CLL13 trial of the GCLLSG/GAIA trial Page 4 of 111

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1 CLL13 trial of the GCLLSG/GAIA trial Page 4 of 111 II. Synopsis Sponsor: Global Principal Investigator and medical contact of the sponsor: Coordinating Physician: Head of the GCLLSG: Participating countries: Title of the clinical trial: Indication: Type of trial, trial design, methodology: Number of patients: Number of sites: Trial objective: Albertus-Magnus-Platz, Cologne, Germany Represented by: PD Dr. med. Barbara Eichhorst (GPI, LKP) PD Dr. med. Barbara Eichhorst Department I of Internal Medicine, Cologne University Hospital Kerpener Strasse Cologne, Germany Dr. med. Julia von Tresckow Department I of Internal Medicine, Cologne University Hospital Kerpener Strasse Cologne, Germany Prof. Dr. med. Michael Hallek Department I of Internal Medicine, Cologne University Hospital Kerpener Strasse Cologne, Germany Germany, Austria, Switzerland, Netherlands, Belgium, Denmark, Sweden, Norway, Finland A phase 3 multicenter, randomized, prospective, open-label trial of standard chemoimmunotherapy (FCR/BR) versus rituximab plus venetoclax (RVe) versus obinutuzumab (GA101) plus venetoclax (GVe) versus obinutuzumab plus ibrutinib plus venetoclax (GIVe) in fit patients with previously untreated chronic lymphocytic leukemia (CLL) without del(17p) or TP53 mutation Fit patients (defined by a cumulative illness rating scale (CIRS) score 6 and a normal creatinine clearance 70ml/min) with previously untreated CLL without del(17p) or TP53 mutation requiring treatment Phase-III trial, prospective, multicenter, open-label, randomized Approximately 920 eligible patients Screening population: A failure-rate of approximately 20% by screening is assumed patients are estimated to be screened for the study. Approximately 160 (80 GCLLSG/Austria, 27 Nordic Group, 38 HOVON, 15 SAKK) The primary objective of the study is to evaluate the efficacy of obinutuzumab (GA101) plus venetoclax (GVe) versus standard chemoimmunotherapy (BR/FCR) [concerning MRD negativity measured by flow cytometry in peripheral blood (PB) at month 15] and obinutuzumab plus ibrutinib plus venetoclax (GIVe) versus standard chemoimmunotherapy (BR/FCR) [concerning progression free survival (PFS)] in previously untreated, fit CLL patients without del(17p) or TP53 mutation. Secondary objectives of the study are the evaluation of the efficacy of rituximab

2 CLL13 trial of the GCLLSG/GAIA trial Page 5 of 111 plus venetoclax (RVe) versus standard chemoimmunotherapy (BR/FCR), GVe and GIVe [concerning MRD negativity measured by flow cytometry in PB at month 15 and PFS]. Rationale: Study endpoints: Chemoimmunotherapy is the standard of care in first-line treatment of CLL patients without del17p or TP 53 mutation; physically fit patients are treated with fludarabine, cyclophosphamide and rituximab (FCR) 1. Due to the high risk of severe neutropenias and infections with FCR, bendamustine and rituximab (BR) must be considered in patients aged >65 years 2. However, these conventional chemoimmunotherapies are associated with side effects caused by the rather unspecific mode of action of the chemotherapy. Therefore, there is an urgent need for alternatives, especially chemotherapy-free regimens. In first line treatment of elderly patients with CLL and coexisting conditions, the anti-cd20-antibody obinutuzumab is the new standard therapy. In the CLL11 trial the combination of obinutuzumab with chlorambucil proved to be safe and lead to markedly improved response rates as well as PFS times in comparison to chlorambucil alone or combined with rituximab 3. The BCL2 antagonist venetoclax (GDC-0199/ABT-199) showed striking activity with tumor lysis syndrome as dose limiting toxicity 4,5 in patients with relapsed and refractory CLL. 400 mg venetoclax was determined to be a safe and efficacious dose. Several patients treated with the combination of venetoclax and rituximab in relapsed refractory CLL even achieved MRD negativity 6. The FDA approved Venetoclax for the treatment of relapsed CLL with 17p/TP53 on 12 th April Therefore, venetoclax plus CD20-antibody based combinations have the potential to induce higher rates of MRD negativity in frontline therapy of CLL and concomitantly induce lower rates of toxicities so that chemotherapy might be replaced. Furthermore, venetoclax and obinutuzumab demonstrated synergistic activity in a preclinical study of a murine Non-Hodgkin lymphoma xenograft model 1, and additive activity in a CLL lymph node model 7. The combination appears tolerable in the firstline treatment of CLL patients with coexisting conditions 8 whilst the toxicity profile of both drugs compares favorably to those of the chemotherapies currently used in the treatment of CLL. Consequently, it should be tested if rituximab can be replaced by obinutuzumab in combination with venetoclax in this trial. Ibrutinib, a selective, irreversible small molecular inhibitor of Bruton s Tyrosine Kinase (BTK), showed excellent responses and a safe toxicity profile 9,10, even in combination with BR. Ibrutinib is approved for treatment of relapsed CLL as well as frontline therapy of CLL by the FDA and EMA (April 29 th 2016). The combination of ibrutinib and venetoclax showed synergy in primary CLL cells 11. Consequently, the aim of the current trial is to evaluate if chemoimmunotherapy in the frontline treatment of physically fit patients in CLL can be replaced by combinations of these targeted drugs with anti-cd20-antibodies, which may induce extremely long lasting remissions. Co- primary endpoints: Negativity rate of minimal residual disease (MRD) in peripheral blood 1 ) communication by the pharmaceutical company F. Hoffmann-LaRoche

