UC-961 (Cirmtuzumab) in Relapsed or Refractory Chronic Lymphocytic Leukemia

This is a first in human, open-label single institution, Phase I dose escalation study of in
patients with relapsed or refractory CLL. Treatment cycle (14 days) will consist of
cirmtuzumab administered intravenously on a bi-weekly (every two weeks) schedule for a total
of 4 doses. Eight dose cohorts (of 3 to 6 patients in size) plus an expansion cohort of 6
patients are planned. In the first 4 dose cohorts, there is intra-patient dose escalation to
monitor for acute toxicities, such as tumor lysis syndrome.

A cycle may be repeated every 14 days if the patient has at least stable disease by clinical
examination (or interim response assessment) and has again met hematologic, renal, and
hepatic laboratory parameters as defined in the eligibility section, and is without ongoing
Grade 3 non-hematologic or Grade 4 hematologic toxicities attributable to cirmtuzumab. The
total duration of study drug administration is 4 cycles. Each cycle consists of clinical and
laboratory evaluation on Day 1 and safety assessments on Days 3 and 8.

INCLUSION CRITERIA:

- Clinical and phenotypic verification of B cell CLL and measurable disease.
Immunophenotyping of the leukemic cells must demonstrate a monoclonal B cell
population with immunophenotype consistent with CLL.

- Relapsed or refractory disease, defined by failure to achieve a partial response
within 6 months of initiation of therapy, or a 50% increase of baseline disease
measurements after achieving a clinical response.

- Not amenable to approved therapies.

- Prior Therapy: Must have progressed after purine-analog or alkylator based therapy, or
be considered inappropriate for chemo-immunotherapy due to one of the following:

- Del 17p, which is associated with poor response to chemo-immunotherapy, or

- Age greater than 70, or

- Age greater than 65 with one of the following:

- Grade ≥ 3 neutropenia, anemia, or thrombocytopenia attributable to cumulative
myelotoxicity from prior administration of cytotoxic agents (as documented by
bone marrow biopsy obtained since last prior therapy), or

- Clinically apparent autoimmune cytopenia which may be exacerbated by fludarabine
therapy, or

- Estimated creatinine clearance (eCCr) <70 mL/min (as determined by the
Cockcroft-Gault method), or

- Eastern Cooperative Oncology Group (ECOG) performance status greater than 0.

- Has recovered from the toxic effects of prior therapy to their clinical baseline.

- Women of childbearing potential must agree not to become pregnant for the duration of
the study. Both men and women must agree to use a barrier method of contraception for
the duration of the study and until 10 weeks after the final dose of cirmtuzumab.

- Subjects must have at least one of the following indications for treatment:

- Symptomatic or progressive splenomegaly;

- Symptomatic lymph nodes, nodal clusters, or progressive lymphadenopathy;

- Progressive anemia (hemoglobin ≤ 11 g/dL);

- Progressive thrombocytopenia (platelets ≤ 100 x 10^9/L);

- Weight loss > 10% body weight over the preceding 6 month period;

- Fatigue attributable to CLL;

- Fever or night sweats for > 2 weeks without evidence of infection;

- Progressive lymphocytosis with an increase of > 50% over a 2-month period or an
anticipated doubling time of less than 12 months.

- Subjects must have an ECOG performance status of 0-2.

- Adequate hematologic function

- Adequate renal function

- Adequate hepatic function

- Adequate coagulation tests

EXCLUSION CRITERIA:

- Pregnant or breast-feeding women will not be entered on this study due to risks of
fetal and teratogenic adverse events as seen in animal/human studies.

- Patients who are currently receiving another investigational agent are excluded.

- Patients who have had chemotherapy (e.g., purine analogues, alkylating agents),
immunotherapy, radiation therapy, or participation in any investigational drug
treatment within 4 weeks of initiation of UC-961 or at any time during the study.

- Patients who have had prior (within 8 weeks of initiation of UC-961) or concurrent
antibody therapy directed against CLL (i.e., Rituxan® and Campath®).

- Current infection requiring parenteral antibiotics.

- Active infection with HIV, hepatitis B virus (HBV), or hepatitis C virus (HCV).

- Concurrent malignancy or prior malignancy within the previous 3 years (other than
completely resected carcinoma in situ, prostate cancer, or localized non-melanoma skin
cancer).

- Known central nervous system (CNS) involvement by malignancy.

- Untreated autoimmunity such as autoimmune hemolytic anemia, or immune
thrombocytopenia.

- Uncompensated hypothyroidism (defined as thyroid-stimulating hormone (TSH) greater
than 2x upper limit of normal not treated with replacement hormone).

- Presence of more than 55% pro-lymphocytes in peripheral blood. Patients with Richter's
transformation are not excluded.

- Insufficient recovery from surgical-related trauma or wound healing.

- Impaired cardiac function including any of the following:

- Myocardial infarction within 6 months of starting study drug;

- A past medical history of clinically significant ECG abnormalities, including QTc
481 milliseconds or greater;

- Other clinically significant heart disease (e.g., congestive heart failure,
uncontrolled hypertension, history of labile hypertension, or history of poor
compliance with an antihypertensive regimen).