Invac-1 in Chronic Lymphocytic Leukemia

The study will be a phase II, open label, single-arm trial of INVAC-1 at a dose of 800 µg in
patients with CLL.

The primary goal of the study is to achieve MRD negativity in each group. 42 patients are to
be included in each study group.

Group 1: Untreated high risk "watch and wait" Newly diagnosed patients not eligible for any
approved treatment (using NCI Working Group criteria), but having some poor prognosis
characteristics (defined by MD Anderson Cancer Center nomogram criteria). Patients will be
treated by INVAC-1 for 6 doses at 4-week intervals and then MRD will be assessed. Patients
will subsequently be managed as per usual care. For MRD negative patients after INVAC-1 who
become MRD+ during follow-up, INVAC-1 can be resumed for one year.

Group 2: Ibrutinib treated patients Patients who are receiving ibrutinib as 1st or 2nd line
treatment. After at least 12 months of ibrutinib, patients will be assessed for MRD.
MRD-positive patients will be treated with ibrutinib + INVAC-1 for 6 months and at the end of
the combined treatment period, MRD will be assessed. MRD-negative patients (defined as <0.01%
of CLL cells in total cells analyzed) will have the option to stop or continue ibrutinib.
Then, they will be followed-up regularly for two years. Patients who become MRD-positive
after being MRD-negative will resume ibrutinib single agent.

Group 1: Untreated high risk "watch and wait"

Inclusion Criteria:

1. Age ≥ 18 years old

2. Rai stage 0 - II without active disease according to IWCLL 2008 criteria

3. Predicted time to first treatment of ≤3 years according to MDACC nomogram.

4. ECOG performance status of 0-2

5. Adequate hepatic function, defined as serum aspartate transaminase (AST) and alanine
transaminase (ALT) < 2.5 x upper limit of normal (ULN), and total bilirubin ≤ 1.5 x
ULN except Gilbert's Syndrome where a direct bilirubin ≤ 1.5 ULN will be used.

6. Adequate renal function, defined as an estimated creatinine clearance ≥30 mL/min using
the Cockcroft-Gault equation

7. Willingness to receive all outpatient treatment, all laboratory monitoring, and all
radiological evaluations at the institution that administers study drug for the entire
study

8. Willingness of male and female patients, if sexually active, to use an effective
barrier method of contraception during the study and for 3 months following the last
dose of study drug

9. Ability to provide written informed consent and to understand and comply with the
requirements of the study

Exclusion Criteria

1. Any investigational agent(s) within 4 weeks prior to entry

2. Uncontrolled autoimmune hemolytic anemia (Hgb < 11g/deciliter) or idiopathic
thrombocytopenic purpura (< 100,000/µl)

3. Any previous treatment (chemotherapy, radiotherapy, and/or monoclonal antibodies)
intended specifically to treat CLL

4. Treatment with corticosteroids other than physiological replacement within the
previous week or treatment with immunosuppressive medication within the previous week.

5. Major surgery within 4 weeks prior to inclusion

6. Currently active, clinically significant cardiovascular disease or a history of
myocardial infarction within 6 months prior to inclusion

7. Uncontrolled active systemic fungal, bacterial, viral, or other infection or
requirement for intravenous (IV) antibiotics

8. Known history of infection with human immunodeficiency virus (HIV)

9. Serologic status reflecting active hepatitis B or C infection.

10. History of stroke or intracranial hemorrhage within 6 months prior to enrolment

11. Current life-threatening illness, medical condition, or organ-system dysfunction that
could compromise patient safety or put the study at risk

12. Breast-feeding or pregnant women, or patients for whom there is a risk of conception
and who are unable or unwilling to use appropriate contraception (for male and female
patients up to 4 months after end of ibrutinib.)

13. Previous malignancy with life expectancy less than 6 months or requiring systemic
treatment (except colorectal cancer, history of basal cell carcinoma of skin or
pre-invasive carcinoma of the cervix with adequate treatment)

14. Known drug abuse/ alcohol abuse

15. Severe organ failures or diseases, including: clinically relevant coronary disease,
myocardial infarction or any other relevant cardiovascular disorder within 12 months
before study entry, severe psychiatric illness and severe infection.

Group 2: Ibrutinib treated patients

Inclusion Criteria

1. Age ≥ 18 years old

2. Males or females with CLL diagnosed according to IWCLL diagnostic criteria who have
been treated with ibrutinib therapy for at least 12 months and have had no more than 1
other treatment for CLL prior to receiving ibrutinib.

3. Currently in complete or partial remission (PR)/PR with lymphocytosis (PRL)

4. MRD positivity defined as >1.0% CLL cells in the bone marrow by flow cytometry

5. ECOG performance status of 0-2

6. Adequate hepatic function, defined as serum aspartate transaminase (AST) and alanine
transaminase (ALT) < 2.5 x upper limit of normal (ULN), and total bilirubin ≤ 1.5 x
ULN, unless Gilbert's Syndrome where a direct bilirubin ≤ 1.5 ULN will be used.

7. Adequate renal function, defined as estimated creatinine clearance ≥ 30 mL/min using
the Cockcroft-Gault equation

8. Willingness to receive all outpatient treatment, all laboratory monitoring, and all
radiological evaluations at the institution that administers study drug for the entire
study

9. Willingness of male and female patients, if sexually active, to use an effective
barrier method of contraception during the study and for 3 months following the last
dose of study drug

10. Ability to provide written informed consent and to understand and comply with the
requirements of the study

Exclusion Criteria

1. Any investigational agent(s) within 4 weeks prior to entry

2. Known involvement of the central nervous system by lymphoma or leukemia

3. History or current evidence of Richter's transformation or prolymphocytic leukemia

4. Uncontrolled autoimmune hemolytic anemia (Hgb < 11g/deciliter) or idiopathic
thrombocytopenic purpura (< 100,000/µl)

5. Any previous treatment (chemotherapy, radiotherapy, and/or monoclonal antibodies)
intended specifically to treat CLL

6. Corticosteroid use within 1 week prior to first dose of study drug, with the exception
of inhaled, topical, or other local administrations. Patients requiring systemic
steroids at daily doses > 20 mg prednisone (or corticosteroid equivalent), or those
who are administered steroids for leukemia control or white blood cell
(WBC)-count-lowering are excluded

7. Major surgery within 4 weeks prior to inclusion

8. Currently active, clinically significant cardiovascular disease or a history of
myocardial infarction within 6 months prior to inclusion

9. Uncontrolled active systemic fungal, bacterial, viral, or other infection or
requirement for intravenous (IV) antibiotics

10. Known history of infection with human immunodeficiency virus (HIV)

11. Serologic status reflecting active hepatitis B or C infection

12. History of stroke or intracranial hemorrhage within 6 months prior to enrollment

13. Current life-threatening illness, medical condition, or organ-system dysfunction that
could compromise patient safety or put the study at risk

14. Requirement for anticoagulation with warfarin, or for treatment with a strong CYP3A4/5
and/or CYP2D6 inhibitor

15. Breast-feeding or pregnant women, or patients for whom there is a risk of conception
and who are unable or unwilling to use appropriate contraception (for male and female
patients up to 4 months after end of ibrutinib.)

16. Previous malignancy with life expectancy less than 6 months or requiring systemic
treatment (except colorectal cancer, history of basal cell or squamous carcinoma of
skin or pre-invasive carcinoma of the cervix with adequate treatment)

17. Known drug abuse/ alcohol abuse

18. Severe organ failures or diseases, including: clinically relevant coronary disease,
myocardial infarction or any other relevant cardiovascular disorder within 12 months
before study entry, severe psychiatric illness and severe infection.