3 CLL13 trial of the GCLLSG/GAIA trial Page 6 of 111 Criteria for evaluation: (PB) measured by flow cytometry at month (MO) 15 for the comparison [GVe versus standard chemoimmunotherapy (SCIT)]. Progression free survival (PFS) for the comparison [GIVe versus SCIT] Secondary endpoints: MRD levels in PB at MO 15 (all other comparisons except for [GVe versus SCIT]) MRD levels in PB at different time points (MO 2, 9 and 13; MRD at later time points might be evaluated according to the discretion of the treating physician at local laboratories) MRD levels measured in bone marrow (BM) at final restaging (RE, 2 month after the end of last treatment cycle) PFS (all other comparisons except for [GIVe versus SCIT]) Overall response rate (ORR) [MO 3, 9, 13, 15] (Clinical) CR / CRi rate [Interim staging [IST], cycle 9 day 1 (or final restaging (RE) for patients in the SCIT arm), IR (or three month after RE for patients in the SCIT arm respectively) and MO 15] (with regard to best response achieved) Event-free survival (EFS) Overall survival (OS) Duration of response in patients with: o complete response (CR) or CR with incomplete recovery of the bone marrow (CRi), o partial response (PR) Time to next CLL treatment Safety parameters: Type, frequency, and severity of o adverse events (AEs) and o adverse events of special interest (AESI) and their relationship to study treatment Health-related quality of life and compliance by MARS and EORTC QLQ- C30 and QLQ-CLL16 questionnaires Exploratory evaluations of potential associations between biomarkers and subject characteristics or outcome measures Exploratory endpoints: Evaluation of relationship between various baseline markers and clinical outcome parameters Correlation between MRD in BM and PB Correlation between MRD in BM and PFS/EFS/OS Correlation between MRD in PB and PFS/EFS/OS Comparison of the outcome between FCR and BR Efficacy: Lymph nodes, spleen and liver measurements by physical examination Computed tomography (CT) or Magnetic Resonance Imaging (MRI) scans at final restaging and additionally if clinically indicated Ultrasound of abdomen for measurement of enlarged lymph nodes (if clinically indicated) Complete blood count (CBC)

4 CLL13 trial of the GCLLSG/GAIA trial Page 7 of 111 Assessment of minimal residual disease (MRD) in peripheral blood at month 1, 2, 9, 13 and 15 using flow cytometry Bone marrow aspirate/biopsy for standard histopathology and MRD assessment at final restaging (RE) by flow cytometry Survival status Survey of start and type of next treatment for CLL Safety: Clinical laboratory evaluations Concomitant medications AEs by NCI CTCAE Version 4 HBV-DNA PCR every month in patients with positive anti-hbc test at screening until at least twelve (12) months after the last treatment cycle pregnancy testing for all women of childbearing potential Accompanying research: Additional blood draw at baseline and on cycle 2 day 1 as well as the time point of relapse (for intracellular staining for Mcl-1/Bcl-XL and other tests including MRD for MRD kinetics) Baseline marker: Physical examination Peripheral blood count/serum Chemistry Peripheral blood samples for central testing of immunophenotyping (for confirmation of CLL diagnosis), serum parameters (beta-2-microglobulin and thymidine kinase), karyotyping, cytogenetics (FISH), TP53 and IGHV mutational status and genome sequencing CT scan or MRI of chest and abdomen (for evaluation of bulky disease and risk assessment for tumor-lysis-syndrome with venetoclax) Assessment of constitutional symptoms ECOG Performance Status / Disease-related B-symptoms Assessment of comorbidity burden by CIRS-Score Health-related quality of life by EORTC QLQ-C30 and QLQ-CLL16 questionnaires Bone marrow aspirate/biopsy (if clinically indicated to prove association with CLL infiltration) Height / Weight / BSA HIV/HBV/HCV test Pregnancy Test Target Population: Patients must meet the following criteria: Inclusion Criteria: 1. Documented CLL requiring treatment according to iwcll criteria Age at least 18 years. 3. Life expectancy 6 months. 4. Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements. 5. Adequate bone marrow function indicated by a platelet count >30

