A Phase 1/2, Open-label, Dose Finding Study to Evaluate CC-122 in Combination With Ibrutinib and Obinutuzumab in Subjects With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Exclusion Criteria

• •1. Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
• •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 or allogeneic stem cell transplant (SCT)/bone marrow transplant within 12 months of signing the ICD. Subjects who received allogeneic SCT ≥ 12 months before signing the ICD may be eligible provided there is no ongoing graft-versus-host disease and no ongoing immune suppression therapy.
• •5. Uncontrolled intercurrent illness including, but not limited to:
• •1. Ongoing or active infection requiring parenteral antibiotics.
• •2. Uncontrolled diabetes mellitus.
• •i. The glycemic targets for subjects with diabetes should take into consideration age, comorbidities, life expectancy, and functional status of the subjects and follow established guidelines (eg, International Diabetes Federation, the European Diabetes Working Party guidelines, and the American Diabetes Association). For younger (\< 70 years old) or subjects with life expectancy ≥ 10 years, the target glycosylated hemoglobin, type A1C (HbA1c) should be \< 7.0%. The target HbA1c for older (≥ 70 years old) subjects or subjects with life expectancy \< 10 years should be \< 8.0%. Consultation with an endocrinologist is recommended when deciding if diabetes is optimally controlled.
• •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:
• •1. Basal cell carcinoma of the skin.
• •2. Squamous cell carcinoma of the skin.
• •3. Carcinoma in situ of the cervix.
• •4. Carcinoma in situ of the breast.
• •5. Carcinoma in situ of the bladder.
• •6. 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. Patients should be referred to a specialist if they are carriers before treatment starts (see PI or SmPC). Subjects who are positive for anti-HBc and/or anti-HBs but negative for HBsAg and HBV DNA may be treated after consultation with a hepatologist.
• •8. Any peripheral neuropathy ≥ NCI CTCAE Grade 2.
• •9. Use of systemic corticosteroids in doses greater than prednisone equivalent to 20 mg/day.
• •10. 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.
• •11. History of hypersensitivity to IMiDs® (lenalidomide, pomalidomide, thalidomide).
• •12. Impaired cardiac function or clinically significant cardiac diseases, including any of the following:
• •1. Left ventricular ejection fraction (LVEF) \< 45% as determined by MUGA scan or echocardiogram (ECHO).
• •2. Complete left bundle branch, or bifasicular, block.
• •3. Congenital long QT syndrome.
• •4. Persistent or uncontrolled ventricular arrhythmias or atrial fibrillation.
• •5. QTcF \> 470 msec on Screening ECG (mean of triplicate recordings).
• •6. Unstable angina pectoris or myocardial infarction ≤ 6 months prior to starting CC 122.
• •7. Uncontrolled congestive heart failure or uncontrolled hypertension.
• •8. 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.
• •13. Chemotherapy, radiotherapy, investigational anticancer therapy or major surgery within 28 days of Day 1 dosing with the following exceptions:
• •a. Arm A: A minimum 5-day washout after discontinuation of ibrutinib therapy (or other BTK inhibitors) is required; only those subjects without rapid disease progression during the 5-day washout will be allowed to enroll into Arm A.
• •i. Rapid disease progression is defined as follows:
• •1\. For subjects with measurable nodal disease, the increase in the sum of diameters of the largest lymph nodes (up to 3 nodes) exceeds
• •1 cm per day OR the diameter of the largest lymph node exceeds 5 cm during the 5 day wash out. 2. For subjects with lymphocytosis, the increase in the ALC exceeds 2x109/L per day OR the ALC exceeds 100,000 x109/L during the 5-day wash out; b. Arm C: No minimum washout is required after discontinuation of ibrutinib (or other BTK inhibitors) c. Approved PI3 kinase inhibitors: Subjects may start study treatment within 3 days of discontinuation of approved PI3 kinase inhibitors.
• •14\. Persistent diarrhea or malabsorption ≥ NCI CTCAE Grade 2, despite medical management 15. Active disease transformation (ie, Richter's Syndrome); subjects with Richter's Syndrome that has resolved \> 2 years from signing the ICD are eligible.
• •16\. Known acute or chronic pancreatitis 17. Pregnant or lactating females
• •Arm B only (CC-122 in combination with ibrutinib):
• •18\. Prior treatment with a BTK inhibitor 19. Presence of transfusion-dependent thrombocytopenia or a history of bleeding disorders or clinical conditions (eg, gastrointestinal bleeding or constitutional disorders) that may increase risk of life-threatening bleeding when thrombocytopenic 20. History of stroke or intracranial hemorrhage within 6 months prior to signing the ICD 21. Medications that are strong inhibitors or inducers of CYP3A4/5 (eg, itraconazole, ketoconazole, clarithromycin, ritonavir, phenytoin, pentobarbital, and rifampin) should be changed; subjects who cannot change these medications must be excluded.
• •22\. Use of concomitant anticoagulation with warfarin or other vitamin K antagonists is prohibited, as is treatment with these agents in the 7 days prior to signing the ICD. The use of other anticoagulants (eg, heparins) and anti-platelet agents is allowed per investigator's discretion.
• •Arm C only (CC-122 in combination with obinutuzumab):
• •23\. Hypersensitivity to obinutuzumab