| 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 |
|
| 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 | 100000004864 |
|
| 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 the efficacy of 6 cycles ibrutinib/obinutuzumab in converting patients who are not in CR or who have detectable MRD on combination ibrutinib and venetoclax in uMRD (BM) CR |
|
| E.2.2 | Secondary objectives of the trial |
- To explore the kinetics of CLL clearance on protocol and in follow up within the different compartments (PB, BM, LN) by regular test methods (MRD, PET -CT and BM)
- To measure the conventional response and outcomes of the combination ibrutinib/venetoclax and intensification with ibrutinib/obinutuzumab
- To evaluate prognostic parameters for response on ibrutinib/venetoclax and intensification with ibrutinib/obinutuzumab
- To evaluate safety of ibrutinib/venetoclax and intensification with ibrutinib/obinutuzumab
Exploratory
- To explore kinetics of CLL clearance on protocol and in follow up within different compartments (PB, BM, LN) by novel test methods (MRD, PET -CT, fine needle aspiration (FNA) of LN)
- To evaluate the impact on immunity (e.g. expression of CD20 and CXCR4/CD5) of ibrutinib/venetoclax and intensification with ibrutinib/obinutuzumab
- To evaluate quality of life (QoL) during and after ibrutinib/venetoclax and intensification with ibrutinib/obinutuzumab
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Documented CLL or SLL requiring treatment according to IWCLL criteria, including minimal required markers (CD5/CD19/CD23 triple positive with light chain restriction);
• WHO performance status 0-3 stage 3 only if attributable to CLL/SLL;
• No prior treatment for CLL/SLL;
• Age at least 18 years;
• Adequate BM function defined as:
- Hb > 5 mmol/l or Hb > 8 g/dL
- Absolute neutrophil count (ANC) ≥ 0.75 x 109/L or 750/μL
- Platelet count ≥ 50 x 109/L or 50,000 /μL
Unless directly attributable to CLL/SLL infiltration of the BM, proven by BM biopsy;
• Estimated Glomerular Filtration Rate (eGFR) (MDRD) or estimated creatinine clearance (CrCl) ≥ 30 l/min (Cockcroft-Gault );
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 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 (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 hepatitis B core antibody, hepatitis B surface antigen, or hepatitis C antibody must have a negative PCR result before enrollment. Those who are PCR positive will be excluded;
• Ability and willingness 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 |
• Transformation of CLL (Richter’s transformation);
• Malignancies other than CLL/SLL currently requiring systemic therapy or not being treated incurative intention before or showing signs of progression after curative treatment;
• Patient with CNS involvement
• Known allergy to xanthine oxidase inhibitors and/or rasburicase;
• Intolerance of exogenous protein administration;
• History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies. Known sensitivity or allergy to murine products;
• Active fungal, bacterial, and/or viral infection that requires systemic therapy;
• 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 or anticoagulant therapy with warfarin or phenoprocoumon or other vitamin K antagonists;
• 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) (CTCAE grade III-IV);
• Severe pulmonary dysfunction (CTCAE grade III-IV);
• Patient with Child Pugh C
• Severe neurological or psychiatric disease (CTCAE grade III-IV);
• Vaccination with live vaccines within 28 days prior to registration;
• Use of any other experimental drug or therapy within 28 days prior to 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 of 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, and/or (2) willing to use a highly effective contraceptive method such as oral contraceptives, intrauterine device, sexual abstinence or barrier method of contraception in conjunction with spermicidal jelly during study treatment and in female patients for 3 months after end of induction treatment and 18 months after end of treatment with obinutuzumab and male patients for 6 months after end of treatment ;
• Current participation in other clinical trial;
• Any psychological, familial, sociological and geographical condition potentially hampering
compliance with the study protocol and follow-up schedule.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| • BM uMRD CR 3 months after end of intensification with ibrutinib/obinutuzumab in patients who were not in CR or who had detectable MRD on combination ibrutinib and venetoclax |
|
| 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) |
• BM uMRD CR 9 months after registration 2 in all subjects
• Best BM MRD level during on protocol
• MRD level in BM and PB at different time points on protocol and in follow up
• Best response by IWCLL on protocol
• Response by IWCLL at different time points
• Response by Deauville criteria on PET scan at different time points
• Progression free survival (PFS), defined as time from registration 1 and from registration 2 to progression or death from any cause, whichever comes first
• Event free survival (EFS), defined as time from registration 1 and from registration 2 to start new CLL treatment, progression or death, whichever comes first
• Overall survival (OS), defined as time from registration 1 and from registration 2 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
• Predictive value of prognostic markers at diagnosis on uMRD and ORR by IWCLL and Deauville criteria at end of ibrutinib/venetoclax and ibrutinib/obinutuzumab
• CTCAE grade ≥2 toxicities
• IWCLL hematological grade ≥ 2 toxicities
Exploratory endpoints
• MRD level in BM and PB at different time points on protocol and in follow up by novel techniques
• Quantification of lesions on 18F-FDG PET-CT at different time points
• Amount of CLL cells in LN biopsy and FNA
• Immune cell subsets and function at different time points
• QoL at different time points on protocol and in follow up
|
|
| 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
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 22 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 26 |
| 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 | 7 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
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