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Clinical picture: CLL (Chronical Lymfatic Leukemia)
Trial: HOVON-associated GLOW study
2. Patient eligibility criteria
3. Registration (& randomization) of patients
4. Participating parties
5. Participating sites
6. Instruction videos
7. Download documentation / forms
A Study of the Combination of Ibrutinib Plus Venetoclax Versus Chlorambucil Plus Obinutuzumab for the First-line Treatment of Participants With Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL).
NL10001 Van Kampen - Zuyderland Sittard
NL10003 Posthuma - RdG Delft
NL10004 Veldhuis - Antonius Sneek
NL10005 Beeker - Spaarne Hoofddorp
NL10006 Droogendijk - ETZ Tilburg
NL10007 Kater - AMC A'dam
NL10008 Levin - ASZ Dordrecht
NL10009 te Boome - MC Haaglanden Den Haag
NL10010 Terpstra - OLVG A'dam
NL10012 De Heer -Flevo ZH Almere
NL10013 Nijziel -Catharina ZH Eindhoven
BE10001 Bron - Jules Bordet
BE10002 Janssens - UZ Leuven
BE10003 Offner - UZ Gent
BE10004 Buvé - Jessa Ziekenhuis
BE10005 Wu - ZNA Stuivenberg
Type of study
Prospective randomized Phase III study
Limited site selection
Echelon level specification
see list above
Type of monitoring for this study
Target number of patients
Date of activation
Primary endpoint: To compare the PFS of Ibrutinib + venetoclax with that of Obinutuzumab + Chloorambucil
- To compare the MRD-negative remission rate of I+VEN with that of G-Clb
- To compare the ORR and CR rate of I+VEN with that of G-Clb
- To determine the response duration
- To compare OS of I+VEN with that of G-Clb
- To compare time-to-next treatment of I+VEN with that of G-Clb
- To compare patient-reported health status and fatigue of I+VEN with that of G-Clb
- To evaluate the safety profile of I+VEN in subjects with previously untreated CLL
- To compare hematologic improvement of I+VEN with that of G-Clb
- To evaluate the trough levels of ibrutinib and venetoclax when given in combination
- To examine molecular and protein markers associated with response to and relapse following
2. Patient eligibility criteria
1. Adult subjects who are:
a. ≥65 years old or,
b. 18 to 64 years old and have at least 1 of the following:
1) Cumulative Illness Rating Scale (CIRS) score > 6 (see Attachment 2)
2) Creatinine clearance (CrCl) estimated <70 mL/min using Cockcroft-Gault equation
2. Diagnosis of CLL or SLL that meets iwCLL criteria.
3. Active CLL/SLL requiring treatment per the iwCLL criteria.
a. Evidence of progressive marrow failure as manifested by the development of, or
worsening of, anemia or thrombocytopenia or both;
b. Massive (ie, at least 6 cm below the left costal margin) or progressive or symptomatic splenomegaly;
c. Massive nodes (ie, at least 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy;
d. Progressive lymphocytosis with an increase of more than 50% over a 2-month period or lymphocyte doubling time of less than six months;
e. Constitutional symptoms, defined as 1 or more of the following:
1) Unintentional weight loss ≥10% within the previous 6 months prior to the start of
2) Significant fatigue (inability to work or perform usual activities);
3) Fevers higher than 100.5°F or 38.0°C for 2 or more weeks without evidence of
4) Night sweats for more than 1 month without evidence of infection.
4. Measurable nodal disease (by computed tomography [CT]), defined as at least one lymph node >1.5 cm in longest diameter.
5. ECOG Performance Status Grade ≤2.
6. Adequate organ function defined as follows:
a. Absolute neutrophil count (ANC) ≥750 cells/μL independent of growth factor support;
b. Platelets ≥50,000 cells/μL independent of transfusion support for at least 7 days prior to randomization;
c. Hemoglobin >8.0 g/dL independent of transfusion support for at least 7 days prior to randomization;
d. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0 x upper limit of normal (ULN);
e. Total bilirubin ≤1.5 x ULN (unless due to Gilbert’s syndrome);
f. Estimated CrCl ≥30 mL/min (Cockcroft-Gault equation).
7. Prothrombin time /international normalized ratio (INR) <1.5 x ULN and PTT (activated partial thromboplastin time [aPTT]) <1.5 x ULN (unless abnormalities are unrelated to coagulopathy or bleeding disorder).
