Relapsed/refractory (R/R) lymphoma or R/R chronic lymphocytic leukemia (CLL) previously treated with at least one systemic therapy MedDRA version: 20.0 Level: HLT Classification code 10029592 Term: Non-Hodgkin's lymphomas NEC System Organ Class: 100000004851
Conditions
Sponsors
Celgene International II Sàrl
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: ALL TREATMENT ARMS (Arm A is discontinued to enrollment of new subjects) 1. Subject is =18 years of age and =80 years of age at the time of signing the ICF. Subjects >80 years of age may be included if they meet criteria defined in the protocol 2. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted 3. Subject is willing and able to adhere to the study visit schedule and other protocol requirements 4. Subject has histologically confirmed and documented eligible histologies as defined in the protocol 5. Subject has been previously treated with at least one prior systemic chemotherapy, immunotherapy or chemoimmunotherapy 6. Subject with high-risk CLL/SLL is defined by the presence of at least one of the following factors: a. Complex karyotype b. del(17p) abnormality c. Mutated TP53 d. Ibrutinib- or other BTK-inhibitor failure or an inadequate tumor response which is less than partial response e. Relapsed/progressive disease within 6 months of completing their last therapy which may include investigational drug 7. Subject is willing and able to undergo biopsy: a. Subject with lymphoma is willing and able to undergo tumor/lymph node biopsy (incisional/excisional or multiple core needle) o During the Screening Period o Any time during Cycle 2 (strongly recommended) o At the time of disease progression from subjects who have achieved objective response (CR/PR) to study treatment b. Subject with CLL is willing and able to undergo bone marrow biopsy during the Screening and Treatment Periods Material from a fine needle aspiration is not acceptable 8. Subject who has documented active relapsed or refractory disease requiring therapeutic intervention 9. Subject who has measurable disease: a. For subject with lymphoma, bi-dimensionally measurable disease on cross-sectional imaging by computed tomography with at least one nodal or extranodal lesion =2.0cm in its longest dimension Note: A previously irradiated lesion is ineligible to be used as a measurable target lesion b. For subject with CLL, in need of treatment as defined by IWCLL Guidelines for the Diagnosis and Treatment of CLL (Appendix I of protocol) 10. Subject who has performance status of 0, 1, or 2 on the ECOG scale 11. Subject who has life expectancy of greater than 6 months 12. Subject who fulfills the laboratory requirements outlined in Table 6 of the protocol 13. Female subject of childbearing potential who is sexually active with a male must: a. Have 2 negative pregnancy tests as verified by the investigator prior to starting any IP therapy. They must agree to ongoing pregnancy testing during the course of the study, and after the last dose of any IP. This applies even if the subject practices true abstinence from heterosexual contact b. Use effective methods (1 highly effective and 1 additional effective [barrier] method) of contraception from 28 days prior to starting durvalumab and must agree to continue using such precautions while taking durvalumab (including dose interruptions) and for 90 days after the last dose of durvalumab. Cessation of contraception after this point should be discussed with a responsible physician The following are examples of highly effective and additional effective methods of contraception: Highly effective methods (defined as one that results in a low failure rate rate [ie, less than 1% per year] when used consistently and correctly): (i) Intrauterine device (IUD); See Protocol Sec
Exclusion criteria
Exclusion criteria: ALL TREATMENT ARMS (Arm A is discontinued to the enrollment of new subjects) 1. Subject who has known or suspected central nervous system or meningeal involvement by lymphoma 2. Subject who has other lymphoma histologies which are not listed on Table 3, Table 4, or Table 5 of the protocol a. Subject has blastoid variants of MCL or MCL with blastoid transformation. b. Dose Confirmation and/or Expansion Parts only: -Transformed lymphoma or Richter’s transformation -DLBCL histology other than: not otherwise specified or T-cell/histiocyte rich 3. Subject who has any histopathologic finding consistent with myelodysplastic syndrome on bone marrow studies 4. Subject who has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study. 