CLL2-GIVe Page 3 of 115

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1 CLL2-GIVe Page 3 of 115 II. Synopsis Sponsor: Global Principal Investigator: Coordinating Physicians: Title of the clinical trial: Indication: Phase: Type of trial, trial design, methodology: Number of subjects: Rationale: Ulm University, Germany Represented by: Prof. Dr. S. Stilgenbauer (Global Principal Investigator [GPI]) Klinik für Innere Medizin III, Universitätsklinikum Ulm, Albert-Einstein- Allee 23, D Ulm, Germany, Stephan.Stilgenbauer@uniklinikulm.de Prof. Dr. S. Stilgenbauer Dr. Simone Edenhofer / Dr. Henriette Huber / Dr. Julia v. Tresckow A prospective, open-label, multicentre phase-ii trial of ibrutinib plus venetoclax plus obinutuzumab in physically fit (CIRS 6 & normal creatinine clearance) and unfit (CIRS > 6 & creatinine clearance 50 ml/min) patients with previously untreated chronic lymphocytic leukemia (CLL) with TP53 deletion (17p-) and/or mutation Physically fit and unfit patients with TP53 deletion (17p-) and/or mutation and previously untreated CLL requiring therapy Phase-II clinical trial Prospective, open-label, multicentre phase-ii trial Approximately 40 eligible patients Chronic lymphocytic leukemia (CLL) with TP53 deletion (17p-) and/or mutation has a poor prognosis. Different therapeutic strategies have been tested over the last decade such as fludarabine-based regimens, alemtuzumab, bendamustine alone or with rituximab, lenalidomide, or ofatumumab, but all without compelling evidence for success. For example, with the FCR regimen as the standard 1st line treatment for fit CLL patients, only 5% (1 of 22) of patients with 17p deletion had a complete response (CR) and 40% of patients were free of disease progression at 12 months in the CLL8 trial (Hallek et al., 2010, Stilgenbauer et al., 2014). New agents like Bruton s Tyrosin Kinase (BTK) inhibitors such as ibrutinib have shown promising results in patients with relapsed or refractory CLL, however, outcome of CLL patients with 17p deletion is inferior to other subgroups (Byrd et al., 2015). The CLL11 trial revealed an impressive improvement in efficacy with GA-101 (obinutuzumab) as compared to rituximab when combined with

2 CLL2-GIVe Page 4 of 115 chlorambucil (Goede et al., 2014). Moreover, the BCL2 antagonist venetoclax (previously GDC-0199/ABT-199), tested as a single agent in relapsed / refractory CLL patients, showed striking activity with tumor lysis syndrome as dose limiting toxicity (Seymour et al., 2013; Souers et al., 2015; Roberts et al., 2016; Stilgenbauer et al., 2016). Consequently, the current trial will test a combination regimen consisting of obinutuzumab, ibrutinib and venetoclax (the GIVe regimen) as first line treatment in CLL patients with TP53 deletion (17p-) and/or mutation with the aim to demonstrate efficacy in this population at highest unmet medical need. Trial objectives: The primary objective of the study is to evaluate the efficacy of the GIVe regimen in patients with TP53 deletion (17p-) and/or mutation and previously untreated CLL requiring treatment. For this, the CR rate at cycle 15 (d1; final restaging) will be used as primary parameter for efficacy. The CR rate is defined as the proportion of patients having achieved a CR or a CR with incomplete recovery of the bone marrow (CRi) as best response (according to iwcll criteria) until cycle 15 (d1; final restaging) from start of therapy. Efficacy of the regimen will be further assessed by evaluation of the proportion of patients free of disease progression (PD-free rate) after 12 cycles of therapy, overall response rate (ORR), minimal residual disease (MRD) and overall survival as well as other time to event endpoints as outlined below. A further secondary objective of the study is to evaluate the safety of ibrutinib, venetoclax and obinutuzumab. Study endpoints: Primary endpoint: Complete response (CR) rate at cycle 15 (d1; at final restaging) (according to iwcll criteria) Secondary endpoints: Proportion of patients free of disease progression (PD-free rate) after 12 cycles of therapy Overall response rate (ORR) (including all patients achieving a complete response (CR), a complete response with incomplete recovery of the bone marrow (CRi), a partial response (PR) and a PR with lymphocytosis)

