Safety and Activity of SNX-5422 Plus Ibrutinib in CLL

Chronic lymphocytic leukemia (CLL) is the most prevalent leukemia in adults and is not
considered curable outside of allogeneic stem cell transplantation.

BTK is a critical kinase in the B cell receptor signaling pathway. This pathway is amplified
in CLL and results in amplification of proliferation and anti-apoptotic signals. By
inhibiting BTK, ibrutinib eliminates the activation of these pro-survival pathways and
microenvironment survival signals. While response to ibrutinib has been high with therapy
well-tolerated overall, some patients have relapsed while others have been taken off therapy
for toxicity or other reasons. Relapse in CLL can be mediated by at least two separate
mechanisms. One is by mutations in BTK, which both decrease ibrutinib's affinity for BTK, and
also changes the binding from irreversible to reversible. This is a proof of concept study to
investigate whether the addition of SNX-5422 to an established dose of ibrutinib will reduce
mutated BTK from CLL cells and/or prevents or delays disease progression of subjects with
CLL.

This is an open-label study of SNX‑5422 combined with ibrutinib. In each 28 day cycle,
SNX‑5422 will be dosed in the morning once every other day for 21 days, followed by a 7‑day
drug‑free period. Subjects will continue to receive daily oral ibrutinib at their established
dose level in the afternoon every day for 28 days. cycle

Inclusion Criteria:

- Males or non-pregnant, non-breastfeeding females 18 years-of-age or older

- A diagnosis of CLL as defined by IWCLL 2008 criteria and currently on treatment with
ibrutinib without evidence of disease progression.

- No more than 4 prior lines of anti leukemia therapy (not including ibrutinib)

- Presence of mutated BTK in ≥ 4% of peripheral blood or bone marrow CLL cells, or ≥1%
and rising on two separate measurements obtained at least 28 days apart.

- Life expectancy of at least 9 months

- Karnofsky performance score 70

- Adequate baseline laboratory assessments

- Signed informed consent form

- Recovered from toxicities of previous anticancer therapy to CTCAE Grade ≤ 1 with the
exception of alopecia

- Subjects with reproductive capability must agree to practice adequate contraception
methods.

Exclusion Criteria:

- Subjects experiencing toxicity with ibrutinib

- Prior treatment with any Hsp90 inhibitor.

- Major surgery or significant traumatic injury within 4 weeks of starting study
treatment.

- Conventional chemotherapy or radiation within 4 weeks.

- The need for treatment with medications with clinically-relevant metabolism by the
cytochrome P450 (CYP) 3A4 isoenzyme within 3 hours before or after administration of
SNX-5422

- Screening ECG QTc interval 470 msec for females, 450 msec for males.

- At increased risk for developing prolonged QT interval unless corrected to within
normal limits prior to first dose of SNX-5422

- Patients with chronic diarrhea or with Grade 2 or greater diarrhea despite appropriate
medical management.

- Gastrointestinal diseases or conditions that could affect drug absorption

- Gastrointestinal diseases that could alter the assessment of safety, including
irritable bowel syndrome, ulcerative colitis, Crohn's disease, or hemorrhagic
coloproctitis.

- History of documented adrenal dysfunction not due to malignancy.

- History of chronic liver disease.

- Active hepatitis A or B.

- Current alcohol dependence or drug abuse.

- Use of an investigational treatment (except for ibrutinib) from 30 days prior to the
first dose

- Glaucoma, retinitis pigmentosa, macular degeneration, or any retinal changes detected
by ophthalmological examination that are considered clinically important by examiner.

- Psychological or social reasons that would hinder or prevent compliance with the
requirements of the protocol or compromise the informed consent process.