Efficacy and Safety of SNX-5422 Added to an Established Dose of 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. Significant advances have
been made in the therapy, notably with the introduction of the Bruton's tyrosine kinase (BTK)
inhibitor ibrutinib.

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. In
addition, although remissions are durable in many patients, very few patients achieve a
complete response (CR), and minimal residual disease (MRD) negativity on single agent
ibrutinib has not been reported. Since it is known that for chemoimmunotherapy as well as
targeted therapies such as venetoclax that attainment of a CR is associated with longer
progression free survival (PFS), it is likely that deepening responses associated with
ibrutinib will result in more durable remissions.

Relapse in CLL can be mediated by at least two separate mechanisms. One is by mutations in
BTK, the other is through a variety of mutations in the immediate downstream target of BTK,
PLCγ2. SNX-5422 is a prodrug of SNX-2112, a potent, highly selective, small molecule
inhibitor of the molecular chaperone heat shock protein 90 (HSP90). Hsp90 inhibitors may
overcome ibrutinib resistance in Mantle cell lymphomas and this study will investigate
whether the addition of SNX-5422 to an established dose of ibrutinib will provide clinical
response in subjects who have residual disease, but have not progressed on ibrutinib after 18
months of monotherapy.

Subjects will receive SNX‑5422 (56 mg/m2) in the morning once every other day for 21 days (11
doses), followed by a 7‑day drug‑free period. Subjects will continue to receive daily oral
ibrutinib at their established dose level in the afternoon

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 for at least 18 months with residual disease and without evidence of disease
progression.

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

- 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

- 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 or could
alter the assessment of safety

- 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.