5 CLL13 trial of the GCLLSG/GAIA trial Page 8 of 111 x10^9/l (unless directly attributable to CLL infiltration of the bone marrow, proven by bone marrow biopsy) 6. Creatinine clearance 70ml/min directly measured with 24hr urine collection or calculated according to the modified formula of Cockcroft and Gault (for men: GFR ((140 - age) x bodyweight) / (72 x creatinine), for women x 0, 85). Dehydrated patients with an estimated creatinine clearance less than 70 ml/min may be eligible if a repeat estimate after adequate hydration is > 70 ml/min. 7. Adequate liver function as indicated by a total bilirubin 2 x, AST/ALT 2.5 x the institutional ULN value, unless directly attributable to the patient s CLL or to Gilbert s Syndrome. 8. Negative serological testing for hepatitis B (HBsAg negative and anti- HBc negative; patients positive for anti-hbc may be included if PCR for HBV DNA is negative and HBV-DNA PCR is performed every month until 12 months after last treatment cycle), negative testing for hepatitis C RNA within 6 weeks prior to registration. 9. Eastern Cooperative Oncology Group Performance Status (ECOG) performance status 0-2. Exclusion criteria: 1. Any prior CLL-specific therapies (except corticosteroid treatment administered due to necessary immediate intervention; within the last 10 days before start of study treatment, only dose equivalents of 20 mg prednisolone are permitted). 2. Transformation of CLL (Richter transformation). 3. Decompensated hemolysis, defined as ongoing hemoglobin drop in spite of three more concurrent treatments being administered for hemolysis 4. Detected del(17p) or TP53 mutation. 5. Patients with a history of PML. 6. Any comorbidity or organ system impairment rated with a single CIRS (cumulative illness rating scale) score of 4 (excluding the eyes/ears/nose/throat/larynx organ system), a total CIRS score of more than 6 or any other life-threatening illness, medical condition or organ system dysfunction that, in the investigator s opinion, could comprise the patients safety or interfere with the absorption or metabolism of the study drugs (e.g, inability to swallow tablets or impaired resorption in the gastrointestinal tract). 7. Urinary outflow obstruction. 8. Malignancies other than CLL currently requiring systemic therapies, not being treated in curative intention before (unless the malignant disease is in a stable remission due to the discretion of the treating physician) or showing signs of progression after curative treatment. 9. Uncontrolled or active infection. 10. Patients with known infection with human immunodeficiency virus (HIV). 11. Requirement of therapy with strong CYP3A4 and CYP3A5 inhibitors/inducers.

6 CLL13 trial of the GCLLSG/GAIA trial Page 9 of Anticoagulant therapy with warfarin or phenoprocoumon, (rotation to alternative anticoagulation is allowed, but note that patients being treated with NOAKs can be included, but must be properly informed about the potential risk of bleeding under treatment with ibrutinib). 13. History of stroke or intracranial hemorrhage within 6 months prior to registration. 14. Use of investigational agents which might interfere with the study drug within 28 days prior to registration. 15. Vaccination with live vaccines 28 days prior to registration. 16. Major surgery less than 30 days before start of treatment. 17. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies, known sensitivity or allergy to murine products. 18. Known hypersensitivity to any active substance or to any of the excipients of one of the drugs used in the trial. 19. Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of treatment; further pregnancy testing will be performed regularly). 20. Fertile men or women of childbearing potential unless: a. surgically sterile or 2 years after the onset of menopause b. willing to use two methods of reliable contraception including one highly effective contraceptive method (Pearl Index <1) and one additional effective (barrier) method during study treatment and for 18 months after the end of study treatment. 21. Legal incapacity. 22. Prisoners or subjects who are institutionalized by regulatory or court order. 23. Persons who are in dependence to the sponsor or an investigator.

7 CLL13 trial of the GCLLSG/GAIA trial Page 10 of 111 Screening and Randomization: Risk stratification: The investigator assumes the responsibility of obtaining written informed consent for each patient before any study-specific procedures are performed. A central medical review of the screening CRF pages and the results of the baseline assessments in the central laboratories will be performed by GCLLSG study physicians for verification of the eligibility of the patient, especially for confirmation of CLL and exclusion of del(17p) or TP53mut. Approval of enrollment by the GCLLSG central study office is mandatory before randomization and initiation of study treatment. Additionally, the GCLLSG study office will notify the sites if a patient is potentially at increased risk for development of TLS based on the baseline assessments. Randomization has to occur within 42 days after registration. Patients will be randomly assigned to treatment groups through 1:1:1:1 randomization process with stratification according to Binet stage, age (with a cut-off of 65 years), and region (study group). Treatment has to start within 14 days after randomization. In the chemoimmunotherapy arm patients below the age of 65 years and including 65 years will be treated with FCR; above the age of 65 years, patients will be treated with BR. Patients with presence of TP53 del/mut in central screening should be treated within another study protocol, if possible (e.g. the German CLL2-GIVe study with obinutuzumab, ibrutinib and venetoclax). Names of investigational medicinal products (IMPs): - Fludarabine (F) - Cyclophosphamide (C) - Bendamustine (B) - Rituximab (R) - Venetoclax (Ven, ABT-199/GDC-0199) - Obinutuzumab (G, GA101, Gazyvaro ) - Ibrutinib (I, Imbruvica )

