A Study of BNC105P Combined With Ibrutinib

A Phase I Trial of BNC105P in combination with BTK inhibitor ibrutinib in patients with
relapsed/refractory chronic lymphocytic leukemia (CLL). Ibrutinib inhibits the pro-survival
BCR signaling of CLL cells in the stromal niche resulting in their egress to the periphery.
Importantly, if administration of ibrutinib is stopped, the CLL cells rapidly return to the
lymph node. In some patients, the drug-induced increase in circulating CLL cells has been
seen for more than a year reflecting the fact that the cells do not readily die once they
exit the lymph node. Resistance to ibrutinib has been observed as mutations in the
drug-binding cysteine in its target, BTK. This resistance is likely to become far more
prevalent as patients remain on ibrutinib for months or years. We propose that ibrutinib will
have far greater efficacy when it is combined with drugs that kill the CLL cells in
peripheral circulation, thereby preventing them from returning to the protective lymph node
niche. BNC105P works through an entirely different mechanism, i.e. tipping the balance of
pro-survival and pro-apoptotic BCL2 family member proteins toward the latter, resulting in
cell death. This pathway of apoptosis occurs at all stages of the cell cycle which is
important considering that the majority of peripheral CLL cells are non-cycling (in G0).

The study consists of a Screening Period with baseline tumor assessment before BNC105P
administration, a Treatment Period with up to six 21-day cycles and Follow-up Period.
Subjects will receive a total of six cycles of therapy unless treatment is discontinued.

Inclusion Criteria:

- Patients who are > 18 years of age, must have histologically or flow cytometry
confirmed diagnosis of B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma
(B-CLL/SLL) according to NCI-WG 1996 guidelines. The malignant B cells must co-express
CD5 with CD19 or CD20. Patients who lack CD23 expression on their leukemia cells
should be examined for (and found NOT to have) either t(11;14) or cyclin D1
overexpression, to rule out mantle cell lymphoma. Patients with CLL who have
progressed on prior ibrutinib therapy will be eligible. Patients with B-cell
prolymphocytic leukemia and patients with Richter's transformation of CLL/SLL are NOT
eligible.

- Active disease meeting at least 1 of the IWCLL 2008 criteria for requiring treatment:

i) A minimum of any one of the following constitutional symptoms:

- Unintentional weight loss >10% within the previous 6 months prior to screening.

- Extreme fatigue (unable to work or perform usual activities).

- Fevers of greater than 100.5 F for ≥2 weeks without evidence of infection.

- Night sweats without evidence of infection. ii) Evidence of progressive marrow failure
as manifested by the development of, or worsening of anemia or thrombocytopenia.

iii) Massive (i.e., >6 cm below the left costal margin), progressive or symptomatic
splenomegaly.

iv) Massive nodes or clusters (i.e., > 10 cm in longest diameter) or progressive
lymphadenopathy.

v) Progressive lymphocytosis with an increase of >50% over a 2-month period, or an
anticipated doubling time of less than 6 months.

vi) Autoimmune anemia or thrombocytopenia that is poorly responsive to corticosteroids.

- Patients must have received at least one prior therapy for CLL comprised of the
following:

i) ≥1 regimen containing an anti-CD20 antibody (e.g., rituximab, obinutuzumab)
administered for ≥ 2 doses ii) ≥1 regimen containing ≥1 cytotoxic agent (eg,
bendamustine, fludarabine, chlorambucil, cyclophosphamide) administered for ≥ 2 cycles

- Patients must have ECOG performance status ≤2.

- Patients must have organ function as defined below:

i) direct bilirubin ≤2 X institutional ULN (unless due to known Gilbert's syndrome or
compensated hemolysis directly attributable to CLL) ii) AST or ALT less than 2.5 X
institutional ULN iii) estimated CrCL using the Cockroft-Gault equation ≥50 mL/min
(see formula in Appendix 2).

iv) platelets ≥50,000/mm3 independent of transfusion support, with no active bleeding, and
absolute neutrophil count ≥1000/mm3, unless due to disease involvement in the bone marrow.