3 CLL2-GIVe Page 5 of 115 ORR after end of maintenance treatment MRD levels (measured in peripheral blood after cycle 9, after cycle 12, at the beginning of cycle 15 (d1), at the beginning of cycle 36 (d1), as well as in bone marrow at the beginning of cycle 15) Progression-free survival (PFS) Event-free survival (EFS) Overall survival (OS) Duration of response in patients with (clinical) CR/CRi, PR Treatment-free survival (TFS) and time to next CLL treatment (TTNT) Evaluation of subsequent treatment for CLL (including proportion receiving allogeneic SCT as consolidation or in relapse) including response to treatment Safety parameters: Type, frequency, and severity of adverse events (AEs) and adverse events of special interest (AESI) and their relationship to study treatment Incidence of Richter s transformation Exploratory: Evaluation of relationship between baseline markers and clinical outcome parameters

4 CLL2-GIVe Page 6 of 115 Criteria for evaluation: Efficacy: Assessment of signs and symptoms Lymph nodes, spleen and liver measurements by physical examination Computed tomography (CT) scans Complete blood count (CBC) Peripheral blood samples for immunophenotyping (for confirmation of CLL diagnosis), genetics and assessment of MRD Bone marrow aspirate and biopsy for standard cytology, histology and MRD (for confirmation of CR or unclear cytopenias) Monitoring of minimal residual disease in peripheral blood (after cycle 9 and 12, at cycle 15 and 36) and bone marrow (at cycle 15) Survival status Survey of start and type of next anti-leukemic treatment Safety: Treatment exposure Mortality 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 pregnancy testing for all women of childbearing potential

5 CLL2-GIVe Page 7 of 115 Target Population: Patients must meet the following criteria: Inclusion Criteria 1. Have documented CLL according to iwcll criteria, and measurable disease (lymphocytosis > 5x10 9 with/without measurable lymph nodes and/or organomegaly) assessed by physical exam and/or CT) 2. Subjects must have untreated CLL, i.e. no prior chemotherapy, antibody therapy or non-chemotherapeutic agent (BTK, PI3K, BCL2 inhibitor or similar). Local irradiation or short term (up to 1 month) corticosteroid treatment for autoimmune phenomena are allowed 3. Subjects must have TP53 deletion (17p-) and/or mutation (in bone marrow or peripheral blood), with pre-existing local test results confirmed by central laboratory in Ulm 4. CLL requiring treatment ( active disease ) according to the iwcll criteria 5. ECOG 2 6. Creatinine clearance 50 ml/min calculated according to the modified formula of Cockcroft and Gault or directly measured after 24 h urine collection 7. Adequate liver function as indicated by a total bilirubin 2 x, AST, and ALT 3 x the institutional ULN value, unless directly attributable to the patient s CLL or to Gilbert s Syndome 8. No cardiovascular disability of New York Heart Association (NYHA) Class > 2. Class 2 is defined as comfortabilty at rest but moderate physical activity causes dyspnoea, angina pain or fatigue 9. Adequate bone marrow function (unless directly attributable

6 CLL2-GIVe Page 8 of 115 to CLL, BM examination required): ANC 1000/µl or ANC < 1000/µl, if attributable to the underlying CLL (growth factor support may be administered after screening) Platelets > /µl (unless directly attributable to the underlying CLL) 10. Hemoglobin 8g/dl (unless directly attributable to the underlying CLL) 11. Negative serological testing for hepatitis B (i.e. HBsAg negative and anti-hbc negative, patients positive for anti- HBc may be included if PCR for HBV DNA is negative) negative testing for hepatitis-c RNA and negative HIV test within 6 weeks prior to registration. [Patients who are HBsAg negative/anti-hbc positive with undetectable serum HBV DNA should be monitored closely (every month) for HBV DNA by a real-time PCR quantification assay with a lower limit of detection of the order of 10 WHO IU/mL until at least 24 months after the last treatment cycle with obinutuzumab. If the HBV DNA assay becomes positive, patients should pre-emptively be treated with a nucleoside analogue (i.e. lamivudine) for at least 24 months after the last cycle of therapy with obinutuzumab or be referred to a gastroenterologist for management.] 12. Age at least 18 years 13. Life expectancy 6 months 14. Must be able to adhere to the study visit schedule and other protocol requirements 15. Able and willing to provide written informed consent and to comply with the study protocol procedures

