Phase 1/2 Study to Determine the Safety, Pharmacokinetics, and Efficacy of Single Agent CC-122 and the Combinations of CC-122 and Ibrutinib, and CC-122 and Obinutuzumab in Subjects with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
There are 2 parts to this study: Part 1 (dose escalation) and Part 2 (dose expansion). The goal of Part 1 of this clinical research study is to find the highest tolerable dose of CC-122, when given alone or in combination with ibrutinib or obinutuzumab,that can be given to patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The goal of Part 2 of this study is to learn if the highest tolerable dose of CC-122 when given in combination with the above drugs can help to control the disease. The safety of the study drug combinations will also be studied. This consent form is only for participants in Part 1 receiving CC-122 alone.
Disease Group: Leukemia
Treatment Agent: CC-122,Ibrutinib,Obinutuzumab,Rituximab
Treatment Location: Both at MDACC & and Other Sites
Sponsor: Celgene Corporation
Primary Objectives ·Determine the safety of single agent CC-122 in subjects with relapsed/refractory CLL/SLL ·Determine the safety and tolerability of the combination of CC-122 and rituximab and determine the recommended Phase 2 dose (RP2D) of the combination in subjects with relapsed/refractory CLL/SLL ·Determine the safety and tolerability of the combination of CC-122 and ibrutinib and determine the RP2D of the combination in subjects with relapsed/refractory CLL/SLL ·Determine the safety and tolerability of the combination of CC-122 and obinutuzumab and determine the RP2D (reccomended phase 2 dose) of the combination in subjects with relapsed/refractory CLL/SLL Secondary Objectives ·To characterize CC-122 pharmacokinetics (PK) in subjects with CLL and assess potential drug-drug sinteractions when CC-122 is given in combination with ibrutinib, rituximab, or obinutuzumab ·To determine ibrutinib concentrations when given alone and in combination with CC-122 ·Determine the preliminary efficacy of single agent CC-122, the combination of CC-122 and rituximab, the combination of CC-122 and ibrutinib, and the combination of CC-122 and obinutuzumab Exploratory Objectives ·Evaluate pharmacodynamic markers and biomarkers (ribonucleic acid [RNA], deoxyribonucleic acid [DNA] and protein) in peripheral blood and/or bone marrow specimens that are predictive of response or toxicity to single agent CC-122 and the combinations CC-122 and rituximab, CC-122 and ibrutinib, and CC-122 and obinutuzumab ·Evaluate immunomodulatory activity of CC-122 ·Identification of prognostic markers indicative of high-risk disease ·To explore trends between CC-122 exposure and indices of response such as relevant pharmacodynamic biomarkers, efficacy endpoints and/or safety endpoints when CC-122 is given alone or in combination with rituximab, ibrutinib or obinutuzumab
IRB Review and Approval Date: 02/22/2017
Recruitment Status: Open
Projected Accrual: Depending on dose levels, up to 440 patients
1) Subjects >/= 18 years age and < 80 years of age at the time of
signing the informed consent form.
2) Understand and voluntarily sign an informed consent form prior to any study related assessments/procedures being conducted.
3) Able to adhere to the study visit schedule and other protocol requirements.
4) Must have a documented diagnosis of CLL/SLL requiring treatment (IWCLL Guidelines for the Diagnosis and Treatment of CLL [Hallek, 2008]).
5) Must meet the criteria for relapsed and/or refractory disease according to the IWCLL guidelines (Hallek, 2008) to >/= 1 prior chemo-immunotherapy regimen but < 6 prior regimens.
6) Subjects must have been treated with an alkylating agent and/or purine analog in combination with rituximab or an alternative anti-CD20 antibody (ie, ofatumumab or obinutuzumab);
7) Subjects must have the following lab values: a. Absolute neutrophil count (ANC) >/= 1,500 cells/mm3 or >/= 1000 cells/mm3 if secondary to bone marrow involvement by disease. b. Platelet count >/= 100,000 cells/mm3 [100 x 10(9)/L] or >/= 50,000 cells/mm3 [50 x 10(9)/L]if secondary to bone marrow involvement by disease. c.Serum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) </= 3.0 x upper limit of normal (ULN) unless due to disease. d. Serum bilirubin </= 1.5 x ULN unless due to Gilbert’s syndrome. o Serum bilirubin </= 1.0 x ULN unless due to Gilbert’s syndrome, Treatment Arm 3 only (CC-122 in combination with ibrutinib) e.Calculated creatinine clearance (Cockcroft-Gault formula (Cockcroft, 1976) of >/= 60 ml/min). f. No evidence of TLS per the Cairo-Bishop definition of laboratory TLS (subjects may be enrolled upon correction of electrolyte abnormalities).
