Sotrastaurin Acetate in Treating Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia, Small Lymphocytic Leukemia, Prolymphocytic Leukemia, or Richter's Transformation

PRIMARY OBJECTIVES:

I. To determine the objective clinical response rate of AEB071 (sotrastaurin acetate)
treatment in patients with relapsed or refractory chronic lymphocytic leukemia (CLL)/small
lymphocytic leukemia (SLL)/prolymphocytic leukemia (PLL)/Richter's transformation (RT).

SECONDARY OBJECTIVES:

I. To determine the feasibility and tolerability of long-term administration of a fixed dose
of AEB071 in patients with relapsed or refractory CLL/SLL/PLL.

II. To examine select downstream pharmacodynamic effects in this population of patients
after receiving AEB071 including assessment of the wingless-type MMTV integration site
family (WNT) signaling pathway.

III. To determine the feasibility and tolerability of AEB071 treatment in patients with
relapsed or refractory mantle cell lymphoma (MCL) as well as to gain preliminary data
regarding efficacy in this patient population.

TERTIARY OBJECTIVES:

I. Determine the proportion of patients with select germline and somatic deoxyribonucleic
acid (DNA) alterations, including in the B-cell receptor (BCR) pathway.

II. Determine how mutational and transcriptional status in key genes affects response to
this therapy and may have affected response to prior therapies.

OUTLINE:

Patients receive sotrastaurin acetate orally (PO) twice daily (BID) on days 1-28. Courses
repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then at least
every 3 months thereafter.

Inclusion Criteria:

- World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) performance
status =< 2

- Life expectancy >= 2 months

- Appropriate histologic diagnosis (a) or (b):

- (a) Histologically documented diagnosis of intermediate or high risk CLL/SLL,
B-PLL, and RT arising from CLL/SLL according to the 2008 guidelines, meeting
criteria for active disease requiring treatment:

- Evidence of marrow failure as manifested by the development or worsening of
anemia or thrombocytopenia (not attributable to autoimmune hemolytic anemia
or thrombocytopenia)

- Massive (>= 6 cm below the costal margin), progressive or symptomatic
splenomegaly

- Massive nodes (>= 10 cm) or progressive or symptomatic lymphadenopathy

- Autoimmune anemia and/or thrombocytopenia that is poorly responsive to
standard therapy

- Constitutional symptoms including any of the following:

- Unintentional weight loss of 10% or more within 6 mos.

- Significant fatigue limiting activity

- Fevers >= 100.5 degrees F for 2 weeks or more without evidence of
infection

- Night sweats > 1 month without evidence of infection

- Need for cytoreduction prior to stem cell transplantation

- (b) Pathologically documented MCL [defined as either t(11;14) or overexpression
of cyclin D1] for the MCL pilot study

- Relapsed after or refractory to at least one prior therapy

- Willingness to undergo all study-related evaluations and procedures

- Ability to understand and willingness to execute a written informed consent document

Exclusion Criteria:

- Prior therapy as follows:

- Major surgery within 2 weeks

- Corticosteroids greater than 20 mg/day prednisone (or equivalent) within 2 weeks
unless used by inhalation or topical route, or unless necessary for
premedication before iodinated contrast dye, or for autoimmune hemolytic anemia

- Cytotoxic chemotherapy or biologic therapy within 4 weeks, excepting BCR kinase
inhibitors for which no wash out is required, or

- Nitrosoureas within the 6 weeks of the planned first dose of the study drug

- Failure to recover toxicity from prior chemo- or radiotherapy to grade 1

- Known active leukemia or lymphoma of the central nervous system (CNS) requiring
therapy

- Inadequate bone marrow function/hematopoietic reserve, except in the case of
documented bone-marrow involvement: absolute neutrophil count (ANC) < 1 x 10^9/L

- Inadequate bone marrow function/hematopoietic reserve, except in the case of
documented bone-marrow involvement: platelets < 30 x 10^9/L

- Serum total bilirubin > 2 x ULN (upper limit of normal)

- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 x ULN, or >
5 x ULN if CLL/lymphoma is present in the liver

- Estimated glomerular filtration rate (GFR) < 30 mL/min

- Patients who are receiving treatment with medications that are known to be strong
inducers or inhibitors of cytochrome P450, family 3, subfamily A, polypeptide 4/5
(CYP3A4/5) and CYP3A4/5 substrates with QT prolongation risk that cannot be
discontinued prior to study entry

- Clinically significant cardiac diseases, including any of the following:

- History or presence of ventricular tachyarrhythmia

- Presence of unstable/uncontrolled atrial fibrillation (with ventricular rate >
100 beats per minute [bpm]); patients with stable atrial fibrillation are
eligible provided that they do not meet any of the other exclusion criteria

- Angina pectoris or acute myocardial infarction within 3 months of starting study
drug

- New York Heart Association (NYHA) functional class III or IV heart failure

- Labile or uncontrolled hypertension

- History of another malignancy that limits survival to less than 2 years in the
estimate of the investigator; basal and squamous cell cancers of the skin, or
squamous cell carcinoma of the cervix in situ, which were completely resected or
otherwise cured, or localized prostate cancer (Gleason < 5) are eligible

- Gastrointestinal dysfunction, including motility or malabsorption syndromes or
inflammatory bowel disease which could limit absorption of AEB071

- Known human immunodeficiency virus (HIV) positivity, or active hepatitis B or C
infection with detectible viral nucleic acid in the blood; testing for these viruses
is not a required part of screening

- Severe systemic infections requiring intravenous antibiotics within the two weeks
prior to initiation of AEB071

- Lactating or pregnant

- Women of child-bearing potential or male partners of women of child-bearing potential
who will not agree to use highly effective method of contraception throughout the
entire study period and for a minimum of 5 terminal half-lives of AEB071
(approximately 36 hours) after the last dose of study drug; highly effective
contraception methods include:

- Total abstinence or

- Male or female sterilization or

- Combination of any two of the following (a+b or a+c or b+c):

- a. Use of oral, injected or implanted hormonal methods of contraception

- b. Placement of an intrauterine device (IUD) or intrauterine system (IUS)

- c. Barrier methods of contraception: condom or occlusive cap (diaphragm or
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal
suppository Women are considered post-menopausal and not of child bearing
potential if they have had 12 months of natural (spontaneous) amenorrhea
with an appropriate clinical profile (e.g. age appropriate, history of
vasomotor symptoms) or have had surgical bilateral oophorectomy (with or
without hysterectomy) or tubal ligation at least six weeks ago; in the case
of oophorectomy alone, only when the reproductive status of the woman has
been confirmed by follow up hormone level assessment is she considered not
of childbearing potential

- Any other life-threatening illness or medical condition that, in the opinion of the
investigator, could compromise the safety of the patient or interfere with analysis
of study endpoints