7 CLL2-GIVe Page 9 of 115 Exclusion criteria 1. Transformation of CLL (i.e. Richter s transformation, prolymphocytic leukemia) 2. One or more individual organ / system impairment score of 4 as assessed by the CIRS definition, excluding the Eyes, Ears, Nose, Throat and Larynx organ system 3. Known central nervous system (CNS) involvement 4. Patients with a history of PML 5. Impairment of plasmatic coagulation as indicated by Quick 60% and / or PTT 50 sec. unless due to iatrogenic measure. 6. Active malignancies other than CLL within the past 2 years prior to study entry, with the exception: Adequately treated in situ carcinoma of the cervix uteri Adequately treated basal cell carcinoma or localized squamous cell carcinoma of the skin Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent and in remission at time of screening 7. Use of agents which would interfere with the study drug within 28 days prior to registration 8. Uncontrolled infection requiring systemic treatment 9. History of severe infusion-related reaction to humanized or murine monoclonal antibodies, and/ or known sensitivity or allergy to murine products or allergy to xanthin oxidase and rasburicase or glucose-6-phosphate dehydrogenase deficiency 10. Requires treatment with the following drugs: Within 7 days prior to the first dose of study drug: No

8 CLL2-GIVe Page 10 of 115 steroid therapy higher than 20 mg prednisolone for antineoplastic intent; No CYP3A inhibitors (e.g. fluconazole, ketoconazole, clarithromycin); No potent CYP3A inducers (e.g., rifampin, phenytoin or carbamazepine); Within 3 days prior to the first dose of study drug: Grapefruit or grapefruit products; Seville oranges (including marmalade); Star fruit. 11. History of stroke or intracranial hemorrhage within 6 months prior to registration 12. Pregnant women and nursing mothers 13. Fertile men or women of childbearing potential unless: a. surgically sterile or 2 years after the onset of menopause b. willing to use two highly effective contraceptive methods (Pearl Index <1) during study treatment and for 18 months after end of study treatment. 14. Vaccination with a live vaccine a minimum of 28 days prior to registration 15. Legal incapacity 16. Prisoners or subjects who are institutionalized by regulatory or court order 17. Persons who are in dependence to the sponsor or an investigator

9 CLL2-GIVe Page 11 of 115 Name of investigational medicinal products (IMP): Dose and method of administration: Venetoclax (ABT-199/GDC-0199), ibrutinib, obinutuzumab (GA101) Ibrutinib, obinutuzumab (GA101), venetoclax (ABT-199/GDC-0199) Obinutuzumab (GA101) will be applied intravenously for the first six cycles (28 days) only. During the first cycle obinutuzumab is administered on days 1 (and 2), 8 and 15. During the following cycles, it is administered on day 1. Obinutuzumab i.v.: Cycles 1: Day 1: Obinutuzumab 100 mg Day 1 (or 2): Obinutuzumab 900 mg Day 8: Obinutuzumab 1000 mg Day 15: Obinutuzumab 1000 mg Cycles 2-6: Day 1: Obinutuzumab 1000 mg The first infusion of obinutuzumab (GA101) may be administered at the full dose (1000 mg) on day 1 of the first cycle if the infusion of a testdose 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. Due to the risk of adverse events, especially infusion related reactions (IRRs) and tumor lysis syndromes (TLS), the safety measures described under must be followed. Ibrutinib will be administered in the mornings (before breakfast) at a daily oral dose of 420 mg as continuous therapy starting on day 1 of the first cycle, before the application of obinutuzumab is started. If MRD negativity is found in the analyses performed after cycle 9 and 12 and a complete response according to iwcll criteria could be confirmed, treatment with ibrutinib will be terminated at cycle 15 (study visit final restaging). Ibrutinib will be continued until cycle 36 if not both of the two consecutive tests (after cycle 9 and 12) show MRD negativity or CR cannot be confirmed. The result of MRD assessment at cycle 15 is not a determinant for therapeutic decisions. Venetoclax will be applied orally for the first twelve cycles. Venetoclax (ABT-199/GDC-0199) 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)