8 CLL13 trial of the GCLLSG/GAIA trial Page 11 of 111 Treatment schedule: Investigational medicinal product dosage and method of administration: Standard chemoimmunotherapy (SCIT) FCR Patients 65 years will receive 6 cycles of fludarabine, cyclophosphamide and rituximab, each cycle with a duration of 28 days. Fludarabine will be given intravenously on days 1-3 (cycle 1-6) at a dosage of 25 mg/m 2. Cyclophosphamide i.v. will be given on days 1-3 (cycle 1-6) at a dosage of 250 mg/m². Rituximab will be administered intravenously before the application of chemotherapy at a dosage of 375 mg/m 2 in the first cycle and at a dosage of 500 mg/m 2 in cycles 2-6 with premedication according to clinical practice of the participating sites. BR Patients > 65 years will receive 6 cycles of bendamustine and rituximab, each cycle with a duration of 28 days. Bendamustine will be given on days 1 and 2 (cycle 1-6) at a dosage of 90 mg/m 2. Rituximab will be administered intravenously before the application of chemotherapy at a dosage of 375 mg/m 2 in the first cycle and at a dosage of 500 mg/m 2 in cycles 2-6 with premedication according to the clinical practice of the

9 CLL13 trial of the GCLLSG/GAIA trial Page 12 of 111 participating sites. Rituximab plus venetoclax (RVe) The RVe treatment consists of 12 cycles, each with a duration of 28 days. Rituximab will be administered intravenously on day one; at a dosage of 375 mg/m² in the first cycle and at a dose of 500 mg/m² in cycles 2-6. The continuous daily administration with a slow dose escalation of venetoclax starts on day 22 of the first cycle. Venetoclax p.o.: Cycle 1: Days 22-28: venetoclax 20 mg (2 tabl. at 10 mg) Cycle 2 Days 1-7: venetoclax 50 mg (1 tabl. at 50 mg) Days 8-14: Days 15-21: venetoclax 100 mg (1 tabl. at 100 mg) venetoclax 200 mg (2 tabl. at 100 mg) Days 22-28: venetoclax 400 mg (4 tabl. at 100 mg) Cycles 3-12: Days 1-28: venetoclax 400 mg (4 tabl. at 100 mg) Due to the risk of adverse events, especially tumor-lysis-syndromes (TLS), the dose of venetoclax will be increased slowly every week until the final dose of 400 mg is reached (ramp-up). In order to diagnose a TLS at an early stage the following safety measures must be followed: 1.) Oral hydration (>2 l over 24 hours) should be maintained during the ramp up period and increased at the initiation of venetoclax and every ramp-up dose, especially in patients at increased risk for TLS. 2.) Prophylaxis with IV hydration and uric acid reducing agents (e.g. rasburicase or allopurinol) should be administered to patients at increased risk for developing TLS or with elevated pre-treatment uric acid levels. Allopurinol should be started 2-3 days prior to the first dose of venetoclax and continued through the ramp-up phase as clinically indicated. 3.) Overnight hospitalization is recommended for patients at increased risk of TLS (high tumor burden (e.g., any lymph node with a diameter 5 cm or high absolute lymphocyte count [ALC 25 x 109/L]), splenomegaly, renal dysfunction (CrCl < 80 ml/min), the presence of pretreatment clinical chemistry abnormalities, or the presence of other comorbidities) in order to allow more intensive prophylaxis and monitoring through the first 24 hours after initiating treatment with venetoclax. 4.) Laboratory assessments are required on the first day of each dose level (i.e. 20 mg, 50 mg, 100 mg, 200 mg and 400 mg venetoclax) predose as well as 6-8 and 24 hours post-dose. Pre-existing electrolyte abnormalities should be corrected before initiation of treatment. Dosing at home will be assessed in the first 50 patients who are not at an increased risk for development of TLS enrolled in the trial. They will receive the dose escalations to 100, 200 and 400 mg at home and their compliance will be assessed. If the compliance was deemed to be good the dosing at home will be extended to all patients who are not at an increased risk for development of TLS treated in this proto-

10 CLL13 trial of the GCLLSG/GAIA trial Page 13 of 111 col. All patients receiving the venetoclax dose at home will have a mandatory pre-dose laboratory assessment within 24 hours prior to dosing (results must be reviewed prior to dosing) and an additional laboratory assessment up to 2 hours after intake (as soon as the patients arrives at hospital/outpatient department) that will serve as baseline for later laboratory results. If the compliance among the first 50 patients is satisfying for all patients without increased TLS risk at home dosing with 20 mg and 50 mg will be possible as well. On days with administration of both, venetoclax and rituximab, oral intake of venetoclax will be followed by intravenous administration of rituximab. Patients will be advised how to administer venetoclax at home (also on days with intravenous administration of rituximab). Obinutuzumab plus venetoclax (GVe) The GVe treatment consists of 12 cycles, each with a duration of 28 days. During the first cycle obinutuzumab is administered intravenously on days 1 (and 2), 8 and 15 as well as on day 1 of cycles 2-6. Obinutuzumab i.v. infusion: Cycle 1: Day 1: obinutuzumab 100 mg Day 1 (or 2): Day 8: Day 15: obinutuzumab 900 mg obinutuzumab 1000 mg obinutuzumab 1000 mg Cycles 2-6: Day 1: obinutuzumab1000 mg The first infusion of obinutuzumab may be administered at the full dose (1000 mg) on day 1 of the first cycle if the infusion of a test-dosage of 100mg is well tolerated by the patient. Alternatively, if the first 100 mg infusion on day 1 is not tolerated well, the remaining 900 mg of the first dose should be administered on day 2. The continuous daily administration with a slow dose escalation of venetoclax starts on day 22 in cycle one. Venetoclax p.o.: Cycle 1: Days 22-28: venetoclax 20 mg (2 tabl. at 10 mg) Cycle 2 Days 1-7: venetoclax 50 mg (1 tabl. at 50 mg) Days 8-14: Days: 15-21: Days 22-28: venetoclax 100 mg (1 tabl. at 100 mg) venetoclax 200 mg (2 tabl. at 100 mg) venetoclax 400 mg (4 tabl. at 100 mg) Cycles 3-12: Days 1-28: venetoclax 400 mg (4 tabl. at 100 mg) Due to the risk of adverse events, especially tumor-lysis-syndromes (TLS), the dose of venetoclax will be increased slowly every week until the final dose of 400 mg is reached (ramp-up). In order to diagnose a TLS at an early stage the

