A Phase 1/2 Open Label Multicenter Study to Assess the Safety and Tolerability of Durvalumab (anti-PD-L1 Antibody) as Monotherapy and in Combination Therapy in Subjects with Lymphoma or Chronic Lymphocytic Leukemia
There are 2 parts to this study: Part 1 (dose finding and confirmation) and Part 2 (dose expansion). The tolerable dose of durvalumab when given alone is known, but this dose needs to be tested and confirmed. The goal of Part 1 of this clinical research study is to find and confirm the recommended dose of durvalumab (MEDI4736) that can be given alone or in combination with standard of care therapy (lenalidomide with or without rituximab, ibrutinib, or rituximab with or without bendamustine) in patients with CLL and lymphoma. This is called dose finding and dose confirmation. The goal of Part 2 of this study is to learn more about the efficacy and tolerability of the dose of durvalumab when given in combination with lenalidomide and rituximab, ibrutinib, or bendamustine and rituximab in patients with CLL and lymphoma. This is called dose expansion.
Disease Group: Malignant neoplasms stated as primary lymphoid haematopoietic
Treatment Agent: Bendamustine HCl,Durvalumab,Ibrutinib,Lenalidomide,Rituximab
Treatment Location: Both at MDACC & and Other Sites
Sponsor: Celgene International II Sarl
Primary 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 recommend phase 2 doses (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 Secondary: Dose finding and 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 (PD) effects of durvalumab as monotherapy Exploratory To explore population PK analyses including the influence of intrinsic and extrinsic factors that may influence durvalumab exposures To determine the immunogenicity of durvalumab as monotherapy and when given in combination To explore PK/PD relationship, explore pharmacodynamic mechanistic biomarkers for durvalumab and other combination agents in the study To explore host immune and tumor molecular markers predictive of response to durvalumab and other agents when given in combination To explore minimal residual disease (MRD) and its correlation with clinical outcome
IRB Review and Approval Date: 02/22/2017
Recruitment Status: Open
Projected Accrual: 253
1) Subjects with R/R lymphoma or CLL requiring therapeutic intervention
must satisfy the following criteria to be enrolled in the study -- APPLY
to ALL TREATMENT ARMS:
2) Subject is >/= 18 years of age and </= 80 years of age at the time of signing the informed consent. NOTE: At the discretion of the investigator subjects > 80 years of age may be included if their ECOG performance status is </= 1; each of their individual organ system scores must be </= 2 using the Modified Cumulative Illness Rating Scale (CIRS) for comorbitidy.
3) Subject must understand and voluntarily sign an informed consent form (ICF) prior to any study-related assessments/procedures being conducted.
4) Subject is willing and able to adhere to the study visit schedule and other protocol requirements.
5) Subject has histologically confirmed and documented eligible histologies as listed in the protocol as assessed by the investigator and local patholgist per 2008 WHO Lymphoma Classification.
6) Subject has been previously treated with at least one prior systemic chemotherapy, immunotherapy, or chemoimmunotherapy. NOTE: Local involved field radiation therapy (IFRT) or antibiotic-based therapy is not deemed as systemic therapy for this study.
7) 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-failure (defined as progression while on ibrutinib treatment [excluding isolated early lymphocytosis]; or an inadequate tumor response which is less than partial response [PR]; e) Relapsed/progressive disease within 6 months of completing their last therapy.
8) 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) during the Screening Period and at the time of disease progression from subjects who have achieved objective response (complete response (CR) or partial response (PR)) to study treatment. EXCEPTION: An archival diagnostic lymph node/tumor formalin fixed paraffin embedded (FFPE) biopsy acquired by a surgical or core needle biopsy within 18 months prior to signing informed consent may be acceptable for enrollment of a subject with poorly accessible tumor following the discussion with the sponsor’s medical monitor; b) Subject with CLL is willing and able to undergo bone marrow biopsy during the Screening and Treatment Periods; NOTE: Material from a fine needle aspiration is not acceptable.
9) Subject who has documented active relapsed or refractory disease requiring therapeutic intervention.
10) Subject who has measurable disease: a) For subject with lymphoma, bi-dimensionally measurable disease on cross-sectional imaging by computed tomography (CT) with at least one nodal or extranodal lesion >/= 2.0 cm in its longest dimension; b) For subject with CLL, in need of treatment as defined by IWCLL Guidelines for the Diagnosis and Treatment of CLL.
11) Subject who has performance status of 0, 1, or 2 on the Eastern Cooperative Oncology Group (ECOG) scale.
12) Subject who has life expectancy of greater than 6 months.
