DCLLSG Studienzentrale CLL2P Protokoll Version CLL2P protocol of the German CLL Study Group (GCLLSG)

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1 2. Protocol Synopsis Title A phase I/II safety and efficacy trial of a combination of bendamustine, rituximab and lenalidomide (BRL) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and a phase II efficacy trial for patients with previously untreated CLL. Short Title Director of clinical investigation Coordinating Investigator Coordinating Physician CLL2P protocol of the German CLL Study Group (GCLLSG) Prof. Dr. C.-M. Wendtner, Cologne / Munich Dr. Kirsten Fischer, Cologne Dr. Natali Pflug, Dr. Christian Maurer, Cologne Rationale Two investigator-initiated phase II studies have demonstrated that lenalidomide is active in relapsed and refractory CLL (Chanan-Khan et al., 2006; Ferrajoli et al., 2007). In heavily pre-treated patients an overall response rate ranging between 34 and 58% was achieved. An international trial has meanwhile defined safety and efficacy of a stepwise dose escalation schedule of lenalidomide monotherapy in patients with relapsed or refractory CLL (CC-5013-CLL-001, Wendtner C.-M. et al., 2011). As to its mechanism of action lenalidomide seems to work rather by immunomodulation than by a direct anti-proliferative activity against CLL cells. Lenalidomide stimulates T- and NK-cells (Hernandez-Ilizaliturri et al., 2005), modulates the tumour microenvironment in CLL and inhibits bone marrow angiogenesis (Reddy et al 2006). There is a rationale to combine lenalidomide with the α-cd20 mab rituximab because lenalidomide enhances NK cell mediated ADCC (antibody dependent cytotoxicity) of rituximab treated NHL cells (Wu et al., ASH 2006). On the other hand, there is increasing evidence that the combination of chemotherapy (fludarabine plus cyclophosphamide, FC) and rituximab results in highest response rates and longest progression-free survivals in treatment naive and relapsed CLL patients (Wierda et al., 2005, Hallek et al. 2010, Robak et al., 2010). Besides FCR the combination of bendamustine, a hybrid alkylating agent with properties of a purine-analogue, with rituximab (BR) seems to be very active in relapsed and treatment-naïve CLL patients based on results of a phase II trial of the GCLLSG (Fischer et. al., 2011; Fischer et al., ASH 2009). Preliminary results with lenalidomide showed a promising response rate of 32% including high risk patients (Ferrajoli et al., 2008). Thus, the combination of BR with lenalidomide may improve the therapeutic activity in both patients with relapsed/refractory disease and previously untreated CLL-patients by combining two immunomodulatory agents with a classic cytotoxic principle. Page 11 of 91

2 Study Objective and Endpoints Primary endpoints: Phase I for patients with relapsed/refractory CLL: - dose-limiting toxicity (DLT) and - maximal tolerable dose (MTD) of BRL DLT, which will be evaluated on day 28 of each cycle or previously if occurred until the respective target dose level of lenalidomide is reached, is defined as: - absolute neutrophil count (ANC) <500/μl for 14 consecutive days or more which is related to study therapy - febrile neutropenia (fever >38,5 C and ANC <500/μl) which is persistent even after adequate i.v. antibiotic therapy - platelet count <20.000/μl which is persistent for 14 consecutive days or more - grade 4 tumor flare reaction - Desquamating (blistering) rash - grade 4 non-desquamating rash - grade 4 non-hematologic toxicity with the following exceptions: nausea/vomiting in the absence of appropriate antiemetic therapy alopecia diarrhoea in the absence of optimal antidiarrheals venous thromboembolic events are not considered to be DLTs as long as anticoagulant therapy can be administered The occurence of a DLT results in definitive interruption of study treatment with BRL regardless of relapsed/refractory or previously untreated CLL. In case of an absolute neutrophil count (ANC) <500/μl for 7 consecutive days or more the use of G-CSF is recommended. If the neutrophil count has recovered to 1000/μl on day 1 of the following cycle dose escalation can be continued as per treatment plan at the discretion of the treating physician. In those cases prophylaxis with G-CSF should be continued during the following cycles. If the ANC was <1000/µl before therapy, the patient is not evaluable for toxicity referable to the ANC and therefore an ANC <500/µl cannot be considered a DLT. If the platelet count was <20.000/µl before therapy the patient is not evaluable for toxicity referable to the platelet count and therefore a platelet count <20.000/µl cannot be considered a DLT. Phase II for relapsed/refractory CLL and previously untreated CLL: Page 12 of 91