11 CLL13 trial of the GCLLSG/GAIA trial Page 14 of 111 following safety measures must be followed: 1.) Oral hydration (>2 l over 24 hours) should be maintained during the ramp up period and increased at the initiation of venetoclax and every ramp-up dose, especially in patients at increased risk for TLS. 2.) Prophylaxis with IV hydration and uric acid reducing agents (e.g. rasburicase or allopurinol) should be administered to patients at increased risk for developing TLS or with elevated pre-treatment uric acid levels. Allopurinol should be started 2-3 days prior to the first dose of venetoclax and continued through the ramp-up phase as clinically indicated. 3.) Overnight hospitalization is recommended for patients at increased risk of TLS (high tumor burden (e.g., any lymph node with a diameter 5 cm or high absolute lymphocyte count [ALC 25 x 109/L]), splenomegaly, renal dysfunction (CrCl < 80 ml/min), the presence of pretreatment clinical chemistry abnormalities, or the presence of other comorbidities) in order to allow more intensive prophylaxis and monitoring through the first 24 hours after initiating treatment with venetoclax. 4.) Laboratory assessments are required on the first day of each dose level (i.e. 20 mg, 50 mg, 100 mg, 200 mg and 400 mg venetoclax) predose as well as 6-8 and 24 hours post-dose. Pre-existing electrolyte abnormalities should be corrected before initiation of treatment. Dosing at home will be assessed in the first 50 patients who are not at an increased risk for development of TLS enrolled in the trial. They will receive the dose escalations to 100, 200 and 400 mg at home and their compliance will be assessed. If the compliance was deemed to be good the dosing at home will be extended to all patients who are not at an increased risk for development of TLS treated in this protocol. All patients receiving the venetoclax dose at home will have a mandatory pre-dose laboratory assessment within 24 hours prior to dosing (results must be reviewed prior to dosing) and an additional laboratory assessment up to 2 hours after intake (as soon as the patients arrives at hospital/outpatient department) that will serve as baseline for later laboratory results. If the compliance among the first 50 patients is satisfying for all patients without increased TLS risk at home dosing with 20 mg and 50 mg will be possible as well. On days with administration of both, venetoclax and obinutuzumab, oral intake of venetoclax will be followed by intravenous administration of obinutuzumab. Patients will be advised how to administer venetoclax at home (also on days with intravenous administration of obinutuzumab). Obinutuzumab plus ibrutinib plus venetoclax (GIVe) The GIVe treatment consists of 12 cycles, each with a duration of 28 days; during the first cycle obinutuzumab is administered intravenously on days 1 (and 2), 8 and 15 as well as on day 1 of cycles 2-6. Obinutuzumab i.v. infusion: Cycles 1: Day 1: obinutuzumab 100 mg Day 1 (or 2): Day 8: obinutuzumab 900 mg obinutuzumab 1000 mg

12 CLL13 trial of the GCLLSG/GAIA trial Page 15 of 111 Day 15: obinutuzumab 1000 mg Cycles 2-6: Day 1: obinutuzumab 1000 mg The first infusion of obinutuzumab may be administered at the full dose (1000 mg) on day 1 of the first cycle if the infusion of a test-dosage of 100 mg is well tolerated by the patient. Alternatively, if the first 100 mg infusion on day 1 is not tolerated well, the remaining 900 mg of the first dose should be administered on day 2. Ibrutinib will be administered as a daily oral dosage of 420 mg starting on cycle 1 day 1 until: MRD negativity (i.e. < 10-4 ) in peripheral blood and confirmed by a bone marrow aspirate 2 months later or by two consecutive peripheral blood samples (cycle 9/12 or 12/15; all other patients will continue treatment) or 36 months of treatment are reached or start of new anti-cll therapy or progression of CLL or unacceptable toxicity, whatever occurs first. Ibrutinib p.o.: Cycles 1-12: Days 1-28 Cycles 13-36: Days 1-28 ibrutinib 420 mg daily ibrutinib 420 mg daily The continuous daily administration with a slow dose escalation of venetoclax starts on day 22 of the first cycle. Venetoclax p.o.: Cycle 1: Days 22-28: venetoclax 20 mg (2 tabl. at 10 mg) Cycle 2 Days 1-7: venetoclax 50 mg (1 tabl. at 50 mg) Days 8-14: venetoclax 100 mg (1 tabl. at 100 mg) Days: 15-21: venetoclax 200 mg (2 tabl. at 100 mg) Days 22-28: venetoclax 400 mg (4 tabl. at 100 mg) Cycles 3-12: Days 1-28: venetoclax 400 mg (4 tabl. at 100 mg) Due to the risk of adverse events, especially tumor-lysis-syndromes (TLS), the dose of venetoclax will be increased slowly every week until the final dose of 400 mg is reached (ramp-up). In order to diagnose a TLS at an early stage the following safety measures must be followed: 1.) Oral hydration (>2 l over 24 hours) should be maintained during the ramp up period and increased at the initiation of venetoclax and every ramp-up dose, especially in patients at increased risk for TLS. 2.) Prophylaxis with IV hydration and uric acid reducing agents (e.g. rasburicase or allopurinol) should be administered to patients at increased risk for developing TLS or with elevated pre-treatment uric ac-