13) Subjects who fulfill the following laboratory requirements (NOTE: Abbreviations cited in Laboratory Values criteria #14-20 are: ANC = absolute neutrophil count; aPTT = activated partial thromboplastin time; AST/ALT = aspartate transaminase / aspartate transaminase; CLL = chronic lymphocytic leukemia; INR = international normalized ratio; LLN = lower limit of normal; NHL = non-Hodgkin lymphoma; PTT = partial thromboplastin time; ULN = upper limit of normal) -- Eligible Laboratory Values:
14) (continuation of #13) ANC (cells/mm^3) -- Arm A >/= 1500; Arm B, C, and D >/= 1000. NOTE: Subjects with ANC >/= 500 (cells/mm^3) may be allowed in the dose confirmation and expansion cohorts only if neutropenia is secondary to bone marrow involvement documented as >/= 80% bone marrow infiltration of CLL cells or >/= 50% bone marrow infiltration of lymphoma cells by pretreatment bone marrow biopsy following the discussion with the sponsor’s medical monitor. These subjects should not have any evidence of active bacterial infection within 14 days of Cycle 1 Day 1 (i.e., off of oral and IV antibiotics for at least for 14 days). These subjects will be excluded from the dose finding cohorts.
15) (continuation of #13) Platelets (cells/mm^3) -- Arm A, B, C, and D >/= 75,000. NOTE: Subjects with platelets >/= 20,000 cells/mm^3 may be allowed in the dose confirmation and expansion cohorts only if thrombocytopenia is secondary to bone marrow involvement documented as >/= 80% bone marrow infiltration of CLL cells or >/= 50% bone marrow infiltration of lymphoma cells by pretreatment bone marrow biopsy following the discussion with the sponsor’s medical monitor. These subjects should not have any evidence of active bleeding or clinically significant coagulopathy. These subjects will be excluded from the dose finding cohorts.
16) (continuation of #13) AST/ALT (ULN) -- Arm A, B, C, and D </= 2.5 x ULN. NOTE: In the case of liver involvement by lymphoma, subjects with AST/ALT </= 5.0 × ULN may be allowed in the dose confirmation and expansion cohorts only following the discussion with the sponsor’s medical monitor. These subjects will be excluded from the dose finding cohorts.
17) (continuation of #13) Total Bilirubin (serum) (ULN) -- Arm A, B, C, and D </= 1.5 x ULN NOTE: In the case of Gilbert’s Syndrome, or documented liver or pancreatic involvement by lymphoma, subjects with total bilirubin </= 3.0 mg/dL may be allowed in the dose confirmation and expansion cohorts only following the discussion with the sponsor’s medical monitor. These subjects will be excluded from the dose finding cohorts.
18) (continuation of #13) Creatinine Clearance (mL/min) based on Cockcroft-Gault formula -- Arm A >/= 60 (eligible for all parts) >/= 40 (ineligible for dose finding cohorts of Arm A); Arm B, C, and D >/= 40.
19) (continuation of #13) PT/INR (ULN) Arm B < 1.5 x ULN.
20) (continuation of #13) PTT/aPTT (ULN) Arm B < 1.5 x ULN.
21) Female subject of childbearing potential (FCBP*) 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 complete 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.
Criteria truncated, please contact Prinicipal Investigator's office for full criteria
1) The presence of any of the following will exclude a subject from
enrollment. APPLY to ALL TREATMENT ARMS:
2) Subject has known or suspected central nervous system (CNS) or meningeal involvement by lymphoma.
3) Subject has other lymphoma histologies which are not listed in the protocol (eg, human immunodeficiency virus [HIV]-associated lymphomas, CNS lymphoma, Waldenstrom’s macroglobulinemia). -- Subject has blastoid variants of MCL or MCL with blastoid transformation, -- Dose Confirmation and Expansion Parts only: Subject has transformed lymphoma or Richter’s transformation.
4) Subject who has any histopathologic finding consistent with myelodysplastic syndrome on bone marrow studies.
5) Subject who has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
6) 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.
7) Subject who has any condition that confounds the ability to interpret data from the study.
8) Subject who has any uncontrolled inter-current illness including, but not limited to, ongoing or active infection, current pneumonitis, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs from durvalumab and/or other investigational treatment regimens, or compromise the ability of the subject to give written informed consent.
9) Subject who is concurrent enrolled in another clinical study, unless in a follow-up period or it is an observational study.
10) Subject who has any concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy for cancer treatment. NOTE: Concurrent use of hormones for noncancer-related conditions (eg, insulin for diabetes and hormone replacement therapy) is acceptable.