10 CLL2-GIVe Page 12 of 115 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 400mg is reached (ramp up). In order to prevent a TLS or diagnose it early, the safety measures described under must be followed. On days with administration of all three study drugs, oral intake of ibrutinib (before breakfast) will be followed by oral intake of venetoclax (during breakfast), at last intravenous administration of obinutuzumab will take place. On days with administration of venetoclax and ibrutinib, oral intake of ibrutinib will be before breakfast and oral intake of venetoclax will be during breakfast. In case of the occurrence of side effects that are possibly caused by the administration of study drugs (e.g. gastrointestinal discomfort), consultation with study office is recommended in order to discuss the further procedure. Patients qualifying for allogeneic stem cell transplantation have the option to stop the study treatment prematurely. Duration of treatment: Study treatment includes six cycles of the combined regimen of all three agents, followed by six cycles of venetoclax and ibrutinib. Beyond this, ibrutinib is continued at least to time point cycle 15 (final restaging). If both of the two MRD analyses, performed after 9 and 12 cycles, show MRD negativity and a complete response according to iwcll criteria has been achieved, ibrutinib is stopped at this time point. Otherwise ibrutinib is continued until cycle 36 within the study and may be continued beyond that (off study) as indefinite therapy at the investigator s discretion with commercially available drug (in-label). Study treatment is stopped in case of progressive disease according to iwcll guidelines or unacceptable AEs. Duration of follow-up: Follow-up visits will take place every three cycles (follow-up 1, 2, 3 etc.). The first follow-up visit will take place three cycles after end of treatment (EOT) is reached. All patients are followed-up until cycle 42. After the last follow-up visit (cycle 42), subjects are considered end of study.

11 CLL2-GIVe Page 13 of 115 Long-term follow-up following the end of the study: Stopping rules: To collect long term follow-up data, each patient will additionally be informed about the importance of long term follow data and asked for his/her consent to the long term follow-up within the GCLLSG 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. Within the non-interventional GCLLSG registry, the observation will be continued after the end of the CLL2-GIVe study. The sponsor has the right to terminate the trial prematurely if there are any relevant medical or ethical concerns, or for reasonable administrative reasons. If such action is taken, the reasons for terminating the trial have to be documented in detail. All trial subjects who are not considered end of study must undergo a final examination which must be documented. 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. The Global Principal Investigator has to be informed without delay if any investigator has ethical concerns. A first safety assessment will be performed after treatment of 6 patients. Safety assessment will be based on an observation period of each patient of at least one cycle (28 days). Thus, the safety assessment will be available one month after recruitment of the sixth patient. The study will continue without adjustment, if the safety profile is deemed favorable as defined by: 1 patient experiencing clinical tumor lysis syndrome despite prophylaxis performed according to protocol 1 patient experiencing neutropenic sepsis related to a study drug < 1 death related to a study drug

12 CLL2-GIVe Page 14 of 115 Otherwise, the safety profile will be reviewed again and the protocol committee verifies the need of a protocol amendment. Thereafter, a close safety assessment every 3 months during the triple drug treatment phase (until the last patient stopped treatment with obinutuzumab) will be performed as described above, followed by safety assessments every 6 months until the end of maintenance therapy of the last patient. Results will be discussed by the coordinating investigator and if necessary by the protocol committee. All deaths during the study, including the post treatment follow up period, will be documented in patients data listings and reviewed to detect unexpected safety signals. Statistical methods and study assumptions: Overview This study is designed to assess the efficacy of the GIVe regimen with regard to the primary endpoint CR rate at cycle 15 (d1; final restaging) in physically fit and unfit patients with previously untreated CLL with TP53 deletion (17p-) and/or mutation. The study consists of three periods: 1) the screening phase, 2) the treatment phase and 3) the follow-up phase. All patients should start the treatment phase (cycle 1, day 1 the start of the treatment phase) within 28 days of entering the screening phase, hence the screening period will last a maximum of 28 days. Upon completion or in case of early withdrawal of the treatment phase all subjects shall then enter the follow-up phase. Study population definitions Full analysis set (FAS): The FAS includes all patients enrolled to the trial who received at least two complete cycles of therapy (efficacy population). The FAS 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 trial treatment, whether withdrawn prematurely or not. The Safety population shall be used for evaluating the safety endpoints.