13 CLL13 trial of the GCLLSG/GAIA trial Page 16 of 111 id levels. Allopurinol should be started 2-3 days prior to the first dose of venetoclax and continued through the ramp-up phase as clinically indicated. 3.) Overnight hospitalization is recommended for patients at increased risk of TLS (high tumor burden (e.g., any lymph node with a diameter 5 cm or high absolute lymphocyte count [ALC 25 x 109/L]), splenomegaly, renal dysfunction (CrCl < 80 ml/min), the presence of pretreatment clinical chemistry abnormalities, or the presence of other comorbidities) in order to allow more intensive prophylaxis and monitoring through the first 24 hours after initiating treatment with venetoclax. 4.) Laboratory assessments are required on the first day of each dose level (i.e. 20 mg, 50 mg, 100 mg, 200 mg and 400 mg venetoclax) predose as well as 6-8 and 24 hours post-dose. Pre-existing electrolyte abnormalities should be corrected before initiation of treatment. Dosing at home will be assessed in the first 50 patients who are not at an increased risk for development of TLS enrolled in the trial. They will receive the dose escalations to 100, 200 and 400 mg at home and their compliance will be assessed. If the compliance was deemed to be good the dosing at home will be extended to all patients who are not at an increased risk for development of TLS treated in this protocol. All patients receiving the venetoclax dose at home will have a mandatory pre-dose laboratory assessment within 24 hours prior to dosing (results must be reviewed prior to dosing) and an additional laboratory assessment up to 2 hours after intake (as soon as the patients arrives at hospital/outpatient department) that will serve as baseline for later laboratory results. If the compliance among the first 50 patients is satisfying for all patients without increased TLS risk at home dosing with 20 mg and 50 mg will be possible as well. On days with administration of more than one study drug, oral intake of ibrutinib (before breakfast) will be followed by oral intake of venetoclax (after breakfast), at least intravenous administration of obinutuzumab will take place if applicable. Patients will be advised how to administer the study drugs at home (also on days with intravenous administration of obinutuzumab). Duration of treatment: Patients randomized for standard chemoimmunotherapy (SCIT) will receive 6 cycles of bendamustine or fludarabine/cyclophosphamide plus rituximab, each with a duration of 28 days unless the administration is delayed. Rituximab or obinutuzumab in combination with venetoclax will be administered for 6 cycles, followed by 6 additional cycles venetoclax alone (each cycle with a duration of 28 days). Accordingly, obinutuzumab in combination with ibrutinib and venetoclax will be administered for 6 cycles, followed by 6 additional cycles venetoclax plus ibrutinib (each cycle with a duration of 28 days). The oral intake of ibrutinib will be continued for a maximum of 36 months or until MRD negativity (in peripheral blood and confirmed by a bone marrow aspirate 3 months later or by two consecutive peripheral blood samples 3 months apart), start of new anti-cll therapy or inacceptable toxicity, whatever occurs first.

14 CLL13 trial of the GCLLSG/GAIA trial Page 17 of 111 All patients will be followed until the end of the clinical trial. This will take place once 213 PFS events are observed what will take place approximately 73 months after first patient has been randomized (FPI). Long-term follow up following the end of the study: Stopping rules: To be able to collect long term follow up data until patient`s death after the end of the CLL13 study, inclusion in a country specific registry (e.g. the register of the German CLL study group (GCLLSG), the Dutch Pharos registry or registry of the Nordic countries) is strongly recommended. For this purpose, each patient will be informed about the importance of long term follow-up data and asked for his/her consent to the long term follow-up within an appropriate registry. For patients with a written informed consent for the registry, data for overall survival, late toxicities such as secondary malignancies, further treatments and the course of the disease will be collected. Patients from countries where no country-specific registry is available can be followed within the ERIC registry. Any decision to prematurely terminate the study as a whole will be made by the sponsor in accordance with the regulatory and ethical principles. During the study, continual monitoring of efficacy and toxicity will be performed by an independent data safety monitoring board (DSMB). Criteria for termination of the study as a whole are: - An unacceptable profile or incidence rate of adverse events/ adverse events of special interest revealed in this or any other study in which at least one of the investigational products of this trial is administered. - Demonstration that the study treatment is ineffective or only insufficiently active. - Significant number of cases of death associated with the study treatment - Any other factor that in the view of the sponsor constitutes an adequate reason for terminating the study as a whole. Statistical methods and study assumptions: Overview This study is designed to assess the superiority of GVe over SCIT with regard to the first primary endpoint MRD negativity rate measured by flow cytometry in peripheral blood (PB) at MO15 as well as the superiority of GIVe over SCIT with regard to the second primary endpoint progression free survival (PFS) in physically fit patients with previously untreated CLL. As for the sequence of the primary analyses, the first primary endpoint MRD negativity rate will be analyzed first followed by the second primary endpoint PFS (see section 13 Statistical methods and sample size calculation). Both co-primary endpoints will be considered as equal, and the interpretation of both endpoint analyses can be made independent from each other. The study consists of three periods: 1) the screening period, 2) the treatment period and 3) the follow-up period. All patients should start the treatment period (cycle 1, day 1 the start of the