8) ECOG PS of 0 or 1.
9) Ability to swallow oral capsules without difficulty.
10) Pregnancy Prevention Risk Management Plan:
1) Any significant medical condition, laboratory abnormality, or
psychiatric illness that would prevent the subject from participating in
2) Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study
3) Any condition that confounds the ability to interpret data from the study.
4) Prior autologous stem cell transplant or allogeneic bone marrow transplant with persistent donor hematopoiesis within 3 months of signing the ICD.
5) Uncontrolled intercurrent illness including, but not limited to: a. Ongoing or active infection requiring parenteral antibiotics. b. Uncontrolled diabetes mellitus as defined by the investigator. c. Chronic symptomatic congestive heart failure (Class III or IV of the New York Heart Association Classification for Heart Disease). d. Active central nervous system involvement as documented by spinal fluid cytology or imaging. e. Uncontrolled autoimmune hemolytic anemia or thrombocytopenia. f. Other concurrent severe and/or uncontrolled concomitant medical conditions that could cause unacceptable safety risks or compromise compliance with protocol.
6) History of second malignancies with life expectancy of </= 2 years or requirement of therapy that would confound study results. This does not include the following: a. Basal cell carcinoma of the skin. b. Squamous cell carcinoma of the skin. c. Carcinoma in situ of the cervix. d. Carcinoma in situ of the breast. e. Carcinoma in situ of the bladder. f. Incidental histologic finding of prostate cancer (TNM stage of T1a or T1b).
7) Known seropositivity for or history of active viral infection with human immunodeficiency virus (HIV), or hepatitis B or C virus (HBV, HCV). a. Hepatitis B screening is mandatory for all patients (HBsAg and anti-HBc). Patients with active hepatitis B disease should not be treated with obinutuzumab or rituximab. Patients should be referred to a specialist if they are carriers before treatment starts.
8) Any peripheral neuropathy >/= NCI CTCAE Grade 2.
9) Prior treatment with ibrutinib or investigational BTK inhibitors; except as indicated in Arm B, Expansion Cohort 2 and Arm D, Expansion Cohort 6.
10) Use of systemic corticosteroids in doses greater than prednisone equivalent to 20 mg/day.
11) Medicines with high probability to cause QT prolongation or torsades de pointes. Subjects on chronic medications in this category may enroll after discussion with the medical monitor if changing these medications are not in the best medical interest of the patient.
12) History of hypersensitivity to IMiDs® (lenalidomide, pomalidomide, thalidomide).
13) Impaired cardiac function or clinically significant cardiac diseases, including any of the following: a. LVEF < 45% as determined by MUGA scan or ECHO. b. Complete left bundle branch, or bifasicular, block. c. Congenital long QT syndrome. d. Persistent or uncontrolled ventricular arrhythmias or atrial fibrillation. e. QTcF > 470 msec on screening ECG (mean of triplicate recordings). f. Unstable angina pectoris or myocardial infarction = 6 months prior to starting CC 122. g. Uncontrolled congestive heart failure or uncontrolled hypertension. h. Troponin-T value >0.4 ng/mL or BNP >300 pg/mL. Subjects with baseline troponin-T >ULN or BNP >100 pg/mL are eligible but must have cardiologist evaluation prior to enrollment in the trial for baseline assessment and optimization of cardioprotective therapy.
14) Chemotherapy, radiotherapy, investigational anticancer therapy or major surgery within 28 days of Day 1 dosing with the exception of those enrolling into Arm B, Expansion Cohort 2 and Arm D, Expansion Cohort 6 (ibrutinib treated subjects). Exceptions include: a. Arm B, Expansion Cohort 2 and Arm D, Expansion Cohort 6: subjects may start study treatment within 3 days of discontinuation of ibrutinib therapy. b. Approved PI3 kinase inhibitors: subjects may start study treatment within 3 days of discontinuation of approved PI3 kinase inhibitors.
15) Persistent diarrhea or malabsorption >/= NCI CTCAE Grade 2, despite medical management
16) Active disease transformation (ie, Richter’s Syndrome); subjects with Richter’s Syndrome that has resolved >/= 2 years from signing the ICD are eligible
17) Known acute or chronic pancreatitis
18) Pregnant or lactating females
Information and next steps
Phase I/Phase II
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