3 - Overall response rate (ORR) Secondary endpoints: - Response rate (including molecular responses) - Safety assessment - Progression-free survival - Overall survival Inclusion Criteria 1. Signed written informed consent years of age or older. 3. Medically fit patients without relevant comorbidity, defined as total CIRS score WHO performance status of Confirmed diagnosis of CLL in need of treatment (Binet C or A/B with active disease) according to the updated IWCLL guidelines (Hallek et al. 2008). Previously untreated patients with need of treatment according to the IWCLL guidelines Patients with relapsed or refractory disease after at least one, but no more than 3 prior regimens. Patients who previously received bendamustine (with or without rituximab) must have had at least a partial response with duration of response of at least six months. 6. Life expectancy > 12 weeks for relapsed/refractory CLL/ > 6 months for previously untreated CLL. 7. CLL therapy, major surgery, or irradiation for CLL was completed > 4 weeks before registration in this study. Patients must have recovered from the acute side effects incurred as a result of previous therapy. 8. Patient is able and willing to receive adequate anticoagulation as specified in this protocol. 9. Adequate liver function as indicated by a total bilirubin, AST, and ALT 2 the institutional ULN value, unless directly attributable to the patient s tumor. 10. Creatinine clearance >60ml/min calculated according to the modified formula of Cockcroft and Gault or directly measured after 24h-urine collection. 11. ANC > 1500/µl and platelet count > /μl, unless decrease is due to bone marrow involvement of CLL 12. Negative serological hepatitis B test, negative testing of hepatitis C Page 13 of 91

4 RNA, negative HIV test within 6 weeks prior to registration. 13. Females of childbearing potential (FCBP) 1 must: Have two negative medically supervised pregnancy tests prior to starting of study therapy. She must agree to ongoing pregnancy testing during the course of the study, and after end of study therapy. This applies even if the subject practices complete and continued sexual abstinence. Either commit to continued abstinence from heterosexual intercourse (which must be reviewed on a monthly basis) or agree to use, and be able to comply with, two reliable forms of effective contraception simultaneously to achieve a PEARL- Index <1 without interruption 28 days prior to starting study drug, during the study therapy (including dose interruptions), and for 28 days after discontinuation of study therapy. Highly effective methods: Intrauterine device (IUD) Hormonal (birth control pills, injections, implants) Tubal ligation Partner s vasectomy Additional effective methods: male condom Diaphragm Cervical Cap Male subjects must agree to use a condom during sexual contact with FCBP, even if they have had a vasectomy, throughout study drug therapy, during any dose interruption and after cessation of study therapy agree not to donate semen during study drug therapy and for at least 28 days after end of study drug therapy All subjects must Have an understanding that the study drug could have a potential teratogenic risk agree to abstain from donating blood while taking study drug therapy and for one week following discontinuation of study drug therapy agree not to share any study drugs with another person and to return all unused study drugs to the investigator or pharmacist Be counseled about pregnancy precautions and risks of fetal exposure Exclusion Criteria 1. Previously treated with > 3 prior regimens for CLL. 2. In case of first line treatment: any prior CLL specific-chemotherapy and/or radiotherapy and/or immunotherapy (except for prednisolone treatment administered due to very high lymphocytic 1 This protocol defines a female of childbearing potential as a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). Page 14 of 91

5 counts starting not earlier than 10 days before first study treatment). 3. Known central nervous system (CNS) involvement of CLL. 4. Patients who have progressed with more aggressive B-cell cancers such as Richter s syndrome or are diagnosed with B-PLL. 5. History of anaphylaxis following exposure to any of the used studydrugs and/or thalidomide. 6. Evidence of TLS per the Cairo-Bishop definition of laboratory TLS (subjects may be enrolled upon correction of electrolyte abnormalities). 7. Participation in another clinical trial and/or use of investigational agents or concurrent anti cancer treatment within the last 4 weeks of registration. 8. Other severe, concurrent diseases, including tuberculosis, mental disorders, serious cardiac functional capacity (class III or IV as defined by the New York Heart Association Classification), severe diabetes, severe hypertension, pulmonary disease (COPD with hypoxemia), or major organ malfunction that could interfere with the patient s ability to participate in the study. 9. Pregnant or lactating women. 10. Any circumstance at the time of study entry that would preclude completion of the study or the required follow-up. 11. Active secondary malignancy requiring treatment within the last 5 years before registration. 12. Active bacterial, viral or fungal infection. 13. Medical condition requiring prolonged use of oral corticosteroids (> 1 month). 14. Cerebral dysfunction, legal incapacity. 15. Patients with contraindications according to Summary of Product Characteristics or Investigator s Brochure. 16. Patients who are employees of the Sponsor (University of Cologne) or the study sites. 17. Persons placed in an institution by legal or official order. Study Design This is a prospective, multicenter, open label, non-randomized, phase I/IIstudy to define safety and efficacy of BRL combination in both relapsed/refractory patients and previously untreated patients with CLL. Study duration Start of recruitment: q1/2011 Relapsed/refractory CLL: End of recruitment: q4/2014 End of study: 2 years after end of treatment of last patient Page 15 of 91