8. Woman of childbearing potential must have a negative, highly sensitive serum (ß-human chorionic gonadotropin [ß-hCG]) or urine pregnancy test at screening.
9. Women of childbearing potential must be practicing a highly effective, preferably userindependent method of birth control (failure rate of <1% per year when used consistently and correctly) during treatment with any drug in this study and for up to 1 month after the last dose of venetoclax, 3 months after last dose of ibrutinib, 6 months after the last dose of chlorambucil, and 18 months after last dose of obinutuzumab, consistent with local regulations regarding the use of birth control methods for subject participating in clinical studies. Women using hormonal contraceptives should add a barrier method.
Examples of highly effective methods of contraception are located in Attachment 3, Contraceptive and Barrier Guidance and Collection of Pregnancy Information.
10. Women must agree not to donate eggs for the purpose of assisted reproduction during treatment and for 3 months after the last dose of ibrutinib and 1 month after the last dose of venetoclax, 6 months after the last dose of chlorambucil, and 18 months after last dose of obinutuzumab.
11. During treatment and for a minimum of 1 spermatogenesis cycle (defined as 90 days) after receiving the last dose of any study treatment, in addition to the user-independent highly effective method of contraception, a man a. who is sexually active with a woman of childbearing potential must agree to use a barrier method of contraception (eg, condom with spermicidal
b. who is sexually active with a woman who is pregnant must use a condom
c. must agree not to donate sperm for the purpose of reproduction
12. Must sign an informed consent form (ICF) indicating that he or she understands the purpose of, and the procedures required for, the study. Subjects must be willing and able to adhere to the prohibitions and restrictions specified in this protocol.
Any potential subject who meets any of the following criteria will be excluded from participating in the study:
1. Prior anti-leukemic therapy for CLL or SLL.
2. Presence of del17p or known TP53 mutation detected at a threshold of >10% variable allele frequency (VAF).
3. Major surgery within 4 weeks of first dose of study treatment. For definition of major surgery, see Section 4.3 or contact the medical monitor.
4. Known bleeding disorders (eg, von Willebrand’s disease or hemophilia).
5. Central nervous system (CNS) involvement or suspected Richter’s syndrome.
6. An individual organ/system impairment score of 4 as assessed by CIRS, except for the eyes, ears, nose, throat, and larynx system, limiting the ability to receive treatment in this study.
7. Uncontrolled autoimmune hemolytic anemia or autoimmune thrombocytopenia (Coombs positivity in the absence of hemolysis is not an exclusion).
8. Chronic use of corticosteroids more than 20 mg/day of prednisone or its equivalent within 7 days of initiation of study treatment.
9. History of prior malignancy, except:
a. Malignancy treated with curative intent and with no known active disease present for ≥24 months before randomization;
b. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease;
c. Adequately treated cervical carcinoma in situ without evidence of disease;
d. Malignancy, which is considered cured with minimal risk of recurrence.
10. Received live, attenuated vaccine within 4 weeks of randomization.
11. History of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, or hepatic condition that in the opinion of the investigator would adversely affect a subject’s participation in the study.
12. Currently active, clinically significant Child-Pugh Class B or C hepatic impairment according to the Child Pugh classification (see Attachment 4 Child-Pugh classification)
13. Uncontrolled active systemic infection or any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator’s opinion, could compromise the subject’s safety or put the study outcomes at undue risk.
14. Inability or difficulty swallowing capsules/tablets, malabsorption syndrome, or any disease or medical condition significantly affecting gastrointestinal function.
15. Stroke or intracranial hemorrhage within 6 months prior to randomization.
16. Active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomization.
17. Anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon) or ongoing treatment with agents known to be strong cytochrome (CYP) P450 3A inhibitors.
18. Positive test for HIV by history or at screening.
19. 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.
20. Known allergy to either xanthine oxidase inhibitors or rasburicase
21. Female subjects who are pregnant, breastfeeding, or planning to become pregnant while enrolled in this study or up to 1 month after the last dose of venetoclax, 3 months of last dose of ibrutinib, 6 months after the last dose of chlorambucil, or 18 months after last dose of obinutuzumab.
22. Male subjects who plan to father a child while enrolled in this study or within 90 days after the last dose of any study treatment.
23. Known hereditary galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption.
24. Any contraindication to one of the study medications including hypersensitivity to the active substance or to any of the excipients of ibrutinib, venetoclax, obinutuzumab or chlorambucil.