| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Lymphocytic Leukemia |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic Lymphocytic Leukemia |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10009310 |
| E.1.2 | Term | CLL |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| - To evaluate efficacy of acalabrutinib/venetoclax (AV) in terms of undetectable minimal residual disease (uMRD) response in bone marrow (BM) after 26 cycles of treatment in patients with CLL previously treated with venetoclax and anti-CD20 mAb |
|
| E.2.2 | Secondary objectives of the trial |
Secondary Objectives
• To evaluate the efficacy of AV.
• To evaluate the safety and tolerability of AV.
Exploratory
• To evaluate prognostic parameters for efficacy
• To evaluate value of different techniques for MRD testing.
• To evaluate the impact on immunological function of AV.
• To evaluate grading for hematological toxicity. according to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) by assessing lab values.
• To evaluate quality of life (QoL) with AV.
• To asses impact on venetoclax pharmacokinetics (PK) in combination with acalabrutinib
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|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Documented CLL or SLL requiring treatment according to IWCLL criteria 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;
• WHO/ECOG performance status 0-3, stage 3 only if attributable to CLL
• Age at least 18 years;
• 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;
• Estimated Glomerular Filtration Rate (eGFR) (MDRD) or estimated creatinine clearance (CrCl ≥ 30ml/min (Cockcroft-Gault appendix E);
Please note: in case eGFR or CrCl is <50ml/min the patient needs to be considered high risk for TLS
• 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);
• Prothrombin time (PT)/International normal ratio (INR) <1.5 x ULN and activated partial thromboplastin time (aPTT) <1.5 x ULN;
• 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;
Please note: For patients positive for anti-HBc HBV-DNA PCR has to be repeated every month until 12 months after last dose of study treatment.
• Patient is able and willing to adhere to the study visit schedule and other protocol requirements;
• Patient is capable of giving informed consent;
• Written informed consent.
|
|
| E.4 | Principal exclusion criteria |
• Any prior therapy with BTK inhibitor;
• Prior treatment with venetoclax other than first line;
• Other therapy with exception of chemo-/immunotherapy which is allowed also after venetoclax first line relapse;
• Transformation of CLL (Richter’s transformation);
• Patient with a history of confirmed progressive multifocal leukoencephalopathy (PML);
• Malignancies other than CLL currently requiring systemic therapy or not treated in
curative intention or showing signs of progression after curative treatment;
• Known allergy to xanthine oxidase inhibitors and/or rasburicase;
• History of drug-specific hypersensitivity or anaphylaxis to any study drug (including active product or excipient components);
• Active bleeding or history of bleeding diathesis (e.g. hemophilia or von Willebrand disease);
• Active fungal, bacterial, and/or viral infection that requires systemic therapy;
Please note: active controlled as well as chronic/recurrent infections are at risk of reactivation/infection during treatment;
• Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled: infection, auto-immune hemolysis, immune thrombocytopenia, diabetes, hypertension, hyperthyroidism or hypothyroidism etc.);
• Patient known to be HIV-positive;
• Patient requiring treatment with a strong cytochrome P450 (CYP) 3A inhibitor/inducer or anticoagulant therapy with warfarin or phenoprocoumon or other vitamin K
antagonists;
Please note: Patients being treated with DOACs apixaban, edoxaban or rivaroxaban can be included, but must be properly informed about the potential risk of bleeding under treatment with acalabrutinib.
• History of stroke or intracranial hemorrhage within 6 months prior to registration;
• Severe cardiovascular disease (arrhythmias requiring chronic treatment, congestive
heart failure or symptomatic ischemic heart disease, myocardial infarction within 6 months) (CTCAE grade III-IV);
• Severe pulmonary dysfunction (CTCAE grade III-IV);
• Severe neurological or psychiatric disease (CTCAE grade III-IV);
• Patient who has difficulty with or are unable to swallow oral medication, or have significant gastrointestinal disease that would limit absorption of oral medication;
• Vaccination with live vaccines within 28 days prior to registration;
• Use of any other experimental drug or therapy within 28 days of registration;
• Major surgery within 28 days prior to registration;
• 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;
• Pregnant women and nursing mothers;
• 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;
• Current participation in other clinical trial (other than follow up HOVON139/HOVON140);
• Any psychological, familial, sociological and geographical condition potentially hampering
compliance with the study protocol and follow-up schedule.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| • uMRD in bone marrow (BM) by flow cytometry after 26 cycles |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| When relevant data of all patients are available and validated |
|
| E.5.2 | Secondary end point(s) |
• Depth of MRD measured in BM after cycle 13 and 26.
• Depth of MRD measured in PB after cycle 8, 10, 13, 16, 19, 22, 26 and every 3-6 months thereafter.
• 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 criteria19.
• Progression free survival (PFS), defined as time from registration to the first occurrence of disease progression or death from any cause (whichever occurs first).
• Event free survival (EFS), defined as time from registration to date start of first CLL treatment off protocol, progression or death, whichever comes first.
• Overall survival (OS), defined as the time from registration to death from any cause.
• 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.
• Incidence and severity of AEs, with severity determined according to NCI CTCAE v5.0.
Exploratory
• Depth of MRD by different techniques (flow cytometry, circulating tumor DNA (ctDNA), next-generation sequencing).
• TruCulture and flow cytometry for immune subsets and function.
• Grading of hematological toxicity according to IWCLL20.
• Disease-related symptoms and health-related quality of life (HRQoL) measured by following questionnaires: EORTC QLQ-C30, EORTC QLQ-CLL17 and PRO-CTCAE.
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|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| When relevant data of all patients are available and validated |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 12 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 12 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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