11) Subject who has received 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). EXCEPTION: The use of hematopoietic growth factors or blood product transfusional support for subjects with extensive marrow involvement by lymphoma or CLL may be allowed during the Screening Period after consultation with the sponsor’s medical monitor in the dose confirmation and expansion cohorts only.
12) 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.
13) 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) Arms C only: bendamustine.
14) Subject who has history of organ transplant or allogeneic hematopoietic stem cell transplantation.
15) Subject who has taken corticosteroids during the last 1 week prior to Cycle 1 Day 1, unless administered at a dose equivalent to </= 10 mg/day prednisone.
16) 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 30 days after the last dose of durvalumab).
17) Subject who has undergone major surgical procedure (as defined by the investigator) within 28 days prior to the first dose of the IP (ie, Cycle 1 Day 1) or still recovering from prior surgery.
18) Subject who has active documented autoimmune disease (including, but not limited to, inflammatory bowel disease, celiac disease, Wegener syndrome, hemolytic anemia, or immune thrombocytopenic purpura) prior to first dose of durvalumab.
19) Subject who has history of primary immunodeficiency or tuberculosis.
20) Subject who has known seropositivity for or active infection for human immunodeficiency virus (HIV) or hepatitis C virus (HCV).
21) Subject who is seropositive for or active viral infection with hepatitis B virus (HBV) (hepatitis B surface antigen [HBsAg] positive and/or detectable viral DNA). Exceptions: a) Antibody to the hepatitis B surface antigen (anti-HBs) positive only with prior HBV vaccination history, b) Anti-HBs positive (no prior HBV vaccination) and/or antibody to the hepatitis B core antigen (anti-HBc) positive but viral DNA negative.
22) Female subject who is pregnant, breastfeeding, or intend to become pregnant during the participation in the study.
23) Subject who has other invasive malignancy within 2 years prior to signing the ICF except for noninvasive malignancies such as cervical carcinoma in situ, non-melanomatous carcinoma of the skin, ductal carcinoma in situ of the breast, or incidental histologic finding of prostate cancer (T1a or T1b using the TNM [tumor, nodes, metastasis] clinical staging system) that has/have been surgically cured. -- Arm A only: Subject who has history of other malignancies, unless the subject has been free of the disease for >/= 5 years prior to signing the ICF. EXCEPTIONS: History of previously treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin and related localized non-melanoma skin cancer, carcinoma in situ of the cervix, carcinoma in situ of breast, incidental histologic finding of prostate cancer (T1a or T1b using the TNM clinical staging system).
24) Subject who has known allergy or hypersensitivity to the active substance or any of the excipients, or to other humanized mAbs.
25) APPLY TO ARM A ONLY: 1) Subjects with CLL or SLL; 2) Subject who has peripheral neuropathy Grade 3 or 4; 3) Subject who is at risk for a thromboembolic event and is not willing to take prophylactic treatment.
26) APPLY TO ARMS A AND C ONLY: 1) Subject who does not have CD20 positive lymphoma or CLL; 2) Subject who has hypersensitivity to rituximab.
27) APPLY TO ARM B ONLY: 1) Subject who has transfusion-dependent thrombocytopenia or a history of bleeding disorders or clinical conditions (eg, gastrointestinal bleeding or constitutional disorders) that may increase the risk of life-threatening bleeding when thrombocytopenic; 2) Subject who has history of stroke or intracranial hemorrhage within 6 months prior to signing the ICF;
28) (continuation of #27) 3) Subject who receives the medications that are strong inhibitors or inducers of CYP3A (eg, itraconazole, ketoconazole, clarithromycin, ritonavir, phenytoin, pentobarbital, and rifampin) and cannot change; 4) Subject who has received concomitant anticoagulation with warfarin, other vitamin K antagonists, or direct thrombin inhibitors (eg, dabigatran) within 7 days prior to signing the ICF and cannot change. The use of other anticoagulants (eg, heparins) and antiplatelet agents is allowed per investigator’s discretion. Investigator questions regarding this should be addressed to the sponsor’s medical monitor or the study country principal investigators.
29) APPLY TO ARM C ONLY: Subject who should concurrently use allopurinol, eg, because of gout, and unwilling to switch to another equivalent medication. (Subjects with gout are advised to switch to another antigout medication, because of the risk of Stevens-Johnson syndrome observed in subjects using bendamustine and allopurinol).
30) NOTE: Lymphoma patients will not be treated in this study. They will be enrolled in companion study 2015-1063 conducted by Dr. Nathan Fowler in the Department of Lymphoma/Myeloma here at MDACC.
Information and next steps
Malignant neoplasms stated as primary lymphoid haematopoietic
Phase I/Phase II
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