15 CLL13 trial of the GCLLSG/GAIA trial Page 18 of 111 treatment period) within 14 days after randomization. Upon completion or in case of early withdrawal of the treatment period all subjects shall then enter the follow-up period. No cross-over between treatment arms will be permitted at any time. Study population definitions Intention-to-Treat (ITT) population: The ITT population is defined as all randomized subjects regardless of whether they received any of the study treatment or not. Subjects will be assigned to treatment groups and analyzed as randomized. The ITT population shall be used for analysis of all study endpoints except safety. Safety population: The Safety population is defined as all subjects enrolled in the study receiving at least one dose of one component of the treatment. The safety population shall be used for evaluating the safety endpoints. Subjects in this population will be analyzed by what they have received (not as originally randomized). Consideration on the standard arm (control; standard chemoimmunotherapy (SCIT)) According to the CLL10 trial of the GCLLSG the population of physically fit CLL patients consists of two subgroups (Fit & 65 years, eligible for receiving FCR; fit & > 65 years, not eligible for FCR). For fit & > 65 years old patients BR is considered as the standard chemoimmunotherapy in the frontline setting. Based on previous study data a mixed control arm for the trial with 50% FCR and 50% BR is assumed. Study assumptions The primary efficacy variables (co-primary endpoints) are the MRD negativity rate in PB at MO 15 and the PFS. With regard to the completely different analysis time-points for MRD negativity rate and PFS, a conservative approach with split alpha into for each testing was anticipated. Therefore, the twosided significance level of 5% will be split equally (2.5% for the comparison of MRD negativity rate in PB at MO 15 [GVe versus SCIT], and 2.5% for the PFS comparison [GIVe versus SCIT]). Thus, both co-primary endpoints will be considered as equal, and the interpretation of both endpoint analyses can be made independent from each other. Accordingly, the inferiority of SCIT compared to a chemo-free regimen can be concluded if at least one null hypothesis is rejected. According to results of the CLL10 study, the extrapolated MRD negativity rate in PB at MO 15 is estimated at 30% for the standard arm consisting of 50% FCR and 50% BR patients. Moreover, estimated median PFS is 48 months. Sample size calculation: The co-primary endpoints MRD negativity rate and median PFS were used to determine the sample size of the study assuming 80% power and two-sided significance level of 5% (split equally 2.5% 2.5% to allow for two co-primary endpoints). The following requirements are given to perform a hypothesis test for clinically

16 CLL13 trial of the GCLLSG/GAIA trial Page 19 of 111 relevant superiority in the co-primary endpoint PFS: Log-rank test at the two-sided significance level Median PFS for SCIT = 48 months 80% power to detect a hazard ratio HR = for the comparison GIVe versus SCIT with median PFS for GIVe increased to 74 months Exponential distribution of PFS One interim analysis for assessing efficacy after 65% of PFS events. PFS will be tested at the significance level determined using the Lan-DeMets alpha spending function with an O`Brien-Fleming boundary so that the overall two-sided type I error rate will be maintained at level. Further, a non-binding futility boundary is included. Based on these assumptions 213 PFS events (defined as a progression of the disease or death from any course) are required for the final PFS analysis. Assuming non-linear accrual of 460 patients [230 patients for SCIT and 230 patients for GIVe] over 33 months, the 213 events will be reached 72 months after first patient has been randomized (FPI). As stated before, the MRD negativity rate in PB at MO 15 for the standard chemoimmunotherapy arm is assumed to be 30%. It is assumed to improve this rate to at least 50% with the GVe regimen resulting in a clinical relevant increase of the absolute percentage difference of at least 20%. With these determined study parameters a two-sided two-sample χ2- test of rates with an overall significance level of α =2.5% will adhere (1 - β) 98.7% power to detect a 20% difference if the total number of patients is 460 [230 patients for SCIT and 230 patients for GVe]. To enable balanced comparisons between all treatment arms, equal recruitment of SCIT, RVe, GVe and GIVe will be considered. The total number of patients to be randomized is therefore 920. Sample size calculations were performed with EAST 6 software. Statistical analysis: Description of study population Background and Demographic Characteristics: Patient`s age, height, weight, and other continuous baseline characteristics will be summarized using descriptive statistics, while gender and other categorical variables will be provided using frequency tabulations. Subject Disposition: Subject disposition (analysis population allocation, entered, discontinued, along with primary reason for discontinuation) will be summarized using frequency and percent for both treatment and follow-up period. Primary efficacy analysis The first co-primary efficacy endpoint is the MRD negativity rate in PB at MO 15. At this specific time point patients will be classified according to their MRD level. The MRD negativity rate in PB at MO 15 is defined as the proportion of MRD negative patients at MO 15 based on the ITT population (= number of MRD negative patients divided by the number of the ITT population). MRD negativity is defined as <1 CLL-cell among 10,000 leukocytes analyzed [0.01%], i.e. < MRD measurement will be based on assessment performed centrally by four-