6 Previously untreated CLL: Start of recruitment: q2/2012 End of recruitment: q4/2014 End of study: 2 years after end of treatment of last patient Number of Patients Relapsed/refractory CLL: A maximum of 34 eligible patients will be enrolled in the study. Previously untreated CLL: 30 eligible patients will be enrolled in the study Study Drug administration Treatment plan: 1.Relapsed/refractory CLL Up to 6 cycles (each 28 days) of the following regimen with intra-individual and inter-individual dose escalation of lenalidomide: Dose level 1 50 mg/m 2 i.v., d1+2 Bendamustine Lenalidomide Rituximab (q4wks) 2 50 mg/m 2 i.v., d mg/m 2 i.v., d mg/m 2 i.v., d1+2 Cycle 1-6: 2,5 mg p.o., d1-28 2,5 mg p.o., d mg p.o., d1-28 2,5 mg p.o., d1-28 Cycle 2: 5 mg p.o., d1-28 Cycle 3-6: 10 mg p.o., d1-28 2,5 mg p.o., d1-28 Cycle 2: 5 mg p.o., d1-28 Cycle 3: 10 mg p.o., d1-28 Cycle 4-6: 15 mg p.o., d mg/m 2 i.v., d1+2 MTD (Maximal tolerable dose) Safety section - dose modification plan: - 3 pts per dose level, 4 dose levels (lenalidomide 2,5; 5; 10 and 15 mg per day) Page 16 of 91

7 - in case of DLT in 1 out of 3 pts, repeat dose level with 3 additional pts - in case of 2 or more DLTs at one dose level, MTD has been reached at the prior (recommended phase II/III) dose level - dose escalation is only allowed if DLT in 0 out of 3 or in max. 1 out of 6 pts is observed - dose escalation is stopped and MTD determination eventually omitted in case of unexpected high efficacy, i.e. if elimination of MRD occurs in 3/3 or 5/6 pts on a dose level (measured in bone marrow at final staging) - to achieve a total number of 16 patients at the MTD dose level, additional patients will eventually be treated (phase II) 2. Previously untreated CLL Cycle1 Cycle2 Cycle3 Cycle4 Cycle 5 Cycle 6 Bendamustine (day 1-2) 90 mg/m 2 Rituximab cycle 1:day 0 / cycle 2-6: day1 Lenalidomide Cycle 1-2: day 8-28/ Cycle 3-6: day mg/m 2 mg/m 2 mg/m 2 mg/m 2 mg/m 2 mg/m 2 5 mg 10 mg 15 mg 15 mg 15 mg 15 mg Concomitant medication for both first-line and relapsed/ refractory disease Premedication: - Antihistamines - Paracetamol/ Acetaminophen - Prednisolone - Allopurinol (stop 24 h before administration of bendamustine and reinitiate only 24 h after last dose of bendamustine for each cycle) Prophylaxis: - Antimycotic and antibiotic prophylaxis if clinically indicated - Anticoagulation with ASA 100 mg daily. If ASA is contraindicated use of low molecular weight heparin or warfarin is recommended. - NSAIDs, corticosteroids, narcotic analgesics in case of tumor flare syndrome (TFS) Study Drug Supplies Lenalidomide and Bendamustine will be supplied for all patients by the pharmaceutical companies. Commercially available preparations of Rituximab will be used. Page 17 of 91

8 Statistics Analysis plan: Sample Size Relapsed/refractory CLL: The number of cases for phase II is planned according to the two-stage optimal design of Simon for phase 2 studies. With type I error of 10% to conclude the efficacy of an uninteresting regimen (response rate 50%) and a type II error of 10% implying the rejection of an active regimen (response rate 80%), it will be necessary to recruit 7 patients for the first stage of the phase II of the trial. If there are only 3 or fewer responses observed during that first stage, the study will be terminated. If 4 responses or more are observed, 9 additional patients will be recruited. If, by the end of the second stage, 11 or more responses are observed in the 16 patients, then the regimen efficacy hypothesis will be confirmed. Sample Size Previously untreated CLL: The number of cases is planned according to the two-stage optimal design of Simon for phase 2 studies. With type I error of 10% to conclude the efficacy of an uninteresting regimen (response rate 70%) and a type II error of 10% implying the rejection of an active regimen (response rate 90%), it will be necessary to recruit 9 patients for the first stage of the trial. If there are only 6 or fewer responses observed during that first stage, the study will be terminated. If 7 responses or more are observed, 19 additional patients will be recruited. If, by the end of the second stage, 23 or more responses are observed in the 28 patients, then the regimen efficacy hypothesis will be confirmed. Analysis plan: The safety analysis will be performed on the basis of all patients, who have received at least one dose of study treatment (safety population). The efficacy analysis will be based on all patients with at least one dose of study treatment and a response assessment, even before cycle 3 (efficacy population). Sample size calculation for phase II will be based on the efficacy population. The per protocol population is defined as all patients with at least 3 cycles of treatment and an interim staging. All safety and efficacy analysis will be repeated on the per protocol population. Toxicity and response rates are calculated, providing confidence intervals. In case of comparison between patients subgroups, these rates will be analyzed by Fisher s exact test, X2 test or Mantel-Haenszel test (or trend test according to Cochran/Armitage), respectively. Event related data (survival, time to progression) will be estimated by the product limit method by Kaplan and Meier (1958). Prognostic subgroups will eventually be compared using the log rank test. Page 18 of 91