- Ability to understand and the willingness to sign a written informed consent document.

- Women of childbearing potential must have a negative serum beta-human chorionic
gonadotropin or urine pregnancy test at screening.

- All patients of reproductive potential (heterosexually active men and women) must
agree to a use of a barrier method of contraception and a second method of
contraception and men must agree not to donate sperm during the study and for 4 weeks
after receiving the last dose of study treatment.

Exclusion Criteria

- Prior therapeutic intervention with any of the following:

- nitrosoureas or mitomycin C within 6 weeks;

- therapeutic anticancer antibodies (including rituximab) within 4 weeks;

- radio- or toxin-immunoconjugates within 10 weeks;

- all other chemotherapy, radiation therapy within 3 weeks prior to initiation of
therapy.

- Inadequate recovery from adverse events related to prior therapy to grade ≤1
(excluding Grade 2 alopecia and neuropathy).

- Chronic use of corticosteroids in excess of prednisone 20 mg/day or its equivalent.

- Stem cell transplant recipients must have no evidence of active graft-versus-host
disease.

- Use of full dose, therapeutic anti-coagulation with warfarin.

- Concomitant use of strong CYP inducers or inhibitors including nutraceutical
preparations, e.g., grapefruit juice and St John's Wort

- History prior malignancy except:

- Malignancy treated with curative intent and no known active disease present for ≥ 2
years prior to initiation of therapy on current study;

- adequately treated non-melanoma skin cancer or lentigo maligna (melanoma in situ)
without evidence of disease;

- adequately treated in situ carcinomas (e.g., cervical, esophageal, etc.) without
evidence of disease;

- asymptomatic prostate cancer managed with "watch and wait" strategy;

- myelodysplastic syndrome which is clinically well controlled and no evidence of the
cytogenetic abnormalities characteristic of myelodysplasia on the bone marrow at
screening.

- Uncontrolled immune hemolysis or thrombocytopenia (positive direct antiglobulin test
in absence of hemolysis or history of immune-mediated cytopenias are not exclusions).

- Thrombotic events (pulmonary embolism; deep venous thrombosis) within 6 month prior to
start of therapy.

- History of Human Immunodeficiency Virus (HIV) infection or active hepatitis B or C.
Intravenous immunoglobulin (IVIG) can cause a false positive hepatitis B serology. If
patients receiving routine IVIG have core antibody or surface antigen positivity
without evidence of active viremia (negative hepatitis B DNA) they may still
participate in the study, but should have hepatitis serologies and hepatitis B DNA
monitored periodically by the treating physician.

- Patients with the following cardiovascular abnormalities:

- Corrected QT interval (QTc) >500 msec within 7 days prior to registration for protocol
therapy. NOTE: if QTc is >450 and ≤500 msec, subject to local cardiology review and
approval, the patient may be enrolled if the QTc elevation is deemed clinically
insignificant.

- Acute cardiovascular events within 6 months prior to C1D1: stroke (transient ischemic
attack permitted), acute coronary syndrome, peripheral arterial obstruction,
clinically significant arrhythmias (e.g., such as paroxysmal atrial
fibrillation/atrial flutter, sick sinus syndrome, second or third degree
atrio-ventricular blockade). A cardiology consultation may be obtained to clarify
clinical significance.

- Clinical cardiac heart failure of New York Heart Association Class III or IV or left
ventricular ejection fraction (LVEF) <50% as assessed by echocardiogram at screening.

- Major surgery (requiring general anesthesia) within 30 days prior to initiation of
therapy.

- Inability to swallow and retain an oral medication. Patients with clinically
significant medical condition of malabsorption, inflammatory bowel disease, chronic
conditions which manifest with diarrhea, refractory nausea, vomiting or any other
condition that will interfere significantly with the absorption of ibrutinib are
excluded.

- Any condition for which participation in the study is judged by the Investigator to be
detrimental to the patient with inter-current illness including, but not limited to an
uncontrolled active infection; unstable angina pectoris; uncontrolled cardiac
arrhythmia or psychiatric/social situations that would jeopardize compliance with
study requirements.