5. Subject who has any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study 6. Subject who has any condition that confounds the ability to interpret data from the study 7. Subject who has any uncontrolled inter-current illness as defined in the protocol 8. Subject who is concurrently enrolled in another clinical study, unless in a follow-up period or it is an observational study 9. Subject who has any concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy for cancer treatment 10. Subject who has received: a. Any systemic antilymphoma/leukemia therapy, or hematopoietic growth factors, blood or platelets transfusions within 14 days prior to the first dose of IP (ie, Cycle 1 Day 1) and/or b. Any radioimmunotherapy within 3 months prior to the first dose of IP (ie, Cycle 1 Day 1) 11. Subject who has unresolved toxicities from prior anticancer therapy, defined as having not resolved to NCI CTCAE v4.03 = Grade 1 with the exception of alopecia and laboratory values listed per the exclusion criteria. Subjects with irreversible toxicity that is not reasonably expected to be exacerbated by durvalumab or other investigational treatments may be included (eg, hearing loss) after consultation with the sponsor’s medical monitor 12. Subject who received any prior mAb against PD-1 or PD-L1 and/or any prior: a. Arm A only: IMiDs (eg, lenalidomide, thalidomide) b. Arm B only: ibrutinib or other BTK inhibitor c. Arm C only: bendamustine (except dose level 1) 13. Subject who has history of organ transplant or allogeneic hematopoietic stem cell transplantation 14. Subject who has taken corticosteroids during the last week prior to the first dose of IP (ie, Cycle 1 Day 1), unless administered at a dose equivalent to = 10 mg/day prednisone. See Protocol for exceptions 15. Subject who has received live, attenuated vaccine within 30 days prior to the first dose of durvalumab. (Note: Subjects, if enrolled, should not receive live vaccine during the study and for 12 months after last dose of rituximab or until recovery of B-cells and for 120 days after the last dose of durvalumab, whichever is longer) 16. Subject who has undergone major surgical procedure (as defined by the investigator) within 28 days prior to the first dose of the IP or still recovering from prior surgery 17. Subject who has active documented autoimmune disease prior to first dose of durvalumab; see Protocol for exceptions 18. Subject who has history of primary immunodeficiency or tuberculosis 19. Subject who has known seropositivity for or active infection for human immunodefi
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Dose finding part (Phase 1): - To assess the safety and tolerability of durvalumab when given in combination with lenalidomide and rituximab; ibrutinib; or bendamustine and rituximab to determine the recommended phase 2 dose (RP2D) of each combination in subjects with lymphoma or chronic lymphocytic leukemia (CLL) Dose confirmation part (Phase 1): - To assess the safety of durvalumab as monotherapy and when given in combination with lenalidomide and rituximab; ibrutinib; or bendamustine and rituximab at the RP2D in subjects with lymphoma or CLL Dose expansion part (Phase 2): - To evaluate the preliminary efficacy of durvalumab when given in combination with lenalidomide and rituximab; ibrutinib; or bendamustine and rituximab in subjects with lymphoma or CLL Arm A is discontinued to enrollment of new subjects. Subjects already enrolled and treated in Arm A who are receiving clinical benefit, based on investigators discretion may continue study treatment after being reconsented.;Secondary Objective: Dose finding & confirmation parts (Phase 1): - To make a preliminary assessment of antitumor activity of durvalumab as monotherapy and when given in combination with lenalidomide and rituximab; ibrutinib; or bendamustine and rituximab in subjects with lymphoma or CLL Dose expansion part (Phase 2): - To assess the safety of durvalumab when given in combination with lenalidomide and rituximab; ibrutinib; or bendamustine and rituximab in subjects with lymphoma or CLL All parts (Phase 1/2): - To characterize the pharmacokinetics (PK) of durvalumab as monotherapy and when given in combination - To characterize the PK of lenalidomide and ibrutinib when given in combination with durvalumab - To determine the pharmacodynamic effects of durvalumab as monotherapy Arm A is discontinued to enrollment of new subjects. Subjects already enrolled and treated in Arm A who are receiving clinical benefit, based on investigators discretion may continue study treatment after | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Dose finding and confirmation (Phase 1): • Preliminary antitumor activity (IWG Response Criteria for Malignant Lymphoma & IWCLL Response Criteria for CLL) All parts (Phase 1/2): • Other efficacy parameters (IWG Response Criteria for Malignant & IWCLL Response Criteria for CLL) • Time to first response (TTR) • Duration of response (DoR) • Progression-free survival (PFS) Dose expansion (Phase 2): • Safety All parts (Phase 1/2): • PK • Pd See Table 2 of the protocol for further detail.;Timepoint(s) of evaluation of this end point: As outlined in the following tables in the protocol: • Table 7: Table of Events – Arm A - Durvalumab and Lenalidomide ± Rituximab (This arm is discontinued to enrollment of new subjects; the procedures apply to continuing subjects in the study) • Table 8: Table of Events – Arm B - Durvalumab and Ibrutinib • Table 9: Table of Events – Arm C – Durvalumab and Rituximab ± Bendamustine • Table 10: Table of Events – Arm D – Durvalumab Monotherapy | — |
Countries
Canada, France, Germany, Italy, Japan, Netherlands, United Kingdom, United States
Contacts
Public ContactClinicalTrialDisclosure
Celgene Corporation
Outcome results
None listed