17 CLL13 trial of the GCLLSG/GAIA trial Page 20 of 111 colour-flow cytometry in the GCLLSG lab in Kiel. According to the ITT principle, all patients without any MRD PB sample at MO 15 will be kept and labelled as non-evaluable' in the analysis. MRD negativity rate of GVe and SCIT will be compared using Cochran-Mantel-Haenszel test. Rates and 97.5% CIs will be reported for each study arm. The first co-primary objective of the study is to compare the following hypothesis: MRD negativity rate in PB at MO 15 of GVe versus SCIT (i.e., H0: GVe = SCIT versus H1: GVe SCIT) The MRD co-primary endpoint will be analyzed as soon as all randomized patients have achieved the landmark 15 MO after randomization. Thus, final MRD analysis will take place as soon as the last patient randomized (LPI) has reached the time point MO 15 and all MRD samples have been analyzed. Giving an estimated 33 months recruitment period, time point of final MRD analysis is projected at month 49. Additionally, comparisons of MRD negativity rate in PB at MO 15 will be performed for other study arms. To account for a control of the 2.5% type I error, other MRD comparisons will be performed according to a hierarchical test sequence. Details will be outlined in the statistical analysis plan. The second co-primary efficacy endpoint is the investigator-assessed PFS, defined as the time from randomization to the first occurrence of progression or relapse (determined using standard IWCLL guidelines [2008]), or death from any cause, whichever occurs first. For patients who have not progressed, relapsed, or died at the time of analysis, PFS will be censored on the date of the last tumor assessment. If no tumor assessments were performed after the baseline visit, PFS will be censored at the time of randomization + 1 day. All patients including patients who discontinue all components of study therapy prior to disease progression (e.g., for toxicity) will continue on study and will be followed for progressive disease and survival regardless of whether or not they subsequently receive new anti-leukemic therapy. The second primary objective of the study is to compare the following hypothesis: Progression-free survival of GIVe versus SCIT (i.e., H0: GIVe = SCIT versus H1: GIVe SCIT) Treatment comparison will be performed using a two-sided stratified log-rank test (at significance level, adjusted for the interim analysis and considering the stratification factors age and Binet stage). If the null hypothesis is rejected and the observed HR is favorable for the GIVe study arm, then it is concluded that GIVe significantly lowers the risk of PFS events as compared to SCIT. A two-sided non-stratified log-rank test will be performed to support the primary analysis. Median PFS and the 97.5% confidence limits will be estimated using Kaplan-Meier survival methodology, with the Kaplan-Meier survival curve presented to provide a visual description. PFS rates for 1, 2 and 3 years etc. after randomization will be reported. Estimates of the treatment effect will

18 CLL13 trial of the GCLLSG/GAIA trial Page 21 of 111 be expressed as hazard ratios including 97.5% confidence limits estimated through a stratified Cox proportional-hazards analysis. Sensitivity analyses utilizing different schemes for censoring will be performed in terms of sensitivity of the primary analysis of PFS and will be described in the statistical analysis plan. At time of final MRD analysis (month 49), it is estimated that the time-point of the PFS interim analysis will be reached (after 65% of the total of 213 PFS events, i.e. 138 PFS events will trigger the interim analysis). PFS comparisons will not be performed for the other study arms at time of PFS interim analysis. In terms of timely completion, the final PFS analysis will be conducted as soon as either 213 PFS occurred (estimated time point = month 72) or 73 months after FPI. At this time point, PFS comparisons for other study arms will be done according to a hierarchical test sequence to account for type I error control. Details will be outlined in the statistical analysis plan. Statistical analysis of other efficacy endpoints: Secondary time-to-event and rate-based endpoints will be analyzed using the same statistical methods described for the primary analyses. Safety analysis Safety parameters will be analyzed on safety population. The recent updated version of NCI Common Terminology Criteria for AEs (NCI-CTCAE) will be used for assessing the severity of AEs. Classifications will be performed using the Medical Dictionary for Regulatory Activities classification system (MedDRA preferred term). Presentations of AEs will include a complete-case and a perpatient analysis. Relative frequencies will be displayed for categorical variables. For continuous variables descriptive statistics including median, mean, minimum, maximum, and standard deviation will be used. Study duration: Expected start of recruitment Expected end of recruitment End of study Q3/2016 Q2/2019 Q3/2022 Statistician: Dr. Dipl.-Math. Jasmin Bahlo Department of Internal Medicine I, Study office GCLLSG,, Kerpener Str. 62, Köln, Germany GCP conformance: The present trial will be conducted in accordance with the valid versions of the trial protocol and the internationally recognized Good Clinical Practice Guidelines (ICH-GCP), including archiving of essential documents.