| Eligibility |
Inclusion Criteria:
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 (per IWCLL
guidelines). In addition:
a. Presence of at least one clinically measurable lesion: i. nodal lesion that
measures = 1.5 cm in longest dimension (LD) and = 1.0 cm in longest perpendicular
dimension (LPD), or ii. spleen that measures = 14 cm in longest vertical dimension
(LVD) with a minimum of 2 cm enlargement, or iii. liver that measures = 20 cm in LVD
with a minimum of 2 cm enlargement, or iv. peripheral blood B lymphocyte count >
5000/uL.
5. Must meet the criteria for relapsed and/or refractory disease according to the IWCLL
guidelines (Hallek, 2008) to = 1 prior treatment (with the exception of Arm B) and
have evidence of disease progression requiring treatment at the time of study entry as
follows:
a. For Arms A and C, subjects must have received either prior chemoimmunotherapy or
therapy with an approved BTK inhibitor with the following exceptions: i.
Chemoimmunotherapy is not required if subjects have specific comorbidities that
preclude the use of standard chemoimmunotherapy meeting at least 1 of the following
criteria;
1. CIRS = 6; 2. Creatinine Clearance < 70 mL/min; 3. Subject is not a candidate for a
chemoimmunotherapy in the opinion of investigator. ii. Treatment with an approved BTK
inhibitor is not required if subject has contraindications or is not a candidate for such a
therapy in the opinion of the investigator. b. For Arm B, subjects with treatment-naïve or
R/R CLL must meet the following criteria: i. Dose Escalation Phase: Subjects must not have
received prior treatment with ibrutinib (or any other approved BTK inhibitors) and must
have either R/R CLL or treatment naïve (ie, first-line) CLL if the subject:
1. has 17p- and/or TP53 mutation; or
2. is unfit for standard chemoimmunotherapy meeting at least 1 of the following
co-morbidity criteria: a. CIRS = 6; b. Creatinine Clearance < 70 mL/min; c. Subject is
not a candidate for a chemoimmunotherapy in the opinion of the investigator. The
reason for not being a candidate must be documented in CRF. ii. Dose Expansion Phase:
Subjects must not have received prior treatment with ibrutinib (or any other approved
BTK inhibitors) and must have high risk CLL. High risk is defined as: 1) 17p- and/or
TP53 mutation positive in treatment naïve CLL; or 2) 17p- and/or TP53 mutation
positive, and/or complex karyotype, and/or progression < 24 months after completion of
1st line chemoimmunotherapy in R/R CLL c. Subjects with R/R SLL or CLL with bulky
disease (at least one lymph node measuring > 5.0 cm in diameter) are considered at
higher risk for developing a TFR and may only be enrolled upon discussion with the
sponsor's medical monitor and agreement to close medical management.
6. Subjects must have the following lab values:
1. Absolute neutrophil count (ANC) = 1,500 cells/mm3 or = 1000 cells/mm3 if secondary to
bone marrow involvement by disease.
2. Platelet count = 100,000 cells/mm3 (100 x 109/L) or = 50,000 cells/mm3 (50 x 109/L) if
secondary to bone marrow involvement by disease.
3. Serum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) < 3.0 x
upper limit of normal (ULN) unless due to disease.
4. 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 B only
(CC-122 in combination with ibrutinib)
5. Calculated creatinine clearance of = 60 ml/min.
6. No evidence of TLS per the Cairo-Bishop definition of laboratory TLS (subjects may be
enrolled upon correction of electrolyte abnormalities).
7. ECOG PS (Eastern Cooperative Group Performance Status) of 0 or 1. 8. Ability to
swallow oral capsules without difficulty. 9. Pregnancy Prevention Risk Management
Plan:
1. Females of childbearing potential (FCBP) must undergo pregnancy testing based on the
frequency outlined in the Pregnancy Prevention Risk Management Plan (PPRMP) and
pregnancy results must be negative.
2. Unless practicing complete abstinence from heterosexual intercourse, sexually active
FCBP must agree to use adequate contraceptive methods as specified in the PPRMP.
*For Arm C, subjects must agree to use adequate contraceptive methods for 18 months
(please refer to the obinutuzumab IB, PI, and SmPC).
- Complete abstinence is only acceptable in cases where this is the preferred and
usual lifestyle of the subject.
- Periodic abstinence (calendar ovulation, symptothermal, post-ovulation methods) and
withdrawal are not acceptable.
3. Males (including those who have had a vasectomy) must practice complete abstinence or
use barrier contraception (condoms) when engaging in sexual activity with FCBP as
specified in the PPRMP.
4. Males must agree not to donate semen or sperm for the duration of the study and for 3
months after the last dose of CC-122.
5. All subjects must:
- Understand that the (investigational Product) IP could have a potential teratogenic
risk.
- Agree to abstain from donating blood while taking IP and following discontinuation
of IP.
- Agree not to share IP with another person.
6. Other than the subject, FCBP and males should not handle the IP or touch the capsules,
unless gloves are worn.
7. Be counseled about pregnancy precautions and risks of fetal exposure.
ARM B ONLY:
10. Enrollment into Arm B will be permitted if ibrutinib is considered the standard of care
in the clinical practice.
EXPANSION COHORT 2 OF ARM C:
11. Subjects in Cohort 2 of Arm C must meet the following criteria:
1. Subject must have received at least one BCR PI (ibrutinib, idelalisib, or other
approved BTK or PI3K inhibitor) and/or venetoclax;
2. Subject must be either resistant to or intolerant of (ie., treatment failures) the
last BCR PI and/or venetoclax. Resistant is defined as relapsed or refractory per
IWCLL2008:
i. Relapse is defined as a patient who has previously achieved a CR or PR, but after a
period of 6 or more months, demonstrates evidence of disease progression. ii. Refractory is
defined as failing to achieve a CR or PR, or disease progression within 6 months after
initiation of treatment with an approved BTK or PI3K inhibitor (eg, ibrutinib, idelalisib)
or venetoclax. iii. Intolerance is defined as the inability to continue treatment with a
BCR PI or venetoclax due to toxicities or due to development of a contraindication that
makes the subject ineligible to receive further treatment with a BCR PI or venetoclax.
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
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