13 CLL2-GIVe Page 15 of 115 Study assumptions The CR rate is a clinical relevant parameter to evaluate the efficacy of treatment of CLL. In February 2014, ibrutinib has been approved for the therapy of relapsed/refractory CLL; in July 2014 the approval has been expanded for first line treatment of patients carrying a TP53 deletion (17p-) and/or mutation. Several clinical studies have been conducted to determine the efficacy of monotherapy with ibrutinib. The CR rates ranged from 0-23% (Farooqui et al., 2015; O Brien et al., 2014; Byrd et al., 2014 and 2015), including diverse patient subgroups (relapsed/refractory, front-line, with or without 17p deletion). In addition to confined follow-up time, the evaluable data for statistical analyses are limited by low patient numbers. For example, in the largest study on 17p- CLL, Farooqui et al. assessed 48 patients with TP53 aberrations of whom 33 were previously untreated. Based on this limited data set, a 25% CR rate is assumed as a favourable CR rate in 17p- CLL front line treatment with ibrutinib monotherapy. Sample size calculation: The CR rate of an uninteresting regimen is assumed to be P 0 (under the null hypothesis); and the new therapy is considered worthy of further research if we can reject the null hypothesis in favour of the alternative hypothesis, where the CR rate is P 1. In this study, a current (uninteresting) therapy can be associated with a CR rate at cycle 15 (d1; final restaging) of P 0=25%, and the GIVe-combination is considered potentially useful if it can increase the CR rate to at least P 1=50%. The two-sided one-sample binomial test with an overall significance level of α=5% provides the sample size n=36, such that statistical significance is achieved with a power of 90%. Including an expected drop-out rate of 10%, a total of 40 analyzable patients are required for this study. The following table describes the minimum number of responders (i.e. having CR/CRi) that are required to warrant further investigation of the new therapy based on different numbers of analyzable patients: NUMBER OF ANALYZABLE PATIENTS MINIMUM NUMBER OF RESPONDERS 35, , 38, , 41, , 44, 45, Sample size calculations were performed with EAST 6 software and validated with the software nquery Advisor.

14 CLL2-GIVe Page 16 of 115 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 primary efficacy endpoint is the CR rate at cycle 15 (d1; final restaging). It is defined as the proportion of patients having achieved a CR or a CR with incomplete recovery of the bone marrow (CRi) as best response (according to the IWCLL guidelines (2008)) until cycle 15 (d1; final restaging) from start of therapy based on the FAS (=number of patients with best response CR/CRi divided by the number of the FAS). Patients without any documented response assessment will be kept and labelled as non-cr/cri in the analysis. The relative frequency of patients having achieved a CR or CRi at cycle 15 including the corresponding 95% Clopper Pearson confidence interval will be reported with respect to the FAS. The primary objective of the study is to compare the null hypothesis H 0: CR rate at cycle 15 with GIVe regimen 25%, whereby P 0=25% denotes the benchmark for ineffectiveness, with the alternative H 1: CR rate at cycle 15 with GIVe regimen 50%. The primary endpoint can be analyzed as soon as all enrolled patients who did not discontinue prematurely have reached the cycle 15 landmark. Statistical analysis of secondary efficacy endpoints Rate based endpoints (PD-free rate, ORR, MRD) shall be assessed showing frequencies and corresponding percentages including 95% Clopper Pearson confidence intervals. Analyses of time to event endpoints will be performed using Kaplan- Meier methods. Kaplan-Meier estimates of median time and rates for 6,

15 CLL2-GIVe Page 17 of , 18 and 24 months after registration will be reported. Comparisons regarding pre-defined subgroups (e.g. gender) will be compared using two-sided non-stratified log-rank tests if applicable. Additionally, hazard ratio calculations with 95%-confidence intervals will be reported if applicable. Safety analysis Safety parameters will be analyzed on the safety population. The 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 per-patient 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: Statistician: Expected start of recruitment Expected end of recruitment Analysis of primary endpoint End of study Final study report Dr. Jasmin Bahlo Study office GCLLSG Department of Internal Medicine I Centre for Integrated Oncology University of Cologne Kerpener Str Köln Germany Q3/2016 Q3/2018 Q4/2019 Q1/2022 Q4/2022 GCP conformance: The present trial will be conducted in accordance with the valid versions of the trial protocol and the internationally recognised Good Clinical Practice Guidelines (ICH-GCP), including archiving of essential documents. 1