fertile men or women of childbearing potential unless: (1) surgically sterile or ≥ 2 years after the onset of menopause; (2) willing to use a highly effective contraceptive method during study treatment and for 30 days after end of treatment\n-Current participation in other clinical trial (other than follow up HOVON139/HOVON140)\n-Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule\n-Other therapy with exception of chemo-/immunotherapy which is allowed also after venetoclax first line relapse\n-Transformation of CLL (Richter’s transformation)\n-Patient with a history of confirmed progressive multifocal leukoencephalopathy (PML)\n-Malignancies other than CLL currently requiring systemic therapy or not treated in curative intention or showing signs of progression after curative treatment\n-Known allergy to xanthine oxidase inhibitors and/or rasburicase\n-History of drug-specific hypersensitivity or anaphylaxis to any study drug (including active product or excipient components)\n-Active bleeding or history of bleeding diathesis (e.g. hemophilia or von Willebrand disease)"}

Primary endpoints

• {"endpoint_text":"-uMRD in bone marrow (BM) by flow cytometry after 26 cycles","definition_or_measurement_approach":"uMRD assessed in bone marrow by flow cytometry after 26 cycles (protocol notes: measured by flow cytometry in BM after 26 cycles; translation: 2 acalabrutinib and 24 AV)"}

Secondary endpoints

• {"endpoint_text":"-Depth of MRD measured in BM after cycle 13 and 26\n-Depth of MRD measured in PB after cycle 8, 10, 13, 16, 19, 22, 26 and every 3-6 months thereafter\n-Best overall response rate (ORR) defined as the proportion of subjects with a complete response (CR), complete response with incomplete marrow recovery (CRi), or partial response (PR) according to IWCLL 2018 criteria\n-Progression free survival (PFS), defined as time from registration to the first occurrence of disease progression or death from any cause (whichever occurs first).\n-Event free survival (EFS), defined as time from registration to date start of first CLL treatment off protocol, progression or death, whichever comes first\n-Overall survival (OS), defined as the time from registration to death from any cause\n-Treatment free interval (TFI), defined as date of last protocol treatment to start date of first CLL treatment off protocol, or death from any cause whichever comes first\n-Incidence and severity of AEs, with severity determined according to NCI CTCAE v5.0\n-Exploratory: Depth of MRD by different techniques (flow cytometry, circulating tumor DNA (ctDNA), next-generation sequencing)\n-Exploratory: TruCulture and flow cytometry for immune subsets and function\n-Exploratory: Grading of hematological toxicity according to IWCLL20\n-Exloratory: Disease-related symptoms and health-related quality of life (HRQoL) measured by following questionnaires: EORTC QLQ-C30, EORTC QLQCLL17 and PRO-CTCAE","definition_or_measurement_approach":"Depth of MRD: measured in bone marrow (BM) and peripheral blood (PB) at specified cycles; ORR defined per IWCLL 2018 criteria; PFS/EFS/OS/TFI defined as time-to-event endpoints as specified; AEs graded per NCI CTCAE v5.0; exploratory MRD techniques include flow cytometry, ctDNA, NGS; QoL measured by EORTC QLQ-C30, QLQ-CLL17 and PRO-CTCAE; immune assessments via TruCulture and flow cytometry; hematological toxicity graded per IWCLL criteria."}

Other endpoints

• {"endpoint_text":"-Exploratory: Depth of MRD by different techniques (flow cytometry, circulating tumor DNA (ctDNA), next-generation sequencing)\n-Exploratory: TruCulture and flow cytometry for immune subsets and function\n-Exploratory: Grading of hematological toxicity according to IWCLL20\n-Exloratory: Disease-related symptoms and health-related quality of life (HRQoL) measured by following questionnaires: EORTC QLQ-C30, EORTC QLQCLL17 and PRO-CTCAE","definition_or_measurement_approach":"Exploratory MRD assessed by multiple techniques (flow cytometry, ctDNA, NGS); immune function by TruCulture and flow cytometry; hematological toxicity graded per IWCLL; HRQoL/symptoms measured by EORTC QLQ-C30, QLQ-CLL17 and PRO-CTCAE."}

Netherlands

Earliest CTIS Part Ii Submission Date

01-11-2024

Latest Decision Or Authorization Date

16-11-2025

Processing Time Days

380

Number Of Sites

17

Number Of Participants

49

Belgium

Earliest CTIS Part Ii Submission Date

01-11-2024

Latest Decision Or Authorization Date

07-11-2025

Processing Time Days

371

Number Of Sites

2

Number Of Participants

5

Denmark

Earliest CTIS Part Ii Submission Date

01-11-2024

Latest Decision Or Authorization Date

06-11-2025

Processing Time Days

370

Number Of Sites

1

Number Of Participants

6

Primary sponsor

Full Name

Haemato Oncology Foundation For Adults Netherlands

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

Netherlands

Third parties

• {"country":"Netherlands","full_name":"Amsterdam UMC Stichting","duties_or_roles":"MRD, biomarker and immunological studies","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Belgium","full_name":"Clinigen Clinical Supplies Management","duties_or_roles":"packaging, storage and distribution of trial medication","organisation_type":"Pharmaceutical company"}